EP3403725A1 - Système d'aide au pipetage - Google Patents

Système d'aide au pipetage Download PDF

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Publication number
EP3403725A1
EP3403725A1 EP17171137.7A EP17171137A EP3403725A1 EP 3403725 A1 EP3403725 A1 EP 3403725A1 EP 17171137 A EP17171137 A EP 17171137A EP 3403725 A1 EP3403725 A1 EP 3403725A1
Authority
EP
European Patent Office
Prior art keywords
sample
pipetting
measuring
sample receiving
arrangement
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP17171137.7A
Other languages
German (de)
English (en)
Inventor
Boris Von Beichmann
Jens Gerken
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eppendorf SE
Original Assignee
Eppendorf SE
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
Application filed by Eppendorf SE filed Critical Eppendorf SE
Priority to EP17171137.7A priority Critical patent/EP3403725A1/fr
Priority to US16/614,336 priority patent/US20200147602A1/en
Priority to PCT/EP2018/062343 priority patent/WO2018210728A1/fr
Priority to EP18724536.0A priority patent/EP3624945B1/fr
Priority to CN201880031082.2A priority patent/CN110621408B/zh
Priority to JP2019562333A priority patent/JP7121754B2/ja
Publication of EP3403725A1 publication Critical patent/EP3403725A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • B01L3/0217—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids of the plunger pump type
    • B01L3/0237—Details of electronic control, e.g. relating to user interface
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/54—Supports specially adapted for pipettes and burettes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/56—Means for indicating position of a recipient or sample in an array
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0621—Control of the sequence of chambers filled or emptied
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/08—Ergonomic or safety aspects of handling devices
    • B01L2200/087—Ergonomic aspects
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/02—Identification, exchange or storage of information
    • B01L2300/025—Displaying results or values with integrated means
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/02—Identification, exchange or storage of information
    • B01L2300/025—Displaying results or values with integrated means
    • B01L2300/027—Digital display, e.g. LCD, LED
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0663—Whole sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates

Definitions

  • the invention relates to a pipetting auxiliary system for assisting the manual pipetting of a plurality of samples of a sample receiving device, in particular a microtiter plate.
  • the invention further relates to components of a pipetting aid system and method.
  • the pipetting of samples in a microtiter plate refers to the aspiration of the sample from a sample receptacle, in particular a sample container, into a sample transfer container, in particular a pipette tip, by means of a pipetting device and also designates the discharge of a sample from such a sample transfer container into the sample receptacle.
  • Sample receiving assemblies such as represented by microtiter plates, include a plurality of sample receptacles for storing the samples or performing reactions in the samples or operations on the samples. Usually before performing the desired application, in part also during such an application, the sample receptacles of such sample receiving assemblies must be successively filled by pipetting or successively processed by pipetting. When using laboratory machines, such filling can take place without user intervention and error-free.
  • the present invention relates to the correct addressing of the sample recordings in successive manual processing by means of pipetting.
  • the selective uptake i. H. the recording of samples from specific wells of a microtiter plate, or the selective delivery and the selective transfer between microtiter plates.
  • the samples can z. B. in another microtiter plate -in the same or in another grid or scheme, or be transferred to other vessels, for. B. in reaction / analysis vessels.
  • the selective processing requires an even higher concentration of the user and carries an even higher risk for pipetting errors.
  • the sample tracking system for microtiter plates described there provides for the user to output the information about the occupation state of a sample holder after pipetting by illuminating the sample holder, in order to avoid an addressing error in the selection of the sample holders to be processed.
  • Detected is the occupancy state after pipetting automatically by successively attached to a robot arm infrared laser of a measuring arrangement above the sample recordings automatically is moved and the transmitted vertically through the sample receiving laser light is detected by the detector.
  • a sample recording with a sample generates a different detection signal than a sample recording without a sample, so that at least one such assignment state of the sample recording can be distinguished.
  • the movement system of the measuring arrangement to be used requires a high outlay on equipment and a complex movement mechanism. Movement mechanics are fundamentally susceptible to error, which can lead to positioning problems and thus to measuring errors as well as to an increased maintenance effort.
  • the robot arm of the movement mechanism is arranged in the space above the microtiter plate, in which the user must handle the pipetting device. Therefore, there is a risk that the movement mechanism is contacted and misadjusted when handling. On the other hand, the handling in this room is difficult because it is occupied by the movement mechanics.
  • the present invention has the object of providing a pipetting aid system for assisting the manual pipetting of a plurality of samples of a sample receiving arrangement, which can be used efficiently and comfortably.
  • the invention achieves this object by the pipetting aid system according to claim 1, the base device according to claim 16 in connection with the sample receiving device according to claim 17, the base device in claim 18, and the methods according to claims 19 and 20.
  • Preferred embodiments are in particular subject matters of the subclaims.
  • auxiliary functions assisting the user are realized by a measuring arrangement which are arranged in the processing position below the level of the positioning space, the risk is greatly reduced that the measuring arrangement is damaged during handling.
  • the space above this level is also freely accessible for visual inspection by the user from any angle and manipulation of the sample recordings by pipetting.
  • the design according to the invention also extends the application flexibility of a pipetting auxiliary system, since the detection of the occupancy state of the one or more sample receptacles is already made possible during pipetting. Since the measurement is not hampered by the handling of the user in the area above the positioning space, already immersing a sample transfer container, in particular a pipette tip, in the Recording space of the sample recording with appropriate design of the measuring arrangement as occupancy state to be tracked in real time.
  • the user can be informed via the output device with the information about the occupancy state of one or more specific sample recordings, so that the user may be warned against possibly incorrect pipetting again by appropriate information output, in particular illumination of the sample recording ,
  • the positioning device guarantees reliable relative positioning of the sample receiving arrangement and of the base device, so that the other system components, in particular the measuring elements and / or the dispensing device, can each assume a single relative position with respect to the sample receiving arrangement and the base device. This improves the precision in handling the pipetting aid system.
  • the plurality of measuring elements is an integral part of the sample receiving device and the dispensing device is an integral part of the basic device.
  • the measuring elements are preferably electrodes that can be realized in particular via electrical lines of the sample receiving arrangement. These electrical lines are realized in particular by electrically conductive polymer, so that the sample receiving arrangement via injection molding, in particular 2K injection molding process can be produced.
  • the pipetting aid system according to the first preferred embodiment preferably has, as output device, a luminous arrangement as a constituent of the base device according to the first preferred embodiment, in whose positioning space the sample receiving arrangement according to the first preferred embodiment can be positioned, which has the multiplicity of measuring elements.
  • the sample receiving arrangement according to the first preferred embodiment and the base device according to the first preferred embodiment preferably each have a coupling device in order to couple the plurality of measuring elements to a line arrangement, which is in particular part of the base device.
  • the Conduit for the conduction of optical and / or electrical signals to be formed is regarded as an independent subject matter of the invention.
  • the sample receiving device according to the first preferred embodiment which is applicable to the base device according to the first preferred embodiment, is considered as a self-contained subject matter.
  • the plurality of measuring elements and the output device are fixed components of the base device.
  • the pipetting assistance system according to the second preferred embodiment comprises the base apparatus according to the second preferred embodiment, in the positioning space of which the sample receiving arrangement according to the second preferred embodiment is positionable.
  • the sample receiving arrangement according to the second preferred embodiment is set up such that the plurality of measuring elements in the processing position can be arranged on the plurality of sample receptacles such that the occupation state of the at least one sample receptacle can be measured. This can in particular take place in that the plurality of measuring elements in the processing position engage in at least one cavity of the sample receiving arrangement.
  • a measuring element can engage in a cavity located between two sample receptacles.
  • the base apparatus according to the second preferred embodiment usable for the sample receiving apparatus according to the second preferred embodiment is regarded as a self-contained subject matter.
  • the sample receiving device according to the second preferred embodiment which is applicable to the base device according to the second preferred embodiment, is considered as a self-contained subject matter.
  • the plurality of sensing elements and a plurality of dispensing means of the dispenser are integral with the sample receiving assembly.
  • the output elements may be light-emitting elements, and in particular may be realized by light-diffusing optical means to which the light is passed through optical fibers of the sample receiving assembly, or may be realized by electroluminescent polymers which are excited via electrical leads of the sample receiving assembly.
