Apparatus and laboratory automaton for culturing plurality of patient samples using plurality of culture vessels

Abstract

The invention relates to a device for culturing a plurality of patient samples using a plurality of culture vessels, comprising a first unit comprising a respective receptacle for a respective culture vessel, and a second unit comprising a respective receptacle for a respective culture vessel, two of the respective units are movably mounted in their respective location positions along a common linear guide axis, and having a respective sensor for providing a respective sensor signal which indicates a respective one of the respective location positions, the device also has a respective magnetic drive unit for changing the respective location position, and a control unit which actuates the respective magnetic drive unit on the basis of the respective sensor signal in order to cause a change in the respective location position.

Description

Technical Field

[0001] The invention relates to a device for culturing a plurality of patient samples using a plurality of culture vessels and to a laboratory robot. Background Art

[0002] The following task is proposed for a variety of technical methods in the fields of biotechnology, pharmacy, diagnosis and medicine, that is, multiple or corresponding patient samples are cultured in corresponding culture vessels. Here, culture is understood to be that the patient sample is in contact with one or more liquids of a so-called test or diagnostic test. For this reason, the patient sample must not only be in contact with one or more such liquids of the test for a short time, but also the corresponding culture vessel must accommodate a certain duration of the patient sample and other liquids. Here, in order to optimize the mixing of the patient sample and such a liquid, the culture vessel is usually moved or shaken rhythmically. In addition, the culture vessel preferably can also be subjected to a predetermined temperature, which then exists within the culture vessel.

[0003] For this purpose, it is desirable for logistical reasons and also for economic reasons to increase the degree of automation of such a cultivation process.

[0004] Devices are known in which individual culture vessels are introduced into a rack and the culture vessels are then also moved or shaken rhythmically by automated movement of the rack. Summary of the invention

[0005] The object of the present invention is to further increase the degree of automation so that the cultivation of a plurality of patient samples in corresponding or corresponding culture vessels can take place at least partially simultaneously.

[0006] The object according to the invention is achieved by a device according to claim 1 and a laboratory robot according to claim 11 .

[0007] The device according to the invention for culturing a plurality of patient samples comprises a first unit with corresponding, ie a plurality of, receptacles for corresponding culture vessels and a second unit with corresponding, ie a plurality of, receptacles for corresponding culture vessels.

[0008] Both units are mounted so as to be movable along a common linear guide axis in each case in their respective location.

[0009] The device further comprises a corresponding sensor for providing a corresponding sensor signal, wherein the corresponding sensor signal indicates a corresponding one of the corresponding location positions of a corresponding unit.

[0010] In this case, the device has a corresponding magnetic drive or a magnetic drive unit, which is respectively designed to bring about or cause a corresponding change in the corresponding location of the corresponding unit.

[0011] Finally, the device also has a control unit which is designed to actuate the corresponding magnetic drive unit based on the corresponding sensor signal in order to bring about or cause a corresponding change in the corresponding location position.

[0012] According to the device of the invention, the two units each have a plurality of culture vessel receptacles, so that a plurality of culture vessels can be subjected to a rhythmic movement or shaking process at the same time. Since the two units are movably supported along the common linear guide axis, the two units can only be moved in translation along the axis, in particular only be placed in oscillation along the axis. In particular, the two units are therefore supported and guided in such a way that the two units have only one common translational degree of freedom along the common linear guide axis. It is thus possible in principle that the mass movement of the two units together with the culture vessels located therein does not occur randomly or chaotically, but rather only along the common linear guide axis, so that in principle the two mass movements can compensate for each other, in particular when the device is installed in an entire laboratory robot.

[0013] By having the knowledge of the corresponding location of the corresponding unit based on the corresponding sensor signal of the corresponding sensor, the control unit can therefore cause the corresponding location on the corresponding unit to be changed accordingly in an advantageous manner by the corresponding magnetic drive unit. If only a single unit is used for cultivation, the rhythmic movement of the single unit unit will have an impact on the entire laboratory automaton and therefore other units in the laboratory automaton may also be placed in oscillation. By having two separate units that are movably supported in the direction of the common linear guide axis, such a mass movement of a single unit can be compensated by the mass movement of the second unit. In particular, the control unit therefore controls the magnetic drive unit in such a way that the mass movement of the first unit is compensated by the mass movement of the second unit. Thus, the overall mass movement of the total mass of each unit is minimized and therefore the mechanical influence on the entire laboratory automaton is also minimized.

[0014] Advantageous embodiments of the invention are the subject of the dependent claims and are explained in greater detail in the description, partly with reference to the drawings.

[0015] Preferably, the two units are each mounted and guided along the common linear guide axis in such a way that the two units have only one common translational degree of freedom. This ensures that mass movements of the units occur only along the one linear guide axis or the one translational degree of freedom and that the control unit therefore only has to be designed to control mass movements of the respective unit only along the translational degree of freedom or along the common linear guide axis in such a way that the mass movements compensate for one another to at least a certain extent.

[0016] Preferably, the respective units are mechanically coupled to a common base plate via respective spring units. In this case, the respective units preferably form together with the respective spring units a respective spring-mass oscillation system. This embodiment is advantageous because the control unit can thus place the respective units in oscillations of a certain frequency via the respective magnetic drive units. In this case, the control unit can utilize the frequency characteristics of the respective spring-mass oscillation system and preferably generate drive energy via the magnetic drive unit only in such a way that the magnetic drive unit compensates for possible energy losses of mechanical friction and / or deviations of the oscillation frequency of the spring-mass oscillation system from a target frequency. Therefore, the control unit is preferably designed to place the respective units in respective oscillations of the same frequency, in particular, via the respective magnetic drive units.

