AUTOMATIC ANALYSER AND METHOD FOR CARRYING OUT CHEMICAL, BIOCHEMICAL AND / OR IMMUNOCHEMICAL ANALYSES

Description

[0001] The invention relates to an automatic analyzer suitable for carrying out chemical, biochemical and / or immunochemical analyses of liquid samples, comprising a sample storage for receiving the liquid samples and at least one reagent storage for receiving liquid reagents, as well as a method for the automatic chemical, biochemical and / or immunochemical analysis of liquid samples.

[0002] Automated analyzers are used routinely, for example in clinical diagnostics, analytics and microbiology, where there is a need to determine various properties and components of liquid samples quickly, accurately and reproducibly, primarily using optical methods.

[0003] Different measurement principles are used in existing analytical devices. On the one hand, devices with a stationary detection unit, for example, a stationary photometer, and a disk-shaped, rotating holder with cuvettes for holding the reaction mixtures of samples and reagents to be measured are used. The cuvettes are successively moved past the detection unit and measured. Consequently, the cuvette carousel must stop each time a new sample or reagent is introduced into a cuvette, or the cuvette is to be washed and prepared for a new test. The rigidly defined cycle times are accompanied by a significant loss of efficiency. Further details can be found in the discussion on the state of the art (see section A). Photometry

[0004] The physical effect underlying photometric measurement is the absorption of light of specific wavelengths by certain substances present in a liquid. The resulting reduction in the intensity of the light passing through the cuvette is measured and allows a quantitative determination of the concentration of a substance using the following equations: T = I / I 0 E = − log T = log I 0 / I E = ε . c . d Lambert-Beer's law where T ... transmission E ... Extinction I 0 ... Intensity in the absence of the light absorbing substance I ... Intensity in the presence of the light absorbing substance c [mol / l] ... mole concentration d [cm] ... thickness of the absorbing liquid layer ε [I mol -1< cm -1< ] ... molar extinction coefficient (substance-dependent quantity)

[0005] The molar concentrationc can therefore be calculated directly from the result of an absorbance or transmittance measurement. This type of measurement is used in chemical and enzymatic reactions to determine the molar concentration of certain analytes present in the sample (blood plasma, urine, etc.). Light-absorbing substances (dyes) are formed or disappeared in the process, and their absorbance or changes in absorbance are then used to determine the molar concentration of the analytes to be determined.

[0006] In the field of clinical-chemical analysis, numerous parameters are determined using photometric methods, e.g. the determination of enzymes (AP, GOT, GPT, γ-GT, amylase, CK), electrolytes (Na +< , K +< , Ca 2+< , Cl -< , Mg 2+< ), organ-specific substances (heart, liver, kidney) and numerous metabolic parameters (bilirubin, total, HDL and LDL cholesterol, triglycerides, glucose, uric acid, creatinine, urea and lactate). Turbidimetry and nephelometry

[0007] This type of measurement is used in homogeneous immunoassays, where specific analytes, such as metabolites, enzymes, peptides, or proteins, are reacted with antibodies. This creates larger structures that cause increased light scattering or turbidity of the reaction mixture.

[0008] While in transmission measurement the intensity of the transmitted light beam decreases with increasing analyte concentration due to increasing turbidity, at a detection angle of, for example, 90° the intensity of the scattered light beam increases with increasing turbidity.

[0009] Turbidity measurement in the form of transmission measurement is called turbidimetry, and the measuring device in question is called a turbidimeter. Scattered light measurement performed at an angle of, for example, 90° to the transmitted light beam is called nephelometry, and the measuring device in question is called a nephelometer. Luminescence / chemiluminescence

[0010] Luminescence (e.g., fluorescence, phosphorescence, chemiluminescence) involves measuring the light emitted by molecules. In chemiluminescence, light emission occurs as a result of a chemical reaction. Luminometric methods are very sensitive and therefore well suited for the detection of markers in immunoassays.

[0011] For a better understanding of the invention, some essential technical terms used in the present application are defined in more detail: Analyzer:Device for carrying out chemical, biochemical and / or immunochemical analyses of liquid samples present in a sample storage unit in the analyzer, with the aid of liquid reagents present in at least one reagent storage unit in the analyzer.

[0012] x-, y- and z-axes: x-axis means the horizontal longitudinal axis, y-axis the horizontal width or depth axis, and z- the vertical height axis of the analyzer (see e.g. Fig. 3a ).

[0013] Cuvette:A cuvette, as defined by the present invention, refers to a vessel that is sealed on all sides, open at the top, and thermostatically controlled for holding sample and reagent liquids and the resulting reaction mixtures. It is used for measuring the reaction mixtures using photometric and / or luminescence-optical methods. A cuvette, as defined by the present invention, has at least one window arranged in a side wall of the cuvette that is permeable to the optical measurement method used, or is entirely optically transparent.

[0014] stationary cuvette array: Refers to a large number of cuvettes arranged in a row, which are arranged in a fixed position in the analyzer and are not moved along any of the x, y and z axes during normal measuring operation.

[0015] linear cuvette array: Refers to a single row of a large number of cuvettes arranged along a straight line.

[0016] Reagent vessel: Vessel or container for holding reagents required to carry out the analysis.

[0017] Sample container: A vessel or container containing the sample to be analyzed in the analyzer, from which smaller sample quantities (aliquots) can be withdrawn multiple times for the analysis of individual analytes or parameters. The analysis is not performed in the vessel containing the sample, but rather after the reagents have been added to the cuvette, which serves as a reaction vessel.

[0018] Analysis sample:The analytical sample (usually simply called a sample or substance sample) is the material introduced into the analyzer to be analyzed. This material is a liquid mixture of substances and can be, for example, a body fluid such as blood serum, blood plasma, urine, and cerebrospinal fluid. Other mixtures of substances include drinking water, wastewater, wine, beer, and fruit juices, as well as liquids from chemical and biochemical manufacturing processes.

[0019] Analyte: Analytes or analytes (also known as parameters) are those substances contained in an analysis sample about which a statement is to be made using an analyzer via chemical analysis with the aid of liquid reagents, i.e. which are to be determined quantitatively by specifying the concentration.

[0020] Analysis:Analysis or test (in immunochemical analyses also known as immunoassay) refers to the qualitative and / or quantitative determination of an analyte to be detected or contained in the analysis sample, carried out automatically with an analyzer using liquid reagents.

[0021] Pipetting unit: Refers to the overall system of an automatic pipetting device for liquid transfer between different vessels, which comprises one or more movable pipettors together with all mobile and stationary components necessary for their function, including supply fluids (hose connections, pumps, valves, containers, etc.), sensors, control and power supply.

[0022] Pipettor:Describes a component of the pipetting unit that can be moved horizontally in at least one direction, linearly or pivotally, relative to the receiving vessels (cuvettes, sample vessels, reagent vessels). The pipettor includes a suspension component with at least one pipetting needle, which can be moved independently or together with the pipettor and lowered into a receiving vessel.

[0023] Pipette needle: Refers to a cannula or hollow needle attached to the pipettor, including its holder, for sucking up samples from the sample vessels and / or for sucking up reagents from the reagent vessels and for metered dispensing of the sucked up liquids into the cuvettes.

[0024] Stationary vending machine component: Automated component which is fixed in the analyzer and is not moved (traversed) along the linear cuvette array during normal measuring operation.

[0025] Movable vending machine component:Refers to an automated component which is not fixed in the analyzer and which can be moved and positioned at least along the linear cuvette array by means of a controlled drive during normal measuring operation.

[0026] optical elements for collimation: These are optical elements designed to create a beam path that is as parallel as possible. Essentially, the light from a more or less point-like source is converted into a parallel beam. Optical elements that essentially align the light emitted by an LED in a parallel manner include converging lenses, TIR lenses, parabolic mirrors, and aperture arrays.

[0027] optical elements for filtering:These are optical components, particularly interference filters, for filtering the transmitted light according to wavelength or frequency, i.e., color-dependent for visible light. Band-stop filters, long-pass filters, short-pass filters, band-pass filters, and dichroic interference filters are used. Band-pass filters are particularly preferred because they exhibit a high transmittance for a specific wavelength band, while shorter or longer wavelengths are absorbed.

[0028] Condenser or condenser lenses: This is an arrangement of one or two lenses that direct as much of the light from an LED as possible into a cuvette, or an arrangement that directs as much of the light emerging from the cuvette as possible onto a photodiode.

[0029] Thermostatting liquid media:The thermostating of liquid media within the meaning of the invention comprises both the heating of a sample-reagent mixture and of particle-containing media or mixtures (suspensions), including the stabilization of a target temperature once it has been reached.

[0030] Analyte / Antigen: An analyte – also referred to as an antigen in the case of immunoassays – is a component in a sample that can be qualitatively and / or quantitatively determined. In immunoassays, the analyte is present in a liquid phase, usually dissolved in a buffer, in diluted body fluids, or other sample fluids. The analyte can also be a particulate structure with antigenic surface characteristics, such as bacteria, viruses, cells, or material particles, present in a suspension and detectable by immunoassays.

[0031] Immunoassay: As an immunoassay (German also: Immunoassay) refers to a series of methods in bioanalytics whose common basic principle is the recognition and thus detection of an analyte (antigen) in a liquid phase by the binding of an antigen to an antibody. Immunoassays, for example, are used in laboratory medicine for the determination of a wide variety of analytes in various body fluids such as blood, serum, urine, or cerebrospinal fluid.

[0032] Competitive immunoassay: A competitive immunoassay is used to detect an antigen when either only a single specific antibody is available for it or when the antigen does not have sufficient binding sites for the unhindered binding of two antibodies. For example, an antibody (capture antibody) is used as the recognition component and an antigen labeled with a marker molecule is used as the competitive component.

[0033] Sandwich assay:To detect an antigen using a non-competitive assay, also known as a sandwich assay, two different antibodies are required that recognize the antigen without interfering with each other's binding to the antigen. A particular advantage when compared to the competitive immunoassay is its higher sensitivity for most applications.

[0034] heterogeneous immunoassay:In a heterogeneous immunoassay of the present invention, in contrast to a homogeneous immunoassay, a change in the liquid phase occurs during the process. When using magnetic particles with bound capture antibodies for selective binding of the antigen, this can be achieved, for example, by depositing the particles onto the vessel wall using a magnetic field, replacing the first liquid with a second liquid, and resuspending the particles in the second liquid. After removing the first liquid, the particles can be subjected to any desired washing steps using the second liquid or a special washing liquid.The washing steps enable the removal of substances non-specifically bound to the particles as well as of interfering substances present in the first liquid. The removal of interfering substances makes the assay significantly more sensitive and achieves low detection limits and concentration ranges for the antigen to be determined.

[0035] magnetic particles (magnetic beads) : These are typically a few µm in size magnetic particles suspended in an aqueous buffer solution, which are coated with the capture antibody for immunochemical tests.

[0036] Capture antibody: These are antibodies that bind to at least one epitope of the analyte and are bound to the solid phase, in the case of the present invention, to the surface of solid magnetic particles.

[0037] Tracer antibody (labeled antibody, conjugate):This is a second antibody to which a marker molecule (label) is chemically bound. In the assay, the antibody selectively binds to analyte molecules through antigen-antibody interactions, or competes with the analyte for binding sites on an antigen (competitive assay). The marker molecule can be a dye that emits light upon addition of one or more chemical substances (chemiluminescence).

[0038] Bound / Free washing, or (B / F) washing: A process step of a heterogeneous immunoassay in which the unbound residue of the labeled tracer antibody added in excess is removed from the surface of the magnetic particles by washing.

[0039] Dispenser (or injector): A dispenser is used to dispense defined quantities of liquid from a storage vessel via a supply line that ends in a nozzle, dispensing opening or dispensing needle, into a vessel, for example a cuvette. State-of-the-art documents: A) Analysis systems with movable reaction vessels / cuvettes arranged in a circle on rotating plates (carousel arrangement)

[0040] US Pat. No. 8,911,685 B2 (HITACHI) discloses a typical automated analyzer for performing chemical and biochemical analyses of liquid samples using photometric measurement methods. Key features of these analyzers are the reaction vessels arranged around the periphery of a rotating plate, which also function as cuvettes, as well as stationary device components arranged along the periphery of the rotating plate, such as pipettors (sample dispensers, reagent dispensers), a mixing device, an optical measuring device, and a cuvette washing unit. Thermostatting of the cuvettes can be integrated into the rotating plate, for example, in the form of a temperature-controlled water bath. The sample containers are arranged on a sample rotating plate, and the reagents are located on a reagent rotating plate.

[0041] From DE 11 2009 002 702 B4 (HITACHI) another automatic analyzer is known whose sample containers and reagent containers are arranged in a carousel arrangement. As in Fig. 1a As shown in the present application, the analyzer comprises a sample disc A, on which a number of sample containers B for receiving a sample can be mounted; a first reagent disc C1 and a second reagent disc C2, on each of which a number of reagent containers D1 and D2 for receiving a first reagent or a second reagent can be arranged; and a reaction disc E, on which a number of cuvettes or reaction containers F are arranged along the circumferential direction.

[0042] A sample dispensing device G is provided between the reaction disc E and the sample disc A, which dispenses a sample sucked up from the sample container B into the reaction container F. Furthermore, a first reagent dispensing device H1 is provided between the reaction disc E and the first reagent disc C1, which dispenses a reagent sucked up from the reagent container D1 on the first reagent disc C1 into the reaction container F. Likewise, a second reagent dispensing device H2 is provided between the reaction disc E and the second reagent disc C2, which dispenses a reagent sucked up from the reagent container D2 on the second reagent disc C2 into the reaction container F. The sample dispensing device G and the two reagent dispensing devices H1 and H2 are arranged in a stationary manner at defined points along the circumference of the reaction disc E.

[0043] On the outer circumference of the reaction disk E, two stationary stirrers J1, J2, which stir the liquid in the reaction containers F after the dispensing of the first reagent and the second reagent, a light source K, which sends light through the reaction containers F, and a container cleaning mechanism L for cleaning the reaction containers F, are provided in this order in the rotation direction of the reaction disk E.

[0044] A stationary spectroscopic system M is arranged in a position opposite the light source K, with the reaction disk E between them. Near the spectroscopic system, a signal processing circuit N is provided, which processes the signals from the spectroscopic system M. The signal processing circuit N is connected to a computer (not shown). The automatic analyzer further includes a controller S, which controls the operation of the analyzer.

[0045] Such analyzers are characterized by the fact that all processes are dictated by rigid cycles of the carousel and must run within predetermined time windows. Actions such as dispensing, mixing, measuring, and washing can only occur when the respective cuvettes are located at the positions of the respective device components.

[0046] Thus, a sample can only be dispensed into an empty cuvette (not at any time, but) when the empty cuvette moves past the position of the sample pipettor and the cuvette carousel stops at that position. A reagent can only be dispensed into a cuvette containing the sample when the cuvette in question moves past the position of the reagent pipettor and the cuvette carousel stops at that position. The same applies to the stirring of reaction mixtures consisting of the sample and reagents in the cuvettes with mechanical stirring and to optical measurements at the position of the optical measuring device.

[0047] For example, a specific cuvette cannot be optically measured at any time or repeatedly at short time intervals, since it is necessary to wait until the cuvette in question is at the position of the optical measuring unit or is moved past it "on the fly" during the measurement.

[0048] When reactions are complete, measurements cannot be taken immediately, and in the case of kinetic measurements, the time intervals between individual measurements are relatively long (at least one turn of the plate). Unfortunately, when measurements are completed, a cuvette cannot be washed immediately and prepared for a new test. A cuvette can only be washed and prepared for a new test when the cuvette in question is located at the cuvette washing station and a wash stop occurs (is planned) at the respective position at a fixed time or period from the start of the test, according to the rigidly defined cycle times. This means that all cuvettes are "blocked" for the same length of time, regardless of whether the measurement duration for the respective tests is short or long.

[0049] The rotationally organized carousel arrangement with moving samples, reagents and cuvettes, but especially the carousel concept with movable cuvettes and stationary machine components, results in relatively high throughput times for the individual tests and limits the number of tests that can be performed per hour on a device with a certain number of cuvettes. B) Analysis systems with circularly arranged, stationary reaction vessels / cuvettes

[0050] US Pat. No. 5,178,833 A (BIOSEMA) discloses an automatic analyzer with circularly arranged measuring cuvettes and reagent vessels that are stationary relative to the device. The measuring cuvettes are arranged in an outer ring and the reagent vessels are arranged in two inner rings. The rotating axis of a stationary pipettor is positioned at the center of the ring-shaped reagent vessels. This rotating axis is surrounded by a ring-shaped wash vessel for the pipettor's lowerable pipetting needle. The analyzer's sample vessels are located on a separate rotating plate at the periphery of the stationary cuvette ring. An optical measuring unit reaches the measuring cuvettes by rotating around the analyzer's central axis. The optical path leads through the liquid surface along the longitudinal axis of the individual measuring cuvettes.The pipetting needle reaches the sample vessels, the measuring cuvettes, the reagent vessels and the washing vessel by means of rotating movements of two horizontal arms of the pipettor around a first, central axis and a further axis.

[0051] Disadvantages include that the disclosed configuration only allows for one independently movable pipetting needle for sample and reagents, that the reagent storage is limited to the area of ​​the inner stationary rings, and that the optical path runs through the reaction liquid surface. A particular disadvantage is that the measuring cuvettes cannot be washed, but must be replaced sector by sector with the outer ring after use. C) Analysis systems with linearly arranged, movable reaction vessels / cuvettes

[0052] From GB 1 321 754 A an automatic analyzer with reaction vessels / cuvettes fixed to linearly movable, circulating endless belts is known.

[0053] US 2014 / 0287523 A1 (ABBOTT) also discloses an analyzer with reaction vessels or cuvettes arranged linearly on belts. The linear endless belts are mounted on two deflection rollers, with corresponding reaction vessels mounted longitudinally, for example, in a "pretreatment lane" and a "primary process lane." By rotating the rollers, the reaction vessels or cuvettes can be moved back and forth in the direction of travel of the belt and can also circumvent the rollers on the underside. The arrangement amounts to a "linear variant" of the classic carousel arrangement, in which the reaction vessels or cuvettes move in a circular path. However, both variants have in common that the reaction vessels or cuvettes are still moved relative to the device and are transported to the processing stations (automatic components). Therefore, essentially the same disadvantages arise as already mentioned in point A) were cited.

[0054] WO 99 / 046601 A1 (HITACHI) shows a linear, movable cuvette array with stationary device components (dispensers for sample liquid and reagents, mechanical stirrers, photometer and cuvette washing station).

[0055] As in Fig. 1bAs shown in the present application, in WO 99 / 046601 A1, a plurality of cuvettes or reaction vessels 2 are arranged in a support frame or transport bar 7 at predetermined intervals in a thermostatted chamber (water bath) 1. The cuvette contents are mixed, for example, by means of ultrasound. The transport bar with the reaction vessels 2 is moved linearly in the direction of arrow 9 with the aid of a drive unit 8. Furthermore, in addition to the thermostatted chamber 1, a sample pipetting unit 3a, a reagent injection unit 3b, an optical measuring unit 4, a cuvette washing unit 5, as well as a first stirring mechanism 6a and a second stirring mechanism 6b for stirring the contents of the reaction vessels 2 again are provided. The stirring mechanism 6a or 6b can also be designed as an ultrasound generator, which acts on the reaction vessels 2 via the water bath in the chamber 1.In this embodiment, the water in the thermostatted chamber 1 is kept at a constant temperature at which the reactions take place and the optical measurement can be carried out.

[0056] During operation of the device, a reaction vessel 2 stops at the sample pipetting unit 3a, which dispenses the sample into the reaction vessel 2. Likewise, the reagent injection unit 3b discharges the reagent used for testing into the corresponding reaction vessel 2. In addition, the first stirring mechanism 6a mixes the reaction solution, and the second stirring mechanism 6b stirs the mixture in the reaction vessel 2 again. The optical measuring unit 4 measures the absorbance in the corresponding reaction vessel. Furthermore, the cuvette washing unit 5 discards the tested reaction solution and cleans the reaction vessel 2. After these operations are completed, the movement of the reaction vessels 2 is started by the drive unit 8. While the reaction vessels 2 continue to move, the sample pipetting unit 3a, the reagent injection unit 3b, and the first and second stirring mechanisms 6a, 6b are washed in a cleaning unit.A number of chemical analyses are performed by repeating the above procedure. As can be seen from the above procedure, the individual components of the device must be arranged in the specified order along the direction of movement 9.

