Patent Description:
In analytical laboratories, in particular in-vitro diagnostic laboratories, a multitude of analyses on biological samples are executed in order to determine physiological and biochemical states of patients, which can be indicative of a disease, nutrition habits, drug effectiveness, organ function and the like.

Sample processing throughput, i.e. the number of biological samples analyzed per hour, as well as the number of different tests that can be carried out, are generally important. For laboratories handling thousands of samples each day, a small delay for each individual sample makes a substantial difference in terms of overall laboratory efficiency.

In order to meet this demand, optimal hardware design and efficient workflow planning are required when developing an automated system for in-vitro diagnostics. In particular, an automated system for in-vitro diagnostic analysis may be required to execute a large number of scheduled process operations, which are repeated at intervals called cycle times and it is important that the cycle times at parity of process operations be as short as possible in order to maximize throughput. Also, it is frequent that different tests require different test conditions, e.g. different reaction times, different types of reagents, different volumes, different detection times, etc.. Thus, the system should be also able to dynamically adapt the scheduled workflow due to the various test requirements and variable sequence of test orders and be able to respond quickly to anomalies, errors due to unexpected events, and the like.

<CIT> discloses an automatic in-vitro diagnostic system and method comprising parallel pipetting of liquids.

<CIT> discloses an analyzer which permits clinical analysis of samples with a variety of assay protocols in a multiple chronology sequence while operating on a predetermined fixed length cycle method of timing control.

<CIT> discloses an analysis apparatus operating in successive operating cycles.

<CIT> discloses an automatic analyzer that is capable of executing a plurality of different measurement sequences in a sequential, parallel manner.

<CIT> discloses a device capable of performing sample preparation, sample assay and detection step, where the device may be capable of processing two or more samples in parallel.

<CIT> discloses an apparatus for performing combinatorial-chemistry synthetic reactions including a liquid dispenser with a plurality of dispensing nozzles, the liquid dispenser being synchronized with an array of reaction vessels when dispensing liquid.

<CIT> discloses an apparatus and method for analyzing specimens, the apparatus including multiple dispensers and transportation means for transporting vials.

A method and a system for in-vitro diagnostic analysis are herein introduced, which enable to achieve higher processing throughput and workflow efficiency. This is achieved by a programmed control of functional units, which operate synergistically in parallel on different samples across different cycle times and also enable a time-saving anticipation of subsequent workflow operations.

The present disclosure refers to an automatic in-vitro diagnostic analysis method according to claim <NUM> and to a system for in-vitro diagnostic analysis according to claim <NUM>.

A "system for in-vitro diagnostics" is an analytical apparatus, i.e. a laboratory automated instrument dedicated to the analysis of test liquids for in vitro diagnostics. Examples of such analytical apparatuses are clinical chemistry analyzers, coagulation analyzers, immunochemistry analyzers, hematology analyzers, urine analyzers and nucleic acid analyzers that are used for the qualitative and/or quantitative detection of analytes present in the test liquids, to detect the result of chemical or biological reactions and/or to monitor the progress of chemical or biological reactions. The analytical apparatus can comprise functional units for pipetting and/or mixing of samples and/or reagents. The analytical apparatus may comprise a reagent holding unit for holding reagents to perform the analysis. Reagents may be arranged for example in the form of containers or cassettes containing individual reagents or group of reagents and placed in appropriate receptacles or positions within a storage compartment or conveyor. It may comprise a consumable feeding unit, e.g. for feeding reaction vessels. The analytical apparatus can further comprise one or more mixing units, comprising e.g. a shaker to shake a vessel containing a test liquid, or a mixing paddle to mix liquids in a vessel or reagent container. The analytical apparatus can further comprise a particular detection system and follow a particular workflow, e.g. execute a number of processing steps, which are optimized for certain types of analysis, e.g. clinical chemistry, immunochemistry, coagulation, hematology, etc..

The analytical apparatus may have different configurations according to the need and/or according to the desired laboratory workflow. Additional configurations may be obtained by coupling a plurality of apparatuses together and/or adding modules. A "module" is a work cell, typically smaller in size and weight than an entire analytical apparatus, which has an auxiliary function to the analytical function of an analytical apparatus and can work only together with an analytical apparatus. In particular, a module can be configured to cooperate with one or more analytical apparatuses for carrying out dedicated tasks of a sample processing workflow, which can occur for example before or after analysis of the sample, e.g. by performing one or more pre-analytical and/or post-analytical steps. Examples of said pre-analytical and/or post-analytical steps are loading and/or unloading and/or transporting and/or storing sample tubes or racks comprising sample tubes, loading and/or unloading and/or transporting and/or storing reagent containers or cassettes, loading and/or unloading and/or transporting and/or storing and/or washing reaction vessels, e.g. cuvettes, loading and/or unloading and/or transporting and/or storing pipette tips or tip racks, reading and/or writing information bearing labels, e.g. barcodes or RFID tags, washing pipette tips or needles or reaction vessels, e.g. cuvettes, mixing paddles, mixing of samples with other liquid, e.g. reagents, solvents, diluents, buffers, decapping, recapping, pipetting, aliquoting, centrifuging, and so on. An example of such a module is a sample loading and/or unloading unit for loading/unloading sample tubes.