[0017] Furthermore, the control unit is preferably designed to control the magnetic drive units in such a way that they are kept in oscillation with essentially the same oscillation amplitude in the direction of the linear guide axis or the translational degree of freedom. The oscillation amplitude can also be referred to as the maximum oscillation amplitude.

[0018] In particular, the control unit is preferably designed to control the magnetic drive units based on the sensor signal by means of a control principle in such a way that the corresponding oscillation frequencies generated by the corresponding units are essentially the same and the corresponding oscillation frequencies have a phase shift of essentially 180 degrees with respect to one another. Particularly preferably, the corresponding oscillation frequencies generated by the corresponding units are identical and have a phase shift of 180 degrees with respect to one another. This embodiment is particularly advantageous because it thus particularly optimizes or enables compensation of the mass movement of the first unit relative to the mass movement of the second unit, so that in particular the overall influence of the common oscillating forces of the two units on the laboratory robot is particularly minimized.

[0019] In particular, the control unit is designed to determine the respective current amplitude or oscillation amplitude and the respective oscillation frequency for the respective unit based on the respective sensor signal, and in addition, in particular, to adjust both units to a common oscillation amplitude and a common identical target oscillation frequency. This achieves particularly good optimization of the oscillation compensation of the two units. The common oscillation amplitude can also be referred to as a maximum oscillation amplitude or a maximum target oscillation amplitude.

[0020] In particular, the two units preferably have the same mass in the unloaded state. In particular, the two spring units are designed in such a way that the two spring units have an identical common spring constant.

[0021] Preferably, the two units, together with the spring units respectively belonging thereto, have corresponding spring-mass oscillation systems, which have the same resonance frequency in the unloaded state, wherein the target oscillation frequency of the control unit's regulation is below this resonance frequency. This embodiment is advantageous because the corresponding total mass of the corresponding unit is increased by loading one or the two units (and in particular the liquid located therein) with a culture vessel and the resonance frequency of the system in the unloaded state is thus reduced to a slightly lower resonance frequency. By the target oscillation frequency of the control unit's regulation being below the resonance frequency of one of the spring-mass oscillation systems in the unloaded state, it is achieved that in the loaded state of the units the target oscillation frequency is in the vicinity of the resonance frequency of the spring-mass oscillation system in the state of the units. In particular, the corresponding units and their corresponding spring units respectively form the same spring-mass oscillation system.

[0022] Preferably, the control unit is also designed to carry out the PI regulation with reference to a common, identical target oscillation frequency. The control unit is also preferably designed to carry out the PI regulation with reference to a common, identical target oscillation frequency and a common, identical maximum oscillation amplitude for both units, wherein in particular the respective oscillation frequencies of the respective units have a phase shift of 180 degrees with respect to one another. This embodiment is advantageous because the PI regulation is particularly stable.

[0023] Preferably, the respective unit has a respective heating unit. This embodiment is advantageous because it allows the desired temperature to be achieved within the culture vessel.

[0024] A laboratory robot with a device for culturing according to the invention is also proposed. The laboratory robot also has a vessel box with a plurality of culture vessels. The laboratory robot also has a container with a patient sample liquid; a container with a buffer liquid; a container with a microbead liquid, which in turn has microbeads coated with antigens or antibodies; and a container with a label liquid, which has antibodies or antigens labeled with a chemifluorescent label. The laboratory robot is therefore in particular a laboratory robot for processing patient samples in the case of using a chemifluorescent assay to verify a target antigen or a target antibody in the patient sample.

[0025] The laboratory robot also has a pipetting unit, which is configured to distribute at least a portion of the patient sample liquid, at least a portion of the buffer liquid, at least a portion of the microbead liquid, and at least a portion of the label liquid into and aspirate from the culture vessel, wherein the label liquid has antibodies or antigens labeled with a chemifluorescent label.

[0026] The laboratory robot also has a gripping unit, which is designed to transport culture vessels from the vessel box to the pipetting unit and from the pipetting unit to the corresponding receptacle in the receptacle, to remove them from the corresponding receptacle and to transport them back to the pipetting unit. The laboratory robot according to the invention is advantageous because, for the purpose of processing chemifluorescence assays when antibodies or antigens marked with chemifluorescence tags are used as part of the assay, patient samples can be cultured or processed according to chemifluorescence assays in the corresponding culture vessels in the two units.

[0027] Furthermore, a laboratory robot is preferably provided which has the embodiments of the device for culturing disclosed here.

[0028] The laboratory robot preferably also has a container, which contains an enzyme for carrying out a chemiluminescent reaction and also has a reading unit for detecting the optical signal of the chemiluminescent reaction. This embodiment is advantageous because the optical signal of the chemiluminescent reaction can then be automatically generated and detected.

[0029] Preferably, the magnetic drive unit of the device is arranged in such a way that the beads contained in the bead liquid are not significantly magnetically influenced by the magnetic field of the magnetic drive unit. This is advantageous because the beads are usually magnetizable particles in the form of metal beads, which should not be moved in a preferred direction or to a preferred location by the magnetic drive during the incubation process during mixing. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The invention is explained in more detail below with the aid of specific embodiments without limiting the general inventive concept with the aid of the accompanying drawings. In the drawings:

[0031] FIG. 1A shows a top view of an exemplary device according to the invention,

[0032] FIG. 1B shows an exemplary detailed view of a unit of a device according to a preferred embodiment,

[0033] Figure 2 A schematic diagram showing the device according to a preferred embodiment,

[0034] Figure 3 Further details of a preferred embodiment of the device are shown.