[0057] The disadvantage of this concept is that the transport bar 7 necessarily requires a lot of free space to the left and right of the stationary device components 3a, 3b, 6a, 6b, and 5 for the linear movement of the reaction vessels 2. This inevitably increases the longitudinal axis of the analyzer by at least twice the length of the transport bar 7.

[0058] The cuvettes or reaction vessels 2 of the device according to WO 99 / 046601 A1 are thus moved past the stationary device components, analogous to the rotary plate variant described above. The system is inflexible, and essentially the disadvantages already mentioned in point A) were cited. D) Systems with circular and / or linearly arranged stationary reaction vessels / cuvettes

[0059] EP 2 309 251 A1 (SIEMENS) discloses an automatic analyzer with stationary sample vessels or cuvettes arranged in a circular or linear configuration, wherein the optical measuring unit is designed to be movable along the sample vessels on a rotatable device. According to one embodiment, the rotatable device, which carries the light source in the form of an LED and the photodetector in the form of a photodiode, can be arranged below the sample vessel holder, thereby making it possible to access the sample vessels at any time using a gripper arm. The rotatable device can also have several LEDs of different wavelengths and several photodiodes so that the samples can be measured at multiple wavelengths. The photodiodes can be replaced by a CCD element.

[0060] The arrangement described in EP 2 309 251 A1 is unsuitable for clinical chemistry analyzers (CC analyzers) and is intended for an analyzer for hemostatic measurements (for determining blood coagulation). This arrangement can also be part of a system comprising multiple devices (e.g., PCR analyzer, refrigeration device). The sample containers are not reused but are passed on to other components of a system, e.g., using a gripper arm, or are disposed of after the coagulation parameters have been determined.

[0061] For coagulation measurements, only whole blood (blood plasma with the blood cells it contains) can be used as a sample in the undiluted form possible. However, whole blood is completely unsuitable for the photometric measurements of this CC analyzer, as the blood cells scatter light, thus distorting the measurement results. Therefore, CC analyzers always use blood plasma or blood serum, which is also highly diluted by the addition of reagents.

[0062] According to EP 2 309 251 A1, the vessels containing the incoming samples (if necessary after the addition of reagents) are used directly for the optical measurement.

[0063] With a CC analyzer, measurements are always taken with cell-free blood plasma / blood serum, which is introduced into the device using sample vessels. Aliquots of the samples are then transferred using a pipettor together with reagents into separate cuvettes, which are then measured photometrically. E) Laboratory robots and automatic pipetting and analysis devices for preparing and / or analyzing samples with stationary reaction vessels / cuvettes in 2D arrangement (microtiter plate)

[0064] A typical analytical device for conducting biochemical analyses of liquid samples using microtiter plates is known, for example, from EP 0 259 386 B1 (TECAN). The analytical device comprises a primary rack for accommodating a plurality of sample vessels, a cross-stage positionable in the xy direction next to the primary rack for accommodating a microtiter plate, a sample distribution arm arranged above the primary rack and the cross-stage and freely positionable in an upper horizontal plane, and a photometer arranged within the positioning range of the cross-stage, the photometer's beam path perpendicularly penetrating the xy plane of the cross-stage.

[0065] Another example of an automated system for the automatic preparation and analysis of samples in the wells of a microtiter plate is known from DE 10 2004 057 450 B4 (CYBIO).

[0066] There are a variety of automated systems of this type that use microtiter plates for the detection and determination of substances. Microtiter plates contain many isolated wells in rows and columns (2D arrays). They are used for a wide variety of processes. Pipetting is performed either manually or, in high-throughput screening (HTS), with the aid of pipetting robots. Photometric determinations, e.g., absorption measurements on microtiter plates in transmitted light using photometers, are carried out in such a way that the light path travels through the well in a vertical direction through the liquid surface. For precise quantitative determinations, however, it is essential to guide the light rays through the measuring liquid along paths and distances that are as precisely defined and known as possible. Any light scattering by particles, turbidity, entrance surfaces, surfaces (e.g.,liquid surface, cuvette wall) leads to light losses which in turn distort the measurement result.

[0067] EP 2 410 342 A2 (HOFFMANN-LA ROCHE) discloses a pipetting device comprising a pipettor with a plurality of flat, juxtaposed frame elements, which, together with their pipetting needles, are movable on a main frame body in a horizontal x-direction perpendicular to the main frame body. The pipetting device serves to transfer samples or reagents from a first row of vessels to a second row of vessels offset in the x-direction. The pipetting needles are first adjusted in the y-direction to the spacing of the vessels in the first row in order to aspirate sample or reagent liquid and then - in order to dispense the sample or reagent liquid - adapted to the spacing of the second row of vessels. However, independent movement of two pipetting needles in the x- and y-directions is not provided.Movement modules for the y-direction and z-direction (raising and lowering the pipetting needles) are arranged in flat, adjacent frame elements with gaps to keep the distance between the individual pipetting needles as small as possible. However, independent movement of the pipetting needles in the y-direction is only possible to a limited extent. For example, the frame elements cannot move past each other on the transfer arm, resulting in a mutual restriction of the y-direction movement of the pipetting needles. Such pipetting devices are particularly useful in conjunction with microtiter plates.

[0068] EP 1 230 553 B1 (MAXMAT) discloses a chemical or biological analyzer comprising a storage module for sample tubes and tubes for reagents. Furthermore, an analysis module with a reaction container in the form of a microtiter plate and a sampling module (pipettor) movable on a rail are provided, each with two pipetting needles arranged at a fixed distance from each other. These pipetting needles operate independently of each other in the z-direction for automatic sample withdrawal and are each equipped with a retractable aspirating pipette for transferring predetermined quantities of samples and reagents from the storage module to the analysis module. In the horizontal x / y plane, the two pipetting needles can only be moved together.

[0069] The analysis module includes a microtiter plate heating plate located near the bottom of the microtiter plate wells to heat the contents of the wells by convection. The sampling unit further includes a mixing device controlled by an electromagnet to cause an alternating back-and-forth movement of the pipetting needle when it is lowered into a well of the microtiter plate to mix the sample and reagent mixture.

[0070] US 5,897,837 A (TOA MEDICAL) discloses an automatic pipetting device suitable for sample pretreatment of an immunoassay analyzer. The device comprises a first pipetting block that can be moved horizontally in the x- and y-directions and is equipped with two pipetting needles positioned side by side that can be raised or lowered independently of each other. One of the two needles can be assigned to reagents, the other to samples. Additionally, a second block that can be moved in the x-y direction and has a lowerable pipetting needle is also provided. A stationary needle washing station is required for needle cleaning. In the horizontal x- / y-plane, the two pipetting needles of the first movable block can, disadvantageously, only be moved together.This has the disadvantage that the masses of the pipettor's robotic components cannot be distributed across the two horizontal axes, x and y. Therefore, the mass of the second pipetting unit must always be accelerated to move to positions in the y direction. Likewise, the mass of the needle washing unit, including the needle washing vessel, must always be accelerated in both horizontal directions. Furthermore, due to the shared horizontal movement, it is not possible to use both needles simultaneously for pipetting at different, non-adjacent positions in a row of vessels. F) Optical system components for automatic analyzers

[0071] US Patent No. 8,675,187 B2 (Hitachi) describes an optical measuring unit for obtaining measurement signals from liquid media and an analysis system equipped with it. As described in Fig. 2aAs shown in the present application, one of several reaction vessels 24 arranged in a circle on a turntable 23 is immersed in a temperature bath 25 filled with water 26 at a constant temperature. A photometer 27 fixedly arranged in the temperature bath 25 has an LED light source 28, the light of which is irradiated into the sample 31 present in the reaction vessel 24 by means of a condenser lens 29 and a deflecting mirror 30. A semiconductor laser can also be used as the light source. A photodetector 32 of the photometer 27 is arranged on the opposite side of the reaction vessel 24. Apertures 34 for the incoming and outgoing radiation are provided at the inlet and outlet sides of the reaction vessel 24 in the measuring position 33 of the photometer 27.The disadvantage is the mechanical and metrological effort associated with reaction vessels that are arranged in a circle on a turntable, since the individual reaction vessels 24 must be moved into a measuring position of the photometer 27 in order to measure the samples.

[0072] US 2013 / 0301051 A1 (Pogosyan) describes a low-cost, portable photometer which - as in Fig. 2bof the present application - has several LEDs with different wavelengths as light sources 35 and a photodiode or photomultiplier as detector 36. The photometer can be used to examine chemical, biological, or pharmaceutical samples located in a sample holder 37 between the light sources 35 and the detector 36. The light from the light sources 35 is directed - if necessary after passing through an interference filter 38 - onto a light-scattering surface 39 and reaches the sample in the sample holder 37 via a collimator lens 40 and a slit diaphragm 41. The detector 36 can - as shown - be pivoted from a first position to a second position. In the geometry shown, a collimator lens functions optimally when the scattering surface is chosen to be very small, almost point-shaped, which, however, reduces the light yield.

[0073] US 8,064,062 B2 (Beckmann) discloses - as in Fig. 2c The present application depicts a photometer with a stationary LED array containing light sources L1 to L5 and a stationary detector array containing photodiodes R1 to R5, with each light source assigned a photodiode. The cuvettes C, located on a rotating plate, are arranged between the LED array and the detector array. When the cuvettes C rotate in the direction of the arrow, the optical beam paths are crossed, and the samples in the cuvettes C can be successively exposed to light of different wavelengths λ1 to λ5.

[0074] AT 510 631 B1 (SCAN Messtechnik) claims a spectrometer with multiple LEDs as light source 44, as in Fig. 2dof the present application. The spectrometer is used to examine the contents of a fluid 42 by means of a light source 44 and a detector 45. The light from the light source 44, having a predetermined spectral range, is guided through an entrance window 47 through the fluid 42 to be examined and through an exit window 48 to the detector 45. The light source 44 is formed by a plurality of LEDs 49 arranged in a holder 50 and connected to control electronics 43, which are designed to emit light of different wavelength ranges within the predetermined spectral range. The control electronics 43 is designed to sequentially control the light-emitting diodes 49. A compensation detector 51 connected to the control electronics 43 is arranged in the holder 50 opposite the light-emitting diodes 49.A lens 46, a diaphragm 52, and a converging lens 53 are arranged in the beam path between the light source 44 and the entrance window 47. To measure the scattered light of the fluid under investigation, an additional detector 54 can be arranged perpendicular to the measuring beam.

[0075] WO 2010 / 122203 A1 (Biosystems) discloses a photometer based on an array of multiple LEDs as a light source for measuring the absorption and turbidity of a sample contained in a cuvette. The light from the individual LEDs is coupled into the beam path in front of the sample using a beam splitter with a bandpass filter. A reference photodiode is also arranged on the light source side. A photodiode is arranged in the beam path downstream of the sample, on the detection side. The individual cuvettes are guided past the photometer. Unfortunately, the light source is very complex and consists of many individual components. Furthermore, the light from the LEDs located farther away from the cuvette must pass through several beam splitters, which leads to a loss of intensity.

[0076] US 4,234,539 (Coulter Electronics) describes an automatic analyzer with rotating disks for sample, reagent, and reaction vessels (cuvettes), with pipetting arms installed between them for transferring the media. A rotor is arranged concentrically to a cuvette rotating disk, on which pairs of light sources and photodetectors are arranged in fixed positions. With appropriate positioning or rotation, the individual cuvettes come to rest between the light source and photodetector. In an alternative embodiment, a single light source is positioned centrally on the rotation axis, and the photodetectors are located (seen in the radial direction) on the opposite side of the cuvettes. While the cuvette rotating disk rotates only slowly, the rotor with the light source rotates much more rapidly, which leads to a significant increase in the measurement frequency.Furthermore, the rotor can have a filter wheel with different filters that can be placed in the beam path between the central light source and the cuvette. However, the rotor must stop at each cuvette, after which the respective filter is selected by rotating the filter wheel. However, the disadvantages of turntable systems or cuvettes attached to rotating disks, as already described above, still apply here.

[0077] EP 2 309 251 A1 (Siemens Healthcare) discloses an automatic analyzer with stationary sample vessels or cuvettes arranged in a circular or linear configuration, wherein the optical measuring unit is designed to be movable along the sample vessels on a rotatable device. According to one embodiment, the rotatable device, which carries the light source in the form of an LED and the photodetector in the form of a photodiode, can be arranged below the sample vessel holder, making it possible to access the sample vessels at any time using a gripper arm. The rotatable device can also have several LEDs of different wavelengths and several photodiodes so that the samples can be measured at multiple wavelengths. The photodiodes can be replaced by a CCD element. G) System components for mixing and thermostatting for automatic analyzers

[0078] A temperature-controlled cuvette arrangement has become known from DE 27 26 498 A1 (HELLMA). As described in Fig. 2e As shown in the present application, a thermostattable cuvette block 55 is provided with several receiving shafts 56 into which cuvettes 57 can be inserted. The downwardly tapered cuvettes 57, which have lateral measuring windows 58, are inserted in a form-fitting manner into a U-shaped, highly heat-conducting adapter 59, which establishes thermal contact with the cuvette block 55 via the walls 60 of the receiving shaft 56. The sample-reagent mixture in each of the cuvettes 57 can be optically measured through a measuring channel 61 in the cuvette block 55.

[0079] The disadvantage is that the temperature of the sample-reagent mixture heats up only slowly to the temperature of the cuvette block. This makes it difficult to achieve high sample throughput in an analyzer, as thermostatting is always one of the most time-consuming processes in sample analysis.

[0080] JP 2007-303964 A (OLYMPUS) discloses - as in Fig. 2fof the present application - a device for thermostatting cuvettes 62 arranged in receptacles of a rotatable carousel 63. The device has a piezoelectric substrate 64 attached to the side wall of each cuvette 62, on which both an electrode structure of an interdigital transducer (IDT) as an ultrasonic transducer 65 and a temperature sensor 66 for non-invasively measuring the temperature of the cuvette contents are integrated. A temperature control unit 68 of a control unit 69, connected via sliding contacts 67, forms, together with the driver unit 70 for the ultrasonic transducer 65, a control loop for thermostatting a reaction mixture in the cuvette 62. The sample-reagent mixture is heated directly to the target temperature by absorbing ultrasonic energy.

[0081] A disadvantage here is that each cuvette 62 requires an attached piezoelectric substrate 64 with an integrated temperature sensor 66, which must be brought into contact with an electronic control unit 68. Furthermore, the temperature measured on the substrate of the ultrasonic transducer 65 can be distorted by the self-heating of the ultrasonic transducer and thus does not correspond to the temperature of the sample-reagent mixture in the cuvette 62.

[0082] Furthermore, the temperature sensor 66 is not in contact with the liquid, but can only record the temperature of the liquid indirectly via the heat conduction of the vessel wall of the cuvette 62, whereby, particularly in the case of very rapid heating of the liquid, a temperature increase in the liquid cannot be measured with sufficient speed and accuracy to be able to exclude a permanent or temporary exceeding of the target temperature by a value that is critical for the sample components.

[0083] From EP 1 995 597 A1 (OLYMPUS) a device for stirring liquids in cuvettes 71 is known, which - as in Fig. 2gof the present application - are arranged on a rotatable carousel 72, with a sound generator 73 (interdigital transducer (IDT)) glued to the side wall of each cuvette for radiating ultrasonic energy into the cuvette 71. According to EP 1 995 597 A1, however, measures must be taken to limit an undesirable temperature increase of the cuvette contents caused by sound absorption and to prevent falsification of the analysis results due to thermal damage.

[0084] The critical heat input caused by the operation of the sound generator 73 is calculated using thermal characteristics of the cuvette contents stored in a control unit 74. The heat input can be limited to a non-harmful value by limiting the operating time, amplitude modulation, or varying the operating frequency of the ultrasonic generator. According to a further measure for limiting the heat input, a separate Peltier element 76 can be applied directly to the substrate of the glued-on sound generator 73 for each cuvette 71 using an actuator 75 in order to actively cool it during operation. The power of the Peltier element 76 is controlled via stored operating parameters; no temperature measurement is provided on the Peltier element. The signal generator 77 for the sound generator 73 is controlled by a driver unit 78 of the control unit 74.

[0085] A precise thermostatization of the liquids in the cuvettes 71 by means of corresponding parameterization alone is not possible or intended, since a pre-calculated ultrasound input alone would be too inaccurate to achieve a target temperature.

[0086] In order to control the mixing or stirring process more precisely and to ensure that a harmful temperature value is not exceeded during stirring, a temperature measurement of the liquid can be carried out from above using a stationary infrared sensor, which can, however, only be carried out on a specific cuvette of the carousel when it is at a standstill.

[0087] Compared to block thermostatting in a cuvette holder with constant temperature, thermostatting with the technical features mentioned has the disadvantage that the system cannot be considered inherently safe with regard to exceeding the target temperature during heating and adjustment.

[0088] JP 2007-010345 A (OLYMPUS) describes an ultrasonic stirring device with which the contents L of a cuvette 81 can be mixed. As in Fig. 2hAs shown in the present application, a piezoceramic ultrasound generator (thickness oscillator 83) is glued to the bottom 82 of the cuvette 81, with the shape and material of the cuvette bottom forming an acoustic lens 84 to focus the ultrasound energy at point F just below the liquid surface. The thickness oscillator 83 made of lead zirconate titanate ("sounding body") has a flat disc 85 with flat, electrical contacts 86 on both sides, with a diameter larger than that of the cuvette bottom 82. H) System components for performing luminometric measurements for automatic analyzers

[0089] US Patent No. 7,998,432 B2 discloses an automatic analyzer for performing biochemical (clinical-chemical) tests and blood coagulation tests, which are measured photometrically. The analyzer is also suitable for performing heterogeneous immunoassays using luminescence detection. Fig. 1cThe device described in the present application is essentially divided into an area 120 for storing samples and reagents and an area 121 for performing optical measurements and analyses. A pipetting device 122 can move along the two areas 120 and 121 and thus pipette liquid samples and reagents from the storage area 120 into the cuvettes on a rotatable cuvette carousel 123. The cuvette carousel 123 is heated to a constant temperature from below by means of an annular thermostatting device. Using the transfer mechanisms provided, individual cuvettes can be exchanged radially between the slot-shaped cuvette receptacles of the carousel and the stationary stations of the analyzer arranged around the cuvette carousel 123 when the cuvette carousel is at a standstill.A station 124 is provided for photometric measurement, a station 125 for dispensing cuvettes to be disposed of, and a station 126 with a dispenser for dispensing coated, magnetic nanoparticles from a storage area 127, which also contains washing reagents and trigger reagents for luminescence measurement. Additional stations are used for magnetic sedimentation and B / F washing 128, luminescence measurement 129, coagulation measurement, or sample dilution. 130 designates a magazine for providing disposable cuvettes. A disadvantage is the considerable mechanical effort associated with transferring the cuvettes between the holders of the cuvette carousel 123 and the individual stations of the analyzer. Although in individual stations (see 128, 129) - due to the removal of the cuvettes - measuring and preparation steps take place which are decoupled from the cycle rate of the cuvette carousel 123, the cuvette transfer in or out isfrom these positions still depend on this clock rate, as do those actions during which the cuvettes remain in the carousel (photometric measurement in station 124 and addition of the magnetic beads in station 126). Thus, the disadvantages already discussed in point A) in connection with carousel arrangements apply.

[0090] US Pat. No. 6,333,008 B1 discloses a measuring system for conducting luminometric serial analyses on liquid samples containing target substances to be detected, labeling substances that can be combined with them in an immunochemical detection reaction, and magnetizable carrier particles. The liquid samples are transported in wells of a multiple-cell cuvette along a conveyor line to an optical measuring station. During transport, permanent magnets designed as rotating double magnets and separation stations, designed to separate excess labeling substance, act on the multiple-cell cuvette. In each separation station, a (B / F) wash step takes place using an injector and a suction needle. In the measuring station, the luminescence radiation is detected by a photodetector.A disadvantage of the known measurement setup is the necessity of transporting the liquid samples to various automated components located along a fixed process path during the analysis process. Furthermore, certain components, such as permanent magnets designed as rotating double magnets and separation stations with injectors and suction needles, must be implemented multiple times.

[0091] Such devices are characterized by the fact that all processes are dictated by rigid cycles of the cuvette conveying mechanism and must run within predetermined time windows. Actions such as dispensing, mixing, separating, and measuring can only occur when the respective cuvettes are located at the positions of the respective device components.