According to certain embodiments, the disclosed system for in-vitro diagnostics comprises a vessel processing area comprising at least one static vessel holder and at least one movable vessel workstation comprising a vessel gripper.

The term "vessel" is herein used to indicate a container comprising a body and an inner space adapted to receive liquids, e.g. to enable a reaction between one or more samples and one or more reagents and/or to enable analyis of a test liquid contained therein. According to certain embodiments the vessel is a cuvette, i.e. a container that is at least in part optically transparent and shaped to allow the photometric measurement, like for example the measurement of changes in optical transmission, such as absorbance and scattering, of a test liquid contained therein. In particular, the cuvette may be used in the performance of absorbance or scattering assays to detect the result of a chemical or biological reaction or to monitor the progress of a chemical or biological reaction, e.g. in a coagulation assay, agglutination assay, turbidimetric assay. According to one embodiment the cuvette body comprises side walls, a closed bottom and an upper opening for allowing liquids to be introduced in an inner space formed by the side walls and the closed bottom. According to one embodiment the cuvette comprises at least one lip projecting outwards of the cuvette body in proximity of the upper opening. This lip may be convenient for gripping the cuvette by the vessel gripper and/or for holding the cuvette in the static cuvette holder. The cuvette may have an inner volume in the milliliter or microliter range.

A "static vessel holder" is a holding device comprising one or more static vessel holding positions, e.g. in the form of a recess, cavity, frame, seat or the like. The term "static" means immovable with respect to the rest of the system. The static vessel holder may be for example embodied as a fixed unit or block in a vessel processing area. The unit or block may have one or more other functions in addition to the holding function. The static vessel holder acts as an incubation station to hold one or more vessels at a certain temperature for a certain time, sufficiently long e.g. for a reaction between a test liquid and a reagent to be completed or to reach an acceptable degree of completion under the reaction conditions, and where the time can extend over more than one cycle time. The static vessel holder also acts as a detection station to allow detection, e.g. a photometric measurement, of a test liquid in a vessel.

The static vessel holder comprises at least one vessel holding position acting as an incubation position and at least one vessel holding position acting as a detection position, where the static vessel holder may be divided in functional subunits on the same block or different blocks, e.g. one subunit for incubation and one subunit for detection. According to certain embodiments the at least one static vessel holder comprises a plurality of linearly arranged vessel holding positions.

A "movable vessel workstation" is a functional unit operatively coupled to the static vessel holder and that can move with respect to the static vessel holder. According to certain embodiments the at least one vessel workstation is translatable relative to the at least one static vessel holder to transfer vessels between different vessel holding positions of the at least one static vessel holder. In particular, the movable vessel work station comprises a gripper for gripping vessels, e.g. a vessel at a time, by which it is possible to place vessels into the vessel holding positions, remove vessels from the vessel holding positions and move vessels between vessel holding positions. In particular the gripper can be embodied as a movable element of the movable vessel workstation capable at least to be translatable in the vertical direction and comprising jaws that can be opened and closed to grip or release a vessel.

According to certain embodiments, the movable vessel workstation comprises a shaking mechanism for shaking the vessel held by the gripper at least in part during transfer of the vessel between different vessel holding positions of the static vessel holder. According to an embodiment the shaking mechanism is an eccentric rotatable mechanism driven by a motor and coupled to the gripper for eccentrically agitating the gripper and thereby a vessel held by the gripper, resulting in a mixing of a liquid contained therein.

According to certain embodiments the vessel processing area further comprises a vessel input station for feeding at least one vessel at a time to the at least one static vessel holder. In particular, the "vessel input station" is a functional unit operatively coupled to the at least one static vessel holder for feeding new vessels to the at least one static vessel holder, e.g. for placing at least one new vessel at a time in at least one vessel holding position of the at least one static vessel holder. According to an embodiment the vessel input station is common to at least two static vessel holders. The vessel input station may be operatively coupled to a vessel distribution unit for feeding individual vessels to the vessel input station starting from a bulk supply. In particular the vessel input station may be embodied as a workstation with a translatable and/or rotatable vessel gripper.

The system for in-vitro diagnostics comprises at least one pipette head comprising at least two pipetting devices movable in a space above the vessel processing area.

A "pipetting device" is a functional unit of the system for pipetting test liquids and/or reagents comprising for this purpose at least one dispensing nozzle that may function also as an aspiration nozzle. The nozzle may be embodied as a reusable washable needle, e.g. a steel hollow needle, or as a pipette tip, e.g. a disposable pipette tip that is adapted to be regularly replaced, for example before pipetting a different test liquid or reagent. At least two pipetting devices are mounted to a pipette head. According to certain embodiments, the pipette head can be moved by a head translation mechanism in one or two directions of travel in a plane, such as with guiding rails, and possibly in a third direction of travel orthogonal to the plane, for example with a spindle drive. According to an embodiment the pipetting head can be moved by a head translation mechanism in one or two directions of travel in a horizontal plane and the pipetting devices are individually movable in the vertical direction of travel orthogonal to the plane. The term "mounted to" is herein broadly used to intend attached to, coupled to, or the like without referring to a particular position.