[0035] Figure 4 A schematic diagram showing a preferred embodiment of the laboratory robot according to the invention is shown.

[0036] FIG5A shows the interaction between the sensor and the magnet.

[0037] FIG5B shows a cluster of characteristic curves together with the signal,

[0038] 6A and 6B show details of a clamping element cooperating with a culture vessel according to a preferred embodiment,

[0039] 7A and 7B show a receptacle for a culture vessel and details of the culture vessel according to a preferred embodiment,

[0040] 8A to 8D show signal and frequency curves,

[0041] FIG. 9A shows details of a preferred embodiment of a partial control unit,

[0042] FIG. 9B shows further details of a preferred embodiment of the control unit,

[0043] Fig.10 Details of an exemplary regulation of another partial control unit are shown. DETAILED DESCRIPTION

[0044] FIG. 1A shows a device V with two units E1, E2, which have corresponding receptacles A for corresponding culture vessels. The units E1, E2 are supported movably along a common linear guide axis LFA (see FIG. 1B ) by means of a linear guide LF. A control unit SE is also shown. The units E1, E2 are supported on a common base plate GP by means of a linear guide element LF.

[0045] FIG. 1B shows the unit E1 in a detailed view as well as the linear guide element LF and the base plate GP enclosed by a dash-dot line.

[0046] A receiving portion A is provided to receive a corresponding culture vessel. A detail view is shown in a vertical sectional view in FIG7A , in which a cross-sectional view through the receiving portion A and a culture vessel IG introduced into the receiving portion A can be seen. A corresponding perspective view of such a sectional view can be seen in FIG7B , wherein here the culture vessel IG has also been introduced into the receiving portion A.

[0047] Figure 2 A preferred embodiment of the device V is shown.

[0048] The units E1, E2 are supported on a base plate GP along a common linear guide axis LFA by means of linear guide units LF1, LF2. The units E1, E2 have corresponding receptacles A for corresponding culture vessels IG. Preferably, the units E1, E2 have corresponding heating units H1, H2.

[0049] The respective units E1, E2 are mechanically decoupled from the common base plate GP by means of respective spring units FE1, FE2. The spring unit FE1 preferably has two spring elements F11, F12. The spring unit FE2 preferably has two spring elements F21, F22.

[0050] By means of the respective sensors S1, S2, respective sensor signals SIG1, SIG2 can be provided, which respectively indicate one of the respective location positions of the respective units E1, E2. To this end, the respective sensors S1, S2 preferably detect the respective magnetic fields which have been generated by the respective magnets M1, M2.

[0051] 5A shows the principle for this purpose, wherein the sensors S1, S2 are in particular designed as Hall sensors so that translational movements can be detected along the linear guide axis LFA of the magnets M1, M2. The magnets M1, M2 are in particular a counter magnet (diametral magnet). The magnets M1, M2 are preferably oriented or positioned centrally in the rest position corresponding to the respective sensors S1, S2.

[0052] 5B shows a characteristic curve cluster KLF, in which the location position OP is given in millimeters in the upper right quadrant I, which follows the corresponding sinusoid SN1 during mechanical oscillation. The magnetic field generated by the detection magnets M1, M2 is shown in the upper left quadrant II. When using the straight section LB of the corresponding characteristic curve KL2 of the magnetic field, a linear transformation of the location position OP can then be used, so that in the lower left quadrant III a corresponding Hall voltage is obtained, which can be converted into a corresponding electrical signal or a corresponding voltage U as a sinusoid SN2 according to the lower right quadrant IV.

[0053] This voltage signal U can then be used as the corresponding signal SIG1, SIG2 according to Figure 2 Provided to the control unit SE.

[0054] The control unit SE can control the corresponding magnetic drive units MA1, MA2 by means of corresponding control signals AS1, AS2. The corresponding control signals AS1, AS2 are preferably pulse width modulated signals PWMS, as shown in FIG. 8C. Here, the time in seconds is plotted on the x-axis, wherein the time t1 is preferably equal to the value of t1=(1 / 16.67) seconds, because the oscillation frequency to be controlled is preferably 16.67 Hz. The voltage U of the pulse width modulated signal PWMS is plotted on the y-axis. Such a signal PWMS is present at the output or interface of the control unit, which preferably has a microcontroller. The maximum signal level of such a pulse width modulated signal PWMS is preferably 3.3 volts.

[0055] If such a pulse width modulation signal PWMS is supplied as actuation signal AS1, AS2 to the inverter WR1, WR2, which is connected to the corresponding coil SP1, SP2, then a corresponding sinusoidal current signal SISIG is generated by the coil, as shown in FIG. 8C. The current intensity I of the current signal SISIG in amperes is also plotted on the y-axis. Thus, a corresponding magnetic field signal is generated in the vicinity of the coil from such a current signal SISIG. The pulse width modulation signal PWMS and the current signal SISIG are particularly phase-shifted with respect to each other.