[0092] For example, a sample can only be dispensed into an empty cuvette (not at any time, but) when the empty cuvette passes the position of the sample pipettor and the cuvette transport mechanism stops at that position. A reagent or wash liquid can only be dispensed into a cuvette containing the sample when the cuvette in question passes the position of the reagent dispenser and the cuvette transport mechanism stops at that position. The same applies to the stirring of reaction mixtures consisting of the sample and reagents in the cuvettes with mechanical stirring and to optical measurements at the position of the optical measuring device.

[0093] For example, a specific cuvette cannot be optically measured at any time or repeatedly at short time intervals, since it is necessary to wait until the cuvette in question is at the position of the optical measuring unit.

[0094] Similar disadvantages also apply to the analytical device according to EP 0 644 426 A1, which has a device for suspending particles. The analyzer, shown in an overview in Fig. 1, has reagent containers arranged flatly in racks, which can be transported to different stationary positions of the analytical device (for example, an incubator, a photometer, or a washing device for individual washing steps in DNA analyses and performing immunoassays) with the aid of a gripper of an xy transport device. The transport device also has a pipetting device with a pipetting needle, with which reagents can be pipetted from corresponding racks of the analyzer into the reagent containers. A disadvantage is the transport of the reagent containers to the individual working positions, and the fact that the transport device and the pipetting device can only be moved together.

[0095] The object of the invention is to avoid the disadvantages mentioned above in automatic analyzers for performing chemical, biochemical, and / or immunochemical analyses of liquid samples—especially in connection with the limited sample throughput of known systems due to rigid clock cycles and processes running within predetermined time windows—and to propose improvements that increase sample throughput without significantly increasing the cost of the individual analysis or the analyzer, while at least maintaining the quality of the analysis. Furthermore, an improved method for the automatic chemical, biochemical, and / or immunochemical analysis of liquid samples is to be proposed.

[0096] This object is achieved according to the invention by an analyzer with cuvettes for receiving the liquid samples and reagents, wherein a plurality of cuvettes is arranged as at least one stationary, linear cuvette array in the analyzer, with movable and stationary automatic components, at least comprising: a pipettor which is designed to be movable in the x-direction along a line of movement defined by the linear cuvette array and whose at least one pipetting needle is designed to be movable in a y-direction substantially perpendicular to the x-direction between the cuvettes and the sample storage and / or the reagent storage, a mixer unit for mixing the samples and reagents in the cuvettes of the stationary cuvette array, an optical measuring unit which is equipped with a spectroscopic unit or a stationary detection unit for obtaining a measuring signal, which is suitable for receiving measuring radiation emerging through a measuring window arranged laterally on the cuvette, a cuvette washing unit designed to be movable in the x-direction for cleaning the cuvettes of the stationary cuvette array, a needle washing unit for cleaning the at least one pipetting needle,and a stationary thermostatting unit for setting a preset measuring temperature in the cuvettes of the stationary cuvette array, , wherein at least two machine components are designed to be movable independently of one another along or parallel to the movement line defined by the linear cuvette array in the x-direction and each have access to different cuvettes or groups of cuvettes in a freely selectable order.

[0097] The method according to the invention for the automatic chemical, biochemical and / or immunochemical analysis of liquid samples present in a sample storage of an analyzer, with the aid of liquid reagents present in at least one reagent storage of the analyzer, for determining at least one analyte concentration in the sample, is characterized by the following steps: Transferring a predetermined amount of a liquid sample from a sample vessel in the sample storage area into a cuvette of a stationary, linear cuvette array using a first pipettor movable along the cuvette array; Transferring a predetermined amount of a reagent liquid from a reagent vessel in the reagent storage area into the cuvette of the stationary, linear cuvette array using the first pipettor or a second pipettor movable independently of the first; Mixing the liquids in the cuvette using a mixer unit and thermostatting the liquids in the cuvette using a stationary thermostatting unit; Optionally, transferring a predetermined amount of another reagent liquid from a reagent vessel in the reagent storage area into the cuvette of the stationary, linear cuvette array using the first or second pipettor;if necessary, further mixing and thermostatting of the liquids in the cuvette; optical measurement of the contents of the cuvette by means of an optical measuring unit and determination of at least one measured value using a spectroscopic unit or a stationary detection unit of the optical measuring unit; calculation and display of the analyte concentration based on the determined measured values ​​and previously known or predetermined reference and calibration values; washing and drying of the cuvette by means of a cuvette washing unit that can be moved along the cuvette array; and preparation of the cuvette for subsequent analysis.

[0098] According to the invention, two automated components must be designed to be independently movable in the x-direction: the pipettor (in the simplest case, a single pipettor with a single pipetting needle) and the cuvette washing unit. The mixer unit and the optical measuring unit can be stationary or movable, while the thermostatting unit must be stationary. It should also be noted that two different, movable automated components that access the cuvette openings cannot access the same cuvette simultaneously. In practice, however, it is not necessary for the pipettor and cuvette washing unit, for example, to access the same cuvette "simultaneously."Furthermore, it should be noted that stationary automated components are designed in such a way that they access each cuvette anyway, for example by assigning such an automated component to each cuvette or group of cuvettes.

[0099] Due to the random access of the machine components that can be moved in the x-direction, in particular the cuvette washing unit to any cuvette and the at least one pipettor (with at least one pipetting needle) to any sample vessels, reagent vessels and cuvettes, the throughput is increased considerably compared to a rotary-organized machine with the same number of cuvettes.

[0100] According to an advantageous embodiment of the invention, the analyzer has two pipettors that can be moved independently of one another in the x-direction.

[0101] Compared to the variant with one pipettor, a further increase in throughput is achieved because the first pipettor can pipette samples into a first cuvette, while the second pipettor can simultaneously pipette reagents into a second cuvette of any choice.

[0102] According to the invention, at least one pipettor has two pipetting needles that can be moved independently of one another and parallel to one another in the y-direction. The two pipetting needles of a pipettor can thus move past each other independently of one another along the same path in the y-direction without colliding.

[0103] According to this advantageous variant, two different needle types can also be used (e.g. for different pipetting volumes, with special coatings for different sample and reagent types, without the need for an additional pipettor or needle exchange station).

[0104] A particularly advantageous variant of the invention provides that the needle washing unit is arranged on the pipettor and is designed to be movable with it.

[0105] Further increasing throughput is the ability to pipette one pipetting needle while the second is being cleaned simultaneously. This also benefits the use of only one pipetting needle on the pipettor, as the pipettor does not have to move to a stationary needle washing unit each time. Since the y-axis movement of each pipetting needle can occur independently of the needle washing unit attached to the pipettor, the moving masses of the robotic components can be distributed across the two horizontal axes, so that the needle washing unit only needs to be accelerated in the x-axis.

[0106] A further object of the invention is to improve an optical measuring unit and an optical measuring method for obtaining measurement signals from liquid media which are contained in cuvettes arranged in series, in such a way that a large number of measurements can be carried out at different wavelengths in the course of the chemical reactions in the individual cuvettes and in short temporal sequence, whereby the kinematic effort, caused by translational and / or rotational relative movements between individual components of the measuring system, is to be reduced as far as possible.

[0107] This further object is achieved according to the invention in that the optical measuring unit is equipped with a light supply unit which has a plurality of LED light sources emitting spectrally differently in the UV / VIS / NIR wavelength range, as well as with a stationary detection unit which is designed such that at least one photodiode is permanently assigned to each cuvette of the cuvette array.

[0108] A particular advantage is that the cuvettes are arranged as an immobile, stationary cuvette array, with each cuvette having its own individual detectors (transmitted light detector (for photometric and turbidimetric measurements) and / or scattered light detector (for nephelometric measurements)). The light emitted from the individual cuvettes - including any dark signals and any incident ambient light - can be measured for an unlimited period of time for the purpose of correction. This eliminates the need to measure while the detectors move past or to position a detector sequentially in front of several cuvettes in stop-and-go operation. This allows more precise measurement results to be obtained in very short time intervals, and measurement sequences to be designed with considerably greater flexibility.

[0109] According to a first variant of the invention, the light supply unit has at least one stationary light distribution device which serves to distribute the light of the individual LED light sources to the individual cuvettes of the cuvette array, wherein the light distribution device has a cavity whose inner surfaces are at least partially mirrored and / or diffusely reflective, and wherein the light distribution device has an inlet opening for each LED light source for feeding the light into the cavity and wherein the light distribution device has an outlet opening for feeding the light into the cuvette for each cuvette of the cuvette array.

[0110] This is a compact, cost-effective variant because the light distribution device, which accommodates several LED light sources of different wavelengths, is stationary and assigned to a row of cuvettes. For cuvette arrays with a large number of cuvettes, the stationary cuvette array can be segmented, with each segment being assigned a separate light distribution device. Overall, this creates an optical measuring unit with no moving components.

[0111] To better distribute the light radiated into the light distribution device by the individual LED light sources of different wavelengths, the inner surface of the light distribution device opposite the inlet openings of the LED light sources is preferably corrugated and reflective. Although different light paths arise between individual LED light sources and cuvettes, intensity differences can be compensated for mathematically, by configuring the hardware setup, and / or by calibration measurements due to the constant geometric conditions.

[0112] In order to homogenize the measuring radiation entering the cuvettes, the inner surface of the light distribution device opposite the outlet openings to the cuvettes is designed to be diffusely reflective.

[0113] According to a second variant of the invention, the light supply unit has at least one one-dimensional, rod-shaped light source array with a plurality of LED light sources, which is aligned along the stationary cuvette array and is movable along the stationary cuvette array such that each LED light source of the light source array can be assigned to each cuvette of the stationary cuvette array.

[0114] This variant benefits from the fact that, on the detector side, the photodiodes permanently assigned to the individual cuvettes of the stationary cuvette array are present as a stationary, linear photodiode array and are preferably arranged on a common circuit board. The minor disadvantage of a rod-shaped light source array that can be moved along the stationary cuvette array is offset by cost-effective production (only one light source array for a large number of cuvettes).

[0115] According to a third variant of the invention, the LED light sources of the light supply unit are arranged as a 2D LED array, wherein each cuvette of the stationary cuvette array is permanently assigned a stationary 2D LED array.

[0116] This variant enjoys the advantages of the first variant described above, since the optical measuring unit can be realized without moving components and each cuvette has an individual photometer, comprising a fixed 2D LED array as light source and a fixed photodiode as detector.

[0117] An optical measuring method according to the invention for obtaining measurement signals from liquid media, in particular in connection with the first variant of the invention, is characterized by the following steps: Adsorption of the liquid media into cuvettes arranged in a row, which form a stationary cuvette array, provision of an inlet radiation radiating into the cuvettes with the aid of at least one stationary light distribution device which optically contacts at least one segment of the cuvette array, wherein in chronological sequence light is radiated into the light distribution device and distributed to the individual cuvettes by several LED light sources emitting spectrally differently in the UV / VIS / NIR wavelength range, and detection of the measuring radiation emerging from the cuvettes with the aid of at least one photodiode of a stationary detection unit which is permanently assigned to each cuvette.

[0118] The measuring radiation emerging from the cuvettes is converted into an electrical measuring signal and, after appropriate processing, displayed in a display unit.

[0119] The analyzer may also comprise an optical measuring unit which is designed as a unit which can be moved along the linear, stationary cuvette array, for example as a spectrometer unit.

[0120] A further object of the invention is to improve methods and devices for mixing and / or thermostatting liquid media introduced into cuvettes arranged in series in a cuvette array such that the time from introducing the liquid media into the cuvette to reaching a predetermined target temperature is shortened without the risk of thermal damage to the sample-reagent mixture. Furthermore, the sample-reagent mixture should be optimally mixed upon reaching the target temperature.

[0121] This object is achieved on the one hand in that the thermostatting unit has a cuvette block which is regulated to a predetermined target temperature, which is equipped with a thermostatting device and is in thermal contact with the individual cuvettes, and on the other hand in that stationary mixer units are assigned to the cuvettes for mixing the samples and reagents, wherein at least one ultrasonic transducer for introducing ultrasonic energy into the cuvettes is attached to each cuvette as a stationary mixer unit, and that the ultrasonic transducer is designed as a piezoelectric oscillator and is connected to a control unit which controls the at least one ultrasonic transducer depending on parameter values ​​of the liquid media.

[0122] The method according to the invention for mixing and thermostatting liquid media which are introduced into cuvettes arranged in a row of cuvettes of a cuvette array, wherein the cuvettes of the cuvette array are arranged in a thermostattable cuvette block, is characterized by the following steps: a) heating the cuvettes to a predetermined target temperature using the thermostattable cuvette block, b) heating the liquid media using the thermostatted cuvette block to reach the predetermined target temperature, c) in the heating phase according to point b), before the target temperature is reached, additional introduction of a predetermined amount of ultrasonic energy using at least one ultrasonic transducer attached to each cuvette to increase the heating rate, and d) simultaneous mixing of the liquid media using the ultrasonic energy introduced in point c).

[0123] In particular, the invention provides that the amount of ultrasonic energy introduced in point c) is determined as a function of predetermined parameter values, such as type, amount, viscosity, thermal conductivity and temperature, of the added liquid media.

[0124] The amount of ultrasonic energy to be introduced can, for example, be determined in a test or calibration step at the factory through test measurements and / or calculations, with the corresponding information then being made available to the user.

[0125] After completion of the calibration for all intended analyte determinations, no measures are required by the user to determine the required amount of ultrasonic energy for the respective analyte determination during ongoing operation of the device for mixing and thermostatting liquid media, since the corresponding values ​​from the test and calibration phase can be accessed.

[0126] With the method according to the invention, any local hotspots that may occur during rapid heating are effectively prevented, since the introduction of ultrasonic energy is regulated by control codes that are stored, for example, in an analysis protocol and are determined as a function of parameter values ​​of the liquid, in such a way that the liquid in the cuvette is heated and always circulated at the same time.

[0127] A key advantage of the invention is that, by parameterizing the applied amount of ultrasonic energy, the temperature of the cuvette contents can never exceed that of the cuvette block, which is pre-thermostatted to a final temperature compatible with the sample. This largely eliminates thermal damage to biological samples and reagents due to hotspots or a brief overshoot of the target temperature.

[0128] Technically, the temperature control of cuvettes arranged in a row using a cuvette block made of a continuous, thermally conductive material, such as a block of anodized aluminum, is particularly simple and reliable. Heating the cuvette contents from a pre-thermostatized heat source typically involves an asymptotic approach to the block temperature T BL , so that heating occurs quickly at first and then becomes increasingly slower. Since the block temperature T BL is never fully reached, a slightly lower temperature of T BL-x is accepted as the target temperature for block thermostatting. When thermostatting biological samples for optical measurements of certain analytes, this temperature is typically in the range of 0.1 - 0.5 °C below the block temperature and must not change by more than 0.1 °C during the analysis (see Fig. 17a, 17b ).

[0129] According to the invention, the ultrasonic energy according to point c) can be introduced into the liquid media in pulsed form in several partial quantities (boosts).

[0130] Furthermore, it is advantageous if at least a portion of the ultrasonic energy introduced in point c) is optimized with regard to the pulse duration, frequency and amplitude for mixing the liquid media in the cuvette.

[0131] A signal shape suitable for combined mixing (by generating convection in the liquid) and heating (by absorbing ultrasound in the liquid) can be selected, starting from a fundamental frequency of the ultrasonic transducer, which can be modulated by an imposed, comparatively lower frequency (frequency "sweep"). Furthermore, the amplitude of the fundamental frequency of the ultrasonic transducer can also be modulated by an imposed, comparatively lower frequency, whereby the amplitude can be varied between full signal output (100%) and signal cut-off (0%). Amplitude modulation with an amplitude ratio of 100:0 would correspond to a burst pattern. In both cases, modulation signal shapes such as sine, square, sawtooth, or similar can be used.

[0132] Particularly good results with regard to the mixing of the liquid media introduced into the cuvette can be achieved if the ultrasonic transducer is operated with a fundamental frequency of 200 kHz to 200 MHz, for example when using a thickness transducer with approx. 0.5 MHz to 10 MHz, and when using an interdigital transducer with approx. 50 MHz to 150 MHz.

[0133] Preferably, a modulation frequency of the amplitude of 1 to 100 Hz is impressed on the fundamental frequency of the ultrasonic transducer.

[0134] For mixing and heating aqueous reagent and sample fluids during analyses in appropriate cuvettes, the fundamental frequency of advantageously used ultrasonic transducers depends on the type of ultrasonic transducer used. If bonded thickness transducers made of piezoceramic are used, the fundamental frequencies of suitable designs (depending on the size and dimensions of the substrate) are between approximately 200 kHz and 10 MHz, preferably between approximately 0.5 and 10 MHz. If bonded interdigital transducers are used, the fundamental frequencies of suitable designs (depending on the size and dimensions of the transducer and the substrate) are between approximately 10 and 200 MHz, preferably between approximately 50 and 150 MHz.

[0135] The analyzer may also include a mixing unit, for example a pipetting needle that can be rotated or vibrated and lowered into the respective cuvettes to mix the samples and reagents.

[0136] The analyzer has a cuvette washing unit which, according to the invention, is designed as a movable automatic component which, in each washing position, has simultaneous access to one cuvette or a group of cuvettes, preferably to two to five cuvettes arranged next to one another.

[0137] According to the invention, according to one variant, the analyzer has a thermostatting unit for setting a predeterminable measuring temperature, which comprises heating foils that thermally contact individual cuvettes or groups of cuvettes and can be subjected to different temperature levels.

[0138] A further object of the invention is to propose an analyzer with which heterogeneous immunoassays can be carried out on the basis of the prior art described, wherein disadvantages, especially in connection with the limited sample throughput of known systems - predetermined by rigid clock cycles and processes running in predetermined time windows - are avoided and improvements are achieved which increase the sample throughput without significantly increasing the cost of the individual analysis or the analyzer, wherein the quality of the analysis is to be at least maintained.

[0139] This object is achieved according to the invention in that the analyzer has a device for carrying out heterogeneous immunoassays, which has access to the cuvettes of at least one terminal segment of the stationary, linear cuvette array.

[0140] According to the invention, the device for carrying out heterogeneous immunoassays has the following components: at least one holding arm which can be moved along the cuvette array and lowered in the direction of the filling opening of a selected cuvette, with at least one suction needle which can be lowered towards the bottom of the cuvette, and with at least one dispenser which can be positioned above or in the respective filling opening for dispensing the liquid media into the cuvette, wherein at least one dispenser is designed to dispense a washing solution for the magnetic particles, at least one magnet arrangement which can be moved along the cuvette array and acts on the contents of the selected cuvette for separating the magnetic particles on an inner surface of the cuvette, and at least one optical detection device which can be moved along the cuvette array and can be aligned with the measuring window of the selected cuvette for recording a measuring signal proportional to an analyte concentration in the selected cuvette.

[0141] According to a preferred embodiment of the invention, the holding arm for the suction needle and the at least one dispenser has a lifting and rotating device which is arranged on a platform which can be moved along the cuvette array, wherein a common suspension for the magnet arrangement and the detection device can be arranged on the movable platform.

[0142] It is particularly advantageous if the holding arm arranged on the movable platform, including the dispenser platform, together with the magnet arrangement and the detection device, forms a measuring and manipulation module that can be moved along the cuvette array and that combines all robotic, fluidic and metrological components for the process steps of magnetic separation of the beads, the so-called B / F washing, as well as the triggering and measurement of the luminescence.

[0143] When determining an antigen using a heterogeneous immunoassay, the first step is to a sample for the determination of the antigen, a suspension of magnetic particles with a capture antibody, and if necessary a tracer antibody or a labelled antigen into a selected cuvette of a stationary cuvette array, whereby the following steps B of an immunochemical analysis, such as a) Separation of the magnetic particles, b) One or more times introducing and aspirating a washing solution, c) Dosing of at least one trigger liquid, and d) Lumimetric measurement of the sample, with the aid of a measuring and manipulation module that can be moved along the cuvette array and is stopped at the selected cuvette to carry out individual or all steps a) to d).

[0144] A particular advantage is that the measuring and manipulation module can be moved to at least one further cuvette of the cuvette array during the execution of time-consuming steps in the immunochemical analysis, such as incubation, etc., in the selected cuvette in order to carry out individual or all steps B of an immunochemical analysis in the further cuvette.