The system for in-vitro diagnostics further comprises a controller. A "controller" is a programmable logic controller running a computer-readable program provided with instructions to perform operations in accordance with an operation plan. In particular, the controller is programmed to control the at least one vessel workstation, the at least one pipette head and the at least two pipetting devices for executing a number of scheduled process operations. The scheduled process operations comprise the addition of a first reagent type and a second reagent type to a first test liquid during a first and second cycle time respectively, the addition of the first reagent type to the first test liquid comprising parallel addition of a second reagent type to a second test liquid during the first cycle time and the addition of the second reagent type to the first test liquid comprising parallel addition of the first reagent type to a third test liquid during a second cycle time, respectively.

The operation plan may however further comprise other operations, such as aspirating a test liquid, dispensing a test liquid, aspirating first and second type reagents, washing aspiration/dispensing nozzles and/or replacing disposable tips, and moving the pipetting head to an aspiration, a dispensing, an end or wash position. The operation plan may further comprise operations other than those associated with pipetting and moving of the pipetting devices. For example, the operation plan may comprise one or more of the following: moving of test liquid containers, opening and/or closing of test liquid containers, piercing caps of test liquid containers, moving of vessels, mixing of test liquids, and in particular detecting the result of reactions. In particular, the controller may comprise a scheduler, for executing a sequence of steps within a predefined cycle time for a number of cycle times. The controller may further determine the order of in vitro diagnostic tests according to the assay type, urgency, etc.. The controller may further dynamically change the operation plan according to unusual occurring circumstances or newly occurring test orders or events.

The term "test liquid" is herein used to indicate either a sample or a mixture or solution of one or more samples and one or more reagents, object of a test, i.e. an in-vitro diagnostic analysis. The term "sample", as used herein, refers to a liquid material suitable for being pipetted and being subjected to an in vitro diagnostic analysis, e.g. in order to detect one or more analytes of interest suspected to be present therein or to measure a physical parameter of the sample as such, e.g. pH, color, turbidity, viscosity, coagulation time, etc.. Examples of in vitro diagnostic tests are clinical chemistry assays, immunoassays, coagulation assays, hematology assays, nucleic acid testing, and the like. In some embodiments, the disclosed system is particularly suitable for coagulation in vitro diagnostic tests.

The sample can be derived from any biological source, such as a physiological fluid, including, blood, saliva, ocular lens fluid, cerebral spinal fluid, sweat, urine, milk, ascites fluid, mucous, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells or the like. The sample can be pretreated prior to use, such as preparing plasma from blood, diluting viscous fluids, lysis or the like; methods of treatment can involve filtration, centrifugation, distillation, concentration, inactivation of interfering components, and the addition of reagents. A sample may be used directly as obtained from the source or following a pretreatment to modify the character of the sample, e.g. after being diluted with another solution or after having being mixed with reagents e.g. to carry out one or more in vitro diagnostic tests. The term "sample" as used herein is therefore not only used for the original sample but also relates to a sample which has already been processed (pipetted, diluted, mixed with reagents, enriched, having been purified, having been amplified etc.. ) According to an embodiment the sample is a citrate treated blood sample.

The term "reagent" is generally used to indicate a liquid or substance required for treatment of a sample. Reagents may be any liquid, e.g. a solvent or chemical solution, which can be mixed with a sample and/or other reagent in order e.g. for a reaction to occur, or to enable detection. A reagent may be for example a diluting liquid, including water, it may comprise an organic solvent, it may comprise a detergent, it may be a buffer. A reagent in the more strict sense of the term may be a liquid solution containing a reactant, typically a compound or agent capable e.g. of binding to or chemically transforming one or more analytes present in a sample. Examples of reactants are enzymes, enzyme substrates, conjugated dyes, protein-binding molecules, nucleic acid binding molecules, antibodies, chelating agents, promoters, inhibitors, epitopes, antigens, and the like.

A "first reagent type" or "reagent of the first type" is a reagent required at an earlier stage of a sample processing workflow for a first reaction to occur and that typically requires a second reagent type or reagent of the second type for a test to be completed. The first reagent type is an incubation reagent, e.g. a reagent that is supposed to remain in contact with a sample under certain condition, e.g. a certain time and at a certain temperature in order for the reaction to be completed or to reach an acceptable degree of completion. A single test may require one or more reagents of the first type, e.g. added sequentially at different times of the reaction. Examples of reagents of the first type are reagents for the determination of coagulation factors and other coagulation parameters, e.g. activated partial thromboplastin time (APTT).

A "second reagent type" or "reagent of the second type" is a reagent that is required at a later stage of a sample processing workflow by a test liquid which has already reacted with one or more reagents of the first type in order for a test to be completed, or is a reagent that is per se sufficient for a test to be completed without requiring the addition of a reagent of the first type. A second reagent type can have therefore the function of continuing the reaction of the first reagent type or to stop the reaction of the first reagent type or to enable detection of the reaction of the sample with the first reagent type. A second reagent type can be the only one or the last reagent to be used in a test before or during detection. The second reagent type is a time-trigger reagent, also called a start reagent, i.e. a reagent that triggers a time measurement from the moment the second reagent type has been added to the test liquid. An example of time-trigger reagent is a coagulation trigger reagent, e.g. a salt solution such as a NaCl or CaCl2 solution.