[0056] In this way, the corresponding magnetic field can then be utilized so that the corresponding magnetic drive unit MA1, MA2 moves the corresponding magnetizable connecting plate or return plate AP1, AP2 along the linear guide axis LFA. Preferably, such magnetization of the connecting plate AP1, AP2 by the magnetic drive unit MA1, MA2 leads to a change in the corresponding location position of the corresponding unit E1, E2. The corresponding unit E1, E2 therefore has a corresponding connecting plate or return plate AP1, AP2, which can be attracted or repelled by the corresponding magnetic drive unit MA1, MA2.

[0057] The respective units E1, E2 form a spring-mass oscillating system via the respective spring blade groups FE1, FE2, wherein in particular the respective units E1, E2 are mechanically coupled to a common base plate GP via the respective spring blade groups FE1, FE2. Thus, in principle it is possible, when the units E1, E2 are coupled to the common base plate GP via the spring units FE1, FE2, to move the two units E1, E2 along the linear guide axis LFA or the translation direction TR in such a way that their respective movements run in opposite directions or are offset by 180 degrees and thus compensate for each other. The spring units FE1, FE2 are preferably formed by compression springs F11, F12, F21, F22.

[0058] The units E1, E2 preferably have a mass of 2.5 kg. The spring units FE1, FE2 preferably have a mass of approximately 11 N / mm 2 Up to 12N / mm 2 The spring constant.

[0059] In this case, the units E1 , E2 preferably carry out sinusoidal oscillations, which are shown in FIG8A . The oscillation amplitude or the location is plotted in millimeters on the Y axis and the time in seconds on the x axis.

[0060] The embodiment of a spring-mass oscillating system with a magnetic drive is more energy efficient than a purely magnetically driven system. In a purely magnetically driven system without a spring, more drive energy is required to control the magnetic drive by the control unit in order to change the position of the location for generating the oscillation. The spring-mass oscillating system can first be set into oscillation and then only energy is applied to maintain the oscillation.

[0061] Since the chemiluminescent assay, which in particular comprises a bead liquid with magnetizable microbeads, is located in a culture vessel, the microbeads must not be attracted magnetically, so that an oscillating movement via a spring-mass oscillation system becomes particularly advantageous, so that particularly high magnetic fields or magnetic forces should not be built up, which could negatively influence the positioning of the magnetizable microbeads in the culture vessel. Figure 3 In this regard, a particular sectional view of a preferred embodiment of a device V with a unit E1 and a corresponding receptacle A is also shown, wherein the unit E1 is mechanically coupled to the base plate GP via a spring unit FE1. The control unit SE actuates an oscillating magnet with a coil SP1 and an inverter WR1. The return plate AP1 can thus be influenced accordingly by means of the magnetic field generated by the coil SP1 in order to influence the oscillation frequency of the unit E1. In particular, mechanical friction losses are minimized in order to maintain the oscillation frequency or a target oscillation frequency.

[0062] Units E1 and E2 can be heated preferably to 37 degrees Celsius by means of heating units H1 and H2. Preferably, units E1 and E2 have 100 receptacles A for reaction vessels or culture vessels IG, respectively. In order to mix the reagents of the assay well, the culture plates are placed in oscillation accordingly. The target frequency of such oscillation is preferably 16 Hz to 17 Hz, and the oscillation amplitude is preferably 1 mm. The magnetic microbeads contained in the reagent or microbead liquid have a higher density than the liquid below, in which the microbeads are located within the culture vessel. Therefore, the precipitation of the microbeads is prevented by the frequency and amplitude of the oscillation, but preferably at the same time, the culture vessel can be clamped out by the clamping unit in continuous operation.

[0063] The proposed laboratory robot LA is therefore preferably a so-called random access machine, in which the gripping unit G can introduce the culture vessels IG into the corresponding receptacles A and also remove them again during continuous operation or with constant oscillation of the units E1 , E2 of the device V.

[0064] This is achieved in particular in that the gripping unit can exert a force from above via the subunit T2 and from below via the subunit T1 onto the edge R of the culture vessel IG, see FIGS. 6A and 6B , so that only friction forces are generated in the translation direction, by means of which the culture vessel IG is held in the gripping unit G. In a direction different from the translation direction, a positive-locking gripping is particularly performed. By means of a friction-locking gripping in the translation direction (and in particular preferably a gripping without a positive-locking gripping), the culture vessel IG can continue to perform a minimal movement in the receptacle A and in the translation direction during the gripping process, which movement is generated in particular by the movement of the units E1, E2, until in particular the culture vessel IG is removed so far upward from the receptacle A that a sufficient distance is generated in particular between the slowly converging lower region UB of the culture vessel IG and the side wall SAE of the receptacle A, see also FIGS. 7A and 7B .

[0065] FIG. 8B shows the frequency characteristic in the form of a characteristic curve LK for the case in which the units E1 and E2 are not loaded. The frequency f in Hertz is plotted on the x-axis, and the standardized frequency characteristic N(f) is plotted on the y-axis. The value N(f)=1 corresponds to the maximum value of the frequency characteristic N(f) for the case in which the units E1 and E2 are not loaded. The corresponding resonant frequency RF1 is also indicated, which is preferably at f=17 Hz. The frequency characteristic in the form of a characteristic curve VK is also shown for the case in which the units E1 and E2 are fully loaded with a full culture vessel. The corresponding resonant frequency RF2 or the target frequency ZF is also indicated, which is preferably at f=16.67 Hz.

[0066] In order to control the magnetic drive units MA1, MA2 by the control unit SE, a target frequency ZF is provided, which is lower than the resonance frequency RF1. The corresponding characteristic curve is provided as a characteristic curve VK. The characteristic curve VK shows, by way of example, the frequency characteristic with the resonance frequency RF2 for the case where the incubator or unit E1, E2 is filled with a culture vessel of the corresponding reagent.