[0145] In particular, the measuring and manipulation module according to the invention can move freely between the cuvettes of the stationary cuvette array in order to carry out a second process step in another cuvette during an assay process step in a first cuvette that is not carried out with the components of the measuring and manipulation module.

[0146] Before or during the movement of the measuring and manipulation module to a cuvette, the needle group of the dispensers and the aspiration needle can be washed in a washing station located on the measuring and manipulation module.

[0147] For example, in a parallelization example, during an incubation step of an assay in a first cuvette, a magnetic separation and B / F washing in a second cuvette can be performed to increase the utilization of the automated components and save time in processing the assays.

[0148] According to the invention, the cuvettes used in the clinical chemical area of ​​the analyzer have inlet and outlet windows arranged in a region near the bottom, preferably plane-parallel to each other, which are permeable to the inlet and outlet radiation or measuring radiation of the optical measuring unit.

[0149] In the area used for conducting heterogeneous immunoassays, where detection is performed via chemiluminescence, the cuvettes of the cuvette array require only a lateral exit window in a region near the bottom that is optically transparent to the luminescence radiation. The invention is explained in more detail below using partially schematic embodiments. They show: Fig. 1a an automatic analyzer with circularly arranged, movable reaction vessels or cuvettes according to the state of the art on rotating plates, Fig. 1b an automatic analyzer with linearly arranged, movable reaction vessels or cuvettes according to the state of the art, Fig. 1c an automatic analyzer for clinical chemical analyses and for carrying out heterogeneous immunoassays according to the state of the art, Fig. 2abis Fig. 2d optical measuring units for obtaining measurement signals from liquid media according to the state of the art, Fig. 2ebis Fig. 2hDevices for mixing or stirring liquids in cuvettes according to the prior art, Fig. 3a a first embodiment of an automatic analyzer according to the invention for carrying out chemical, biochemical and / or immunochemical analyses of liquid samples with a linear, stationary cuvette array in a three-dimensional overall view, Fig. 3b a sectional view of the analyzer according to line IV-IV in Fig. 3c , Fig. 3c a simplified plan view of the analyzer according to Fig. 3a , Fig. 4 two independently movable pipettors of the automatic analyzer according to Fig. 3a in a three-dimensional view, Fig. 5 a movable optical measuring unit of the automatic analyzer according to Fig. 3a in a sectional view, Fig. 6 a movable cuvette washing unit of the automatic analyzer according to Fig. 3a in a three-dimensional view, Fig. 7 a needle washing unit of the automatic analyzer according to Fig. 3a in a three-dimensional, partially cut-away view, Fig. 8 a thermostating unit for the cuvettes of the automatic analyzer according to Fig. 3a in a three-dimensional, partially cut-away view, Fig. 9aFluidic elements of a pipetting needle of a pipettor according to Fig. 4 in a schematic representation, Fig. 9bFluidic elements of a needle washing unit according to Fig. 7 in a schematic representation, as well as Fig. 9cFluidic elements of a cuvette washing unit according to Fig. 6 in a schematic representation. Fig. 10a shows a second embodiment of an automatic analyzer according to the invention for carrying out chemical, biochemical and / or immunochemical analyses of liquid samples with a linear, stationary cuvette array in a three-dimensional overall view, Fig. 10b shows a sectional view of the analyzer according to line IV-IV in Fig. 10c , Fig. 10c a simplified plan view of the analyzer according to Fig. 10a , Fig. 11a a first variant of an optical measuring unit according to the invention for obtaining measurement signals from liquid media in a three-dimensional view, looking towards the light supply unit according to Fig. 10a to 10c , Fig. 11bthe variant according to Fig. 11a in a three-dimensional view, looking towards the detection unit, Fig. 11c a sectional view of the light supply unit according to Fig. 11a to line II-II in Fig. 11d , Fig. 11a sectional view of the light supply unit according to Fig. 11a to line III-III in Fig. 11c , Fig. 11e a three-dimensional detailed representation of a tube body of the light supply unit according to Fig. 11a , Fig. 11fine enlarged detail from Fig. 11c , Fig. 12a a block diagram for the electronic control of the optical measuring unit according to Fig. 11a, Fig. 12b first diagram illustrating a measuring sequence (modes 1 and 2), Fig. 12c a second diagram illustrating a measuring sequence (mode 3), Fig. 13a a second variant of an optical measuring unit according to the invention for obtaining measuring signals from liquid media in a three-dimensional view of an automatic analyzer according to Fig. 10a to 10c , Fig. 13b an enlarged sectional view through the axis of a cuvette, normal to the cuvette array according to Fig. 13a , Fig. 14a a third variant of an optical measuring unit according to the invention for obtaining measurement signals from liquid media in a three-dimensional view of an automatic analyzer according to Fig. 10a to 10c , Fig. 14b an enlarged sectional view through the axis of a cuvette, normal to the cuvette array according to Fig. 14a , Fig. 14c an enlarged detail from Fig. 14a. Fig. 15a a device according to the invention for mixing and thermostatting liquid media in a three-dimensional representation of an automatic analyzer according to Fig. 10a to 10c , Fig. 15bthe device according to Fig. 15a in a sectional view according to Fig. 15a , Fig. 15c a cuvette including ultrasonic transducer of the device according to the invention according to Fig. 15a in a three-dimensional view, Fig. 16 a block diagram for the electronic control of the device for mixing and thermostatting liquid media according to Fig. 15aFig. 17a shows a temperature diagram illustrating a first embodiment of a thermostatting and mixing process for a liquid. Fig. 17b shows a temperature diagram illustrating a second embodiment of a thermostatting and mixing process for a liquid. Fig. 18a shows a third embodiment of an automatic analyzer according to the invention for carrying out chemical, biochemical and / or immunochemical analyses of liquid samples with a linear, stationary cuvette array and a device for carrying out heterogeneous immunoassays in a three-dimensional overall view. Fig. 18b shows a top view of the automatic analyzer according to Fig. 18a , Fig. 19a the device according to the invention for carrying out heterogeneous immunoassays according to Fig. 18a in a three-dimensional view, Fig. 19b detail of the device according to Fig. 19ain an enlarged sectional view, Fig. 20 a schematic example of the process of a heterogeneous immunoassay, Fig. 21 a fluid circuit diagram of the device according to Fig. 19a , and Fig. 22 a block diagram for the electronic control of the device according to Fig. 19a .

[0150] Parts with the same function are provided with the same reference symbols in the different versions.

[0151] The automatic analyzers and their components shown in Figs. 1a to 1c and 2a to 2h are examples of the prior art and are described in detail in the introduction to the description.

[0152] The one in the Fig. 3a to 3cThe automatic analyzer 100 shown in a first embodiment is used to perform chemical, biochemical, and / or immunochemical analyses of liquid samples. For simplicity, only those components of the analyzer 100 that are essential to the present invention are shown, with analyzer components such as pumps, valves, evaluation, control, and drive units not being discussed in detail.

[0153] The liquid samples are present in sample vessels 921 in a sample storage 920 of the analyzer 100 and are analyzed with the aid of liquid reagents that are present in reagent vessels 951a, 951b in two reagent storages 950a, 950b of the analyzer 100.

[0154] The cuvettes 201 for holding the liquid samples and reagents are arranged in the form of a stationary, linear cuvette array 200 in the analyzer 100 and remain in their original position throughout a multitude of individual analyses. In the example shown, the cuvette array 200 is arranged between the first reagent storage 950a and the second reagent storage 950b.

[0155] The automatic analyzer 100 is equipped with mobile and stationary automatic components, namely: with two pipettors 300a, 300b movable in the x-direction along a line of movement defined by the linear cuvette array 200, each equipped with two pipetting needles 301a1, 301a2 and 301b1, 301b2, respectively, which are designed to be lowered in the z-direction into the cuvettes 201, into the sample vessels 921 located in the sample storage 920 and into the reagent vessels 951a, 951b located in the reagent storages 950a, 950b and are designed to be movable in a y-direction substantially normal to the x-direction between the cuvettes 201 and the sample storage 920 and / or the two reagent storages 950a, 950b; with a mixer unit 400 for mixing the samples and reagents in the cuvettes 201; with an optical measuring unit 500, which - to obtain a measuring signal - receives measuring radiation emerging through a measuring window 202, 203 arranged on the side of the cuvette 201 (see Fig. 5 ); with a cuvette washing unit 600 for cleaning the cuvettes 201, which can be moved in the x-direction along the line of movement defined by the cuvette array 200, with needle washing units 700a1, 700a2, 700b1, 700b2 for cleaning the pipetting needles 301a1, 301a2, 301b1, 301b2 of the two pipettors 300a, 300b; and with a stationary thermostatting unit 800 for setting a predeterminable measuring temperature in the cuvettes 201.

[0156] The pipettors 300a, 300b are attached to the parallel rails 111a, 111b by means of movable mounting elements (not shown). Furthermore, a corresponding rail 113 including a movable mount 501 is provided for the optical measuring unit 500, as well as a rail 112 including a movable mount 601 for the cuvette washing unit 600. The movable mounts of the pipettors 300a, 300b, and the mounts 501 and 601 are driven, for example, by means of toothed belts and stepper motors (not shown here) at one end of the rails 112, 113, 111a, and 111b.

[0157] As particularly in Fig. 3b As can be seen, at least two - in the example shown, several - of the machine components are designed to be movable independently of one another along or parallel to the movement line defined by the linear cuvette array 200 in the x-direction, and can each access different cuvettes 201 or groups of cuvettes 201 in a freely selectable order.

[0158] In the illustrated version according to Fig. 3a bis 3c The analyzer 100 has a sample storage area 920, a first reagent storage area 950a, and a second reagent storage area 950b. The storage areas can be fully or partially cooled.

[0159] To load the analyzer 100 with sample material, vessels 921 containing analysis samples are placed manually or by robotics into predetermined positions in the sample storage 920. The desired analyses for the individual analysis samples are entered into the control system of the analyzer 100.

[0160] To load the analyzer with reagents, reagent vessels 951a, 951b containing reagents for the analysis of different analytes are inserted manually or by robotics into the two reagent stores 950a, 950b of the analyzer 100 in predetermined positions.

[0161] Vessels containing calibration fluids and reference samples can also be placed in the sample or reagent storage areas.

[0162] In the embodiment shown, the analyzer has two pipettors 300a, 300b that can be moved independently of one another in the x-direction and that - with the exception of the same cuvette - can access individual cuvettes 201 of the cuvette array 200 completely independently of one another and in a freely selectable order.

[0163] The two pipettors 300a, 300b according to Fig. 4 Each has a vertical tower 303a, 303b, as well as an arm 304a, 304b aligned horizontally in the y-direction, forming a substantially L-shaped support structure (pipettor 300a) for the two pipetting needles 301a1, 301a2, or a T-shaped support structure (pipettor 300b) for the two pipetting needles 301b1, 301b2, respectively, which is movable along the rail 111a or 111b in the x-direction. Each pipettor thus has two pipetting needles 301a1, 301a2, or 301b1, 301b2, with their cannulas or hollow needles 307, which can be moved independently of one another and parallel to one another in the y-direction. The pipetting needles 301a1, 301a2, and 301b1, 301b2 are mounted to the left and right of the arms 304a and 304b by means of a holder 305 that can be moved in the y-direction, allowing them to pass each other unhindered. Each holder 305 has a downwardly projecting rail section 306, along which the needle can be lowered in the z-direction into the cuvettes 201 of the cuvette array 200.

[0164] The individual pipetting needles 301a1, 301a2 and 301b1, 301b2 each have a needle holder 308 with a projecting area in the direction of the cuvette array 200, which carries the hollow needle 307. This leaves sufficient space for the L-shaped pipettor 300a to move past the T-shaped pipettor 300b, even when the hollow needle 307 of the pipetting needle 301b2 is aligned or lowered with the cuvette 201 (see Fig. 3b ).

[0165] In the example shown, the pipettor 300b or its two pipetting needles 301b1, 301b2 can only access the sample vessels 921 in the sample storage 920 and the reagent vessels 951b in the reagent storage 950b, whereas the pipettor 300a or its pipetting needles 301a1, 301a2 can only access the reagent vessels 951a arranged in the reagent storage 950a. All pipetting needles 301a1, 301a2 or 301b1, 301b2 can be moved to the level of the cuvette array 200 and lowered into the individual cuvettes 201.

[0166] A significant increase in sample throughput can be achieved by arranging the needle washing units 700a1, 700a2 or 700b1, 700b2 on the pipettor 300a or 300b and arranging them so that they can be moved with it. In the illustrated embodiment, each pipetting needle 301a1, 301a2, 301b1, 301b2 has its own needle washing unit 700a1, 700a2, 700b1, 700b2, which can be arranged, for example, on the vertical tower 303a or 303b of the pipettor 300a or 300b. Thus, one of the pipetting needles 301a1 or 301b1 can be washed in the associated needle washing unit 700a1 or 700b1, while the other pipetting needle 301a2, 301b2 is immersed in a cuvette 201 (see Fig. 4 ).

[0167] Simpler versions of the analyzer are also conceivable, featuring only one pipettor. This can either be designed as an L-shaped pipettor 300a, movable along the side of a sample or reagent storage area and featuring only one movable pipetting needle 301a1, or it can have a T-shaped support structure and be movable between a sample and reagent storage area.

[0168] The Fig. 5 The optical measuring unit 500 shown is designed as a unit that can be moved along the linear, stationary cuvette array 200 on the rail 113 with the aid of the holder 501. This consists of the Fig. 5 The example shown comprises a light supplying unit 520 on one side of the cuvette array 200 and a spectroscopic unit 530 on the other side, which are rigidly connected to one another via the holder 501. The optical measuring unit 500 comprises a light source 521, for example a halogen lamp, a beam path for the inlet 502 and the outlet or measuring radiation 503 with lenses 522, 523, 532, 533, filters 524, deflecting mirrors 525, 531, and a spectrometer 535, which records the spectrum of the measuring radiation or the intensity of the measuring radiation at individual predetermined wavelengths in the range from 300 to 800 nm. The spectrometer 535 consists of the Fig. 5 The example shown consists of a polychromator comprising an entrance slit 536, a deflection mirror 539, and a concave diffraction grating 537, which images the spectrum of the measuring radiation 503 onto a sensor array 538, for example, a photodiode array. In the example shown, the liquid in the cuvette 201 is measured in transmitted light, with the entrance radiation 502 entering the cuvette 201 through a lateral entrance window 202 and exiting the cuvette 201 through an opposite exit window 203.

[0169] The optical measuring unit 500 preferably comprises a reference detector 526 for measuring and compensating for fluctuations in the intensity of the light emitted by the light source 521. This detector consists, for example, of a beam splitter 528 located in the beam path for the incoming radiation 502, an aperture 529, and a photodetector 527, for example a photodiode.

[0170] With the optical measuring unit 500 described above, various optical measurements can be performed at single and / or multiple wavelengths in the ultraviolet and visible light wavelength range. Examples include photometric, turbidimetric, and luminometric measurements.

[0171] The following describes an optical measurement process using the example of a photometric measurement. The input radiation 502 originating from the polychromatic light source 521 passes through the reaction mixture in the cuvette 201, consisting of the sample and the reagents added for the respective analysis, enters the spectroscopic unit 530 as measurement radiation 503, and is split into wavelengths by the diffraction grating 537 in the spectrometer 535 and recorded by the sensor array 538. The individual light-receiving elements of the sensor array 538 of the spectrometer 535, for example, photodiodes, as well as the reference photodiode 527 of the reference detector 526, emit a photocurrent corresponding to their respective measurement wavelength, which is converted into a digital measured value by a signal processing circuit and an AD converter.In an operating unit, depending on the respective analysis, individual or periodically measured digital values ​​over time and at one or more wavelengths are calculated with the previously known reference and calibration values ​​assigned to the respective analysis to obtain a concentration value of the analyte.

[0172] For mixing the samples and reagents, a stationary mixer unit 400 is assigned to the entire cuvette array 200, preferably to individual groups or segments 210 of cuvettes 201 (not shown in detail here). Fig. 6 The cuvette washing unit 600 shown is mounted on a holder 601 along the rail 112 (see Fig. 3b ) is designed to be movable in the x-direction. The head 602 of the unit 600 can be moved up and down in the z-direction with the aid of a vertically aligned rail section 603, which is guided in the holder 601, in order to introduce either the washing bodies 610 or the drying stamps 620 into the cuvettes 201 of the cuvette array 200. An adjusting element 604, which is guided in the head 602 and carries, for example, four drying stamps 620 and washing bodies 610, can be switched from the washing position to the drying position by displacement in the y-direction. Individual fingers 605, which carry the washing bodies 610 and drying stamps 620, can be pivoted upwards - as indicated by arrow 691 - so that only one or a few cuvettes 201 are washed at a time.

[0173] Fig. 7 shows in an enlarged sectional view the structure of a needle washing unit marked with the general reference numeral 700, which has the essentially identical construction, at different positions in the Fig. 3a bis 3c and 4, and a pipetting needle marked with the general reference numeral 301, which corresponds to the essentially identically constructed, at different positions in the Fig. 3a bis 3c and 4corresponds to the pipetting needles 301a1, 301a2, 301b1, 301b2 shown. The hollow needle 307 of the pipetting needle 301 is inserted through a receiving opening 711 in the housing 710 of a needle washing unit 700, whereby the lumen of the hollow needle 307 can be cleaned with a system liquid 712 and the outside of the needle with a rinsing liquid 714 supplied from an annular chamber 715 via lateral cleaning nozzles 713. For internal and external cleaning of the hollow needle 307 by repeatedly sucking in and expelling washing solution from the lower part of the needle washing unit 700, washing solution can be introduced via a radial inlet 716, which can then be emptied via a suction opening 717.

[0174] Fig. 8 shows an enlarged section of the linear cuvette array 200 of the analyzer 100 with the partially cut-open housing 892 and a cuvette 201 arranged therein, which is contacted by a heating foil 891 of a thermostatting unit 800 for setting a predeterminable measuring temperature, the electrical contact pins 893 of which emerge from the housing 892. Additional electrical contact pins 894 can be provided for contacting a temperature sensor. The cuvette 201 has measuring windows arranged laterally in a region near the bottom, preferably plane-parallel to one another, in the example shown, inlet and outlet windows 202, 203 (exit windows not visible), which are permeable to the inlet radiation and the outlet or measuring radiation of the optical measuring unit 500. In the area of ​​the inlet and outlet windows 202, 203 of the cuvette 201, the housing 892 has corresponding openings 895.The individual contact pins 893, 894 snap into corresponding contact openings. Molded onto the bottom of the housings 892 are locking elements 896, which serve to secure the cuvette array 200.

[0175] Fig. 9a shows the fluidic circuit diagram of a pipetting needle 301, whose hollow needle 307 is connected to a precision piston pump 325, preferably a stepper motor-driven positive displacement pump (dilutor), via a pressure transmission channel 712 filled with a degassed liquid. The positive displacement pump has an additional fluid connection on the side, which is connected via a solenoid valve 326 to a supply unit 320 for a system fluid. The supply unit 320, via a flushing pump 321, pumps, for example, degassed, deionized water from a storage vessel 322. This water can be refilled or pressurized via a solenoid valve 323.

[0176] To detect malfunctions, the pressure transmission channel 712 has a further connection to a pressure sensor 324 near the pipetting needle 301, which is connected to an evaluation and control unit not shown here, for example for detecting blockages in the hollow needle 307. Beschreibung eines Pipettiervorgangs

[0177] To transfer a defined amount of liquid with the pipetting needle 301, the needle is first moved horizontally to a first vessel, 5 µL of air (spacer) is sucked into the tip of the hollow needle 307, and the pipetting needle 301 is lowered towards the liquid surface of the first vessel. To ensure a sufficient, but not excessive, immersion depth of the pipetting needle 301, the downward movement of the hollow needle 307 is stopped at a defined immersion depth by a signal from a liquid surface detection device (not shown), for example, with a capacitive detection principle. To aspirate a defined amount of liquid with high accuracy in the µL range, the working piston is then moved downwards to Fig. 9a A negative pressure is generated in the hollow needle 307 of the pipetting needle 301 by the positive displacement pump (dilutor) shown, which causes the aspiration of a corresponding volume of liquid from a first vessel. The pipetting needle 301 is then moved, together with the aspirated liquid, which is separated from the system liquid by a separating air bubble (spacer), to a second vessel, with the process now running in the reverse direction and the aspirated liquid being dispensed into the second vessel via the tip of the hollow needle 307. At least between two pipetting processes with different liquids to be pipetted, the pipetting needle 301 is always cleaned internally and externally in a needle washing unit 700 (see Fig. 7 ).