  • the pipetting assisting system according to the third preferred embodiment has the sample receiving device having the plurality of sensing elements and the plurality of output elements of the lighting device.
  • the sample receiving assembly according to the third preferred embodiment and the base apparatus according to the third preferred embodiment preferably each comprise coupling means for coupling the plurality of sensing elements to a conduit assembly forming part of the base apparatus and coupling the plurality of dispensing members to another conduit assembly which is part of the basic device.
  • each of these line arrangements can be designed to conduct optical and / or electrical signals.
  • the base apparatus according to the third preferred embodiment usable for the sample receiving apparatus according to the third preferred embodiment is regarded as an independent subject matter.
  • the sample receiving device according to the third preferred embodiment which is applicable to the base device according to the third preferred embodiment, is regarded as an independent subject matter of the invention.
  • the sample receiving assembly comprises electrical leads.
  • These electrical lines are in particular realized by one or more electrically conductive polymers, so that the sample receiving arrangement is preferably completely made of polymer, in particular via injection molding, in particular 2K injection molding, or by a thermoforming process.
  • An electrically conductive polymer can be formed in particular by enriching a carrier polymer, in particular PP, PE, PS, PC, with electrically conductive filling material such as graphite, carbon, carbon nanotubes, and fragments of these substances, in particular if the filler 40 to 80 percent by mass of makes electrically conductive polymer.
  • a carrier polymer in particular PP, PE, PS, PC
  • electrically conductive filling material such as graphite, carbon, carbon nanotubes, and fragments of these substances, in particular if the filler 40 to 80 percent by mass of makes electrically conductive polymer.
  • An electrically conductive polymer can be chosen in particular as intrinsically conductive polymer: suitable are, in particular, poly-3,4-ethylenedioxythiophene (PEDOT, also PEDT), in particular with polystyrene sulfonate (PSS) as counterion (PEDOT: PSS); Polyaniline (PAni); Polyparaphenylene (PPP); particularly preferred: polypyrrole (PPy); Doped polythiophene (PT).
  • PEDOT poly-3,4-ethylenedioxythiophene
  • PSS polystyrene sulfonate
  • PAni Polyaniline
  • PPP Polyparaphenylene
  • PPP polypyrrole
  • PT Doped polythiophene
  • the measuring arrangement preferably has sensor devices , in particular a multiplicity of sensor devices.
  • a sensor device preferably has one or two measuring elements. It can also have more measuring elements.
  • the sensor devices are preferably arranged in a pattern. This pattern preferably corresponds to the pattern in which the sample receptacles of the sample receiving arrangement are arranged.
  • each sample holder is assigned a sensor device. This can be done such that at least one measuring element of each sensor device is positioned adjacent to at least one sample holder, in particular is positioned adjacent to exactly one sample holder.
  • the at least one measuring element is preferably arranged laterally of the sample holder in the processing position.
  • the direction “upwards” denotes a direction perpendicular to the plane A, which in the intended use of the pipetting auxiliary system is the direction against gravity, that is to say a direction designation in the conventional range.
  • “Lateral” accordingly means a position perpendicular to the central vertical axis of the sample holder, in particular to a substantially vertical side wall of the sample holder in the radial direction. This also applies if the sample receiving wall has an oblique course, which is the usual typical conical course, which can facilitate the introduction of sample containers or pipette tips in the sample holder.
  • the measuring arrangement in particular a sensor device, is preferably set up to measure a capacitance or a change in the capacitance.
  • the measuring arrangement in particular a sensor device, preferably has at least one pair of electrodes, which are in particular electrically insulated from one another and in particular so as to at least partially enclose the receiving space of at least one sample receptacle as a dielectric of the condenser space.
  • the change in permittivity caused by changing the content of the condenser space is then measurable electrically. In this way it can be determined, in particular, whether there is a sample in the receiving space of the sample holder or not.
  • the receiving space can preferably be distinguished by whether the receiving space is filled to 1/4, 1/2, 3/4 or 4/4 (completely), is overfilled, or is not filled. A precise determination of the filling volume is not possible in this way and is not sought in this embodiment. The preferred measurement resolutions of the sensor device will be described below.
  • the shape of an electrode for capacitive measurement may be rod-shaped, and / or is preferably in the form of a plate (plate member) whose shape is adapted to the shape of the sample receptacle or the receiving space of the sample holder.
  • the electrode preferably has the shape of a corresponding cylinder jacket section, which is arranged adjacent to the receiving space or the sample receptacle.
  • the electrode preferably has the form of a corresponding planar, in particular rectangular, plate section, which is arranged adjacent to the receiving space or the sample receptacle.
  • the electrode preferably has the shape of a corresponding at least partially spherical shaped plate portion, which is arranged adjacent to the receiving space or the sample receiving means.
  • the electrode In the case of a sample receptacle which is conically shaped at least partially, for example in the region of the bottom area, and / or in the case of an at least partially conically shaped receiving space, the electrode preferably has the shape of a corresponding at least partially conically shaped plate portion which is arranged adjacent to the receiving space or the sample receptacle ,
  • These design options address the proven, commercially available designs of microtiter wells. These are especially available as microtiter plates with F-bottom (flat), U-bottom (round) and V-bottom (conical).
  • a plate element can each also have a film nature.
  • An electrode preferably extends in substantially the entire length of the receiving space in the vertical direction in order to perform both a measurement at very low occupancy volumes and when fully filled can efficiently. From the receiving space, the electrode in the processing position is preferably separated by an insulation, in particular an insulating layer, in order to prevent electrochemical reactions at the electrode when a liquid sample is arranged in the processing position in the sample holder.
  • the electrode is preferably foil-like.
  • the electrode is preferably an electrically conductive polymer, and is produced in particular by means of injection molding or by a thermoforming process.
  • the electrode may also be made of metal or have metal, in particular aluminum, copper or silver.
  • the course of the electrode may in particular be meandering.
  • a second electrode which is connected in particular to ground, and which is arranged at a distance from the first electrode and in particular can run parallel to this first electrode.
  • Pairwise electrodes may each have finger elements that are arranged intercalating or comb-like to the finger elements of the opposite electrode. These electrodes can be arranged in a meandering intercalating manner.
  • a first Electrode may be formed as a core electrode, in particular a circular electrode, and the second electrode may be arranged as a hole electrode substantially in the plane of this core electrode outside the core surface of the core electrode, so that the core electrode is arranged in the hole of the hole electrode.
  • the second electrode can also be arranged parallel to the core electrode, in particular below the core electrode, and can be designed in particular as a cup electrode, in that at least one side wall of the cup electrode rises from a bottom section of the cup electrode to the height of the core electrode, the electrodes always being spaced apart are.
  • the electrode or several or all electrodes of the measuring arrangement can be connected to an electronic control device by at least one line, in particular at least one or more strip conductors , which are arranged in particular on the sample receiving arrangement.
  • Conductor tracks may consist of electrically conductive plastic or have such. These conductive structures could also be realized by injection molding, in particular 2-component injection molding. Alternatively, both the electrodes and the conductor tracks could be realized by electrically conductive foil elements.
  • the sample receiving device in particular a microtiter plate, can be contacted externally via suitable landing surfaces, for example by means of spring contact pins / contact needles of the base device.
  • contact springs or pins could also be encapsulated in the conductive plastic of the microtiter plate and then connected to corresponding land surfaces on the base device.
  • Each sensor device can be assigned at least one or two, in particular exactly one or two, lines , by which the at least one measuring element can be connected to an electronic circuit, which can be part of the electronic control device .
  • Such an arrangement with individual contacting of each measuring element offers a particularly high measuring accuracy. In the case of 96 sample recordings, therefore, in particular a total of 96 or 192 lines can be provided.
  • the sample receiving assembly has no electronic circuit.
  • contact points are preferably provided for producing an electronic contact.
  • the contact points of the sample receiving arrangement can each be connected via at least one contact point with a corresponding contact of an electronic control device.
  • the contact point is analogous by a replaced optical coupling point , which allows the transmission of a light signal through the coupling point.
  • At least one measuring element is arranged in the upper half of a sample holder, in particular on an upper edge of a sample holder.
  • a sensing element configured as a single electrode is preferably placed in the upper half of a sample receptacle to measure the capacitance change of that electrode with respect to a ground electrode, the latter being made available through the base device.
  • the individual electrode can in particular be designed as a ring electrode, which can be arranged in the processing position at the upper edge of a sample holder.