[0067] By selecting the target frequency ZF so that it is below the resonance frequency RF1 of the units E1, E2 in the unloaded state, the following situation is advantageously shown during the control or regulation process, namely that further masses or mass elements in the form of culture vessels can be located in the units E1, E2 and thus the energy required to maintain the corresponding target frequency ZF is further minimized.

[0068] exist Figure 2 9B shows a control unit SE which determines actuation signals AS1, AS2 based on sensor signals SIG1, SIG2 in order to actuate magnetic drive units MA1, MA2. FIG. 9B shows a preferred embodiment of a control unit SE having subcontrol units SE1, SE2 and SZ.

[0069] The sensor signal SIG1 is received at the interface IFA. The control unit SE also has an interface IFB for receiving the sensor signal SIG2. The sensor signal SIG1 is processed and edited by means of the lower unit SE1. The determined variables or signals are then provided to the central control unit SZ.

[0070] The same situation occurs in the subcontrol unit SE2 based on the signal SIG2. The central subcontrol unit SZ then determines the actuation signals AS1, AS2 and makes them available at the corresponding interface IF1 or IF2.

[0071] The control signals AS1 and AS2 are pulse width modulated signals, such as the signal PWMS. Figure 8c The control signals AS1 , AS2 are synchronized with respect to their pulse duty factor and are modulated only with respect to their pulse width.

[0072] FIG. 9A shows the details of the partial control unit SE1. The unit E1 is mechanically coupled to the base plate GP as described above by means of the spring unit FE1. The magnet M1 is monitored or detected with the aid of the sensor S1 regarding its position. The sensor S1 outputs the sensor signal SIG1 as a voltage signal. At the interface IFA, the partial control unit SE1 receives the sensor signal SIG1. The partial control unit SE1 derives the amplitude measurement signal ASIG1 and preferably also the frequency measurement signal FSIG1 from the sensor signal SIG1. Particularly preferably, the partial control unit SE1 also determines the calibration signal KSIG1 based on the sensor signal SIG1 to provide the following signal, which indicates the zero point in the teaching process before the device finally starts to run. The sensor signal SIG1 is amplified by the preamplifier VV1. Then preferably followed by a high-pass filter HP, and then followed by a low-pass filter TP1, thereby forming a bandpass filter. The generated signal is then amplified by another preamplifier VV2, thereby generating the amplitude measurement signal ASIG1. From the amplitude measurement signal, the frequency measurement signal FSIG1 can also be preferably determined by means of a comparator KO. The sensor signal SIG1 amplified by the preamplifier VV1 can also be preferably filtered by means of a low-pass filter TP2 in order to determine the calibration signal KSIG1. The determined signals ASIG1, FSIG1, KSIG1 can then be provided to the central control unit SZ. Preferably, at least the determined signals ASIG1, i.e. the amplitude signal, and FSIG1, i.e. the frequency signal, are provided to the central control unit SZ.

[0073] The partial control unit SE2 in FIG. 9B determines corresponding signals in the form of amplitude measurement signals, frequency measurement signals and preferably calibration signals based on the second sensor signal SIG2 and also provides these signals to the central partial control unit SZ. Further details can be found in Fig.10 It is concluded that Fig.10 An embodiment of a partial control unit SZ is shown.

[0074] The purpose of determining the control signals AS1, AS2 is that the generated position or oscillation amplitude of the two moving units is presented as shown by the corresponding signals SIG1, SIG2 in FIG. 8D. The time is shown on the x-axis, wherein the time t2 is preferably equal to the value of t1=(3 / 16.67) seconds, because the oscillation frequency to be controlled is preferably 16.67 Hz. The sensor voltage USIG in volts is plotted on the y-axis. The corresponding oscillation frequencies generated by the corresponding units then have a phase shift of 180 degrees with respect to each other. For this purpose, the control unit thus determines the amplitude measurement signal or amplitude ASIG1 and the oscillation frequency or frequency measurement signal FSIG1 based on the sensor signal SIG1 by means of the sub-control unit SE1. The sub-control unit SE2 also determines the amplitude measurement signal or amplitude ASIG2 and the oscillation frequency or frequency measurement signal FSIG2 and preferably the calibration signal KSIG2 based on the sensor signal SIG2. The control unit then determines the control signals AS1, AS2 in particular by means of the sub-control unit SZ in such a way that the two units are adjusted to a common oscillation amplitude and a common, identical target oscillation frequency. The oscillation frequencies then have a phase shift of 180 degrees with respect to one another. The control performed by the control unit SE is a regulation, in particular a PI regulation with reference to a common, identical target oscillation frequency.

[0075] After analog-to-digital conversion by an AD converter, the amplitude measurement signal ASIG1 is then rectified by means of a peak rectifier SGR. The digital signal is then converted into millimeters by means of a conversion unit UE1. The difference unit DE1 receives a theoretical value of preferably 1 mm from the theoretical value unit SW1 and then determines the control deviation RA1 as a difference, which is supplied to the control unit RE1. The control unit RE1 implements a PI control, which preferably uses a KP value of 0.03 as a value and a value of 0.6 as a KI value. The control deviation RA2 is determined based on the sensor signal ASIG2 by means of an AD converter AD, a peak rectifier SGR and a conversion unit KE2, wherein the theoretical value here is also 1 mm, which is predetermined by the theoretical value unit SW2, so that the difference unit RA2 determines the control deviation RA2. A PI control is then performed in the control unit RE2 using the same KP value and KI value of the unit RE1.