[0178] Fig. 9b shows the fluidic circuit diagram of a needle washing unit 700 according to Fig. 7 with the hollow needle 307 of the pipetting needle 301 lowered therein. The housing 710 of the needle washing unit has a concentrically circumferential annular chamber 715 in the upper area, which functions as a media supply for several internal, concentrically aligned cleaning nozzles 713, and which is each connected via solenoid valves to a supply unit 719 for a rinsing liquid (for example, deionized water) and a supply unit 727 for dry air.

[0179] An inlet 716 arranged radially in the middle of the height of the housing 710 of the needle washing unit 700 is also connected to a solenoid valve and serves exclusively for the supply of surfactant-containing washing solution from a supply unit 723.

[0180] The supply units 719 for a rinsing liquid and 723 for a washing solution each have a pump 720, 724, which pumps a surfactant-containing washing solution or rinsing liquid from the respective storage containers 721, 725, which can each be refilled or pressurized via a solenoid valve 722, 726. The supply unit 727 for air has an air pump 728 for providing compressed air and, if necessary, a drying reservoir (not shown).

[0181] The suction opening 717 located at the bottom of the needle washing unit 700 is connected via a solenoid valve 718 to the vacuum-operated wastewater collection unit 729, which essentially consists of a collection tank 730, which has a connection to a vacuum pump 731 in the gas space above the liquid, which is connected to the collection tank 730 via a solenoid valve. The collected wastewater can be discharged via a solenoid valve 732 at the bottom of the collection tank 730 and fed to further wastewater treatment. Beschreibung eines Nadelwaschvorgangs

[0182] In a typical washing process for the pipetting needle 301, it is first moved horizontally to the needle washing unit 700 and lowered into the lower holding position of the washing chamber. All wastewater generated during the cleaning of the pipetting needle 301 is suctioned off through the suction opening 717 located at the bottom, collected, and, if necessary, treated. Subsequently, the Fig. 9a The precision piston pump 325 shown in the figure first empties and sucks out any residual amounts of the last pipetted liquid in and at the tip of the pipetting needle 301. Finally, the lowered pipetting needle 301 is lowered from behind by means of the Fig. 9a shown supply unit 320 for system fluid.

[0183] In the next step (with the solenoid valve 718 at the suction opening 717 closed), a defined volume of surfactant-containing washing solution is introduced through the inlet 716 in the housing 710 of the needle washing unit 700, filling the lower part of the chamber with a defined level of washing solution. The hollow needle 307 of the pipetting needle 301 is lowered far enough so that the outside of the needle can be wetted by immersion in the washing solution, and the inside of the hollow needle 307 can be wetted by suction of the washing solution into the interior of the needle. The aspirated washing solution is then expelled; the process of suctioning and expelling the washing solution can be repeated several times to improve the cleaning effect.

[0184] In a final step, the contaminated washing solution is sucked off and the interior of the hollow needle 307 is rinsed with system fluid (e.g., degassed, deionized water), while the exterior of the hollow needle 307 is simultaneously rinsed with rinsing fluid from the supply unit 719 through the concentrically arranged cleaning nozzles 713 located above, whereby the tip of the hollow needle 307 is moved from bottom to top to improve the cleaning effect.

[0185] After the simultaneous internal and external rinsing is complete, the hollow needle 307 is moved back to the lower holding position, the media supply of the cleaning nozzles 713 is switched to the compressed air supply unit 727, and the tip of the hollow needle 307 is again moved from bottom to top, allowing adhering water droplets to be quickly removed from the needle surface. The pipetting needle 301 can now be moved out of the needle washing unit 700 and, after aspiration of a separation air spacer (5 µL), is ready for pipetting again.

[0186] Fig. 9c shows the fluidic circuit diagram and the longitudinal section of a finger 605 of the cuvette washing station 600, which is hinged to the adjustment element 604, with a washing body 610 and a drying stamp 620 (see also Fig. 6 ), whereby the descriptions of the supply units 630 (rinsing liquid), 634 (washing solution) and 638 (air), as well as the waste water collection unit 640, the supply units 719 (rinsing liquid), 723 (washing solution), 727 (air) and 729 (waste water) of the figure description to Fig. 9b can be taken from the Fig. 9c The units shown are functionally identical or structurally identical.

[0187] The washing body 610, as well as the drying stamp 620 of the finger 605 of the cuvette washing station 600 can be lowered successively into the cuvette 201 to be washed of a linear cuvette array by horizontal and vertical translational movements, wherein after lowering into the cuvette 201, a circumferential gap of less than 1 mm remains free between the inside of the cuvette 201 and the washing body or drying stamp in order to enable a controlled flow of the cleaning media along the inner cuvette wall.

[0188] The washing body 610 has an elastomer seal 611 at its upper end, which prevents the cleaning media from escaping between the upper cuvette edge and the underside of the finger 605 during the washing process. A ring-shaped media supply is arranged around the shaft of the rising channel 612 running in the center of the washing body 610 for extracting the wastewater and exhaust air, allowing the interior of the cuvette to be rinsed from top to bottom (see arrows). The washing body 610 can be supplied via appropriate solenoid valves with surfactant-containing washing solution from the supply unit 634, rinsing liquid (e.g., deionized water) from the supply unit 630, or with compressed air from the supply unit 638. These liquids are discharged via the vacuum-operated wastewater collection unit 640 by being fed to the vacuum-operated wastewater collection unit 640 via a solenoid valve.The wastewater collection unit 640 essentially consists of a collection tank 730, which has a connection to a vacuum pump 642 in the gas space above the liquid, which is connected to the collection tank 641 via a solenoid valve. The collected wastewater can be discharged via a solenoid valve 643 at the bottom of the collection tank 641 and fed to further wastewater treatment.

[0189] The drying piston 620 is made of a porous, air-permeable material and has a longitudinal channel 621 inside that does not quite reach the bottom. This channel serves to supply and distribute the compressed air through the wall of the porous drying piston 620 into the cuvette 201. The drying piston 620 does not seal against the underside of the finger 605, but protrudes slightly when lowered, forming a circumferential air outlet gap between the top side of the cuvette 201 and the underside of the finger (see horizontal arrows). The drying piston 620 can be connected to compressed air from the supply unit 638 via a solenoid valve. Beschreibung eines Küvettenwaschvorgangs

[0190] In a step preparing for the actual cleaning, the washing body 610 is lowered into the cuvette 201 to be washed and the reagent / sample mixture, which is located in the cuvette 201 after the analysis, is sucked off via the central riser channel 612 and fed to the wastewater collection unit 640.

[0191] In a first cleaning step, washing solution from the supply unit 634, rinsing liquid from the supply unit 630 and finally compressed air from the supply unit 638 are used for rinsing, whereby this cleaning sequence can be repeated several times with the said media in order to improve the cleaning effect.

[0192] The washing body 610 is now lifted out of the washed cuvette 201, which still contains residual moisture, and the finger is moved in the y-direction.

[0193] In a second cleaning step, the dry stamp 620 is now lowered into the cuvette 201 in the z-direction and air is blown past the inside of the cuvette with dry compressed air from the supply unit 638 for a certain period of time, whereby the air required for this purpose emerges evenly from the porous body of the dry stamp 620, passes from bottom to top along the inside of the cuvette 201, and exits at the shaft of the dry stamp 620. Beispiele:

[0194] The automatic analyzer according to Fig. 3a bis 3c works, for example, as follows: Before an analysis, ie the determination of an analyte A x of an analysis sample P x, the control unit of the analyzer compiles all the data required for the analysis of the analyte A x from the known and previously entered information (analysis protocol, positions of the vessels 921, 951a, 951b with the analysis sample and with the reagents required for the analysis, position of a free cuvette 201 in the cuvette array 200, cuvette temperature, selection of the measurement sequence, the calibration data, the measurement and evaluation algorithms). Beispiel: Einzelanalyse Phase 1

[0195] At the beginning and during the analysis, the temperature of the cuvette 201 intended for the analysis is regulated to a predetermined temperature by means of the thermostatting unit 800 assigned to the cuvette 201.

[0196] The first pipetting needle 301b1 of the T-shaped pipettor 300b takes a predetermined amount of a first analysis sample from a first sample vessel 921 in the sample storage 920 and dispenses a predetermined amount of it into a free cuvette 201. Following the pipetting process, the pipetting needle 301b1 is washed and prepared in the first needle washing unit 700b1 of the pipettor 300b. Phase 2

[0197] A pipetting needle 301a1 of the L-shaped pipettor 300a takes a predetermined amount of a first reagent liquid from a first reagent vessel 951a in the reagent storage 950a and pipettes a predetermined amount into the cuvette 201. The two liquids are then mixed in the cuvette by briefly (a few seconds) switching on the mixer unit 400 assigned to the cuvette. Following the pipetting process, the pipetting needle 301a1 is washed and prepared in a first needle washing unit 700a1 of the L-shaped pipettor 300a. Phase 3

[0198] Depending on the respective analysis protocol, the second pipetting needle 301b2 of the T-shaped pipettor 300b in the reagent storage 950b takes a predetermined amount of a second reagent liquid from a reagent vessel 951b and dispenses a predetermined amount of this into the cuvette 201. The contents of the cuvette are then mixed by briefly (a few seconds) switching on the mixer unit 400 assigned to the cuvette 201. Following the pipetting process, the pipetting needle 301b2 is washed and prepared in the second needle washing unit 700b2 of the T-shaped pipettor 300b. Phase 4

[0199] Phase 4 begins with the photometric measurements on cuvette 201, usually after completion of Phase 2.

[0200] The optical measuring unit 500 periodically scans the linear cuvette array 200 and, as it passes ("on the fly"), generates a measured value at the entrance window 202 or exit window 203 of the cuvette 201—if provided for by the measurement protocol at the time of the pass. Alternatively, the optical measuring unit 500 can also pause briefly while passing and measure while stopping to obtain a more precise measured value.

[0201] While the chemical reaction between sample and reagent takes place in cuvette 201, measurement points can be generated at defined time intervals. Depending on the respective analysis protocol, singular or – in the case of kinetic measurements – time-dependent measurement values ​​obtained at one or more wavelengths are calculated and displayed with previously known reference and calibration values ​​assigned to the respective analysis to produce a concentration value of the analyte.

[0202] Depending on the type of analysis and sample, the measurement process - especially in the case of kinetic measurements - can extend over very different periods of time, from a few seconds to the double-digit minute range.

[0203] Immediately after the completion of the photometric measurement, the cuvette 201 is released for washing with the cuvette washing unit 600. The washing process using the cuvette washing unit 600 takes place immediately after the cuvette has been released, preferably together with several neighboring cuvettes 201 that have also been released for washing, and after the movable cuvette washing unit 600 has become free. After washing and drying, the cuvette 201 is prepared for the next analysis. Beispiel: multiple Analysen

[0204] Prior to performing multiple analyses, the sample storage 920 is manually or automatically loaded with samples P 1 to P n. The type and number of analyses A 1 to A n to be performed for each sample P x ​​are entered into the control system of the analyzer 100. If necessary, the reagent storages 950a, 950b are loaded or replenished with the reagents required for the analyses to be performed.

[0205] For each analysis P x A x to be performed, phases 1 to 4 described above are run through, starting with phase 1.

[0206] After the pipettor 300b is occupied in phases 1 and 3 by the analysis P x A x to be performed, phase 1 of the subsequent analyses P x A x+1 or P x+1 A x can only begin after the completion of phase 1 and outside of phase 2 of the ongoing analyses, and for as many subsequent analyses as there are "free" cuvettes, ie cuvettes not occupied by other analytical processes.

[0207] The inventive concept makes it possible - in contrast to the systems described above - that after the measurement has been completed, a cuvette can be washed immediately and made available for a new test without adversely disrupting the ongoing analysis processes.

[0208] The Fig. 10a bis 10c The second embodiment variant of the automatic analyzer 100 described above has the components already explained in detail in connection with the first variant, such as pipettors 300a, 300b movable along the stationary cuvette array 200, preferably needle washing units 700a1 to 700b2 moving along with the pipettors 300a, 300b, as well as a cuvette washing unit 600 movable along the cuvette array 200 and differs primarily in the optical measuring unit 500, which according to a first variant (see Fig. 11a bis 11f ) is stationary and is permanently assigned to the individual cuvettes 201.

[0209] The optical measuring unit 500 has the following basic elements: a light supply unit 540 for emitting an inlet radiation into the cuvettes 201 of the cuvette array 200, wherein the light supply unit 540 has a plurality of LED light sources 541 emitting spectrally differently in the UV / VIS / NIR wavelength range, and a detection unit 550 for detecting a measuring radiation emerging from the cuvettes 201 of the cuvette array 200 and converting the measuring radiation into an electrical measuring signal, wherein the detection unit 550 is designed such that at least one photodiode 551 is fixedly and stationary assigned to each cuvette 201 of the cuvette array 200.

[0210] The Fig. 11a bis 11f The first variant of the optical measuring unit 500 according to the invention shown has at least one stationary light distribution device 542 which distributes the light of the individual LED light sources 541 to the individual cuvettes 201 of the stationary cuvette array 200.

[0211] The light distribution device 542 has a cavity formed by walls, the inner surfaces 543, 544, 545 of which, as well as the rear wall and the two end faces, are at least partially mirrored and / or diffusely reflective. The light distribution device 542 has an inlet opening 546 in the bottom surface 545 for each LED light source 541 for feeding the light into the cavity and has an outlet opening 547 for each cuvette 201 of the cuvette array 200 for feeding the light into the cuvette 201.

[0212] According to the invention, the inner surface 544 on the cover surface of the light distribution device 542, which is opposite the inlet openings 546 of the LED light sources 541, is designed to be corrugated and reflective, wherein the waves of the corrugated inner surface 544 are preferably aligned normal to the longitudinal extent of the light distribution device 542 in order to optimally distribute the light entering from the individual LED light sources 541 in the longitudinal direction of the light distribution device 542 (see Fig. 11d ).

[0213] In order to ensure that the cuvettes 201 are exposed to the measuring radiation as homogeneously as possible, the inner surface 543 of the light distribution device 542, which is opposite the outlet openings 547 to the cuvettes 201, is designed to be diffusely reflective at the upper part (see Fig. 11c ). Barium sulfate (BaSO 4 ), for example, is suitable as a material for coating the inner surface 543 in the field of view starting from the entrance window 202 of the cuvette 201.

[0214] At least individual LED light sources 541 of the light supply unit 540 for improving the spectral characteristics and for feeding the light into the light distribution device 542 have optical elements for collimation and a narrow-band filter on the output side.

[0215] As in Fig. 11a and in detail in Fig. 11c As shown, the LED light source 541 may comprise an LED 548 arranged in a TIR lens 549, a tube body 552 for eliminating non-parallel beam components of the LED, and a narrow-band filter, preferably an interference filter 553, on the inlet side into the light distribution device 542.

[0216] The tube body 552 can have elongated through-openings 570 running parallel to the longitudinal axis of the LED light source 541, the walls 571 of which are made of a light-absorbing material or are coated with such a material (see detailed illustration according to Fig. 11e ). Thus, within a certain tolerance, only parallel rays reach the interference filter 553, since deviating rays are absorbed by the tube body 552.

[0217] The light guidance or light control in the optical measuring unit takes place in several steps to meet the requirements: In the first step, the spatially broadly emitted light of the LEDs 548 is collected, parallelized, and directed toward the interior of the light distribution device 542 using optical lenses, TIR lenses 549, or parabolic mirrors. In the (optional) second step, the tube body 552 or other tube-like components are used to prevent the further propagation of insufficiently parallelized portions of the light. In the third step, optical bandpass filters, for example, interference filters 553, are provided to obtain a predetermined, narrow-band light spectrum. In the fourth step, the light generated by the individual LED light sources 541 is distributed and directed as homogeneously as possible into the individual cuvettes 201 in the interior of the light distribution device 542. For this purpose, the essentially cuboid-shaped light distribution device 542 is designed such that the cover surface has a corrugated structure 544 (see Fig. 11d ) and the other inner surfaces are flat and mirror-like or diffusely reflecting, so that light is reflected as effectively as possible over a spectral range of approximately 340 to 800 nm. A diffusely reflecting surface 543 is arranged opposite the outlet openings 547, and all other inner surfaces of the light distribution device 542 have mirror-like and / or diffusely reflecting surfaces. The outlet openings 547, through which the light can reach the entrance windows 202 of the cuvettes 201, are arranged in the rear wall of the light distribution device 542. In the fifth step, a beam of rays directed into the interior of the cuvette 201 is generated through a feedthrough 578, if necessary with the interposition of one or more diaphragms between the light distribution device 542 and the cuvette 201. In the sixth step, the measuring radiation is directed from the exit window 203 of the cuvette 201, if necessary.directed to the photodiode 551 of the detection unit 550 with the interposition of an aperture.

[0218] According to the invention, monitor or reference detectors 575 are arranged on the light distribution device 542 on the output side of through-openings or pinholes 576 arranged in a wall, for example the rear wall, of the light distribution device 542, with which fluctuations in the measuring radiation can be detected at any time. A pinhole 576 including a reference detector 575 can be assigned to each cuvette 201. If a reference photodiode is assigned to each cuvette 201, these are preferably located at the outlet openings 547 of the light distribution device 542. It is also possible to provide only two or three pinholes 576 including reference detectors 575 in the light distribution device 542 (see Fig. 11a ).

[0219] As in the Fig. 11a / b, the stationary cuvette array 200 can be segmented or divided into several sections, with each segment 210 being permanently assigned a separate light supply unit 540.

[0220] Each segment 210 is assigned a common light distribution device 542 extending over the entire length of the segment, which has a sufficient number of installation positions for LED light sources 541 for up to 16 optical channels with light of different wavelengths (λ1 to λ16). The individual LEDs of the LED light sources 541 can preferably be arranged in the form of an LED array on a common printed circuit board 582, for example made of aluminum. Adjacent installation positions (see Fig. 11a ) can be equipped with LED light sources of the same wavelength to increase the intensity. In the area of ​​the front entrance window 202 of each cuvette 201, adjacent to the light distribution device 542, the light distribution device 542 has a circular opening, the so-called exit opening 547, through which the light generated by the LEDs is radiated through the entrance window 202 into the interior of the cuvette 201. The feedthrough 578 in the cuvette holder 579, between the exit opening 547 and the entrance window 202 into the cuvette 201, can be channel-shaped, possibly contain apertures, and preferably consist of a light-absorbing material (see Fig. 11f ).

[0221] Due to the distribution of the light within the light distribution device 542 by multiple scatterings and reflections on the inner walls, the light of each optical channel of the LED light sources 541 passes through the circular exit openings 547 into the entrance window 202 of each associated cuvette 201.

[0222] Measuring the intensity I The light transmitted through the cuvettes 201 is detected by means of a stationary array of photodiodes 551 (at least one photodiode per cuvette), each of which is fixedly positioned behind the rear exit window 203 of the cuvettes 201 facing away from the light distribution device 542.

[0223] Optionally, a second photodiode (not shown) can be arranged on each cuvette 201 at an angle rotated by, for example, 90° from the continuous beam path for carrying out nephelometric scattered light measurements.

[0224] In order to ensure a constant ambient temperature of the LED light sources 541, a solid aluminum block 583 is attached to the circuit board 582 of the LED light sources 541, for example, with the help of Peltier components (cooling and heating option).

[0225] The Fig. 12a The schematically illustrated electronics for the optical measuring unit 500 consists of several circuit units that are distributed on several printed circuit boards and are geometrically placed on the stationary cuvette array 200 (see arrow) according to their function.

[0226] In the example shown, the circuit board of the transmitter unit 580 contains 16 parallel current sources 581, each assigned to a specific light source (LED 548) with a specific wavelength. The current sources 581 can be controlled in terms of current intensity and pulse length by an optical controller (584), so that a desired current pulse can be set in terms of length and intensity for the light pulse. The LED supply voltage can also be individually controlled for each LED channel. The circuit board of the transmitter unit 580 is provided with an aluminum block 583 including cooling fins 577 for thermostatting purposes (see Fig. 11b ) and controlled by Peltier elements to an adjustable temperature, for example, between 29°C and 41°C. The thermal drift of the current sources 581 can thus be reduced to a minimum. The power loss in the current sources 581 is evened out by sequential activation. Only one current source 581 is activated per unit of time, thus only generating light with a specific, predetermined wavelength.