  • the ring electrode may in particular be firmly connected to the sample receiving arrangement.
  • one sensor can be assigned to two sensor devices. One of them may in particular have the single electrode described, in particular in the upper region.
  • the other sensor device comprising one or two electrodes, can be arranged in particular in the lower region of the sample holder.
  • the invention is based on the experimentally determined technical teaching that a sample transfer container filled with an electrically conductive sample and itself non-electrically conductive is suitable for realizing such a measurable change in capacitance of a single electrode. It has been shown experimentally that the parasitic coupling through the plastic housing and the user himself, who holds the pipette in the hand, and the wider environment to the circuit ground sufficient to obtain a measurable change in capacitance due to the proximity of the pipette tip. A pipette tip made of conductive plastic can be detected both filled and unfilled. A non-electrically conductive pipette tip can be detected if, for example, it is filled with water. In this way, a sample receiving arrangement or a pipetting aid system can be provided at a relatively low cost.
  • a measurement of the occupancy state can not be done only via an electrical capacitance measurement.
  • the measuring arrangement is further preferably configured to use an optical signal transmission, in particular to measure a quality of light or its change, in particular a light intensity or light color after passage of the light through the receiving space of a sample receptacle or the measuring space to the occupation state of the receiving space or measuring space to investigate.
  • a first measuring element serving as a light emitter is arranged on a sample receptacle, and a second measuring element serving as a light receiver is provided.
  • the measuring element can be designed in particular as a light-deflecting element, in particular as a prism element or reflective element.
  • a Lichtqán, in particular LED may be part of the base device.
  • the sensor device is a capacitive sensor device that detects a change in a capacitance value caused by a pipetting process.
  • the sensor device is an optical sensor device which detects a change in an optical property. The measurement is performed in such a way that a change in the occupancy state of a measurement space is detected, wherein this measurement space contains at least part of the sample intake or the entire sample intake.
  • the occupancy state changes when an object is introduced into the measurement space.
  • the object may in particular be a liquid sample or a pipette tip, in particular a pipette tip filled with aqueous solution or with electrolyte, as is typical in pipetting operations.
  • a sensor device is preferably designed to generate at least one measurement signal which is characteristic of a predetermined occupation state.
  • Occupancy status is characterized by the unique and distinguishable occupancy of at least one measurement room.
  • two distinguishable occupancy states are understood to mean that there are two different arrangements each consisting of a measurement space and an object in different states that can be distinguished with the sensor device.
  • the number M becomes in the present case also referred to as measurement resolution of the sensor device.
  • a small measurement resolution M is sufficient, since an exact determination of the filling volume is not the aim of the invention, but only the unambiguous distinction of the occupation state.
  • a measurement resolution M is considered to be a preferred problem solution if two occupancy states of a sample intake are distinguishable by the measurement at which the two fillings of the sample intake differ by preferably 50% or preferably 25% of the total sample intake volume, in particular at least two of the fill states Sample intake to 0%, 25%, 50%, 75% or 100% is filled with a liquid sample.
  • the measurement resolution is such that all occupancy states 0%, 25%, 50%, 75% or 100% can be distinguished from each other.
  • a measurement resolution is considered a preferred problem solution even if the occupancy states 0% and 50%, and optionally also 100%, can be distinguished from each other.
  • a measurement resolution is considered as a preferred problem solution even if the introduction and / or removal of the filled with aqueous solution pipette tip can be detected in the sample holder, or in the upper edge region of the sample holder.
  • Such low measurement resolutions M are not suitable for determining an accurate level of a sample receiver, but are suitable for the purposes of the present invention.
  • the measuring arrangement is not set up to determine a fill level of the at least one sample receptacle.
  • the sensor device can be set up to carry out an impedance measurement, in particular by applying an alternating voltage to an electrode serving as a transmitting element, while another electrode serves as a receiving element, for carrying out a suitable measuring method for the purpose of determining the filling level.
  • the measuring arrangement has a microcontroller for controlling in particular at least one, in particular at least two, or in particular for the individual or in particular pairwise control of the plurality of measuring elements designed as electrodes.
  • this microcontroller has a touch sensing controller (TSC), as it is used in particular for the measurement of touch-sensitive surfaces in touch sensors.
  • TSC touch sensing controller
  • Such microcontrollers with TSC are in particular commercially available from STMicroelectronics, Geneva, Switzerland, in particular the model STM32L073xx is suitable.
  • such a microcontroller has special hardware called a touch sensing controller (TSC) for querying capacitive "touch keys", ie touch-sensitive surfaces as an input tool.
  • TSC touch sensing controller
  • the standard application of this Touch Sensing Controller is to measure the capacitance of a contact surface in relation to ground potential.
  • the application of the TSC-MCU can in particular provide the following procedure, which can be carried out accordingly by means of the electronic control device in combination with the TSC-MCU: it becomes this Capacitance, here the capacity of the electrode (s), repeatedly charged and discharged into a reference capacitor. This process is repeated until the voltage of the reference capacitor reaches a threshold value.
  • the number of charge / discharge cycles required is counted and stored in dedicated MCU registers. The larger the number of cycles, the greater the measured capacitance.
  • the capacitance between the two electrodes on the walls of a sample receptacle can be measured.
  • one of the two electrodes is connected to the circuit ground (GND) and the other to an input of the TSC of the MCU. In this way, the capacitance of the device relative to the circuit ground can be measured.
  • a pipette tip or a dispenser tip in particular Eppendorf Combitips®
  • an electrode can be mounted in the upper region of a sample receptacle, in particular at the upper edge, and connected to a measuring input of the Touch Sensing Controller. If an electrically conductive pipette tip or dispenser tip is now connected to the circuit ground, the capacitance of the electrode in the upper region of a sample receptacle to the circuit ground increases as the pipette tip / dispenser tip approaches.
  • the electronic control device of the pipetting auxiliary system which is arranged in particular in the base device, and a further electronic control device of the pipetting device or the dispensing device are adapted to communicate with each other via a signal connection, in particular a data connection, ie in particular analog or digital, in particular wired or wireless, eg via a Bluetooth connection or a wireless network (WLAN).
  • a signal connection in particular a data connection, ie in particular analog or digital, in particular wired or wireless, eg via a Bluetooth connection or a wireless network (WLAN).
  • a WLAN can generally be set up according to the standard of the IEEE 802.11 family.
  • communication devices are respectively provided on the electronic control device, for example a network adapter.
  • the data connection is used to exchange data, unidirectional and / or bidirectional.
  • the said control devices in particular the control programs executed by their data processing devices, can be set up to exchange data via the communication devices. For example, the transmission of control data with the content of the message "liquid dispensed" to the electronic control device of the pipetting auxiliary system there could trigger an occupancy state measurement and feedback to the user on the successful delivery in the correct sample recording by means of the output device, in particular a light assembly done.
  • one of the electrodes is designed as a transmitting element and the other electrode as a receiver element.
  • no accurate impedance measurement is desired.
  • no permanently temporally sinusoidally variable voltage is applied to the electrode for the measurement, and in particular no AC voltage is applied.
  • Such measurements are complex and are not necessarily required in the present case in order to obtain the desired, relatively low measurement resolution by means of capacitive measurement.
  • an optical sensor device as measuring elements on at least one optical transmitter element and at least one optical receiver element, which are preferably arranged parallel to a sensor surface of the sensor portion, the in particular parallel to the plane A.
  • Light guide elements can be provided to guide the light between the optical transmitter element and the receiver element through the measuring space, in particular light guide elements selected from the group: lens element, prism element, mirror element, optical fiber.
  • the at least one transmitter element and the at least one receiver element are arranged opposite one another on opposite sides of the measuring space or a portion of the measuring space. In this way, it is possible in particular to realize a sensor device which operates on the principle of a light barrier.
  • the transmitter element of an optical sensor device is preferably an LED, in particular OLED, preferably a laser diode, in particular a vertically emitting laser (VCSEL), since such light sources with a compact structure that can be integrated on an IC substrate simultaneously have a high luminosity, in particular a low energy consumption and In particular, have a relatively low ratio of luminosity / energy consumption.
  • LED in particular OLED
  • VCSEL vertically emitting laser
  • the transmitter element of an optical sensor device is furthermore preferably an LED, in particular OLED, in particular an infrared LED.
  • an LED in particular OLED, in particular an infrared LED.
