The invention relates to an apparatus for processing a laboratory sample contained in a laboratory sample container, to a laboratory automation system comprising such an apparatus and to a method for pipetting a laboratory sample.

EP 2 770 317 A1 discloses an apparatus for determining a vertical position of at least one interface between a first component and at least one second component, the components being comprised as different layers in a sample container or sample tube.

It is an object of the invention to provide an apparatus for processing a laboratory sample contained in a laboratory sample container, a laboratory automation system comprising such an apparatus and a method for pipetting a laboratory sample having improved properties regarding the prior art.

The invention solves this object by providing an apparatus for processing a laboratory sample contained in a laboratory sample container according to claim 1 , a laboratory automation system comprising such an apparatus according to claim 8 and a method for pipetting a laboratory sample according to claim 1 1 .

The apparatus is adapted to process, in particular pipette, a laboratory sample contained in a laboratory sample container.

The apparatus comprises an optical sensing unit. The optical sensing unit is adapted to sense an (optical power) transmittance (also called transmission) through the laboratory sample container. Transmittance typically is defined as the ratio of the optical power of the transmitted light exiting the laboratory sample container after having passed through the laboratory sample container comprising the laboratory sample to the incident optical power of light applied to the sample container. Transmittance is typically a numerical value between zero, i.e. all light is absorbed, and one, i.e. no light is absorbed. Regarding the term transmittance, reference is also made to the relevant technical literature. In the following transmittance is defined as the ratio between the optical power detected by a respective light detector to the optical power emitted by a respective light source. The apparatus may further comprise a tip sensing unit comprising a tip, in particular a pipetting tip, wherein the tip sensing unit is adapted to provide a tip sensing signal depending on a position, in particular a vertical position, of the tip relative to the sample. The tip sensing signal may be representative regarding a liquid level of the laboratory sample inside the laboratory sample container. The tip sensing unit may e.g. comprise a resistive sensing unit rLLD measuring a tip resistance, a capacitive sensing unit cLLD measuring a tip position dependent capacitance, and/or a pressure based liquid sensing unit pLLD, each providing the tip sensing signal, inter alia, dependent on a liquid level of the laboratory sample inside the laboratory sample container. The optical sensing unit may comprise an array or any suitable arrangement of a plurality of corresponding sensing elements, e.g. arranged vertically spaced. The optical sensing unit may e.g. comprise two optical sender diodes and two corresponding receiver diodes.

The apparatus further comprises a process control unit, e.g. in form of a Personal Computer. The process control unit is adapted to control the processing of the laboratory sample in response to the transmittance and/or in response to further sensing signals being representative of the liquid level of the laboratory sample being provided by the further sensing units, in particular in response to the tip sensing signal.

The process control unit may initiate and/or control the processing of the laboratory sample in response to the transmittance and in response to the further sensing signals, in particular in response to the tip sensing signal.

The laboratory sample container is typically designed as a tube made of glass or transparent plastic and typically has an opening at an upper end. The laboratory sample container may be used to contain, store and transport the laboratory sample such as a blood sample, (blood) serum or plasma sample, a urine sample, separation gel, cruor (blood cells) or a chemical sample. Some parts of the sample may occur in a distance of the liquid level in the laboratory sample container during sample preparation as foam, a liquid film or droplets, in particular by manual and/or automatic pipetting, by transporting the laboratory sample container between different laboratory stations, by handling the laboratory sample container, by capping/decapping or by shaking the laboratory sample container. The laboratory sample container may be rotationally symmetric and this symmetry axis may be a vertical axis.

In an embodiment, the process control unit is further adapted to determine a first (liquid) level of the laboratory sample in the laboratory sample container in response to the transmittance. The laboratory sample container may contain the (liquid) laboratory sample and at least a second component, in particular air. The first (liquid) level may describe a vertical position in the laboratory sample container where the (liquid) laboratory sample ends and the second component begins. In other words, the first (liquid) level may describe a vertical position of a boundary layer between the (liquid) laboratory sample and the second component. Additionally, a transition phase may be located between the (liquid) laboratory sample and the second component. The transition phase may comprise a mixture of the (liquid) laboratory sample and the second component, in particular the mixture may be a bubble, several bubbles, foam or a film of a liquid or droplets. The first (liquid) level may be the vertical position of a boundary layer between the (liquid) laboratory sample and the transition phase.

The laboratory sample, the transition phase, if any, and the second component may differ in their transmittance and, thus, it may be possible to sense boundary layer(s) between the laboratory sample and the transition phase, if any, and the second component.