A "cycle time" is a recurring time window, typically having a fixed length, during which a certain number of process operations, also called "jobs" or "work packages", are repeatedly carried out in a controlled sequence, called "cycle". This does not necessarily mean however that all process operations which are carried out in a cycle are repeated in another cycle. In particular, some process operations may repeatedly occur at every cycle, others may occur every two or more cycles. Also new process operations may be introduced in a cycle, depending on newly added test orders and/or newly occurring circumstances, so that a cycle may be dynamically adapted. Also, there may be extraordinary cycles or changes during a cycle in response to extraordinary conditions, e.g. in case of clogging of a pipetting device, in case of errors detected in pipetting or liquid level, in case of errors in handling vessels, or the like. In general only some process operations among all process operations occurring in a single cycle time are dedicated to the performance of one test. This means that in a single cycle, typically at least two tests are being carried out simultaneously, although typically at different stages, i.e. different process operations are dedicated to different tests respectively in a single cycle time. Thus a test is typically completed over a plurality, e.g. two or more, cycle times, where different process operations for carrying out the test occur in different cycle times, and with possible time intervals between cycle times, e.g. the time interval, during which a test liquid is being incubated. When reference is made to a "first cycle time" it is intended any cycle time and when reference is made to a "second cycle time" it is intended any cycle time coming after a first cycle time, where "after" means the next cycle time or two or more cycle times after the first cycle time. The term "adding to a test liquid" or "addition to a test liquid" is not necessarily limited in time with respect to the presence of a test liquid. In particular, the addition of a first reagent type may occur before or after the addition of a test liquid as long as the test liquid and the reagent or reagents come together as a result of the addition.

"Parallel adding" or "parallel addition" means that a first reagent type and a second reagent type are added simultaneously to two respective test liquids. The term "simultaneously" however does not necessarily mean starting and ending at the same time as this may depend on several factors, such as e.g. the volumes being added, which may be different. The term thus includes at least in part overlapping or one comprised in the other.

The term "dispensing" more specifically refers to a pipetting operation, which is typically preceded by an aspiration operation of the liquid being dispensed. Parallel dispensing does not necessarily imply parallel aspiration.

The controller is programmed to control the at least two pipetting devices and the at least one vessel workstation to add the first reagent type into a vessel held by the static vessel holder and to add the second reagent type into a vessel held by the gripper of the movable vessel workstation.

According to certain embodiments the gripper is controlled to hold the vessel at a different height than the vessel held by the static vessel holder during the parallel addition of the first reagent type and the second reagent type.

According to certain embodiments the controller is further programmed to control the vessel workstation to move the gripper to a dispensing position for dispensing the second reagent type into the vessel held by the gripper, wherein the dispensing position is defined based on the position of the vessel held by the static vessel holder that within the same cycle time requires the first reagent type, and based on the distance between respective pipetting devices on the same pipette head.

After addition of the second reagent type, the controller is further programmed to control the vessel workstation for transferring the vessel held by the gripper to the at least one detection position.

According to certain embodiments where the vessel workstation comprises a shaking mechanism the controller is further programmed to control the shaking mechanism for shaking the vessel held by the gripper at least in part during transfer of the vessel between different positions of the static vessel holder.

According to an embodiment the system comprises a static vessel holder and a sample/reagent pipette head comprising at least two reagent pipetting devices and at least one sample pipetting device.

According to an embodiment the system comprises at least two static vessel holders, a reagent pipette head comprising at least three reagent pipetting devices and a sample pipette head comprising at least two sample pipetting devices.

According to the present invention, a system for in-vitro diagnostic analysis is defined by claim <NUM>.

According to certain embodiments, the controller is further programmed to control the vessel workstation for holding the vessel by the gripper at a different height than the vessel held by the static vessel holder. According to certain embodiments, the at least two pipetting devices are mounted to a single pipette head and the controller is further programmed to control the vessel workstation to move the vessel held by the gripper to a dispensing position for dispensing the reaction-trigger reagent into the vessel, wherein the dispensing position is defined based on the position of the vessel held by the static vessel holder, which within the same cycle time requires an incubation reagent, and based on the distance between the respective pipetting devices on the single pipette head. According to certain embodiments the method further comprises shaking the vessel held by the gripper while moving the vessel towards a detection position.

A further system for in-vitro diagnostic analysis is herein also disclosed, the system comprising a vessel processing area comprising two static vessel holders and a common vessel input station for feeding vessels to the static vessel holders, the vessel processing area further comprising two movable vessel workstations, each comprising a vessel gripper and being translatable relative to a respective static vessel holder to transfer vessels between different vessel holding positions of the respective static vessel holder, the system further comprising a reagent pipette head comprising at least three reagent pipetting devices and a sample pipette head comprising at least two sample pipetting devices. With this system it is possible to nearly double the overall sample processing throughout (number of tests per hour) compared to a system with one single static vessel holder and one sample/reagent pipette head without doubling the number of functional units. In particular this configuration is mostly optimized for high-throughput testing of two of the most frequently ordered coagulation tests, like the Prothrombin time (PT) test and the activated partial thromboplastin time (APTT) test, where the PT test requires only a time-trigger reagent and the APTT test requires an incubation reagent in a first stage and a time-trigger reagent in a second stage. An even higher throughput can be achieved if the tests are alternated in a test order sequence. The two static vessel holders may be advantageously dedicated to different tests respectively.