[0227] The actual light sources are implemented on a separate, cooled aluminum circuit board 582 using 16 selected LEDs 548 with the desired 16 wavelengths. The aluminum circuit board 582 is used for better thermal coupling of the LEDs; it is screwed to the aluminum block 583 and thus operated at a constant temperature (e.g., +37°C). Despite different pulse lengths, the LEDs maintain a constant average temperature and thus generate a low spectral shift.

[0228] The aluminum circuit board or board 582 with the LEDs is directly connected to the light distribution device 542 (see Fig. 11a ) to ensure the best possible light coupling into the light distribution device 542. The light of the LEDs 548 is first aligned in parallel via TIR lenses 549 and tube bodies 552, then spectrally filtered via optical filters 553 and finally distributed evenly and diffusely inside the light distribution device 542 so that the light is directed to the 16 cuvettes 201 of the stationary cuvette array (see arrow 200 in Fig. 12a ) can be decoupled.

[0229] Another circuit board 585 is equipped with up to 16 monitor or reference photodiodes 575, which detect the light generated by the LEDs 548 before the respective cuvette passes through. However, only two global monitor or reference photodiodes 575 can also be used. In this case, the light is not measured directly in front of each cuvette, but rather at several points on the light distribution device 542. Due to the constant geometric conditions, the light in front of each cuvette can be converted using a geometry factor.

[0230] The circuit board 586 of the detector unit 550 is located on the output side of the cuvettes of the cuvette array 200. This circuit board contains 16 photodiodes 551 for the transmitted light emerging from the cuvettes 201. The detector unit processes two analog values ​​of the two assigned photodiodes 551, 575 for transmitted light and monitor or reference light per cuvette. For scattered light measurement (nephelometry), a third analog value can be recorded from each cuvette by a laterally arranged photodiode. However, for reasons of clarity, its signal path is shown in Fig. 12a is not further shown.

[0231] The two signal paths originating from photodiodes 551 and 575 are processed synchronously by two 16:1 multiplexers 587, inverters, integrators, and ADCs, and converted into a digital measured value. The multiplexers 587 allow, for example, the 16 cuvette channels to be selected and switched sequentially in a configurable order.

[0232] If the stationary cuvette array 200 is segmented, and each segment 210 is assigned a separate light distribution device 542 (see Fig. 11a / b ), additional circuit boards indicated by dashed lines are used for the transmitter unit 580, the circuit board for the LEDs 582, the circuit board for the monitor or reference diodes 575, and, if applicable, the circuit board for the detector unit 586. For example, with an arrangement of 96 cuvettes 201 in the stationary cuvette array 200, six separate light distribution devices 540, each with 16 outlet openings to the permanently assigned cuvettes 201, can be provided.

[0233] The central circuit board 584 for the optical measuring unit 500 is equipped with the optical controller. The optical control unit is implemented as a state machine using programmable logic (FPGA) and can simultaneously operate the transmitter unit 580 and the detector unit 586. To generate the correct timing, the individual light measurements are broken down into light and dark measurements and can be parameterized differently line by line in a configuration memory. The state machine processes these configuration lines sequentially, although lines can also be skipped. The distinction between light and dark measurements is defined by a flag in the configuration line, as are the desired cuvette channel and light source.Furthermore, the configuration line contains the desired delay settings, current strength and pulse length, as well as the selection of the reference photodiode, the LED supply voltage, the oversampling and averaging settings and the period duration.

[0234] The detector unit 586 is controlled synchronously with the transmitter unit 580 and can be configured with averaging or oversampling settings using global parameters. Furthermore, the desired integration time with which the light signal is to be integrated is read from the configuration line. The delay time for the integrator and the integration slope can also be selected here using global parameters, allowing the settling times of the measurement signal and the integration speed to be switched.

[0235] The analog measured value is thus selected from the corresponding photodiode 551 with transimpedance converter via the multiplexer 587 and measured using an inverter, integrator, and optional logarithmic amplifier. It is digitized with a high-resolution ADC with or without oversampling. Finally, if a scattered light measurement is also performed, three analog measured values ​​(transmitted light, monitor or reference light, scattered light) are digitized simultaneously with three ADCs and stored line by line as raw measured values ​​in the internal memory. It is essential that the measurements of transmitted light and monitor or reference light, as well as any scattered light, are performed simultaneously.

[0236] The internal memory contains all raw data and is cyclically read by the evaluation processor using software and converted into a final measured value using a conversion algorithm. The conversion takes into account the dark value and the light value, as well as the I 0 Measurement and I 1 Measurements are taken before and after the reagents are added. The temporal changes in the measured values ​​can also be recorded through consecutive measurements. It is important that the measurements are taken periodically and, according to the set period duration, result in a repeatable measurement cycle.

[0237] The calculated data are packaged into defined data packets for each cuvette and transmitted to the main computer 588 via a local Ethernet interface. This data reduction makes it possible to process all cuvettes of the cuvette array 200 of the optical measuring unit 500 and transfer them to the main computer 588.

[0238] In the measurement procedure, the measurement of I or I 0 in rapid succession for each cuvette with a high sampling frequency (>1 Hz). There are various ways to control and read the multiple LED light sources 541 and photodiodes 551 of the detection unit 500.

[0239] The periodic control signal of the individual LED light sources 541 is defined with regard to pulse and integration duration as well as the current level used for each combination of cuvette and wavelength for the measurement mode used and does not change during operation.

[0240] In the example presented, 16 LED light sources 541 are controlled via 16 separate power sources 581 and their surrounding hardware. The exposure of each cuvette with each spectral channel of the LED light sources 581, as well as the integration times used, are defined individually (16 x 16 combinations). During a measurement cycle, the individual LEDs (or, in certain positions to increase the intensity, several LEDs) each emit a light pulse in sequential order. This pulse is reflected several times at the inner walls of the light distribution device 542 and finally reaches the 16 assigned cuvettes 201 through the 16 outlet openings 547 (see Fig. 11c ).

[0241] Different measurement modes are provided: Mode 1: Detection of the dynamic LED flash signal with constant integration time and variable current and pulse duration (256 flashes) Mode 2: Detection of the static LED signal with variable integration time (256 LED triggers) and variable current Mode 3: Detection of the static LED signal with variable integration time (16 LED triggers)

[0242] The measurement is carried out individually for each combination of cuvette and wavelength, with modes 1 and 2 generating a light pulse for each measuring point.

[0243] As in Fig. 12b As shown, in modes 1 and 2 the spectral channels (λ1 ... λ16) of the individual LED light sources 581 are activated and deactivated in a fixed sequence. The resulting light flashes are detected and measured by the photodiode 551 selected by the multiplexer 587. After all spectral channels have been scanned, the sensor switches from cuvette position K1 to cuvette position K2 and the required light flashes are generated in the same sequence. After a complete scan of all 16 cuvette positions (i.e. 16 x 16 light flashes), one sampling is completed and the next can be initiated. This sequence allows up to four samplings per second to be realized. In modes 1 and 2, dark and light measurements are carried out alternately one after the other, so that a total of 512 individual measurements are performed per sampling.

[0244] The measurement method according to modes 1 and 2 is characterized by the fact that the spectral channels λ1 ... λn of the individual LED light sources 581 are activated and deactivated in a predetermined sequence, whereby the photodiode 551 arranged in a first cuvette position K1 is detected in each case. After all spectral channels in the first cuvette position K1 have been scanned, the system switches to the next cuvette position K2. The time for one cycle in measurement mode 1 or 2 is >= 0.25 seconds.

[0245] In measurement mode 3, shown schematically in Fig. 12c , the LED light sources 541 are switched in a different order than in mode 1 or 2.

[0246] Each LED light source 541 or each spectral channel is switched on only once in the cycle (indicated by the dot-dash line), and then all 16 cuvettes are measured consecutively, with no dark measurement taking place between these individual measurements. The first cuvette K1 is measured with a delay so that the associated photodiodes 551 of the detector unit 550 have sufficient time to settle. The remaining cuvettes K2 to K16 can be measured more quickly one after the other without additional settling time.

[0247] Within a cycle, each LED is switched on only once, and all 16 cuvettes are measured. If a dark measurement is required, a dark value is measured once, for example, at the beginning or end of the cycle to measure all 16 cuvettes.

[0248] With 16 wavelengths or 16 spectral channels (λ1 ... λ16) and 16 cuvette positions, 16 x 16 light measurements are required. Adding the 16 dark measurements (once per cycle) results in 272 individual measurements. The time for one cycle in measurement mode 3 is >= 0.5 seconds.

[0249] The measuring method according to mode 3 is thus characterized in that the spectral channel λ1 of the first LED light sources 581 is activated, wherein the photodiodes 551 arranged in the cuvette positions K1 ... Km are detected in a predetermined order, wherein after passing through all cuvette positions K1 ... Km, the next spectral channel λ2 of the next LED light sources 581 is activated.

[0250] Advantage of Mode 3: Mode 3 is faster overall than the 512 alternating dark / light measurements of Mode 1 and Mode 2 because fewer measurements and less settling time for the photodiodes are required. The settling time of the photodiodes only needs to be taken into account before the first light measurement of cuvette K1; the remaining 15 cuvettes K2 to K16 can follow immediately. Overall, this results in significantly shorter sampling times per cycle compared to Mode 1 or 2.

[0251] In the Fig. 13a und 13b In the second variant of the optical measuring unit 500 according to the invention shown, the light-providing unit 540 has at least one one-dimensional, rod-shaped light source array 554 with a plurality of LED light sources 541, which is aligned along the stationary cuvette array 200, for example, an analysis device, and is designed to be movable along the stationary cuvette array 200. Each LED light source 541 of the light source array 554 can thus be assigned to each cuvette 201 of the stationary cuvette array 200.

[0252] In this embodiment, an LED light source 541 is preferably arranged together with a beam splitter 555 and a reference detector 556 in a common, for example, tubular, housing 560. The light paths of the individual, adjacently arranged LED light sources 541 can thus be separated.

[0253] Individual LED light sources 541 of the rod-shaped light source array 554 can have optical elements 557 for collimation to feed the light into the cuvettes 201 and a narrowband filter 558 to improve the spectral characteristics of the light. Furthermore, a condenser, preferably a converging lens 559, can be provided to focus the light into the cuvette 201.

[0254] If individual LED light sources 541 are designed as narrow-band emitting and parallel aligned light laser diodes, the optical elements 557 for collimation, filtering 558 and bundling 559 can be omitted entirely or at least partially.

[0255] The photodiodes 551 of the detection unit 550, which are permanently assigned to the individual cuvettes 201 of the stationary cuvette array 200, are preferably arranged as a photodiode array on a common circuit board 572. The detection unit 550 has, starting from each cuvette 201 of the stationary cuvette array 200, a tubular receptacle 573, for example, in which optical elements 569 for focusing the measuring radiation onto the photodiode 551 and, if necessary, a filter element 574 are arranged.

[0256] With this module variant, various photometric and turbidimetric measurements can be performed on multiple cuvettes 201 of a stationary linear cuvette array 200 at single and / or multiple wavelengths in the ultraviolet and visible light wavelength range by sequentially positioning the individual LED light sources 541 of different wavelengths of the light supply unit 540 in front of the individual cuvettes 201. The intensity of the light passing through the respective cuvette 202 is then measured by the permanently assigned, stationary detector unit 550. As an alternative to positioning, a measurement "on the fly," i.e., while passing by, is also possible.

[0257] In the Fig. 14a bis 14c In the third variant of the optical measuring unit 500 according to the invention shown, the LED light sources 541 of the light-providing unit 540 are arranged as a 2D LED array 561, with each cuvette 201 of the stationary cuvette array 200 being permanently assigned a stationary 2D LED array 561. In this embodiment, similar to the first variant, there is no relative movement between the cuvettes 201 of the cuvette array 200 on the one hand and the light-providing unit 540 and the detection unit 550 on the other hand, whereby the measuring processes can be significantly accelerated by eliminating mechanical movements within the optical measuring unit 500.

[0258] According to a sub-variant of the third embodiment, the LED light sources 541 can be arranged in the light supply unit 540 as a single 2D LED array 561 (as shown in the detailed illustration according to Fig. 14c ), wherein the light supply unit 540 is designed to be movable along the entire stationary cuvette array 200 or a segment 210 of the cuvette array 200 (similar to Fig. 13a shown), such that the 2D LED array 561 can be assigned to each cuvette 201 of the cuvette array 200 or to each segment 210 of the cuvette array 200. When the cuvette array 200 is segmented, a light-providing unit 540 with a 2D LED array 561 is provided for each segment 210.

[0259] A 2D lens array 562 is provided to collimate the light from the individual LEDs 548 of the 2D LED array 561 into the cuvettes 201. Furthermore, a 2D filter array 563 is arranged in the beam path to narrow-band filter the light to improve the spectral characteristics. The filter array 563 may not have a filtering function in certain positions, for example, if a narrow-band, parallel-emitting laser diode is arranged in this position of the 2D LED array 561.

[0260] Furthermore, at least one condenser, preferably a converging lens 564, is provided in the beam path to concentrate the light into the individual cuvettes 201.

[0261] Particularly preferred are embodiments in which the 2D LED array 561 consists of LED emitters bonded on a single substrate 565, wherein the 2D lens array 562 is a 2D microlens array and the 2D filter array 563 is a 2D microinterference filter array.

[0262] An LED light source 541 comprising a 2D LED array 561, a 2D lens array 562, a 2D filter array 563 and a converging lens 564 can preferably be arranged together with a beam splitter 566 and a reference detector 567 in a common housing 568.

[0263] In this variant, each cuvette 201 has an individual photometer unit consisting of a light supply unit for light with up to 9, 12 or 16 different wavelengths (λ1 to λn) generated by individual LEDs 548. When using commercial LEDs (side length approx. 2 mm and a spacing of approx. 0.5 mm) that are soldered onto a circuit board using through-hole mounting, an area of ​​approx. 10 x 10 mm 2 can be expected for a 4 x 4 array.

[0264] By arranging the semiconductors of the individual LEDs as a COB (chip-on-board), they can be implemented in a space-saving area of ​​less than 5 x 5 mm². With COB technology, the LED chips are preferably bonded directly to a highly thermally conductive aluminum circuit board.

[0265] With an edge length of 300 to 900 µm and a pitch of approximately 100 µm, for example, 16 LED chips can be accommodated on a square area with an edge length of 1.6 to 4 mm. Accordingly, the individual collimator lenses of the 2D microlens array and the interference filters of the 2D interference filter array have diameters of up to 900 µm. To further improve collimation (parallelization), a pinhole array can be mounted on the LED array, allowing the light-emitting surfaces to be displayed as sufficiently point-like, regardless of the size of the emitting semiconductor surfaces.

[0266] The LED chips can be arranged on the 2D array in columns or rows, e.g. 3 x 3, 3 x 4 or 4 x 4, or in concentric circles.

[0267] As already mentioned in connection with the variant according to Fig. 13a / b, the detection unit 550 has, starting from each cuvette 201 of the stationary cuvette array 200, a tubular receptacle 573, for example, in which optical elements 569 for focusing the measuring radiation onto the photodiode 551 and - if necessary - a filter element 574 are arranged.

[0268] The photodiodes 551 of the detection unit 550, which are permanently assigned to the individual cuvettes 201, are preferably arranged as a photodiode array on a common circuit board 572.

[0269] The Fig. 15a bis 15c The combined device 810 shown for mixing and thermostatting liquid media serves to thermostat the liquid media introduced into the cuvettes 201 arranged in a row of cuvettes 200 of a cuvette array 200. In the example shown, this is a linear, stationary cuvette array 200.

[0270] The individual cuvettes 201 of the cuvette array 200 are arranged in a thermostattable cuvette block 820, for example, made of aluminum, with the walls of the funnel-shaped receptacles 823 positively abutting the walls of the cuvettes 201 to ensure optimal heat transfer. The cuvette block 820 consists of a base part 821 with the receptacles 823 and a front part 822 that can be opened by a lateral pushing movement.

[0271] A thermostatting device 830 is arranged on the cuvette block 820, for example on the base part 821, which has a cooling and heating device, for example in the form of one or more Peltier elements 831 and cooling fins 832. To regulate the temperature of the cuvette block 830, a temperature sensor 833 is arranged in a receptacle between the base part 821 and the Peltier element 831.

[0272] On the hinged front part 822 of the cuvette block 820, connection surfaces 824 are visible, which can also be used for attaching a cooling and heating device, for example, Peltier elements. Furthermore, the front part 822 has openings 825 corresponding to the measuring windows 202 of the cuvettes 201 to enable optical measurement of the liquid media in the cuvettes 201.

[0273] An ultrasonic transducer 840, for example a thickness transducer, is attached to the bottom 204 of each cuvette 201, e.g., glued or injected during manufacture of the cuvette, with which ultrasonic energy can be introduced into the cuvette 201. The introduced ultrasonic energy is used both for mixing the liquid media and for targeted additional heating—in addition to the base load from the thermostatting by the cuvette block 820.

[0274] The ultrasonic transducer 840 is designed as a piezoelectric thickness oscillator, which - as in Fig. 15c shown in detail - essentially consists of a disc-shaped, piezoelectric element 842 and contact electrodes 841 and 843 on both sides. The cuvette-side electrode 841 is plated through to the lower electrode 843 via lateral contact strips 844, where it forms crescent-shaped contact surfaces 845.

[0275] For each cuvette 201 and its ultrasonic transducer 840, a contact block 847 is provided, supported by a spring contact board 846. The contact block has four contact springs 848, two of which contact the crescent-shaped contact surfaces 845 and two of which contact the lower contact electrode 843 of the ultrasonic transducer 840. The cuvette 201 has a collar 205 at the filling opening 207 and stop bars 206 on opposite sides, with which the cuvette 201 is held in the cuvette block 820 against the pressure of the contact springs 848.

[0276] The spring contact board 846 is inserted into a horizontal groove 826 of the cuvette block 820 and is supported on the downwardly projecting decoder board 850, whose circuits are in Fig. 16 be explained in more detail.

[0277] In Fig. 16 is a block diagram for the electronic control of the device for mixing and thermostatting liquid media according to Fig. 15a which includes the functional blocks personal computer 588, controller board 860, decoder board 850, cuvette block 820, and a temperature control circuit 865.

[0278] The controller board 860 has an FPGA (Field Programmable Gate Array) as processor 861 and is used to control the decoder board 850 and the temperature control circuit 865. The personal computer 588 can be connected to the controller board 860, for example, via an Ethernet interface and, depending on the mixing and thermostatting task to be performed in one of the cuvettes 201 of the cuvette block 820, transmits corresponding orders for executing firmware programs on the controller board 860, as well as for transmitting control data, such as the measured temperatures for the thermostatting of the cuvette block 820.

[0279] In the cuvette block 820, cuvettes 201 together with the associated ultrasonic transducers 840 are arranged at the positions K1 to K16 and P1 to P16, respectively, whereby for the thermostatization in the example shown, a Peltier element 831 together with the associated temperature sensor 833 is provided in the positions PE1 to PE4 and T1 to T4, respectively.

[0280] The temperature control circuit 865 thus has four temperature control circuits 866, each consisting of a Peltier element 831, a temperature sensor 833, and PID (proportional, integral, derivative) controllers R1 to R4, and is connected via an interface to the controller board 860 for data exchange (receiving parameters such as temperature setpoints and transmitting measured temperatures from the temperature control circuit 865 back to the controller board 860).

[0281] The decoder board 850 is also connected to the controller board 860 via an interface and receives control signals from the latter for selecting individual ultrasonic transducers 840 via the decoder circuit 851 implemented on the decoder board 850 and the associated optoswitches 857 in positions S1 to S16, as well as control signals for parameterizing the oscillator circuit 852. The oscillator circuit 852 receives control signals for adjusting the frequency, duty ratio (duty factor, or duty cycle), burst pattern, amplitude, phase, and the ON and OFF states of the oscillator's signal generation. The oscillator circuit 852 includes a voltage-controlled oscillator (VCO) 853, whose frequency signal can be modulated by a burst generator 854. The amplitude of the modulated signal can be further adjusted via an adjustable preamplifier 855 and a downstream amplifier output stage 856.The final amplified signal is transformed up to the required operating voltage of the ultrasonic transducers 840 via a transmitter and is connected to one of the 16 piezoelectric ultrasonic transducers 840 on the cuvettes 201 on the cuvette block 820 via the optoswitch 857 selected by the decoder circuit 851 in S1 to S16.