The process control unit is further adapted to determine a second liquid level of the laboratory sample in response to the signal of the tip sensing unit. The liquid level detection based on the capacitance and/or pressure and/or resistance of/in the pipetting tip is known as capacitive/pressure/resistance Liquid Level Detection (c/p/rLLD), respectively. Reference is also made to the technical literature regarding the basic functional principles of LLD, e.g. US 5648727 A. These LLD techniques are used to reliably control the movement of the pipetting tip relative to the sample surface, i.e. the liquid level. The pipetting tip is moved towards the sample in the tube and stops after detection of the liquid level by LLD and is afterwards immersed into the sample with a defined fixed immersion depth. During pipetting of the sample the pipetting tip is further immersed into the sample to account for the drop of the liquid level during pipetting, i.e. suction of the sample into the pipetting tip. With regard to the tip sensing unit, it may be impossible to distinguish between the laboratory sample and the transition phase by sensing the capacitance, resistance and/or pressure. Thus, the second level of the laboratory sample may describe a vertical position of a boundary layer between the transition phase and the second component, if a transition phase is present, or may describe a vertical position of a boundary layer between the laboratory sample and the second component, if no transition phase is present. If no transition phase is present, the first level and the second level are typically identical.

The process control unit may be adapted to cause or initiate a pipetting of the laboratory sample, if the first level and the second level differ less than a given threshold, and the process control unit may be adapted to cause a discarding of the laboratory sample, if the first level and the second level differ more than the given threshold. Discarding may denote that a pipetting step is omitted. Additionally, discarding may denote that that the laboratory sample is flagged by a defined flag and receives a specific treatment, e.g. the sample is positioned in an output area of the laboratory analyzer to be inspected by a laboratory assistant, assistant, or by automatically destroying the transition phase by e.g. sucking it out, slightly blowing in the sample container or other appropriate actions.

In an embodiment, the optical sensing unit comprises a first light source emitting light having a first wavelength, wherein the light having the first wavelength is applied to the laboratory sample container and is then transmitted through the laboratory sample container.

The light of the first light source may propagate as a beam through the laboratory sample container and the laboratory sample. The beam of the first light source may propagate substantially perpendicular to a vertical axis of the laboratory sample container, for example at an angle relative to a vertical axis of the sample container of between 85 degrees and 95 degrees, such as between 89 degrees and 91 degrees. Further, the beam may propagate substantially through the vertical axis of the sample container.

The optical sensing unit may further comprise a first light detector being adapted to detect light having the first wavelength transmitted through the laboratory sample container and being adapted to generate a first light detector signal being indicative of the transmittance through the laboratory sample container at the first wavelength.

The first wavelength may be substantially transmitted by the laboratory sample and the second component.

The optical sensing unit may comprise a second light source emitting light having a second wavelength, wherein the light having the second wavelength is applied to the laboratory sample container and is then transmitted through the laboratory sample container.

The light of the second light source may propagate as a beam through the laboratory sample container and the laboratory sample. The beam of the second light source may propagate substantially perpendicular to a vertical axis of the laboratory sample container, for example at an angle relative to a vertical axis of the sample container of between 85 degrees and 95 degrees, such as between 89 degrees and 91 degrees. Further, the beam may propagate substantially through the vertical axis of the sample container. The optical sensing unit may further comprise a second light detector being adapted to detect light having the second wavelength transmitted through the laboratory sample container and being adapted to generate a second light detector signal being indicative of the transmittance through the laboratory sample container at the second wavelength. The second wavelength may be substantially absorbed by the laboratory sample and may be substantially transmitted by the second component.

The process control unit may be supplied with the first light detector signal and the second light detector signal, and may be adapted to control the processing of the laboratory sample in response to the first and second light detector signal and the tip sensing signal. The process control unit may be adapted to determine the first level in response to the first light detector signal and to the second light detector signal. The first light detector signal may be used as a reference signal, e.g. by calculating a quotient between the first light detector signal and the second light detector signal. Reference is made to EP 2 770 317 A1 regarding the use of two wavelengths for liquid level detection. The process control unit may be supplied with the tip sensing signal for determining the second level.

In an embodiment, the first light source emits light having a wavelength in the range between 150 nm and 1380 nm, in particular in the range between 400 nm and 1380 nm.

The wavelength of the first light source may have low water absorption. The second light source emits light having a wavelength in the range between 1400 nm and 4000 nm, in particular in the ranges between 1400 nm and 1600nm or 1900 nm and 2500 nm.

In particular the wavelengths for the second and first light source are chosen such that the ratio of their absorption in water is in the range between 2 and 1 Ό00Ό00.