An automatic in-vitro diagnostic analysis not forming part of the present invention is herein also disclosed, the method comprising adding a first reagent type and a second reagent type to a first test liquid during first and second cycle times, respectively. In particular, the addition of the first reagent type to the first test liquid comprises parallel addition of a second reagent type to a second test liquid during the first cycle time, and the addition of the second reagent type to the first test liquid comprises parallel addition of a first reagent type to a third test liquid during the second cycle time, respectively.

An automatic in-vitro diagnostic analysis method according to the invention is defined in claim <NUM>.

According to certain embodiments the method further comprises holding the vessel by the gripper and the vessel by the static vessel holder at different heights respectively during parallel dispensing. According to certain embodiments the method comprises moving the gripper to a dispensing position for dispensing the time-trigger reagent into the vessel held by the gripper, wherein the dispensing position is defined based on the position of the vessel held by the static vessel holder that within the same cycle time requires an incubation reagent, and based on the distance between respective pipetting devices on the single pipette head. According to certain embodiments the method further comprises shaking the vessel held by the gripper while moving the vessel towards a detection position.

Other and further objects, features and advantages will appear from the following description of exemplary embodiments and accompanying drawings, which serve to explain the principles more in detail.

<FIG> shows an example of system <NUM> for in-vitro diagnostic analysis, and in particular a coagulation analyzer. The system <NUM> comprises a reagent holding unit <NUM> for holding reagents of the first type and of the second type to perform different coagulation tests. The reagent unit <NUM> is embodied as a closed and tempered storage compartment, comprising access holes <NUM> for a pipetting nozzle to enter the compartment and withdraw an aliquot of reagent. The system <NUM> further comprises a sample loading/unloading unit <NUM> for loading/unloading sample tube racks <NUM> comprising sample tubes. The system further comprises a central vessel processing area <NUM> (shown and explained in greater detail in relation to <FIG>). The vessel processing area <NUM> comprises one linear static vessel holder <NUM>, the static vessel holder <NUM> comprising a plurality of vessel holding positions <NUM>. The vessel processing area <NUM> further comprises a vessel input station <NUM> for feeding a vessel at a time to the static vessel holder <NUM>. The vessel processing area <NUM> further comprises a movable vessel workstation <NUM> linearly translatable with respect to the static vessel holder <NUM> and functionally coupled to the static vessel holder <NUM> to transfer vessels between vessel holding positions <NUM> of the static vessel holder <NUM>.

The system <NUM> further comprises a pipette head <NUM> comprising three pipetting devices (shown in <FIG>). In particular, the pipette head <NUM> is translatably mounted on a horizontal arm <NUM> and the arm <NUM> is translatably coupled to an orthogonal guide rail <NUM>. The pipette head <NUM> is thus movable in a space above the reagent unit <NUM>, above the vessel processing area <NUM>, and above the sample loading/unloading unit <NUM>. In addition, the pipetting devices are each individually translatable in a vertical direction such as to be able to access a reagent container in the reagent unit <NUM> via holes <NUM>, a sample tube in the sample loading/unloading unit <NUM> and a vessel in the vessel processing area <NUM>. In particular, with the same pipette head <NUM>, test liquids can be aspirated from sample tubes in the sample loading/unloading unit <NUM>, reagents can be aspirated from reagent containers in the reagent unit <NUM> and both test liquids and reagents can be dispensed into vessels in the vessel processing area <NUM>.

The system <NUM> further comprises a controller <NUM> programmed to control the execution of a number of scheduled process operations including operation of the movable vessel workstation <NUM>, of the pipette head <NUM> and of the pipetting devices (described more in detail in relation to <FIG> and <FIG>).

<FIG> shows another system <NUM>', which is a variant of the system <NUM> of <FIG>. One difference between the system <NUM>' and the system <NUM> is that the system <NUM>' comprises a vessel processing area <NUM>', which compared to the vessel processing area <NUM> of the system <NUM> further comprises a second linear static vessel holder <NUM>' and a second movable vessel workstation <NUM>' linearly translatable with respect to the second static vessel holder <NUM>' and functionally coupled to the static vessel holder <NUM>' to transfer vessels between vessel holding positions <NUM>' of the second static vessel holder <NUM>'. Another difference between system <NUM>' and system <NUM> is that the system <NUM>' comprises two pipette heads <NUM>', <NUM> translatably mounted on two respective horizontal arms <NUM>, <NUM>. As better shown in <FIG> the first pipette head <NUM>' comprises three reagent pipetting devices adapted to aspirate reagents from the reagent unit <NUM> and dispense the reagents into vessels in the vessel processing area <NUM>'. The second pipette head <NUM> comprises two sample pipetting devices adapted to aspirate test liquids from sample tubes in the sample loading/unloading unit <NUM> and dispense the test liquids into vessels in the vessel processing area <NUM>'. The arms <NUM>, <NUM> are translatably coupled to the same orthogonal guide rail <NUM>. The two static vessel holders <NUM>, <NUM>' are arranged parallel to each other and the vessel input station <NUM>, which is identical to that of <FIG>, is symmetrically arranged between the two static vessel holders to feed vessels to both static vessel holders <NUM>, <NUM>'. Another difference between system <NUM>' and system <NUM> is that the system <NUM>' further comprises a sample rack tray unit <NUM>, which is functionally coupled as a module to the sample loading/unloading unit <NUM> for loading/unloading sample racks <NUM> into/from the sample loading/unloading unit <NUM>.