  • infrared light offers the advantage that the sensor surface may be covered by a layer of material that is not transparent to visible light, in particular a protective layer or soiling Increases the choice of available material layers compared to the use of visible emitting LEDs and makes reading more reliable.
  • infrared light is absorbed according to the infrared spectrum of water in the aqueous solution of the pipetted into the receiving space liquid sample in a technically sufficiently usable manner, so that the occupation of the sample receptacle with aqueous solution can be detected by means of infrared light.
  • the output device is preferably part of the base device.
  • the dispenser is preferably located below the plane A, and is preferably located below the sample receiving assembly in the processing position.
  • the output device may have a plurality of output elements.
  • One, preferably each, output element is preferably assigned to one or exactly one sample receptacle of the sample receiving arrangement in the processing position, in particular arranged below a sample receptacle.
  • An output element may comprise a mechanical display element, for example a rotatable element having different appearing, especially colored, display surfaces which can be presented to the user by rotation and which represent the occupying state.
  • the display element may be driven from below by the base device, and in the processing position, in particular, in each case through an opening in the sample receiving assembly into the field of view of the user. In the case of a transparently designed sample receiving assembly, a display element may be disposed in the processing position below the sample receiving assembly.
  • the dispenser is also preferably part of the sample receiving assembly.
  • the dispenser may also be part of another laboratory device that forms part of the pipetting aid system.
  • This laboratory device may be the pipetting device or dispensing device with which the user manually pipettes the samples to the sample receiving assembly.
  • the output device is preferably configured to output optical signals, in particular via a lighting arrangement or a display. However, it can also, in particular in addition, be set up to emit acoustic signals.
  • the output device can in particular have a voice output device.
  • the electronic control device can be set up to output at least one information depending on the measured occupancy state of the at least one sample holder, in particular the information about the position of the measured sample holder and / or the information about the occupancy status measured there.
  • Information can be displayed on the display by means of a graphic symbol, in particular a written description, and / or can be coded by voice output and output via the voice output device.
  • a position of the measured sample receptacle can be output as a coordinate: in the case of microtiter plates, a coordinate system of letters and numbers is typically used.
  • the output device is designed as a light-emitting arrangement
  • the output element corresponds to a light-emitting element
  • the lighting arrangement has a plurality or multiplicity of lighting elements.
  • a light-emitting element is preferably a light source, but may also be a light-emitting element.
  • a light-emitting element can be formed by the output of a light-conducting fiber, which is in particular coupled to at least one light source.
  • a light source is preferably formed by at least one light emitting diode (LED), in particular a semiconductor LED or an organic LED (OLED), or has such.
  • the light source can be formed in particular by means of a photoluminiscent polymer.
  • the light source may in particular be a laser diode, preferably a surface emitter laser (VCSEL: English "vertical-cavity surface-emitting laser").
  • a lighting element is preferably set up to illuminate exactly one or at least one sample receptacle in the processing position. This is done so that the user, who viewed the sample receiving device usually from above the plane A, the illumination of an individual sample holder can clearly recognize and also clearly distinguish from the illumination of another, in particular adjacent sample holder. It is preferred that the light emitted by the light emitting element in the preferably at least partially transparent designed sample receptacle or sample receiving assembly is coupled and this leaves again at the top, directed or by scattering at the sample receiving or sample receiving device, in particular its surface.
  • the sample receptacle or sample receiving arrangement can also have at least one opening or recess in order to allow the light emitted by the luminous element preferably to emerge from below through this opening or recess in the direction of the observer. If the light-emitting elements are arranged in the processing position at the top of the sample receiving arrangement, a transmission of the light through the sample receiving arrangement is not necessary, but is not excluded with appropriate light guidance.
  • the light emitted by a luminous element can be restricted to a solid angle or focused onto a region of the sample-receiving arrangement or sample receptacle.
  • a light guiding element may be provided, in particular a lens element, a diaphragm, a prism, a mirror element, etc.
  • the lighting arrangement preferably has a multiplicity of light-emitting diodes, in particular a light-emitting diode matrix with which the individual sample recordings can be illuminated. This serves to guide the user and to provide an optical feedback for the purpose of informing about the metering of liquid into the respective sample receptacle.
  • the lighting arrangement preferably has lighting elements, in particular a plurality of lighting elements.
  • the luminous elements are preferably arranged in a pattern or a matrix. This pattern preferably corresponds to the pattern in which the sample receptacles of the sample receiving arrangement are arranged.
  • each sample holder is assigned a light-emitting element. This can be done so that at least one luminous element is positioned adjacent to at least one sample receptacle, in particular is positioned adjacent to exactly one sample receptacle, in particular below the plane of the bottom walls of the sample receptacles is arranged and in particular is arranged vertically below the sample holder.
  • the at least one luminous element can, however, also be arranged laterally of the sample receptacle in the processing position. If the sample receiving arrangement has the luminous arrangement, the luminous elements can each also be arranged at the upper edge of the sample receptacles.
  • a lighting element is preferably adapted to be operated in a predetermined illumination mode.
  • the electronic control device is preferably configured to control the at least one lighting element in a predetermined type of lighting.
  • the type of illumination can be defined by the light emitted by the luminous element or by the light passing from the illuminated sample receptacle to the observer: light color or wavelength, intensity, temporal change of these parameters, in particular the intensity, ie pulse frequency or continuous light.
  • the type of illumination of the illumination of a sample receptacle depends in particular on the individually measured occupancy state of the sample receptacle. In particular, the intensity of the illumination can be zero, so that formally a deactivated illumination can also be regarded as a type of illumination.
  • the electronic control device also referred to as a control device, in particular its electronic circuit or microcontroller, is preferably a component of the base device, which is preferably a separate device from the sample receiving device.
  • a data processing device is preferably part of the electronic control device that controls functions of the pipetting auxiliary system.
  • the functions of the control device are implemented in particular by electronic circuits.
  • the controller may include a microprocessor that may include the data processing device.
  • the control device and / or the data processing device is preferably designed for carrying out a control method, which is also referred to as control software or control program.
  • the functions of the pipetting aid system and / or the control device can be described in method steps. she can be implemented as components of the control program, in particular as subroutines of the control program.
  • a control device generally has, in particular, the data processing device, in particular a processing unit (CPU) for processing data and / or a microprocessor, or is the data processing device.
  • the data processing device of the control device of the pipetting auxiliary system is preferably also set up for controlling a treatment process and / or individual treatments which are carried out by one or more in particular optional treatment devices of a laboratory device.
  • the data processing device is preferably a device which is arranged outside the pipetting auxiliary system and separate from it, also referred to as external device or external data processing device.
  • the data processing device and the pipetting aid system are then preferably in a signal connection or a data connection and are preferably components of a network for data exchange.
  • the data processing device and the pipetting auxiliary system are in particular components of a system according to the invention for monitoring a manually performed pipetting process.
  • the pipetting auxiliary system can be equipped without an electrical control device and, in particular, essentially serves as an adapter device with which the control of the measuring arrangement and the luminous arrangement is mediated between the external electronic control device or the external data processing device and the sample receiving device .
  • the control device has a data storage device, in particular a measurement data memory, for storing the at least one measurement value defining the occupancy state.
  • a data storage device in particular a measurement data memory, for storing the at least one measurement value defining the occupancy state.
  • the data storage device is preferably housed in a physically rewritable memory device, such as RAM, FLASH memory, EEPROM, but may also be arranged in other memory devices.
  • the pipetting auxiliary system or its electronic control device is in particular configured to exchange data with an electronic laboratory book (ELN), a laboratory information and management system (LIMS) or a laboratory device management system. Occupancy state data and / or data of a pipetting program and / or control data can be exchanged with one of the systems in order to archive this data, in particular for documentation purposes, or to realize control of at least one laboratory device, in particular one Control of the pipetting aid system.
  • ESN electronic laboratory book
  • LIMS laboratory information and management system
  • laboratory device management system Occupancy state data and / or data of a pipetting program and / or control data can be exchanged with one of the systems in order to archive this data, in particular for documentation purposes, or to realize control of at least one laboratory device, in particular one Control of the pipetting aid system.
  • this has as a system component the pipetting device (or the dispensing device, not always mentioned separately below), by means of which the user performs the pipetting operations on the sample receiving device.