In an embodiment, a driving unit is adapted to provide a vertical movement of the laboratory sample container relative to the optical sensing unit. The driving unit or a further driving unit is adapted to provide a vertical movement of the laboratory sample container relative to the tip sensing unit, i.e. the (pipetting) tip is moveable with respect to the laboratory sample container. The movement of the laboratory sample container may be in the direction of the vertical axis of the laboratory sample container.

The control unit receives respective signals of the driving unit and/or of the further driving unit, if any, to relate the detected liquid level of the optical sensing unit and the detected liquid level of tip sensing unit. The driving unit may provide a respective movement signal or position signal to the process control unit, indicating the respective relative vertical positions of the optical sensing unit and of the tip relative to the sample and/or sample container.

The two detected liquid levels can be related to each other by e.g. taking care that the sample container is always at the same level in space during operation or by detecting the sample container edge or a sample container holder edge by well-known techniques, e.g. a light barrier, or fixed touch probes or fixed distant measurement sensors like ultrasonic sensors.

In another embodiment the driving unit and the further driving unit are the same and e.g. drive the sample container trough the optical sensing unit towards the pipetting tip.

The process control unit may be adapted to control the processing of the laboratory sample in response to the transmittance sensed by the optical sensing unit for different relative positions between the laboratory sample container and the optical sensing unit and in response to the tip sensing signal for different relative positions between the laboratory sample container and the tip.

In an embodiment, the driving unit is adapted to rotate the laboratory sample container. The driving unit may rotate the laboratory sample container around a vertical axis of the laboratory sample container.

The process control unit may be adapted to control the processing of the laboratory sample in response to the transmittance and the signal of the tip sensing unit for the rotated laboratory sample container. In an embodiment, the apparatus comprises a light barrier adapted to detect the introduction of the laboratory sample container into the apparatus. The apparatus may be adapted to activate the optical sensing unit and/or the tip sensing unit and/or the process control unit when the introduction is detected. The deactivation of the optical sensing unit and/or of the tip sensing unit and/or the process control unit may initiate a standby modus for reducing energy consumption of the apparatus. The inventive laboratory automation system is adapted to handle and/or process laboratory samples comprised in the laboratory sample container. The laboratory automation system comprises the inventive apparatus described above.

The laboratory automation system further comprises a number (e.g. 1 to 100) of laboratory stations functionally coupled to the apparatus. The laboratory stations may e.g. be pre- analytical, analytical and/or post-analytical stations.

Pre-analytical stations may be adapted to perform any kind of pre-processing of samples, sample containers and/or sample container carriers.

Analytical stations may be adapted to use a sample or part of the sample and a reagent to generate a measuring signal, the measuring signal indicating if and in which concentration, if any, an analyte is existing.

Post-analytical stations may be adapted to perform any kind of post-processing of samples, sample containers and/or sample container carriers.

The pre-analytical, analytical and/or post-analytical stations may comprise at least one of a decapping station, a recapping station, an aliquot station, a centrifugation station, an archiving station, a pipetting station, a sorting station, a tube type identification station, a sample quality determining station, an add-on buffer station, a liquid level detection station, and a sealing/desealing station.

In an embodiment of the laboratory automation system, the laboratory automation system comprises a laboratory pipetting station, wherein the laboratory pipetting station is controlled by the process control unit.

The laboratory pipetting station may be adapted to operate in response to the first level and/or the second level of the laboratory sample to securely and reliably perform the aspiration of the laboratory sample. The laboratory pipetting station may perform the aspiration of the laboratory sample at a specific vertical aspiration position depending on the first and/or second level.

The laboratory pipetting station may comprise the tip sensing unit.

In an embodiment at least one of the number of laboratory station is adapted to analyze the laboratory sample. The method for pipetting a laboratory sample contained in a laboratory sample container, in particular using the apparatus for processing a laboratory sample, comprises the following steps: sensing a transmittance through the laboratory sample container for a number (e.g. 1 to 100) of vertical positions, sequentially or simultaneously sensing a tip sensing signal in form of a capacitance, resistance and/or pressure of/in the tip depending on the vertical pipetting tip position relative to the sample, and pipetting the laboratory sample in response to the transmittance, the capacitance, resistance, and/or pressure.

The invention will be described in detail with respect to the drawings schematically depicting embodiments of the invention. In detail:

Fig. 1 schematically depicts an apparatus for processing a laboratory sample contained in a laboratory sample container, and

Fig. 2 schematically illustrates a laboratory automation system comprising the apparatus depicted in Fig. 1 . Fig. 1 schematically depicts an apparatus 100 for processing a laboratory sample 1 in form of liquid (blood) serum contained in a laboratory sample container 2.