The system <NUM>' further comprises a controller <NUM>' programmed to control the execution of a number of scheduled process operations including operation of the movable vessel workstations <NUM>, <NUM>', of the pipette heads <NUM>', <NUM> and of the pipetting devices (described more in detail in relation to <FIG> and <FIG>).

<FIG> area partial top views of the vessel processing area <NUM>' (without pipetting devices) according to the embodiment of <FIG>. In particular, <FIG> show from top the arrangement of the two static vessel holders <NUM>, <NUM>' and the two respective movable vessel workstations <NUM>, <NUM>' with respect to each other and with respect to the vessel input station <NUM>. The first static vessel holder <NUM> and the second static vessel holder <NUM>' are identical and arranged longitudinally parallel in front of each other. Their orientation is however inverted, with the second static vessel holder <NUM>' being rotated on itself <NUM> degrees with respect to the first static vessel holder <NUM>. The first and second static vessel holders <NUM>, <NUM>' are embodied as linear blocks, each comprising an array of linearly arranged vessel holding positions <NUM>, <NUM>' respectively, part of which acting as incubation positions and part of which acting as detection positions (as more in detail described with reference to <FIG>).

The vessel input station <NUM> comprises a vessel gripper <NUM> and is arranged between the first static vessel holder <NUM> and the second static vessel holder <NUM>' in as symmetrical manner so that upon rotation of the vessel gripper <NUM> of <NUM> degrees a vessel <NUM> can be placed by the same vessel gripper <NUM> either in a vessel holding position <NUM> of the first static vessel holder <NUM> or in a vessel holding position <NUM>' of the second static vessel holder <NUM>'. The first movable vessel workstation <NUM> and the second movable vessel workstation <NUM>' are identical to each other and arranged parallel to the respective static vessel holders <NUM>, <NUM>' on the outer sides of the respective static vessel holders <NUM>, <NUM>' and opposite to the central vessel input station <NUM>. In particular, the first movable vessel workstation <NUM> is translatable with respect to the first static vessel holder <NUM> along guide rail <NUM> and the second movable vessel workstation <NUM>' is translatable with respect to the second static vessel holder <NUM>' along guide rail <NUM>' independently from the first movable work station <NUM>. Thus, the first movable workstation <NUM> is functionally coupled to the first static vessel holder <NUM> to transfer vessels between vessel holding positions <NUM> of the first static vessel holder <NUM> and the second movable vessel workstation is functionally coupled to the second static vessel holder <NUM>' to transfer vessels between vessel holding positions <NUM>' of the second static vessel holder <NUM>'.

The vessel input station <NUM> is fixed in space with respect to the static vessel holders <NUM>, <NUM>' so that only the vessel gripper <NUM> can be translated vertically and can be rotated towards either of the static vessel holders <NUM>, <NUM>'. Thus, the vessel input station <NUM> can place a new vessel <NUM> at a time into only one input vessel holding position <NUM> of the first static vessel holder <NUM> (<FIG>) and into only one input vessel holding position <NUM>' of the second static vessel holder <NUM>' (<FIG>). These two input vessel holding positions <NUM>, <NUM>' are detection positions dedicated to carry out a photometric blank measurement of each new vessel <NUM> placed in each static vessel holder <NUM>, <NUM>'. The two respective movable vessel workstations <NUM>, <NUM>' can then transfer the vessels <NUM> from the two input vessel holding positions <NUM>, <NUM>' to any other vessel holding positions <NUM>, <NUM>' according to the scheduled process.

<FIG> shows in perspective the vessel processing area <NUM>' of <FIG>, with in addition the two pipette heads <NUM>', <NUM> above the vessel processing area <NUM>'. The vessel input station <NUM> is embodied as a vessel lift comprising a vessel gripper <NUM> that is vertically translatable along a guide rail <NUM> and rotatable in a horizontal plane. In particular, the vessel gripper <NUM> can be operatively coupled to a vessel distribution unit (not shown) for feeding individual vessels <NUM> to the gripper <NUM> at a lower position with respect to the guide rail <NUM>. The vessel gripper <NUM> can thus transport one vessel <NUM> at a time from a vessel distribution unit at a lower position to one of the vessel holding positions <NUM>, <NUM>' of the static vessel holders <NUM>, <NUM>' at an upper position.