[0282] The diagram according to Fig. 17a shows a first example of a thermostatting process according to the invention of a sample-reagent mixture in a cuvette which is stored in a thermostattable cuvette block (see Fig. 15a ) is arranged.

[0283] The temperature curve α shows the heating of the sample-reagent mixture only by the cuvette block thermostatted to the temperature T BL , whereby the target temperature at which the sample-reagent mixture can be measured is only reached at time t 2 . The required target temperature is reached much earlier, at time t 1 , if ultrasonic boosts are introduced in the time periods M and A to C, as shown in the temperature curve β. The thermostatization of the cuvette block occurs at an essentially constant electrical power P BL . 1) Preheat the cuvette block containing empty cuvettes to a block temperature T BL (typically 37.0 to 37.5°C) and stabilize the block temperature to 0.1°C. 2) Fill an empty cuvette with a sample-reagent mixture at temperature T 0 . Typically, the sample-reagent mixture has a temperature of 10-15°C after pipetting into the cuvette, because the pipetted reagents originate from a storage area cooled to 5°C and warm up to 10-15°C in the pipettor and in the feed lines.3) Emitting an ultrasonic signal for a predefined cumulative time period M, which, for an ultrasonic signal with the average electrical power PP, introduces an amount of energy M x PP into the sample-reagent mixture and causes a calculated temperature shift ΔT M , which is calculated from variable properties of the sample-reagent mixture known from the data of the analysis to be performed, such as heat capacity, viscosity, thermal conductivity and its volume, and constant data stored in the device. The amount of energy introduced during the time period M is sufficient to sufficiently mix the sample-reagent mixture. Typically, a mixing time of 1 to 3 seconds is sufficient for homogeneous mixing, whereby the temperature shift ΔT M of a 2-second mixing pulse, for example, can be approximately 3 °C.Alternatively, the mixing time M required to obtain a stable measurement signal or incubation process at a given ultrasonic power PP can be determined by testing various sample-reagent mixtures and stored in the device. As another alternative method, an optical signal from an analyte measurement can be continuously measured from the sample-reagent mixture, and the mixing process can be stopped as soon as a stable signal is obtained. As mentioned above, the temperature shift ΔT M is calculated from known thermal characteristics.4) Observing a pause of >1 s (to cool the cuvette base and the adhesive point to the ultrasonic transducer) 5) Emitting one or more ultrasonic signals, possibly interrupted by pauses of > 1 s, at a calculated temperature TA for a predefined cumulative time period A + B + C + n, which corresponds to an additional calculated temperature swing ΔTA + ΔTB + ΔTC + ΔTn, whereby after emitting the last ultrasonic pulse a temperature TBL-y below the temperature TBL-x is reached. From this temperature onwards the temperature is transferred into the cuvette contents purely via heat conduction between the cuvette block 820 and the cuvette contents. 6) Reaching a temperature TBL-x that is acceptable for the analysis and is below the temperature of the cuvette block by the value x, where x is typically a fixed value of 0.1 - 0.5 °C. The acceptable temperature is defined and lies between 36.5 and 37.5 °C.The temperature stability during the subsequent optical measurement should be approximately 0.1°C.

[0284] The diagram according to Fig. 17b shows a second example of a thermostatting process according to the invention of a sample-reagent mixture in a cuvette which is stored in a thermostattable cuvette block (see Fig. 15a ) is arranged. 1) (as example 1) Preheat the cuvette block with empty cuvettes inside to a block temperature T BL (typically 37.0 to 37.5°C) and stabilize the block temperature to 0.1°K 2) (as example 1) Fill an empty cuvette with a sample-reagent mixture at temperature T 0 . Typically, the sample-reagent mixture has a temperature of 10-15°C after pipetting into the cuvette because the reagents pipetted in come from a storage area cooled to 5°C.3) (as example 1) Emitting an ultrasonic signal for a predefined cumulative time period M, which, with an ultrasonic signal with the average electrical power PP, introduces an amount of energy M x PP into the sample-reagent mixture and causes a calculated temperature swing ΔT M, which is calculated from variable properties of the sample-reagent mixture known from the data of the analysis to be carried out, such as heat capacity, viscosity, thermal conductivity and its volume, and constant data stored in the device. Typically, the suitable cumulative time duration of the required stirring processes ranges from 1 to 3 seconds, depending on the stirring task, whereby the temperature swing . ΔT M of a 2-second stirring pulse, for example, can be about 3 °K. Alternatively, the mixing time M required to obtain a stable measurement signal, a washing or incubation process at a given ultrasonic power P P determined by experiments on different sample-reagent mixtures and stored in the device. As an alternative method, an optical signal from the sample-reagent mixture can be continuously measured, and the mixing process can be stopped as soon as a stable signal is obtained, whereby the temperature variation ΔT M here, as mentioned, is calculated from known thermal characteristics. 4) (as in example 1) maintaining a pause of >1 s (to cool down the base of the cuvette and the bonding point to the ultrasonic transducer) 5) Emitting one or more ultrasonic signals, possibly interrupted by pauses of > 1 s, only at a calculated temperature 0.5 x (T BL - T 0 ), for a predefined cumulative time period A + B + n, which corresponds to an additional, calculated temperature increase ΔT A + ΔT B + ΔT n, whereby after the last ultrasonic pulse has been emitted, a reliably calculable temperature T BL-y is reached which is below the acceptable temperature T BL-x. From this temperature onwards, the temperature is transferred into the cuvette contents purely by heat conduction between the cuvette block and the cuvette contents.6) (as in Example 1) Achieving a temperature T BL-x acceptable for analysis, which is lower than the temperature of the cuvette block by the value x, where x is typically a fixed value of 0.1 - 0.5 °K. The acceptable temperature is fixed and lies between 36.5 and 37.5 °C. The temperature stability during the period of a subsequent optical measurement should be approximately 0.1 °K.

[0285] The Fig. 18a , 18band 19a to 22, has the components already explained in detail in connection with the first and second embodiments, such as pipettors 300a, 300b movable along the stationary cuvette array 200, preferably needle washing units 700a1 to 700b2 moving with the pipettors 300a, 300b, as well as a cuvette washing unit 600 movable along the cuvette array 200, and additionally a device for carrying out heterogeneous immunoassays 410.

[0286] The one in the Fig. 18a and 18b The automatic analyzer 100 shown is extended by a device for carrying out heterogeneous immunoassays 410 (HetIA module), which is arranged directly in extension of the stationary cuvette array 200.

[0287] The cuvettes 201 of the HetIA module, which are arranged in a thermostatted cuvette block 820 to hold liquid media (samples, reagents, suspensions with magnetic particles, washing solutions), form a terminal segment 210 of the stationary, linear cuvette array 200 of the analyzer 100, such that the pipettors 300a, 300b, which can be moved along the cuvette array 200, can also supply the cuvettes 201 of the HetIA module with samples and reagents from the sample and reagent storage 920, 950a, 950b, as well as with magnetic particles and washing solutions. Furthermore, the cuvette washing station 600, which can be moved along the cuvette array 200, also has access to the cuvettes 201 of the HetIA module.

[0288] If cuvettes 201 of the HetIA module or in other areas of the cuvette array 200 need to be replaced, they can be removed from a cuvette magazine 116 (arranged, for example, at the end of the cuvette array 200) with the aid of a gripping mechanism (not shown), for example the pipettor 300b, or the cuvette washing unit 600, with used cuvettes being disposed of in a waste chute 117.

[0289] The automated analyzer 100 can also be equipped with an ISE measuring station 115, in which ion-selective measurements are performed on the samples. The samples are removed from the sample storage 920 using the pipettor 300b and pipetted into the filling opening 118 of the ISE measuring station 115.

[0290] In the Fig. 19a and 19b the device 410 according to the invention (HetIA module) is shown in detail.

[0291] A pivotable holding arm 420 of the device 410 is designed to be movable along the cuvette array 200 and can be lowered toward the filling opening 207 of a cuvette 201 selected by the control logic of the device. The holding arm 420 is equipped with a suction needle 423, including a suction line 427, that can be lowered toward the bottom 204 of the cuvette 201, as well as with at least one dispenser 424a to 424d that can be positioned above or in the respective filling opening 207 for dispensing the liquid media into the cuvette 201. At least one dispenser 424a, 424b is designed to dispense a washing solution for the magnetic particles 411.

[0292] The supply lines to the dispensers 424a, 424b are designated by 426, in particular a wash line 426a leads to the dispenser 424a, a wash line 426b to the dispenser 424b, a supply line 426c to the dispenser for a pre-trigger solution and a supply line 426d to the dispenser 424d for a trigger solution.

[0293] Furthermore, a magnet arrangement 430 is provided, which can be moved along the cuvette array 200 and acts on the contents of the selected cuvette 201 for separating the magnetic particles 411 on an inner surface of the cuvette 201, as well as an optical detection device 435, which can be moved along the cuvette array 200 and can be aligned with the measuring window 202 of the selected cuvette 201 in order to obtain a measuring signal proportional to the analyte concentration in the selected cuvette 201.

[0294] For the sake of simplicity, only those components of the device 410 are shown which are essential for the present invention, whereby analyzer components such as sample and reagent storage, pumps, valves, evaluation, control and drive units are not discussed in detail.

[0295] The cuvette array 200 is arranged in a thermostattable cuvette block 820, wherein in particular Fig. 19b The Peltier elements 831 provided for thermostatting can be seen, arranged between cooling fins 832 and the cuvette block 820. The cuvette block 820 has access openings 825 on the front side aligned with the measuring windows 202 of the cuvettes 201.

[0296] A dispenser platform 421, which can be lowered onto the filling opening 207 of the cuvette 201, is attached to a spring-loaded holder (see spring element 422) on the movable holding arm 420. In the example shown, the dispenser platform 421 has four dispensers 424a to 424d for dispensing liquid media into the cuvette 201. The suction needle 423 attached to the holding arm 420 passes through a central opening in the dispenser platform 421, so that after the dispenser platform 421 is in contact with the filling opening 207 of the cuvette 201, it can be lowered to the bottom 204 of the cuvette 201.

[0297] The dispenser platform 421 has a sealing surface 425 made of an opaque material on the side facing the cuvette 201, so that when the dispenser platform 412 is lowered, the ingress of ambient light is excluded during the optical measurement of the cuvette contents.

[0298] According to the invention, a dispenser 424a for dispensing a washing solution for the magnetic particles 411 has an outflow direction (straight washing needle) aligned parallel to the longitudinal axis of the cuvette 201, and a second dispenser 424b - also for dispensing a washing solution - has an outflow direction (oblique washing needle) aimed at an inner side surface of the cuvette 201.

[0299] Of the additional dispensers 424c, 424d of the dispenser platform 412, whose outflow directions are aligned parallel to the longitudinal axis of the cuvette 201, an optional third dispenser 424c is configured to dispense a pre-trigger solution, if necessary, and a fourth dispenser 424d is configured to dispense a trigger solution. For chemiluminescence-based immunoassays that require only one trigger solution, the third dispenser 424c can remain unused or be omitted.

[0300] The Fig. 19a and 19bThe illustrated embodiment is characterized by a platform 440 that can be moved along the cuvette array 200 and has a lifting and rotating device 445 with which the holding arm 420, including the suction needle 423 and the dispensers 424a to 424d of the dispenser platform 421, can be lowered. Preferably, a common suspension 446 for the magnet arrangement 430 and the detection device 435 is also arranged on the movable platform 440, so that a movable measuring and manipulation module 450 is realized that combines all robotic, fluidic, and metrological components for the process steps of magnetic separation of the beads, the so-called B / F washing, as well as the triggering and measurement of the luminescence.

[0301] The movable platform 440 of the measurement and manipulation module 450 is connected to the frame of the device 410 via a lateral rail 441 running parallel to the cuvette array 200, and can be moved to the position of a selected cuvette 201 via a movement mechanism such as a stepper motor-driven toothed belt, a spindle, or a linear motor. To supply and control the measurement and manipulation module 450, flexible electrical and fluidic connecting lines, for example in the form of so-called energy chains (not shown), can be brought to the platform 440.

[0302] According to one embodiment variant, a washing station 442 for the suction needle 423 and the at least one dispenser 424a to 424d of the dispenser platform 421 can also be arranged on the movable platform 440, onto the opening 443 of which the holding arm 420 is designed to be lowerable after a rotational movement, so that the entire needle group at the head of the pivotable holding arm 420 can be inserted into the opening 443.

[0303] The needle washing station 442 has an upper suction line 444a and a lower suction line 444b that limit the fill level. This allows the opening 443 to be approached by an up-and-down movement with a 90° pivot while simultaneously lowering the holding arm 420 below the upper edge of the cuvette array 200, allowing other robotic components, such as any pipettors, etc., to move unhindered along the cuvette array 200.

[0304] The pivoting support arm 420 of the measurement and manipulation module 450 is attached to a tower 449 that can pivot 90° in a horizontal plane and is also vertically movable. The pivoting movement is enabled by a rotary actuator, for example, driven by a stepper motor. Additionally, the tower is equipped with a lifting device, which includes, for example, a stepper motor-driven spindle or a toothed belt, for generating a vertical translational movement of the support arm 420. Both types of movement can be integrated into the combined lifting and rotating device 445 at the base of the vertical tower 449.

[0305] According to one embodiment variant, the needle washing station can also be positioned stationary at a position below the movable platform 440 along its horizontal travel space.

[0306] A variant of the design may also consist in that the needle washing station is positioned stationary at the end of the cuvette array 200, whereby the holding arm of the needle group does not have to be pivotable in this variant.

[0307] According to a preferred embodiment, the common suspension 446 for the magnet arrangement 430 and the detection device 435 is suitable for performing a translational or rotational movement in order to exchange the positions of the magnet arrangement 430 and the detection device 435 in front of the selected cuvette 201.

[0308] For example, the magnet arrangement 430 and the detection device 435 can be attached to a rotor arm 447 mounted in the suspension 446 at the same distance from a common axis of rotation 448.

[0309] Preferably, the rotor arm 447 mounted in the suspension 446 can be designed to be translationally displaceable in the direction of the rotation axis 448 in order to bring the magnet arrangement 430 or the detection device 435 to the access opening 825 in the cuvette block 820 and thus to the measuring window 202 of the selected cuvette 201. The photomultiplier 435 and the magnet arrangement 430 can be aligned with their respective optical main or polar axis to the corresponding access opening 825 in the cuvette block and, by a horizontal movement, can dock light-tight to the respective opening or, to generate the highest possible magnetic flux density, can be optimally approached to the wall of the cuvette 201.

[0310] The magnet arrangement 430 can consist of one or more magnets, which are preferably rare earth magnets with high field strength, such as Nd 2 Fe 14 B (neodymium iron borate), but can also be designed as an electromagnet. The magnet arrangement 430 is preferably made of neodymium bar magnets with two different bar radii, wherein an inner bar 431 is essentially surrounded by an outer, hollow cylindrical bar 432 with a non-magnetic intermediate layer 433 in between, and the two bars of different length and diameter have a conical transition. The arrangement tapers into a slender end region with a locally high magnetic flux density, which can be brought close to the window 202 of the cuvette 201 through the opening 825 in the cuvette block 820.The magnet arrangement 430 can also be composed of several individual magnets to increase the magnetic field strength required for magnetic separation on a cuvette wall or to reduce stray fields in neighboring cuvettes. An example of a magnet arrangement is shown in . Fig. 19b wherein a bipolar end of a concentric magnet arrangement 430 with a non-magnetic intermediate layer 433 is directed towards the cuvette 201.

[0311] According to one embodiment, a second magnet arrangement (not shown) can be provided, which can be moved along the cuvette array 200 and acts on the contents of the selected cuvette 201, preferably forming a magnetic NS bridge with at least one of the magnetic poles of the first magnet arrangement 430. The movable platform 440 of the measuring and manipulation module 450 can, for example, have a C-shaped boom that extends beneath the stationary cuvette array 200, allowing a second separation magnet to be aligned along the magnetic axis of action of the first separation magnet and to be moved along the other side of the cuvette block 820.In this case, a second opening comparable to the first access opening 825 of the respective cuvette 201 is not required, since the magnetic field lines of the second magnet arrangement penetrate the material of the cuvette block, which is not made of ferromagnetic material (aluminum). Ideally, the polarity of the two separation magnets is oppositely oriented, creating a magnetic series connection (NS), which leads to a localized increase in the magnetic flux density and a reduction in the unwanted stray field on the neighboring cuvettes.

[0312] The stray field adversely affects the magnetic beads located in neighboring cuvettes, since the beads in the neighboring cuvettes may be in other process stages where magnetic separation or agglomeration is undesirable.

[0313] The second magnet arrangement can consist of one or more electromagnets or permanent magnets. In the case of permanent magnets, an actuator must be provided to selectively move the magnet arrangement closer to or further away from the cuvette. The actuator mechanism can be designed analogously to that for the first magnet arrangement 430 and can, in a known manner, have a belt drive, a drive spindle, or a solenoid.

[0314] According to a further conceivable configuration, it is provided that the second magnet arrangement can be moved on a separate rail independently of the first magnet arrangement 430 past the components of the measuring and manipulation module 450, so that in addition to the above-mentioned advantages of a traveling second separation magnet, a simultaneous magnetic separation on another cuvette is possible in order to pre-separate magnetic beads for a washing step of a second assay in the other cuvette and thus save time.

[0315] The detection device 435 is preferably implemented as a compact photomultiplier and serves to measure the amount of light during the chemiluminescence triggered by the addition of the two trigger solutions. It can be equipped with Peltier cooling to obtain a more constant, lower-noise signal. To avoid stray light during the measurement at one of the access openings 825 of the cuvette block 820, the access openings 825 and the light inlet opening of the photomultiplier can have concentrically stepped contact surfaces at the edge of the two openings. Furthermore, a shutter element, for example a mechanically actuated one, can be provided to protect the photomultiplier from the ingress of ambient light in the idle state.

[0316] To measure luminescence at low analyte concentrations, a digital photomultiplier is preferably used. This triggers each incoming photon and generates a 10 ns digital pulse. These short pulses are counted by the FPGA of the HetIA Controller 460 and summed as a counter reading over an adjustable sampling time. As long as the number of photons is small, the irregularly generated pulses can be output individually; the number of pulses per unit of time then corresponds to the number of photons per unit of time.

[0317] According to the invention, a reference light source 436a for the detection device 435 can be arranged on the movable platform 440. The reference light source 436a serves to calibrate the photomultiplier and has a light exit opening oriented toward the entrance opening of the detection device 435 (e.g., photomultiplier). The reference light source 436a can be arranged at any location along the line of movement of the detection device 435, but ideally such that calibration of the photomultiplier occurs when the magnet arrangement 430 is located directly in front of the respective access opening 825 of the cuvette block 820.

[0318] As an alternative to this variant, a reference light source 436b can also be arranged stationary at the end of the cuvette block 820 and have a light exit opening along the access openings of the cuvette block 820, whereby its thermostatting device can also be used for the reference light source 436b.

[0319] The process example of a heterogeneous immunoassay is shown in steps S1 to S9 in Fig. 20 shown.

[0320] The present example of a heterogeneous immunoassay refers to the required mechanical processes in a so-called "sandwich assay." In this assay, the analyte molecule 413 (a body's own protein, e.g., prostate-specific antigen) forms a bridge through antigen-antibody interactions between a first antibody (capture antibody 412) immobilized on the surface of the magnetic particles 411 and a second antibody, to which signaling molecules are bound (tracer antibody 414). Upon addition of a pre-trigger fluid and a trigger fluid, this second antibody produces a chemiluminescence proportional to the amount of analyte, lasting for a few seconds. Both antibody types are present in excess of the analyte.For analyte molecules that are too small to have binding sites for two different antibodies, so-called competitive immunoassays are used, whereby the tracer antibodies compete directly with the analyte molecules for binding sites on an immobilized antibody.

[0321] In a simple 1-step assay according to Fig. 20 First, the sample (containing the analyte 413), a suspension of magnetic particles 411 (Magnetic Beads) coated with a capture antibody 412, and a solution of the tracer antibody 414 are pipetted into the cuvette 201 using a pipettor not shown here (S1, in Fig.20 ).

[0322] During the subsequent incubation (approx. 10 min) at 37 °C, the solution is periodically stirred, for example, by ultrasound, to prevent the beads from settling and agglomerating. Each analyte molecule is now sandwiched between a capture antibody 412 immobilized on the beads 411 and a tracer antibody 414. Furthermore, there are nonspecifically bound tracer antibodies 415 (S2, in Fig. 20 ).