In addition to the serum 1 , the laboratory sample container 2 further contains a second component 7 in form of air and a transition phase 6 in form of foam comprising a mixture of serum 1 and air 7. The serum 1 , the transition phase 6 and the air 7 are formed as separate layers inside the sample container 2.

The apparatus 100 comprises an optical sensing unit 3 comprising a first light source 3a in form of a laser diode emitting light having a first wavelength of 800 nm. Light having this wavelength is respectively substantially transmitted by the material of the sample container 2, the serum 1 , and the air 7. The optical sensing unit 3 further comprises a second light source 3c in form of a laser diode emitting light having a second wavelength of 1550 nm vertically spaced by a given vertical distance E. Light having the second wavelength is respectively substantially transmitted by the material of the laboratory sample container 2, and the air 7, but blocked or absorbed by the serum 1 . The first light source 3a and the second light source 3c respectively emit a light beam having a beam diameter of approximately 0,8 mm, such that the corresponding light beams propagate through the laboratory sample container 2 and the respective component or components along a horizontal propagation path. A first light detector 3b in form of a photo diode is arranged at a vertical level which is the same as the vertical level of the first light source 3a. The light detector 3b generates a first light detector signal LDS1 in response to a light power having the first wavelength being applied to the light detector 3b. The first light detector signal LDS1 is representative for a transmittance through the laboratory sample container 2 according to the first wavelength of the first light source 3a.

A second light detector 3d in form of a photo diode is arranged at a vertical level which is the same as the vertical level of the second light source 3c. The light detector 3d generates a second light detector signal LDS2 in response to a light power having the second wavelength being applied to the light detector 3d. The second light detector signal LDS2 is representative for a transmittance through the laboratory sample container 2 according to the second wavelength of the second light source 3c.

The apparatus 100 further comprises a tip sensing unit 4 comprising a pipetting tip 1 1 . A tip sensing signal tLDS provided by the tip sensing unit 4 depends on the position of the pipetting tip 1 1 relative to the sample 1 , because it measures the capacitance of or the resistance of or the pressure in the pipetting tip 1 1 . Thus, the tip sensing signal tLDS provided by the tip sensing unit 4 typically depends on the liquid level of the serum 1 inside of the sample container 2. Consequently, the liquid level of the serum 1 can be determined based on the tip sensing signal tLDS. Reference is also made to the technical literature regarding the basic functional principles of Liquid Level Detection (LLD). Capacitive, resistance and/or pressure sensing can be used as a single measurement method or in any combination.

The pipetting tip 1 1 is placed at an end of a conventional pipetting tube e.g. used to suck out a portion of the sample 1 . Reference is made insofar to the relevant technical literature.

The apparatus 100 further comprises a process control unit 5. The process control unit 5 is adapted to control the processing of the serum 1 in response to the transmittance sensed by the optical sensing unit and the tip sensing signal tLDS, e.g. representing the capacitance of the pipetting tip 1 1 . The apparatus 100 further comprises a driving unit 8 in form of a pick-and-place unit for vertically moving the laboratory sample container 2 relative to the optical sensing unit 3 and the pipetting tip 1 1 . The driving unit 8 is further adapted to rotate the laboratory sample container 2 around a vertical axis V of the laboratory sample container 2. The driving unit 8 is further adapted to insert the laboratory sample container 2 into a conventional laboratory sample container carrier 10. The driving unit 8 is further adapted to generate a position signal z. The position signal z represents a vertical position of the laboratory sample container 2.

The apparatus further comprises a position sensing unit in form of a light barrier 9. The light barrier 9 is functionally coupled to the driving unit 8. The light barrier 9 detects the introduction of the laboratory sample container 2 into the apparatus 100. The apparatus 100 is adapted to activate the optical sensing unit 3 and/or the tip sensing unit 4 and/or the process control unit 5 when the introduction is detected. Moreover, the light barrier 9 defines a vertical position as a zero or reference position, i.e. a position signal z from the driving unit 8 for this reference position has a defined reference value, e.g. zero. Thus, the driving unit 8 outputs a position sensing signal z indicative of a vertical position of the laboratory sample container 2, wherein the vertical position of the light barrier 9 is defined as a vertical reference position.