  • the electronic control device of the Pipettierwhissystems and / or the base device and the pipetting device each have a communication device, so that a wired or preferably wireless data connection for data exchange is buildable.
  • the electronic control device of the pipetting auxiliary system is a component of this pipetting device, by means of which the user performs the pipetting operations on the sample receiving device.
  • the pipetting assistance system also includes the pipetting device.
  • the pipetting device controls in particular: the execution of a pipetting program which guides the user during manual pipetting, in particular according to a predetermined sequence; - triggering a measurement with at least one measuring element of the measuring arrangement on at least one sample receptacle; - The output of the information on the occupancy state at this at least one sample holder.
  • control device has at least one program data memory in which a program code can be stored.
  • the program code is preferably designed to use the at least one measured value and to evaluate it.
  • a pipetting auxiliary system or a control device which is designed or set up to form a specific function
  • a pipetting auxiliary system or such a control device which is not only suitable for performing this function in principle, e.g. after applying software, but already has all the means to actually fulfill this function, e.g. the necessary electronics, the required program code or the required software already has, in particular in the form of a firmware of the pipetting auxiliary system or its control device.
  • the means for performing this function include in particular an evaluation device.
  • the evaluation device e.g. have correspondingly designed electrical circuits, e.g. evaluate an analog signal representing the measured value and, e.g.
  • control device preferably has an electrical evaluation device.
  • the electronic control device is in particular configured to electrically actuate the measuring arrangement in the processing position and to evaluate the measurement signals obtained.
  • the electronic control device is in particular configured to perform a measuring method on the measuring arrangement in order to determine the occupancy state of at least one sample receptacle.
  • the electronic control device is in particular configured to perform a measuring method on the measuring arrangement in order to determine the occupancy state of a plurality of sample receptacles, eg a column of sample recordings in the case of a matrix-like arrangement of sample recordings.
  • the measuring arrangement is electrically controlled, in the case of an optical measurement, the measuring arrangement is preferably controlled by light signals.
  • the electronic control device is set up to carry out a calibration method on an unfilled sample receiving device and / or during a filling process of a sample receiving device, in particular of a certain type of sample receiving device .
  • the measurement results are recorded, which result at vacancy or in a known occupancy state on the sample receiving device.
  • Such measurement results of a calibration method are preferably stored as reference data in a data storage device, which may be part of the electronic control device and / or the base device. These reference data can be used in an evaluation method carried out by the electronic control device in order to determine the respective occupancy state by comparison of measured values with reference values of the reference data.
  • the electronic control device is adapted to perform a diagnostic procedure on an unfilled sample receiving assembly or with a base device which is not equipped with a sample receiving assembly but which is optionally equipped with a test plate.
  • the lines are electrically or optically driven to one, several or all of the measuring elements and / or output elements / luminous elements and the measurement results obtained are compared with reference values.
  • the adjacent contact points of a sensor device to be contacted which are preferably provided on the base device, can be assigned or assigned a specific reference capacitance. Defects or soiling of these contact points can be determined by this diagnostic method.
  • the test plate may have reference blocks which each replace a sample receptacle provided with measuring element.
  • the electronic control device be set up or adjustable by the user so that the calibration procedure on an empty sample receiving assembly is made mandatory for each sample receiving assembly after and / or once the sample receiving assembly is located in the positioning space.
  • a short position test method can be provided, in which the arrival of the sample receiving arrangement in the positioning space is registered, in particular via at least one position sensor connected to the electronic control device.
  • the position sensor may be, for example, an optical sensor or a mechanical pressure switch.
  • the measuring arrangement can also be repeatedly interrogated at intervals. In the process, a determination is made as to whether or when a typical measurement value for the presence of a sample receiving arrangement in the positioning space is determined.
  • the electronic control device can be set up such that the user is signaled the success or possibly the failure of the calibration, in particular by means of an optional signal device or the output device, in particular the light assembly - see the comments on the connection test method below.
  • the user can make the success or, if appropriate, the failure of the calibration via the display of a laboratory device associated with the pipetting auxiliary system, in particular via the display of the pipetting device, with which the user also performs the pipetting operations on the sample receiving device.
  • the reliability of the determination of the occupancy state or of all occupancy states can be improved.
  • the individual calibration of the sample receiving arrangement offers the advantage that dimensions and tolerances are less critical. The effort involved in the manufacture of the sample receiving arrangement can be reduced if the tolerances for the dimensions of the structures relevant for the measurement may be greater. Such structural dimensions are in particular the positioning of the contact points or coupling points or the positioning of the measuring elements on the sample receiving device.
  • the electronic control device is in particular configured to perform a position test procedure on an unfilled sample receiving device. It is used to determine whether the machining position has been correctly established.
  • at least one position sensor connected to the electronic control device can be provided on the base device, with which the processing position can be verified.
  • the processing position can be verified for carrying out the position test method by means of the measuring arrangement and the sample receiving arrangement accommodated in the positioning space.
  • the electronic control device is set up to carry out a connection test procedure on an unfilled sample receiving arrangement, with which it is checked whether each of the sensor devices of the measuring arrangement is connected in an acceptable manner to the electronic control device, in particular electrically or optically.
  • measurement results are not necessarily stored as data.
  • the electronic control device can be set up to signal the user, in particular by means of an optional signaling device, if at least one of the sensor devices has not been connected correctly, and optionally to signal which of the sensor devices has not been correctly connected. Alternatively or additionally, it is also possible to signal if all sensor devices have been correctly connected, and / or it is possible to signal which of the sensor devices have been correctly connected. This can be done in particular by means of the output device, in particular a lighting arrangement.
  • the output device in particular the lighting arrangement, can be set up to signal to the user the information about the result of a registration method, a diagnostic method, an individual calibration method, a position test method and / or a connection test method by means of the output device, in particular the light-emitting device, in particular differentiated signal.
  • the result of each said method or other method can be determined by means of a different output quality, in particular color or a temporal luminous frequency, in particular a continuous or flashing output / lights to signal at least one or all output elements / light elements of the output device / light assembly.
  • the electronic control device is preferably set up to illuminate the sample receiving arrangement in the processing position by the lighting arrangement, in particular not to activate the lighting arrangement, if no sample receiving arrangement is arranged in the positioning space.
  • the electronic control device is preferably configured to control the output device, in particular the lighting arrangement, in dependence on a pipetting program.
  • a pipetting program implements a control plan by means of which the user is guided by the corresponding output of information about target positions to be pipetted. This guidance takes place by outputting information in dependence on a pipetting plan stored, for example, in the control device, by means of the output device, which indicates to the user the target positions for the pipetting operations to be performed manually.
  • the target positions correspond to certain sample receptacles of the sample receiving assembly.
  • the user will be instructed to systematically fill the sample receiving assembly, eg, column by column, and gradually.
  • the user will be asked to step-fill the sample-receiving arrangement, ie according to a random pattern or a pattern not disclosed to the user but stored in the pipetting apparatus.
  • the electronic control device is preferably configured to control the output device, in particular the light-emitting device, as a function of the occupancy state of the at least one sample holder detected by means of the measuring arrangement.
  • the electronic control device preferably has a logic device for outputting information at least one sample holder, in particular for illuminating at least one sample holder.
  • the logic device can be realized by an analog and / or digital electronic circuit.
  • measurement results of the measuring arrangement can be evaluated electronically and, in dependence on this electronic evaluation, the output of the information / illumination of the sample receiving arrangement can be controlled electronically by means of at least one output element / luminous element.
  • the addressing of the relevant output element / luminous element and its activation or deactivation can be controlled electronically.
  • the logic device can also be realized by a control program or a control software .
  • the electronic control device is preferably set up for data processing.
  • the external devices and the base device can exchange, store and document data with one another, for example via cable or wirelessly, in particular with regard to the information about the correctness of the planned and manually performed pipetting process.
  • the pipetting auxiliary system is set up for the execution of the following function:
  • the user successively leads a pipetting device / a dispensing device from sample receptacle (s) to sample receptacle (s).
  • the pipetting aid system recognizes the approach of the at least one sample transfer container connected to the pipetting device / dispensing device to the at least one sample receptacle.
  • the pipetting device / the dispensing device automatically dispenses the respective intended volume to the at least one sample receptacle, in particular without an actuation of the release button for manually releasable delivery to the pipetting device / the dispensing device by the user.