[0076] The frequency measurement signal FSIG1 is provided to the averaging unit MWE via the digital input DI1. The corresponding situation occurs or is implemented by supplying the frequency measurement signal via the digital input DI2 and providing it to the averaging unit MWE. The setpoint value unit SWF provides a setpoint value, which is preferably 16.67 Hz, so that the difference unit DEF then determines the difference between the frequency mean value FMW and the setpoint variable as the control deviation RAF. The control unit REF determines the PI control based on the input signal or the control deviation RAF by means of the PI control and the parameter values ​​KP=0.009 and KI=0.09 in the following way, that is, the corresponding internal control signal IS11 or IS22 is provided to the corresponding modulator PM1 or PM2.

[0077] The synchronous clock generator TG controls the corresponding pulse width modulator PM1 or PM2. The pulse width modulator PM1 is controlled in terms of its pulse width by the signal IS1 of the amplitude control unit RE1 and the signal IS11 of the frequency control unit REF and then generates the control signal AS1. The pulse width modulator PM2 is controlled in terms of its pulse width by the signal IS2 of the amplitude control unit RE2 and the signal IS22 of the frequency control unit REF and then generates the control signal AS2.

[0078] As already described above, the detail view of FIG. 7A shows a vertical sectional view in which a cross-sectional view through the receptacle A and a culture vessel IG introduced into the receptacle A can be seen. The corresponding perspective view of such a sectional view can be seen in FIG. 7B , wherein the culture vessel IG is also already introduced into the receptacle A here.

[0079] The culture vessel IG preferably converges in a tapered manner in a lower region UB and has a peripheral edge R in its upper region which projects beyond the side wall SWE of the vessel.

[0080] The culture vessel IG rests with its edge R on the upper side OSE of the unit E1 when it is introduced into the receiving part A. The culture vessel IG is thus at least partially held in the receiving part A. The culture vessel IG is also preferably held in such a way that a positive fit occurs at least partially between the receiving part A and the culture vessel IG.

[0081] FIG. 6A shows a culture vessel IG with its edge R and side walls SWE, wherein the culture vessel IG is held by a gripping unit G. Such a representation is also shown in an oblique view in FIG. 6B .

[0082] The first part T1 of the clamping mechanism of the clamping unit G grips under the edge R or on the lower side UR of the edge of the culture vessel IG on both sides. The second part unit T2 of the clamping mechanism of the clamping unit G also clamps the culture vessel in the following way, that is, the second part unit T2 is pressed from above onto the upper side OR of the edge of the culture vessel IG by the spring unit GF. Therefore, the part units T1 and T2 of the clamping unit cooperate with each other to generate a friction force for holding the culture vessel. Thus, the clamping unit G can clamp the culture vessel IG.

[0083] exist Figure 4 , a schematic diagram of a preferred embodiment of a laboratory robot LA according to the present invention is shown. The laboratory robot LA has a gripping unit G for gripping a culture vessel IG. The laboratory robot LA also has a vessel box MAG comprising a plurality of culture vessels IG. With the aid of the gripping unit G, the culture vessel IG can be transported from the vessel box MAG to the pipetting unit PE. The preferably arranged pipetting base PB of the pipetting unit PE is then provided with a receptacle A for accommodating the culture vessel IG. The pipetting unit PE can therefore be accommodated in particular in the receptacle A of the culture vessel IG.

[0084] The laboratory robot LA also has a container B1 including a patient sample liquid PPF. The laboratory robot LA also has a container B2 including a buffer liquid PUF. The laboratory robot LA also has a container B3 including a bead liquid BF. The laboratory robot also has a container B4 including a label liquid AF, the label liquid having an antibody labeled with a chemifluorescent tag or an antigen labeled with a chemifluorescent tag.

[0085] The laboratory robot LA also has a device V according to the invention.

[0086] The gripping unit G is therefore also designed to place the culture vessel IG from the pipetting unit PE in the corresponding receptacle of the corresponding unit E1, E2 of the device V and also to remove it again, in particular to transport the culture vessel from the device V to the pipetting unit PE again. For this purpose, the gripping unit G can preferably be moved or moved in the X direction, the Y direction and the Z direction. The gripping unit G can automatically grip the culture vessel IG and also release or put it down.

[0087] The pipetting unit PE has one or more pipetting needles PN, which can preferably be moved or displaced in the X, Y and Z directions. With the aid of such pipetting needles PN, different liquids of the liquids PF, PUF, WF, AF can be pipetted from containers B1, B2, B3, B4 into the culture vessel IG and aspirated therefrom.

[0088] In order to carry out the chemiluminescent test, the laboratory robot LA preferably also has a reading station LS. Therefore, the laboratory robot LA preferably also has a container B5 containing a liquid or trigger liquid E which in turn has an enzyme for realizing a chemiluminescent reaction.

[0089] Preferably, the enzyme E is introduced into the culture vessel IG via the dispensing unit DIS, which is preferably located in the receiving portion A of the base BA. The corresponding light radiation or the generated optical signal OS can preferably be detected by means of the reading unit LE. Preferably, the corresponding digital signal DSI can then be evaluated by the computing unit RC after the detection of the optical signal OS and preferably sent via a data network via the data interface of the computing unit RC. The computing unit RC is a preferably integrated component of the laboratory robot LA. The reading station LS therefore has a reading unit LE and a computing unit RC.