The movable vessel workstations <NUM>, <NUM>' are linearly translatable parallel to the static vessel holder <NUM>, <NUM>' respectively along guide rail <NUM>, <NUM>' respectively. Also, the movable vessel workstation <NUM>, <NUM>' each comprise a vessel gripper <NUM>, <NUM>' respectively that is translatable in the vertical direction. Thus, the movable vessel workstations <NUM>, <NUM>' can independently move along the respective static vessel holders <NUM>, <NUM>' to bring the vessel grippers <NUM>, <NUM>' in correspondence to any of the vessel holding positions <NUM>, <NUM>' and by vertically translating the vessel grippers <NUM>, <NUM>' they can grip and pull a vessel <NUM> out of any vessel holding position <NUM>, <NUM>' or place a vessel <NUM> into any free vessel holding position <NUM>, <NUM>' of the respective static vessel holder <NUM>, <NUM>'. Vessels <NUM> can thus readily be transferred between different vessel holding positions <NUM>, <NUM>' of the same static vessel holder <NUM>, <NUM>' respectively, e.g. between an incubation position and a detection position, by the movable vessel workstations <NUM>, <NUM>'.

The first pipette head <NUM>' is a reagent pipette head comprising three reagent pipetting devices and in particular two reagent pipetting devices <NUM>' adapted to pipette reagents of the second type and one reagent pipetting device <NUM>' adapted to pipette reagents of the first type. In particular, the reagent pipetting devices <NUM>' each comprise a heating element <NUM>' for heating a reagent of the second type to an optimal temperature between reagent aspiration and reagent dispensing. The second pipette head <NUM> is a sample pipette head comprising two sample pipetting devices <NUM>' adapted to pipette samples from sample tubes, e.g. including aspiration through a closure of a sample tube by piercing the closure.

The embodiment of <FIG> enables to achieve double sample processing throughput for at least some tests compared to the embodiment of <FIG> without however duplicating the number of functional units. In particular, at least one reagent needle can be spared and one common vessel input station <NUM> can be used.

<FIG> shows in perspective the vessel processing area of the system <NUM> of <FIG>, comprising only one static vessel holder <NUM>, only one movable vessel workstation <NUM> and only one pipette head <NUM>. In particular, the static vessel holder <NUM>, the movable vessel workstation <NUM> and the vessel input station <NUM> as well as their functional relationship are the same as in <FIG>. The pipette head <NUM> is a sample/reagent pipette head comprising a first reagent pipetting device <NUM>, a second reagent pipetting device <NUM> and a sample pipetting device <NUM>. In particular the first reagent pipetting device <NUM> is adapted to pipette reagents of the first type whereas the second reagent pipetting device <NUM> is adapted to pipette reagents of the second type. In particular, the second reagent pipetting device <NUM> comprises a heating element <NUM> for heating a reagent of the second type to an optimal temperature between reagent aspiration and reagent dispensing. The sample pipetting device <NUM> is adapted to pipette test liquids from sample tubes, e.g. including aspiration through a closure of a sample tube by piercing the closure.

<FIG> (a magnification of a detail of FIG. 5A) show further details of part of the embodiment of <FIG> during operation, controlled by the controller <NUM>'. In particular, only one static vessel holder <NUM> with the respective movable vessel workstation <NUM> and only one pipette head <NUM>' are shown for clarity. In particular, the process of parallel addition of a first reagent type and a second reagent type is shown. The same applies also to the embodiment of <FIG>, except that a different pipette head is used.

The static vessel holder <NUM> comprises a plurality of vessel holding positions <NUM> for holding a plurality of vessels <NUM>. In particular, the static vessel holder <NUM> comprises an incubation subunit 140A comprising a plurality of incubation positions 141A (in this example twenty) embodied as cavities in an aluminum block complementary in shape to the shape of a vessel <NUM>. In particular, the incubation subunit 140A comprises a temperature regulating unit (not shown) for regulating the temperature of vessels <NUM> contained in the incubation positions 141A, e.g. for maintaining the vessels <NUM> at an optimal reaction temperature.

The static vessel holder <NUM> further comprises a detection subunit 140B comprising a plurality of detection positions 141B (in this example thirteen). In particular, the detection subunit 140B comprises a photometric unit <NUM>, the photometric unit <NUM> comprising a light source <NUM> on one side of the detection positions 141B and an optical detector (not shown) arranged inside the detection subunit 140B on the other side of the detection positions 141B. In particular, for each detection position 141B there is an optical fiber <NUM> for guiding light from the light source <NUM> through a vessel <NUM> placed in the detection position 141B and an optical detector placed on the opposite side of the detection position to detect light passing through the vessel <NUM> in the detection position 141B. Thus, each detection position 141B is arranged in an optical path between an optical fiber <NUM> and an optical detector. The vessels <NUM> can therefore conveniently be embodied as cuvettes comprising two parallel and transparent walls, which can be placed in the optical path. Light of different wavelengths may be guided through different optical fibers <NUM> and/or light of different wavelengths may alternately be guided in the same optical fibers <NUM>. In particular, the light source <NUM> may be common to all optical fibers <NUM> and comprises a multi-wavelength light source, e.g. a broad spectrum light source or a plurality of light emitting elements with individual wavelengths or wavelength ranges.