  • the pipetting aid system preferably has a pipetting device and / or a dispensing device, which are in a data connection with the electronic control device, in particular the base device.
  • the electronic control device is set up to pass on the information about the occupancy state to the pipetting device and / or a dispensing device in the form of occupancy state data as soon as the approach of the tip of the sample transfer container to a sample receptacle has been recognized as a change in the occupancy state of the sample receptacle.
  • the pipetting device and / or the dispensing device then performs a pipetting stroke of the pipetting piston of the pipetting device and / or the dispensing device, preferably corresponding to a specific pipetting volume, which can be individual, in particular for this sample receptacle, depending on the occupancy state data.
  • the pipetting device and / or the dispensing device can then output in particular an optical and / or acoustic signal to the user, with which the success of the automatic pipetting stroke is signaled.
  • the pipetting aid system in particular the base apparatus, also communicates the position of the sample holders (eg "B11") to the pipetting device and / or the dispensing device via data connection and / or or the dispensing device can allocate the correct volume regardless of a sequence. This could provide advantages in randomizing assays to get fixed effects, always same pipetting schemes to avoid. Overall, the filling of plates would be much more comfortable and failsafe.
  • the triggering stop which is then activated when the user delivers the sample a second time over the same first sample holder into which a sample has already been dispensed in the course of the randomized sequence. If necessary, the user no longer knows which sample holders have already been filled with liquid by him.
  • the base device is preferably a tabletop device on which the sample receiving assembly is placed and / or attached to produce the processing position.
  • the electrical contact between the contact points of the base device and the contact points of the sample receiving assembly is made;
  • the optical coupling between the coupling points of the base device and the coupling points of the sample receiving device is produced analogously.
  • the base device preferably has a positioning region over which the positioning space for receiving the sample receiving arrangement is located.
  • the positioning region can have a flat surface, in which preferably the output device, in particular the luminous arrangement and in particular a matrix of contact points or coupling points, is provided in order to connect the measuring arrangement to the electronic control device in the processing position.
  • the base device in particular the electronic control device, can also be networked or networked with other laboratory devices, such as an electronic pipetting device or a computer, via a data connection, in particular in order to transmit the information about the occupancy state of the individual sample receptacles.
  • laboratory devices such as an electronic pipetting device or a computer
  • the base device in particular the electronic control device, may also be part of a laboratory device, in which case the pipetting aid system for assisting manual pipetting is partially integrated in this case. While no manual pipetting aid is needed in the process of automatic pipetting, it is conceivable that manual filling and pipetting may be desired in a laboratory machine.
  • the pipetting auxiliary device or the basic device can also be part of a laboratory automaton. This laboratory automaton can be set up to store and / or process and / or forward the information about the occupancy statuses detected by means of the measuring arrangement as data.
  • the base device preferably has the output device or the lighting arrangement .
  • the pipetting aid system preferably has at least one first and one second base device , in particular at least two base devices designed according to the invention.
  • the pipetting aid system preferably has at least two measuring arrangements.
  • a first measuring arrangement of the first base device is assigned and associated with a second measuring arrangement of the second base device.
  • the pipetting aid system preferably has at least two dispensing devices.
  • a first output device is assigned to the first base device and a second output device is assigned to the second base device.
  • control device is set up to control both the first measuring arrangement, the second measuring arrangement, the first output device and / or the second output device.
  • control device is set up to determine the first occupancy state of at least one sample receptacle arranged on the first base device by controlling the first measurement arrangement in the processing position, and preferably by controlling the first output device to the user in FIG Depend on the first occupancy state of the at least one sample receiving the information about their first occupancy state.
  • the control device is preferably set up to output to the user, depending on the first occupancy state measured on the first base device, information about the target position to be pipetted according to a pipetting plan program on the second base device. This serves, in particular, to provide the user with assistance in transferring samples from a first sample receiving arrangement (eg microtiter plate) into a second sample receiving arrangement (eg microtiter plate).
  • a first sample receiving arrangement eg microtiter plate
  • second sample receiving arrangement eg microtiter plate
  • the control device is preferably set up to determine the second occupancy state of at least one sample receptacle arranged on the second base device by controlling the second measurement arrangement, and preferably by controlling the second output device the user in dependence on the second occupancy state of the at least one sample receptacle output via the second occupancy state.
  • a sample receiving device is preferably a microtiter plate (English: Wellplate), which can be made in particular according to SBS standard.
  • a sample receiving assembly is preferably a solid composite of a plurality of sample receptacles.
  • the sample holders can be connected via a connecting plate or via connecting webs.
  • the sample holders may be containers that are open at the top.
  • the sample receptacles may be arranged in a grid array of typically 12, 48, 96, 384 or more sample receptacles. For example, rows and columns of the sample holders are perpendicular to one another, in particular in the known geometries of 3x4, 6x8, 8x12, 16x24.
  • the measuring elements and / or the lighting elements are preferably provided in the same arrangement, or in an adapted to this sample receiving geometry arrangement.
  • a sample receiving arrangement is preferably a coherent, in particular integrally formed component.
  • a sample receptacle may be a holder for a sample container, wherein the sample container may be a single vessel or a multiple vessel.
  • a sample receiving arrangement may be a holding frame with openings or recesses or without openings or Ausaprept, each of which may be designed to receive a single vessel or a well of a microtiter plate.
  • one or two measuring elements can each be arranged in the processing position at an opening, in particular by being firmly connected to the holding frame.
  • the pipetting device is preferably a hand-held device.
  • it preferably has a grip portion.
  • the base body is formed as a handle portion which is gripped by the user's hand to hold the pipetting device, and in particular to move and operate.
  • the pipetting device is designed for one-handed operation, so that all operations required for pipetting can be performed with one hand.
  • the pipetting devices include in particular hand-operated pipettes.
  • single-channel devices and multi-channel devices with single-channel devices containing only a single delivery channel and multichannel devices containing a plurality of delivery channels, which in particular allow the parallel dispensing / picking up of the sample.
  • a dispenser typically has a fluid transfer container with a larger maximum receiving volume than a pipette, and serves to enable the user to perform a variety of dispensing steps without having to refill the fluid transfer container more often.
  • dispenser also responsible for the suction / discharge displacement piston in the fluid transfer container, namely the Dispenserspitze is housed.
  • Examples of hand-operated pipettes are the Eppendorf Reference® 2 and Eppendorf Research® plus by Eppendorf AG, Hamburg, Germany; an example of a hand-operated dispenser is the Multipette® M4 from Eppendorf AG; Examples of electronic pipettes are the Eppendorf Xplorer® and Eppendorf Xplorer® plus by Eppendorf AG; Examples of electronic dispensers are the Multipette® E3 and E3x from Eppendorf AG.
  • the base body of the pipetting device preferably has a housing in which the movement device can be arranged at least partially or completely.
  • the control device is at least partially or completely arranged in the base body.
  • the movement device serves for the movement of the fluid for its transfer and serves in particular for the admission of the fluid into the container and the discharge of the fluid from the container.
  • a hand-operated movement device this preferably has an actuating element, in particular a control knob, by the actuation of which the user applies the force to move the fluid.
  • the force for moving the movement device is applied by means of an electrical energy source, which in particular can be a battery or an accumulator and which can be a component of the pipetting device, in particular of the base body.
  • the movement device preferably has a piston device with a piston which is movable in a cylinder of the piston device in order to generate a negative pressure in this cylinder.
  • the movement device can also be designed to move a piston which is only partially or not at all part of the pipetting device, such as e.g. during the movement of the piston of a syringe container is the case.
  • the pipetting device and / or the pipetting aid system preferably has at least one communication device and / or a user interface, in particular a control element, which in particular serves for the input and / or output of information between the user and the control device.
  • the Control element may have at least one control knob or keyboard, at least one display, in particular touchscreen and / or at least one speaker.
  • the positioning device is configured to effect a reliable relative positioning of the sample receiving arrangement and of the base device, so that the further system components, in particular the measuring elements and / or the lighting arrangement, each assume a single relative position with respect to the sample receiving arrangement and the base device. This improves the precision in handling the pipetting aid system.
  • the positioning means may comprise one or more support portions provided on the base device for supporting, holding or suspending the sample receiving assembly.
  • a support portion may be a support portion, in particular a plate portion on which the sample receiving assembly is parked. By at least one, two three or four further support portions, the sample receiving assembly can be positioned clearly and backlash in the lateral direction.