[0323] The beads 411 together with the substances bound to them are now fixed to the inner wall of the cuvette 201 using the magnet arrangement 430 (S3, in Fig. 20 ) and the entire liquid is removed with the suction needle 423 lowered from the dispenser platform 421 (S4, in Fig. 20 ).

[0324] Subsequently, a washing solution is introduced through a washing needle 424b directed obliquely towards the inner wall of the cuvette 201 in order to remove unbound tracer antibodies adhering to the beads 430 and remaining in the reaction solution by carefully rinsing the beads, whereby the beads 411 are still held magnetically to the vessel wall (S5, in Fig. 20 ).

[0325] The cuvette 201 is then sucked dry again, whereby the beads 411 and the substances bound to them are still magnetically fixed to the inner wall of the cuvette 201 (S6, in Fig. 20 ).

[0326] A second, vertically aligned wash needle 424a, on the other hand, creates turbulence in the liquid when injecting wash solution or dilution liquid, so that the beads 411 are resuspended in the liquid when the magnets are undocked (S7, in Fig. 20 ).

[0327] After this washing step, which can be carried out several times in succession, the photomultiplier 435 is moved to the cuvette 201. The two dispensers 424c and 424d now dispense pre-trigger (S8, in Fig. 20 ) and trigger solution (S9, in Fig. 20 ). This triggers a chemiluminescence L (flash luminescence) lasting only a few seconds, which can be measured by the photomultiplier 435. The dispenser platform 421 of the holding arm, which is placed on the filling opening 207 of the cuvette 201 for this purpose, simultaneously ensures the necessary darkening of the cuvette 201.

[0328] The used cuvette 201 is then sucked empty using the aspiration needle 423 and either replaced with a disposable cuvette or cleaned and reused so that a new immunoassay can be performed in the previously used cuvette position.

[0329] To wash the cuvette, the manipulator must be moved away from the cuvette so that the cuvette washing station can approach and start washing.

[0330] In principle, however, other, slightly modified immunoassays which comprise a magnetic separation with B / F washing as a process step can also be carried out with the device according to the invention, wherein, if necessary, a detection method other than measuring chemiluminescence can also be provided for the detection.

[0331] As in Fig. 21 schematically shown, the movable measuring and manipulation module 450 of the invention according to Fig. 18a via a fluidic system 451 for supplying the dispenser platform 421 with washing liquid WF, pre-trigger liquid PTF, trigger liquid TF, and compressed air DL. Furthermore, devices are provided for extracting reaction mixture or washing liquid from the cuvettes 201 of the cuvette array 200 and the container or washing trough of the washing station 442.

[0332] The fluidic system 451 is controlled by the HetIA Controller 460 (see Fig. 22 ) and comprises a series of magnetically actuated 3-way valves 457 and precision piston pumps as dispensing pumps 455, which are connected to the movable platform 440 (see Fig. 19a ) are connected via flexible hose connections (indicated by wavy lines).

[0333] The dispenser platform 421, which can be moved in the x, y and z directions via the combined degrees of freedom of the movable platform 440 and the pivotable holding arm 420, comprises a group of dispensers 424a to 424d, which is supplemented by the lowerable suction needle 423.

[0334] The dispensing unit 452 comprises a separate dispensing pump 455 for the supply of washing liquid WF, pre-trigger PTF, and trigger liquid TF. The liquid flow from the dispensing pump 455 for the washing liquid can be connected to the straight 424a or the angled washing needle 424b via a 3-way valve 457. The four selectively feedable supply lines are made of a flexible plastic at the movable points and are guided in energy chains (not shown).

[0335] The dispensing pumps 455 of the dispensing unit 452 are each connected to the valve network 453 via their own supply lines, whereby for rinsing and cleaning purposes, in particular for cleaning the dispensers 424a to 424d and the suction needle 423, compressed air DL or system water SW (deionized water) can be switched on via a corresponding 3-way valve 457 and supplied to the dispensing pumps 455 instead of the primary conveying medium.

[0336] The container of the washing station 442 for cleaning the dispensers 424a to 424d and the suction needle 423 has two suction lines 444a, 444b, one of which is located in the bottom of the container, and a second in the upper half of the container to function as an overflow for setting a stable fill level. The suction unit 454 is connected to both suction lines 444a, 444b and to the suction needle 423 via flexible hoses arranged in energy chains (not shown). Shut-off valves 458 are provided to prevent unwanted backflow of suctioned liquids. The three drain lines lead into a common supply line of a suction pump 456 (e.g. a self-priming displacement pump), which feeds the extracted waste liquids W to a collection or treatment area in the device (not shown).

[0337] Fig. 22 shows a block diagram for the electronic control of the device according to the invention according to Fig. 19a The HetIA Controller 460 of the controller board 461 operates the electrical and mechanical components of the HetIA module and is controlled and programmed by a main computer 588 (e.g., a personal computer). The PC controls the sequence and order of the subprocesses; the HetIA Controller 460 is responsible for executing the individual actions.

[0338] The functions of the HetIA Controller 460 can be summarized as follows (see Fig. 22 ): Communication with PC 588 via Ethernet interface Robotic functions RF by means of stepper motors ∘ Movement of the platform 440 in the x-direction to the respective cuvette 201 of the stationary cuvette array 200 (or to the stationary reference light source 436b in the cuvette block 820, if no moving reference light source 436a is provided) ∘ Rotational movement of the rotor arm 447 to exchange the position of the detection device 435 (photomultiplier) and magnet arrangement 430 ∘ y-movement for docking the photomultiplier 435 or the magnet arrangement 430 to the measuring window of the cuvette 201, orto a reference light source 436a traveling on the platform 440 Control FV of the fluidic valves 457, 458 of the fluidic system 451 Control DP for the metering pumps 455 Control UM for the ultrasonic transducer 840 ∘ Has its own US oscillator that is independent of the controller board 461 ∘ Decoder function for the piezoelectric transducers 840 on the individual cuvettes 201 Control DE for the detection device 435 and the reference light source 436a Temperature control TR for the thermostatization (37°C) ∘ Peltier controller for the detection device 435 (photomultiplier) ∘ Peltier controller for the cuvette block 820 .

[0339] Certain functions that need to be triggered precisely in real time (see brackets "S" in Fig. 22 ), are implemented in the FPGA of the HetIA Controller 460. These include, for example: Timely triggering of the DP control of the dosing pump in time with the DE control for the detection device 435 (photomultiplier measurement) Triggering of the reference light source in time synchronization with the measurement of the photomultiplier ultrasonic mixing process of the respective cuvette.

Claims

1. Automatic analyzer (100) suitable for carrying out chemical, biochemical and / or immunochemical analyses of liquid samples, with a sample store (920) for receiving the liquid samples, und with at least one reagent store (950a, 950b) for receiving liquid reagents, having cuvettes (201) suitable for receiving the liquid samples and reagents, wherein a plurality of cuvettes (201) is arranged as a stationary, linear cuvette array (200) in the analyzer, having movable and stationary machine components, at least comprising: • a pipettor (300a, 300b) which is designed to be movable in the x-direction along a line of movement defined by the linear cuvette array (200), said pipettor being equipped with at least one pipetting needle (301a1, 301a2, 301b1, 301b2) which is designed to be lowerable in the z-direction into the cuvettes (201) and which is designed to be movable in a y-direction, substantially normal to the x-direction, between the cuvettes (201) and the sample store (920) and / or the reagent store (950a, 950b), • a mixer unit (400) for mixing the samples and reagents in the cuvettes (201) of the stationary cuvette array (200), • an optical measurement unit (500) which is equipped with a spectroscopic unit (530) or a stationary detection unit (550) for obtaining a measurement signal, and which is suitable for receiving measurement radiation that exits through a measurement window (203) arranged on the side of the cuvette (201), • a cuvette washing unit (600), designed to be movable in the x-direction, for cleaning the cuvettes (201) of the stationary cuvette array (200), • a needle washing unit (700a1, 700a2, 700b1, 700b2) for cleaning the at least one pipetting needle (301a1, 301a2, 301b1, 301b2), and • a stationary temperature control unit (800) for setting a predefinable measurement temperature in the cuvettes (201) of the stationary cuvette array (200), wherein at least two machine components are designed to be movable in the x-direction independently of one another along or parallel to the line of movement defined by the linear cuvette array (200) and each have access to different cuvettes (201) or groups of cuvettes (201) in a freely selectable order.

2. Analyzer according to claim 1, characterized in that the analyzer (100) has two pipettors (300a, 300b) which are movable in the x-direction independently of one another.

3. Analyzer according to claim 1 or 2, characterized in that at least one pipettor (300a, 300b) has two pipetting needles (301a1, 301a2, 301b1, 301b2) which are movable in the y-direction independently of one another and parallel to one another.

4. Analyzer according to any one of claims 1 to 3, characterized in that the needle washing unit (700a1, 700a2, 700b1, 700b2) is arranged on the pipettor (300a, 300b) and is designed to be movable therewith.

5. Analyzer according to any one of claims 1 to 4, characterized in that the optical measurement unit (500) has a unit which is movable along the linear, stationary cell array (200) and which consists of a light-supplying unit (520) and a spectrometer (535) of the spectroscopic unit (530).

6. Analyzer according to any one of claims 1 to 4, characterized in that the optical measurement unit (500) is equipped with a light-supplying unit (540) which has a plurality of LED light sources (541) emitting in a spectrally different manner in the UV / VIS / NIR wavelength range, and also with the stationary detection unit (550) which is configured such that at least one photodiode (551) is fixedly assigned to each cuvette (201) of the cuvette array (200).

7. Analyzer according to claim 6, characterized in that the light-supplying unit (540) has at least one stationary light distributor device (542) which serves to distribute the light from the individual LED light sources (541) among the individual cuvettes (201) of the cuvette array (200), wherein the light distributor device (542) has a cavity, the inner surfaces (543, 544, 545) of which are designed to be at least partially mirrored and / or diffusely reflective, and wherein the light distributor device (542) has, for each LED light source (541), an inlet opening (546) for feeding the light into the cavity, and wherein the light distributor device (542) has, for each cuvette (201) of the cuvette array (200), an outlet opening (547) for feeding the light into the cuvette (201).

8. Analyzer according to claim 7, characterized in that the inner surface (543) of the light distributor device (542) that is located opposite the outlet openings (547) to the cuvettes (201) is designed to be diffusely reflective.

9. Analyzer according to claim 7 or 8, characterized in that the inner surface (544) of the light distributor device (542) that is located opposite the inlet openings (546) of the LED light sources (541) is designed to be corrugated and reflective.

10. Analyzer according to any one of claims 7 to 9, characterized in that the stationary cuvette array (200) is configured in a segmented manner, and a separate light-supplying unit (540) is fixedly assigned to each segment (210).

11. Analyzer according to claim 6, characterized in that the light-supplying unit (540) has at least one unidimensional, rod-shaped light source array (554) comprising a plurality of LED light sources (541), which light source array is oriented along the stationary cuvette array (200) and is movable along the stationary cuvette array (200) such that each LED light source (541) of the light source array (554) can be assigned to each cuvette (201) of the stationary cuvette array (200), wherein at least some LED light sources (541) have optical elements (557, 559) for collimating and focusing the light into the cuvette (201) and also have a narrowband filter (558) for improving the spectral characteristic.

12. Analyzer according to claim 6, characterized in that the LED light sources (541) of the light-supplying unit (540) are arranged as a 2D LED array (561), wherein a stationary 2D LED array (561) is fixedly assigned to each cuvette (201) of the stationary cuvette array (200), wherein a 2D lens array (562) is provided for collimating the light from the individual LEDs, and a 2D filter array (563) is provided for the narrowband filtering of the light, and a condenser (564) is provided for focusing the light into the individual cuvettes (201).

13. Analyzer according to claim 12, characterized in that the 2D LED array (561) consists of LED emitters bonded to a single substrate (565), wherein the 2D lens array (562) is a 2D microlens array and the 2D filter array (563) is a 2D micro-interference filter array.

14. Analyzer according to any one of claims 1 to 4, characterized in that the temperature control unit (800) for setting a predefinable measurement temperature comprises heating foils (891) which thermally contact individual cuvettes (201) or groups of cuvettes (201) and to which different temperature levels can be applied.

15. Analyzer according to any one of claims 1 to 4, characterized in that the temperature control unit (800) has a cuvette block (820) which is regulated to a predefined target temperature, said cuvette block being equipped with a temperature control device (830) and being in thermal contact with the individual cuvettes (201).

16. Analyzer according to any one of claims 1 to 4, characterized in that, in order to mix the samples and reagents, a stationary mixer unit (400), for example a vibration transmitter which acts on the cuvette array (200), is assigned to the entire cuvette array (200), preferably to individual groups or segments (210) of cuvettes (201).

17. Analyzer according to any one of claims 1 to 4, characterized in that stationary mixer units are assigned to the cuvettes (201) in order to mix the samples and reagents, wherein at least one ultrasonic transducer (840) is attached as a stationary mixer unit to each cuvette (201) in order to introduce ultrasonic energy into the cuvettes (201), and in that the ultrasonic transducer (840) is configured as a piezoelectric vibrator and is connected to a control unit (860) which actuates the at least one ultrasonic transducer (840) as a function of parameter values of the liquid media.

18. Analyzer according to claim 15 and 17, characterized in that the stationary devices for mixing and controlling the temperature of the liquid media introduced into the cuvettes (210) of the stationary cuvette array (200) are configured as a combined mixing and temperature control device (810).

19. Analyzer according to claim 18, characterized in that the temperature control device (830) has a cooling and heating device, for example at least one Peltier element.

20. Analyzer according to any one of claims 17 to 19, characterized in that the cuvette block (820) consists substantially of a base part (821) with form-fitting receptacles (823) for the cuvettes (201) and an openable front part (822).

21. Analyzer according to any one of claims 1 to 4, characterized in that the cuvette washing unit (600) for cleaning the cuvettes (201) is configured as a movable machine component which in each washing position has access to one cuvette (201) or to a group of cuvettes simultaneously, preferably to two to five cuvettes (201) arranged next to one another.

22. Analyzer according to any one of claims 1 to 4, characterized in that the analyzer has a device (410) for carrying out heterogeneous immunoassays, which has access to the cuvettes (201) of at least one terminal segment (210) of the stationary, linear cuvette array (200).

23. Analyzer according to claim 22, characterized in that the device (410) for carrying out heterogeneous immunoassays has the following components: • at least one support arm (420) which is movable along the cuvette array (200) and which is lowerable toward the filling opening (207) of a selected cuvette (201), said support arm having at least one aspirating needle (423) which is lowerable toward the bottom (204) of the cuvette (201), and also having at least one dispenser (424a to 424d), which can be positioned above or in the respective filling opening (207), for dispensing the liquid media into the cuvette (201), wherein at least one dispenser (424a, 424b) is designed to dispense a washing solution for the magnetic particles (411), • at least one magnet assembly (430) for separating the magnetic particles (411) on an inner surface of the cuvette (201), said magnet assembly being movable along the cuvette array (200) and acting on the contents of the selected cuvette (201), and • at least one optical detection device (435) for receiving a measurement signal that is proportional to an analyte concentration in the selected cuvette (201), said optical detection device being movable along the cuvette array (200) and being alignable with the measurement window (202) of the selected cuvette (201).

24. Analyzer according to claim 23, characterized in that the at least one dispenser (424a to 424d) for dispensing the liquid media is arranged in a dispenser platform (421) which can be lowered onto or into the filling opening (207) of the cuvette (201), the lowerable aspirating needle (423) passing through said dispenser platform.

25. Analyzer according to claim 23 or 24, characterized in that a first dispenser (424a) for dispensing a washing solution for the magnetic particles (411) has an outflow direction which is oriented substantially parallel to the longitudinal axis of the cuvette (201), and in that a second dispenser (424b) for dispensing a washing solution for the magnetic particles (411) has an outflow direction which is directed onto an inner lateral surface of the cuvette (201).

26. Analyzer according to any one of claims 23 to 25, characterized in that, of further dispensers (424c, 424d), the outflow directions of which are oriented substantially parallel to the longitudinal axis of the cuvette (201), optionally a third dispenser (424c) is designed to dispense a pretrigger solution and a fourth dispenser (424d) is designed to dispense a trigger solution.

27. Analyzer according to any one of claims 23 to 26, characterized in that the support arm (420) for the aspirating needle (423) and the at least one dispenser (424a to 424d) has a lifting and rotating device (445) which is arranged on a platform (440) that is movable along the cuvette array (200).

28. Analyzer according to any one of claims 23 to 27, characterized in that the support arm (220) arranged on the movable platform (440) forms, along with the dispenser platform (421) together with the magnet assembly (430) and the detection device (435), a measurement and manipulation module (450) which is movable along the cuvette array (200) and which combines all the robotic, fluidic and metrological components for the process steps of a heterogeneous immunoassay.

29. Analyzer according to any one of claims 1 to 21, characterized in that the cuvettes (201) have, in a region close to the bottom, inlet (202) and outlet windows (203) which are preferably arranged plane-parallel to one another and which are transparent to the inlet and outlet radiation or measurement radiation of the optical measurement unit (500).

30. Method for automatic chemical, biochemical and / or immunochemical analysis of liquid samples, which are present in a sample store (920) of an analyzer, with the aid of liquid reagents, which are present in at least one reagent store (950a, 950b) of the analyzer, in order to determine at least one analyte concentration in the sample, characterized by the following steps: a) transferring a predetermined quantity of a liquid sample from a sample vessel (921) in the sample store (920) into a cuvette (201) of a stationary, linear cuvette array (200) by means of a first pipettor (300b) which is movable along the cuvette array; b) transferring a predetermined quantity of a reagent liquid from a reagent vessel (951a) of the reagent store (950a) into the cuvette (201) of the stationary, linear cuvette array (200) by means of the first pipettor (300b) or by means of a second pipettor (300a) which is movable independently of the first; c) mixing the liquid in the cuvette (201) with a mixing unit (400) and controlling the temperature of the liquids in the cuvette (201) via a stationary temperature control unit (800); d) optionally transferring a predetermined quantity of a further reagent liquid from a reagent vessel (951b) of the reagent store (950b) into the cuvette (201) of the stationary, linear cuvette array (200) by means of the first or second pipettor (300a, 300b); e) optionally once again mixing and controlling the temperature of the liquids in the cuvette (201); f) optically measuring the contents of the cuvette (201) by means of an optical measurement unit (500); and determining at least one measured value under use of the spectroscopic unit (530) or a stationary detection unit (550) of the optical measurement unit (500); g) calculating and displaying the analyte concentration based on the measured values determined in point f) and on previously known or predetermined reference values and calibration values; h) washing and drying the cuvette (201) by means of a cuvette washing unit (600) which is movable along the cuvette array (200); and i) providing the cuvette (201) for subsequent analysis.

31. Method according to claim 30, characterized in that, when optically measuring of the contents of each cuvette (201), light is irradiated into the inlet windows (202) of the individual cuvettes (201) one after the other in temporal succession by a plurality of LED light sources (541) which emit in a spectrally different manner in the UV / VIS / NIR wavelength range, and the measurement radiation exiting from the outlet windows (203) of the individual cuvettes (201) is detected with the aid of at least one photodiode (551), fixedly assigned to each cuvette (201), of a stationary detection unit (550).

32. Method according to claim 30, characterized in that the following steps are carried out in mutual succession in order to mix and control the temperature of the contents of the cuvette (201): a) heating the cuvette (201) to a predefined target temperature with the aid of the temperature-controllable cuvette block (820), b) heating the liquid media with the aid of the temperature-controlled cuvette block (820) in order to reach the predefined target temperature, c) in the heating phase according to point b), before the target temperature is reached, additionally introducing a predetermined quantity of ultrasonic energy with the aid of at least one ultrasonic transducer (840), which is attached to each cuvette (201), in order to increase the rate of heating, and d) simultaneously mixing the liquid media with the aid of the ultrasonic energy introduced in point c).

33. Method according to claim 32, characterized in that the ultrasonic energy according to point c) is introduced into the liquid media in a pulsed manner in multiple boosts.

34. Method according to claim 32 or 33, characterized in that, in order to assist the mixing process, at least a portion of the liquid volume introduced into the cuvette (201) is aspirated and dispensed back into the cuvette (201) at least once.