[0090] The laboratory robot is in particular a laboratory robot for processing patient samples using a chemifluorescence assay for the verification of a target antigen or a target antibody in the patient sample.

[0091] The patient sample is in particular a liquid patient sample. The patient sample liquid may have a homogeneous liquid phase. Preferably, the patient sample liquid is a human sample removed and optionally processed for diagnostic testing, preferably for example blood, preferably serum, urine, cerebrospinal fluid, saliva or sweat.

[0092] For a variety of automated systems, in order to verify a certain antigen or target antigen or a certain antibody or target antibody in a patient sample to obtain knowledge about the possible health status of the patient, a so-called chemifluorescence method or chemifluorescence assay is used. Here, microbeads are particularly used as carriers for reagents. For example, the microbeads can be carriers for stable antigens, and the antibodies or target antibodies to be verified in human samples are bound to the stable antigens. The microbeads of so-called microbead liquids are usually supplied in an aqueous solution and stored until use. Microbeads are particularly magnetizable particles, particularly metal magnetizable particles. If such microbeads are cultured with liquid patient samples, antigen-antibody complexes are formed in the presence of target antibodies, and the antigen-antibody complexes are stable on the microbeads. After a washing step with a flushing liquid or a buffer liquid, the complex can be cultured with a suitable reagent, particularly a so-called conjugate. This is particularly a label liquid with a chemifluorescence label, and the chemifluorescence label is particularly preferably in the form of acridine, a labeled secondary antibody. The secondary antibody is preferably an anti-human antibody, preferably an anti-human IgG antibody. According to this principle, the so-called chemifluorescence laboratory robot available on the market, which can preferably also be a random access analyzer. In order to generate an optical signal, an enzyme is added to the solution or trigger solution at the end of the chemifluorescence method treatment to cause a chemifluorescence reaction between the enzyme and the chemifluorescence label, thereby generating an optical signal. The generated optical signal is used for the antibody concentration in the patient sample and can be automatically converted into a concentration by the laboratory robot after detection. The label liquid is also called a conjugate liquid in particular.

[0093] To verify the antigen, instead of the antibody, magnetic particles coated with antibodies, so-called microbeads, are incubated with patient samples and antigen-specific biotinylated antibodies. During the incubation period, the antigen is bound not only by the antibody coupled to the magnetic particles but also by the biotinylated antibody. In a further step, a conjugate is added, which binds to the biotinylated antibody. The reaction pellet is then doped with an activation solution, which induces a chemiluminescent reaction.

[0094] Immunodiagnostic tests or assays which function according to this principle for a large number of indications are described in the prior art, for example in EP 2 199 303, DE 10 2009033281, WO 2010 / 009457 or EP 12183919.5. The principle of the chemiluminescence method is likewise described in EP 3160 646 B1.

[0095] Suitable reagents are described in the prior art, for example in Ireland, D. and Samuel, D. (1989), "Enhanced Chemiluminscence ELISA for the detection for antibody to hepatitis B virus surface antigen", J. Biolum. Chemilumin., 159-163, and in "Acridinium Esters as Highly Specific Activity Labels in Immunoassays," Clin. Chemistry 19: 1474-1478 (1984) and in US Pat. No. 4,842,997A.

[0096] Inhomogeneous microbead liquids present a particular problem, such as suspensions of microbeads in aqueous solutions, where the density of the microbeads is higher than that of water, so that the microbeads may sink to the bottom. During the cultivation process, precipitation of the microbeads may occur in the culture vessel. Alternatively, it may occur that such microbeads easily accumulate on the surface in the liquid phase. Therefore, the culture vessel is regularly moved during the cultivation or is placed under shaking.

[0097] But the microbead liquid may also have an inhomogeneous phase and may include either two liquids that cannot be mixed or can only be mixed to a limited extent or may include a solid in the liquid. In a preferred embodiment, the liquid is a microbead in an aqueous solution. Such microbeads can be provided with a stable biological reagent, such as a polypeptide that acts as an antigen. Different microbeads for a large number of applications are available on the market, mainly based on carbohydrates (such as agarose) or plastic bases. It contains active or activatable chemical groups, such as carboxyl groups, which can be used to stabilize reagents such as antibodies or antigens. It is preferably related to microbeads with an average diameter of 0.2mm to 5mm, 0.5mm to 1mm, 0.75mm to 100mm or 1mm to 10mm. The microbead can be coated with an antigen that binds to a diagnostically relevant antibody, or the position can be coated with an affinity ligand, such as biotin or glutathione. Preferably, the liquid comprises the microbeads in the form of an aqueous suspension having a microbead content of 10 to 90%, more preferably 20 to 80, more preferably 30 to 70, still more preferably 40 to 60% (w / w).

[0098] In a particularly preferred embodiment, paramagnetic microbeads are involved, which can be easily concentrated on a surface by means of a magnet. For this purpose, the paramagnetic microbeads commonly found on the market mostly contain paramagnetic minerals, such as iron oxide.

[0099] The buffer liquid can also be referred to as flushing liquid. Such buffers or flushing liquids are known to those skilled in the art, in particular from EP 3 160 646 B1.