The process control unit 5 is supplied with the signals LDS1 , LDS2 and z and is adapted to determine a liquid level of the serum 1 in the laboratory sample container 2 in response to the first and second light detector signals LDS1 , LDS2 as a first liquid level. Both light detector signals are mapped to the bottom end of the laboratory sample container 2. The first and second light detector signals LDS1 , LDS2 are misaligned by z = E due to the vertical distance E between the first light source 3a and the second light source 3c.

Before analyzing the light detector signals LDS1 and LDS2, the process control unit 5 matches the first light detector signal LDS1 and the second light detector signal LDS2. After matching the light detector sensing signals LDS1 and LDS2, the process control unit 5 computes a liquid level out of the extinction and release of the signals LDS1 and the matched LDS2. A vertical position for which the result of the comparison changes is determined as the first (liquid) level of the serum 1 . For further details regarding this aspect reference is made to EP 2 770 317 A1 . If labels are glued to the laboratory sample container 2 or other extinctive elements are present in the optical paths, the light detector sensing signals LDS1 and LDS2 may not have sufficient signal strength. In this case, the process control unit computes a quotient Q (including signal smoothing, limiting, etc.) between the matched second light detector signal and the light detector signal LDS1 , wherein the quotient Q is compared with a given threshold value. If this is still not sufficient the driving unit 8 may rotate the laboratory sample container 2 around the vertical axis V of the laboratory sample container 2 to cause a measurement path eventually crossing a decreased number of label layers and may repeat the measurement. As such, a measurement path having less label layers may be found, thus increasing the signal-to-noise ratio of the sensing signals.

The process control unit 5 is adapted to determine a level of the serum 1 in the laboratory sample container 2 in response to the tip sensing signal tLDS of the tip sensing unit 4 and the signal z as a second liquid level. For that purpose, the process control unit 5 is functionally coupled to the tip sensing unit 4 such that the signal tLDS indicating the capacitance, resistance and/or pressure of/in the tip sensing unit 4 is provided to the process control unit 5. The resistance, or capacitance of the tip 1 1 or the pressure in the tip 1 1 will also change when the tip 1 1 gets into contact with a liquid film, a droplet at the surface of the sample container 2, or foam above the proper liquid level. The principle of the determination of the second liquid level is known as capacitive/pressure/resistance Liquid Level Detection (c/p/rLLD). Reference is also made to the technical literature regarding the basic functional principles of LLD with tips.

In the discussed example of Fig. 1 the second liquid level and the first level deviate from each other due to the presence of a transition phase 6 or e.g. an incorrect placement of the sample container in a sample container holder. The process control unit 5 is adapted to determine a deviation, e.g. an absolute value of a difference, between the first and the second liquid level and compare the deviation with a given threshold, e.g. 3 mm. If the deviation is smaller than the given threshold, the process control unit 5 causes a pipetting of the laboratory sample 1 . If the deviation is larger or equal than the given threshold, the process control unit 5 causes a discarding of the laboratory sample 1 .

Fig. 2 schematically illustrates a laboratory automation system 200 comprising the apparatus 100 depicted in Fig. 1 , an exemplary laboratory station 210, a centrifuge station 230, an aliquoter unit 240 including a pipetting station 250.

The apparatus 100 and the pipetting station 250 are functionally coupled by means of a conventional data or field bus. Self-evidently, the system may include further laboratory stations, such as pre analytical stations, analytical stations and post analytical stations. The pipetting station 250 transfers part of the sample 1 to one or more secondary tubes (not shown). The pipetting station 250 is adapted to pipette the sample 1 , if the process control unit 5 initiates the pipetting of the sample 1 in the event that the deviation between the two liquid levels is smaller than the given threshold. The pipetting station 250 is adapted to discard the complete sample, i.e. to omit a pipetting step, if the process control unit 5 controls the discarding of the serum 1 in the event that the deviation between the two liquid levels is larger than or equal to the given threshold.

The system 200 further includes a sample container transport unit adapted to transport sample containers 2 between the apparatus 100, the pipetting station 250 and further laboratory stations, e.g. the laboratory station 210. The sample container transport unit includes a number of sample container carriers 10 and a conveyor 220, wherein the sample container carriers 10 are attached to the conveyor 220.

The optical sensing unit 3 and the tip sensing unit 4 may alternatively be provided at different locations of the laboratory automation system 200. The optical sensing unit 3 may e.g. be provided at a so called in-sort Station where the laboratory sample containers 2 comprising the corresponding samples are inserted into the system 200. Thus, the first liquid level may be determined when inserting the sample container into the system 200. The tip sensing unit 4 may be functionally coupled to the aliquoter unit 240 such that the second liquid level may be determined before and/or during pipetting the laboratory sample 1 .