  • These support sections may be realized by projection devices which serve as stops whose position is precisely matched to the external dimensions of the sample receiving arrangement.
  • the positioning device can have at least one position sensor with which the manual arrangement of the sample receiving arrangement in the positioning space is registered by the electronic control device of the base device.
  • the invention further relates to a method for measuring an occupation state of a sample holder by means of a pipetting auxiliary system according to the invention. Further preferred aspects of this method can be taken from the present description of the invention.
  • the method comprises the steps of measuring the occupation state by measuring a capacitance value or its change by means of at least one measuring element designed as an electrode, when a conductive sample transfer container or a sample transfer container is made of non-conductive material Material, filled with a conductive sample, is brought to this electrode and in particular touches the plane or passes through the plane.
  • the invention further relates to a production method for producing a sample receiving arrangement according to the invention by means of an injection molding technique, in particular the realization of at least one electrical line or an electrode or an electrical contact point of the sample receiving device by means of a conductive polymer.
  • Fig. 1a shows a typical application scenario underlying the invention.
  • a complete filling of the microtiter plate by means of successive column-wise pipetting in the direction F is carried out by means of a manually operated multichannel pipette 70.
  • Eight pipette tips 71 correspond to the number and pattern of a 8-column of the 96-well microtiter plate. In the example, the pipette tips 71 are refilled successively to fill all the sample receptacles of the microtiter plate by the successive pipetting.
  • Pipetting requires positioning the pipette 70 over the target well of the wells of the microtiter plate, lowering along the vertical direction V, and properly contacting the wells' openings with the pipette tips 71, further lowering into the wells, and dispensing the sample by pipetting. This is followed by the lifting of the pipette from the lowered position and the movement along the direction F by exactly one column spacing. Above the second column, the described processes are repeated accordingly, as well as in the columns number 3 to 12.
  • Fig. 1b shows a scenario in which the user has to fill a microtiter plate 69 by means of a single-channel electric pipette 70 '.
  • the task for the user in this figure is to reliably adhere to the microtiter plate a pipetting plan, which includes the pipetting to individual vessels according to a non-successive approach.
  • coordinates of the sample containers or sample containers to be filled or the sample containers can be known to the user, on each of which a sample is to be removed by pipetting and, for example, transferred.
  • a significant effort of the user is necessary to pipette to the correct well. Even more difficult for the user in the case of a sample plate with more than 96 wells, eg 384 wells.
  • the invention offers a very advantageous solution.
  • Fig. 2a shows a sample receiving assembly 20 according to the first preferred embodiment of the invention in one embodiment, as a preferred part of an exemplary pipetting aid according to the invention.
  • the sample receiving assembly 20 is in the format of a microtiter plate made to SBS standard.
  • the sample receiving assembly 20 is essentially made of transparent plastic by means of 2K injection molding and has a matrix of 96 sample receptacles 21 (wells), of which a series with 12 sample receptacles 21 is shown in cross section.
  • the sample receiving arrangement 20 has a measuring arrangement 28 with a multiplicity of measuring elements, here for example 192 measuring elements, of which in each case a pair 22, 23 arranged as electrodes measuring elements are arranged so that they include the receiving space of the sample holder 21 as a dielectric between Kondenatorplatten.
  • Fig. 2c the processing position is shown pipetting from the pipette tips 71 in order to successively fill the entire microtiter plate 20.
  • the measuring elements 22, 23 of the measuring arrangement 28 are arranged at least in the processing position below the plane A, wherein with a pair 22, 23 of electrodes, the occupation state of at least one sample holder 21 in the processing position can be detected.
  • the electrodes and tracks are formed of a conductive polymer, as are the pads 26 and 27 of the sample receiving assembly 20, which are electrically connected to the tracks 24 and 25, which in turn are electrically connected to the electrodes 22, 23.
  • Fig. 2b shows a base device 10 according to the first preferred embodiment of the invention in one embodiment, as a preferred part of an exemplary pipetting aid according to the invention, in particular usable with the sample receiving device 20 in FIG Fig. 2a
  • the base device 10 comprises: a positioning device having a plurality of projection elements 12a, 12b and arranged to position the sample receiving device in the machining position within a positioning space 11 of the base device which is open at least along a plane A for pipetting.
  • the base device 10 has a lighting arrangement 18 arranged in the processing position below this plane A, with which the sample receptacles of the sample receiving arrangement 20 can be illuminated as a function of the respectively measured occupancy states measured by means of the measuring elements 22, 23 of the sample receiving arrangement 20.
  • the light-emitting elements 19 formed in each case in the form of LEDs can be controlled individually by the electrical control device 13 via the lines of a line bundle 14, with which they are electrically coupled via an electrical interface 13a.
  • the base device preferably has a solid housing made of metal and / or plastic, in which the lighting arrangement and the control device are arranged.
  • the measuring elements 22, 23 of the microtiter plate 20 are electrically connected via electrical contact points 26, 27 with corresponding contact points 16, 17, which are arranged on the upper side of the plate-like receiving region of the base device 10 in the receiving space 11.
  • the contact points 16, 17 are each connected via lines 15a, 15b to an electrical interface 13b, with which the measuring elements are coupled to the control device 13. All first measuring electrodes 22 of the sensor devices of the series of sample receptacles 21 shown here are connected here to the line 15a, all second measuring electrodes 23 of the sensor devices of the series of sample receptacles 21 shown here are connected here to the line 15b. Due to the sensitive measuring electronics for measuring very small capacitances reliable occupation state measurements are successively possible on all sensor devices of the series in this line-saving manner, wherein in each case 8 sensor devices are measured simultaneously in columns.
  • the positioning device 12a, 12b reliably positions the microtiter plate 20 in the positioning space 11.
  • Fig. 2c shows a pipetting auxiliary system, in the processing position, comprising the sample receiving arrangement of Fig. 2a and the base device of Fig. 2b
  • the pipetting auxiliary system 1 serves to assist the manual pipetting of a plurality of samples in a processing position of a sample receiving device 20, the pipetting auxiliary system 1 comprising: a base device 10 having a positioning device 12a, 12b for positioning the sample receiving device 20 in the processing position within a positioning space 11 of FIG Base device 10 is arranged, which is open at least along a plane (A) for pipetting, the sample receiving assembly 20 having a plurality of sample receptacles 21, a measuring assembly 28 with a plurality of measuring elements 22, 23, at least in the processing position below this Level A are arranged and with which the occupancy state of at least one sample holder 21 in the processing position can be detected, and a arranged at least in the processing position below this plane A light assembly 18, with which the sample receiving assembly 20 and its sample holders 21 in dependence on the respectively detected occupancy states of this at least
  • the plurality of measuring elements 22, 23 is an integral part of the sample receiving device 20 and the lighting device 18 is an integral part of the base device 10.
  • Fig. 3a shows a sample receiving assembly according to another embodiment of the invention, as a preferred part of an exemplary pipetting aid according to the invention.
  • the sample receiving arrangement 40 here has a respective individual ring electrode 42 at the upper edge of a sample receptacle, the function of which is based on the FIGS. 6a and b is explained. Accordingly, in comparison with the design according to Fig. 2a fewer lines 44 and pads 46 are provided on the sample receiving assembly, and compared to the design of FIG Fig. 2b fewer lines 35a, and contacts 36 are provided. In addition, the functionality of pipetting systems in Fig. 2a-c and 3a-c similar.
  • the single electrode in the upper part of the sample holder, according to Fig. 3a and 6a is particularly preferably also combinable with the variant in Flg. 2a and Fig. 5a / 5c in which electrodes extend in pairs in a vertical direction along most of the length of the sample holders. Functionally, it is achieved in this way that information can be obtained with a single pipetting aid system as to whether or when a pipette tip approaches the measuring space and what occupation state with liquid sample has the sample receptacle in its receiving space.
  • Fig. 4a to Fig. 4d each show different phases of the pipetting assisted by means of an exemplary pipetting aid 1 according to the invention on a sample receiving device 20, and shows these by means of a lighting program the Pipettierangesvorraum effected optical marking of the pipetted or pipetted sample receptacles.
  • the sample holder When lowering a pipette tip through the plane A ( Fig. 4b ), the sample holder is illuminated, for example, from below in yellow color, which is symbolized here by a lighter hatching of the outside right sample recordings.