[0100] The features disclosed in the preceding description, the claims and the drawings may be essential both individually and in any combination for realizing the exemplary embodiments in different embodiments and may be combined with one another as desired, unless otherwise indicated in the description. Although some aspects are described in conjunction with an apparatus, in particular in the form of a laboratory robot, these aspects also constitute, of course, a description of the corresponding method, so that a block or a component of the apparatus can also be understood as a corresponding method step or a feature of a method step. Similarly, aspects described in conjunction with or as a method step also constitute a description of a corresponding block or detail or feature of the corresponding apparatus or laboratory robot.

[0101] According to certain implementation requirements, the embodiments of the present invention can be implemented in hardware or software, in particular a control unit and / or a reading unit and / or a reading station. The programmable hardware component can be formed in particular by a microcontroller, a processor, a computer processor (CPU=Central Processing Unit), a graphics processor (GPU=Graphics Processing Unit), a computer, a computer system, an application-specific integrated circuit (ASIC=Application-Specific Integrated Circuit), an integrated circuit (IC=Integrated Circuit), a system on a chip (SOC=System on Chip), a programmable logic element or a field programmable gate array (FPGA=Field Programmable Gate Array) including a microprocessor or only an FPGA without a microcontroller.

Claims

1. A device for culturing a plurality of patient samples using a plurality of culture vessels, the device comprising: a first unit (E1) having a corresponding receptacle (A) for a corresponding culture vessel (IG), - and a second unit (E2) having a corresponding receptacle (A) for a corresponding culture vessel (IG), in, Two of the respective units (E1, E2) are each mounted movably in their respective locations along a common linear guide axis (LFA), The two units (E1, E2) are each mounted and guided along the common linear guide axis (LFA) in such a way that they have only one common translational degree of freedom, The equipment: - also having a corresponding sensor (S1, S2) for providing a corresponding sensor signal (SIG1, SIG2) indicating a corresponding one of the corresponding location positions, - also having corresponding magnetic drive units (MA1, MA2), which are used to change the corresponding location positions accordingly, - and also having a control unit (SE) which is designed to actuate the respective magnetic drive unit (MA1, MA2) based on the respective sensor signal (SIG1, SIG2) in order to bring about a corresponding change in the respective location position, The control unit (SE) is designed to control the magnetic drive units (MA1, MA2) by means of regulation based on sensor signals (SIG1, SIG2) so that the corresponding oscillation frequencies generated by the corresponding units are essentially the same and have a phase shift of essentially 180 degrees with respect to each other.

2. The device according to claim 1, wherein: A respective unit (E1, E2) is mechanically coupled to a common base plate (GP) via a respective spring unit (FE1, FE2).

3. The device according to claim 2, wherein: A respective unit (E1, E2) is mechanically coupled to the common base plate (GP) via a respective spring unit (FE1, FE2), so that the respective unit (E1, E2) together with the respective spring unit (FE1, FE2) forms a respective spring-mass oscillating system.

4. The device according to claim 1, wherein: The control unit (SE) is designed to control the magnetic drive units (MA1, MA2) so that the units (E1, E2) are each held in oscillation with substantially the same oscillation amplitude in the direction of the linear guide axis (LFA).

5. The device according to claim 1, wherein: The control unit (SE) is designed to determine the respective current amplitude and the respective oscillation frequency for the respective unit (E1, E2) based on the respective sensor signal (SIG1, SIG2), Furthermore, the control unit (SE) is designed to adjust the two units (E1, E2) to a common oscillation amplitude and a common identical target oscillation frequency.

6. The device according to claim 2 or 3, wherein: The two units (E1, E2) together with the respective spring units (FE1, FE2) each have a spring-mass oscillating system which, in the unloaded state, has a respective identical resonance frequency (RF1), And the target oscillation frequency is below the resonance frequency (RF1).

7. The apparatus according to claim 1, wherein: The control unit (SE) is designed to carry out a PI regulation with reference to a common, identical target oscillation frequency.

8. The apparatus according to claim 1, wherein: Both units (E1, E2) have corresponding heating units (H1, H2).

9. A laboratory robot (LA) having a device (V) according to claim 1, The laboratory robot also has - a vessel magazine (MAG) comprising a plurality of culture vessels (IG), - a container (B1) comprising a patient sample fluid (PPF); a container (B2) comprising a buffer fluid (PUF); a container (B3) comprising a bead fluid (BF) having beads coated with an antigen or coated with an antibody; and a container (B4) comprising a label fluid (AF) having an antibody or antigen labeled with a chemifluorescent tag, a pipetting unit (PE) configured to dispense at least a portion of the patient sample liquid, at least a portion of the buffer liquid, at least a portion of the microbead liquid and at least a portion of the label liquid into a culture vessel and to aspirate from the culture vessel, - the laboratory robot also has a gripping unit (G) which is configured to hold the culture vessel Transport from the container magazine (MAG) to the pipetting unit (PE), and are transported by the pipetting unit (PE) into the corresponding receptacle in the receptacles (A), removed from the corresponding receptacle (A) and transported again to the pipetting unit (PE).

10. The laboratory robot according to claim 9, wherein: The laboratory robot also has a container (B5) containing a liquid containing an enzyme (E) for carrying out a chemiluminescent reaction, and in particular also has a dispensing unit for introducing the liquid containing the enzyme into a culture vessel. The laboratory robot also has a reading unit (LE) for detecting an optical signal (OS) of a chemiluminescent reaction.

11. The laboratory robot according to claim 9, wherein: The magnetic drive units (MA1, MA2) are arranged so that the microbeads contained in the microbead liquid (BF) are not significantly magnetically affected by the magnetic field of the magnetic drive units (MA1, MA2).

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