  • the already filled shots are illuminated from below in green light, resulting in Fig. 4c and 4d is symbolized by a dark hatching of the corresponding sample recordings.
  • Fig. 5a and 5b show a simplified lateral cross-sectional view through a capacitive by means of two electrodes sensor device of an exemplary pipetting aid, in the unfilled and filled state of the single sample holder shown.
  • the space between a pair of electrodes 22, 23, each having a cylindrical shell segment shape placed around the receiving space 21, forms a dielectric penetrating the electric field E, so that a capacitance change is detected when the occupying state changes in FIG. Fig. 5b ).
  • the arrangement of Fig. 5c and 5d is different from that of Fig. 5a and 5b essentially in that the receiving space 21 'of the variant in Fig. 5c and 5d has a substantially spherical shaped bottom (round bottom).
  • the electrodes 22 ', 23' are in this case adapted to this spherical shape and therefore have a spherical plate shape in their lower region. Accordingly, the arrangement differs Figs. 5e and 5f from that of the Fig. 5a and 5b essentially in that the receiving space 21 "of the variant in Figs. 5e and 5f has a substantially conically shaped bottom (cone bottom).
  • the electrodes 22 ", 23" are in this case adapted to this conical shape and therefore have a conical plate shape in their lower region.
  • Fig. 6a and 6b show a simplified lateral cross-sectional view through an electrode by means of an electrode capacitively measuring sensor device of another exemplary Pipettierwhissystems, in the unfilled and filled state of the single sample holder shown. It is detected by means of a single ring electrode 42, which is arranged at the upper edge of the sample holder, the approach of a conductive or stocked with leimonter aqueous solution pipette tip of non-conductive material. The Bringing the pipette tip increases the measured capacitance, so that at a suitable threshold, the occupancy state "pipette tip is on" recognizable.
  • Fig. 7a and 7b show a simplified lateral cross-sectional view through a means of two optical measuring elements optically measuring sensor device of another exemplary Pipettierwhissystems, in the unfilled and filled state of the single sample holder shown.
  • a light beam (infrared) emitted by the LED 66 is incident on the mirror element 83, which directs the beam through the measuring space 81 and to the next mirror element 84. From there, the beam is directed to the light sensor 67, which may in particular be a photodiode or a CMOS sensor.
  • the electrical control of the optical sensor device associated optical measuring elements 66, 67 which are arranged in the base device 60, via the likewise arranged there individual lines 65a, 65b.
  • Fig. 8a shows a sample receiving assembly 120 according to the second preferred embodiment of the invention in one embodiment, as a preferred part of an exemplary pipetting aid according to the invention.
  • the light-emitting elements 118a are arranged here in each case centrally and vertically below the sample holder 21, so that it can be illuminated symmetrically.
  • Fig. 8b shows a base device according to the second preferred embodiment of the invention in one embodiment, as a preferred part of an exemplary pipetting aid according to the invention, in particular usable with the sample receiving device in Fig. 8a .
  • Analogous to Fig. 2b is the Positonier Tooth 112 a, 112 b made.
  • the control device 113th is the Positonier Tooth 112 a, 112 b made.
  • Fig. 8c shows a pipetting auxiliary system, in the processing position, comprising the sample receiving arrangement of Fig. 8a and the base device of Fig. 8b , In the in Fig. 8b
  • the plurality of measuring elements 116, 117 and the lighting arrangement 118 with luminous elements 118a Solid components of the base device 110.
  • the sample receiving assembly 120 has a plurality of opening portions 122, 123 for receiving the measuring elements 116, 117 in the processing position.
  • Such a sample receiving assembly 120 which need not have electrical leads or electrically conductive portions, can be manufactured simply and precisely by injection molding.
  • Fig. 9a shows a sample receiving assembly according to the third preferred embodiment of the invention in one embodiment, as a preferred part of an exemplary pipetting aid according to the invention.
  • the plurality of measuring elements 222, 223 of the measuring arrangement 228 and a multiplicity of luminous elements 224 of the lighting arrangement 229 are fixed components of the sample receiving arrangement.
  • the remaining parts are essentially analogous to the embodiments in FIGS Fig. 2c and 8c manufactured.
  • Fig. 9b shows a base device according to the third preferred embodiment of the invention in one embodiment, as a preferred part of an exemplary pipetting aid according to the invention, in particular usable with the sample receiving device in Fig. 9a ,
  • Fig. 9c shows a pipetting auxiliary system, in the processing position, comprising the sample receiving arrangement of Fig. 9a and the base device of Fig. 9b ,
  • Fig. 10 shows a perspective view of a pipetting system 300 according to the invention according to another preferred embodiment.
  • Two base devices 10, 10 " which are essentially, for example, the in Fig. 2b can correspond to the base device shown are connected via the signal exchange / data exchange line "D" in connection.
  • the sample receiving devices are designed here as in Fig. 2a shown.
  • the controllers of this base device which can communicate with each other, are arranged to assist the user of the manual pipetting device 70 in performing a transfer process.
  • the user should, in accordance with a pipetting program, receive at least a control device is carried out, take samples from first columns of the sample plate 20 by means of a pipette 70 and transfer them into second sample columns of the sample plate 20 "The pipetting program or the control device executing this is set up to illuminate the first column of the sample plate 20 in color in Fig. 10 symbolized by the darker tint of the first column of sample receptacles of the sample plate 20. The user now picks up the samples by pipetting in this column. After removal, the user is signaled the success or failure of the removal from this first column of the sample plate 20 by the system by changing the illumination of this first column of the sample plate 20.
  • the target position for the samples now contained in the pipette tips 71 here the fourth column from the right, is indicated to the user by illumination
  • the user is signaled the success or failure of dispensing into this fourth column of the sample plate 20 "by the system by changing the illumination of this fourth column of the sample plate 20"
  • Sample plate 20 " This assistance in transferring the samples between two sample receiving assemblies monitored by the pipetting aid system continues until the pipetting program is completed.
  • a pipetting auxiliary system By means of a pipetting auxiliary system according to the invention, users work confusion-proof in, in particular, sample receiving arrangements consisting of plates, strips and vessels. The user always knows which wells are to be filled next in a process and which occupancy state exists in each case.
  • the basic device is a mobile, compact plate-receiving tool with a small footprint It is particularly built-in laboratory workstations for additional control of experiments performed.
  • a sample receiving assembly can be made as required as a closed system, particularly when using 2K injection molded sample receiving assemblies, which in particular comprise a conductive polymer as electrically conductive regions.
  • a sample receiving arrangement can also be made as an "open system”, ie with openings or recesses for receiving eg capacitive sensor plates or sensor columns (see Fig. 8a ), which are arranged on the base device.

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  • Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Human Computer Interaction (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Devices For Use In Laboratory Experiments (AREA)
  • Sampling And Sample Adjustment (AREA)
EP17171137.7A 2017-05-15 2017-05-15 Système d'aide au pipetage Withdrawn EP3403725A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP17171137.7A EP3403725A1 (fr) 2017-05-15 2017-05-15 Système d'aide au pipetage
US16/614,336 US20200147602A1 (en) 2017-05-15 2018-05-14 Pipette auxiliary system
PCT/EP2018/062343 WO2018210728A1 (fr) 2017-05-15 2018-05-14 Système auxiliaire de pipetage
EP18724536.0A EP3624945B1 (fr) 2017-05-15 2018-05-14 Système d'aide au pipetage
CN201880031082.2A CN110621408B (zh) 2017-05-15 2018-05-14 吸移辅助系统
JP2019562333A JP7121754B2 (ja) 2017-05-15 2018-05-14 ピペット操作補助システム

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP17171137.7A EP3403725A1 (fr) 2017-05-15 2017-05-15 Système d'aide au pipetage

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EP18724536.0A Active EP3624945B1 (fr) 2017-05-15 2018-05-14 Système d'aide au pipetage

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EP (2) EP3403725A1 (fr)
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WO (1) WO2018210728A1 (fr)

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US20200147602A1 (en) 2020-05-14
EP3624945A1 (fr) 2020-03-25
EP3624945B1 (fr) 2022-04-27
JP7121754B2 (ja) 2022-08-18
CN110621408A (zh) 2019-12-27
CN110621408B (zh) 2022-06-17
WO2018210728A1 (fr) 2018-11-22
JP2020520302A (ja) 2020-07-09

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