One of the detection positions 141B' is a blank measurement position for taking a blank measurement of each new vessel <NUM>. In addition, the blank measurement position 141B' is the input vessel holding position where a new vessel <NUM> at a time is placed by the vessel gripper <NUM> of the vessel input station <NUM>.

The static vessel holder <NUM> further comprises a waste port <NUM> embodied as a hole though the static vessel holder <NUM> located between the incubation subunit 140A and the detection subunit 140B, the hole <NUM> leading to a vessel waste bin (not shown) located underneath the static vessel holder <NUM> for disposing used vessels <NUM> by the vessel gripper <NUM>.

With reference to all embodiments, part of an exemplary process is now described. In particular, the following process describes some of the process operations that can occur in a cycle time. The vessel input station <NUM> places a new vessel <NUM> at a time into the input vessel holding position 141B' of the static vessel holder <NUM> and/or into a corresponding input vessel holding position <NUM>' of the second static vessel holder <NUM>', depending on whether an embodiment with one or two static vessel holders <NUM>, <NUM>' is used. A photometric blank measurement of each new vessel <NUM> in each static vessel holder <NUM>, <NUM>' is then first carried out. After taking a photometric blank measurement of the vessel <NUM>, the respective movable vessel workstations <NUM>, <NUM>' transfer the vessels <NUM> to a free incubation position 141A, <NUM>' of the respective static vessel holder <NUM>, <NUM>'.

With reference to <FIG>, <FIG>, <FIG> the sample pipette head <NUM> moves to the sample loading/unloading unit <NUM> and aspirates two test liquids from two sample tubes or two aliquots from the same sample tube with the two respective pipetting devices <NUM>'. The sample pipette head <NUM> then moves to the first static vessel holder <NUM> to dispense a test liquid into a vessel <NUM> in an incubation position 141A and to the second static vessel holder <NUM>' to dispense the other test liquid into another vessel <NUM> into an incubation position <NUM>' of the second static vessel holder <NUM>' or into another vessel <NUM> into an another incubation position 141A of the first static vessel holder <NUM>. The reagent pipette head <NUM>' moves to the reagent unit <NUM> and aspirates one reagent of the first type and two reagents of the second type with reagent pipetting devices <NUM>' and <NUM>' respectively.

The gripper <NUM> of the first movable vessel workstation <NUM> grips a vessel 10B from an incubation position 141A. The first movable vessel workstation <NUM> then moves to a dispensing position for dispensing the second reagent type into the vessel 10B held by the gripper <NUM>. The dispensing position as shown in <FIG> is defined based on the position of a vessel 10A held in an incubation position 141A of the static vessel holder <NUM> that within the same cycle time requires the first reagent type, and based on the distance between respective reagents pipetting devices <NUM>', <NUM>' on the reagent pipette head <NUM>'.

In particular, the reagent pipette head <NUM>' moves with respect to the first static vessel holder <NUM> such that a reagent pipetting device <NUM>' containing a reagent of the first type is positioned above the vessel 10A requiring the reagent of the first type and the reagent pipetting device <NUM>' containing the reagent of the second type is placed above the vessel 10B held by the vessel gripper <NUM> and requiring a reagent of the first type. The reagent pipetting devices <NUM>', <NUM>' are then lowered at different heights into respective vessels 10A, 10B for the parallel addition of the first reagent type and the second reagent type respectively. The reagent pipetting devices <NUM>', <NUM>' are then raised and the vessel 10B held by the gripper <NUM> is transported to a free detection position 141B of the detection subunit 140B for detection, by linearly translating the movable vessel workstation <NUM>. While moving the movable vessel workstation <NUM> between the dispensing position and a detection position 141B the gripper shakes the vessel 10B for mixing the test liquid and the reagent of the second type contained therein. By parallel addition of an incubation reagent and a time-trigger reagent with the same pipetting head and by synergistic cooperation of the movable vessel workstation, the use of functional resources can be optimized and workflow efficiency can be increased with significant time savings, space savings and cost reduction. By holding the vessel 10B by the gripper <NUM> and pipetting a time-trigger reagent in the vessel 10B held by the gripper, the time between addition of the time-trigger reagent and start of detection can be minimized. By shaking the vessel 10B during transportation the time for mixing is also minimized thus contributing to minimize the time between addition of the time-trigger reagent and start of the detection.

After parallel addition of the a reagent of the first type and a reagent of the second type into two vessels 10A, 10B at the first static vessel holder <NUM>, the reagent pipette head <NUM>' moves to the second static vessel holder <NUM>' for dispensing the second reagent of the second type into a vessel <NUM> held by the vessel gripper <NUM>' of the second static vessel holder <NUM>'.

The vessel <NUM>, 10A that has received a reagent of the first type remains in incubation for one or more cycle times before receiving a reagent of the second type in a subsequent cycle time.

In an embodiment, the first static vessel holder <NUM> is dedicated at least temporarily to a test type, e.g. to carry out APTT tests, whereas the second static vessel holder <NUM>' is dedicated to a different test type, e.g. to carry out PT tests. Thus in a cycle, parallel addition of an incubation reagent and a time-trigger reagent take place at the first static vessel holder <NUM> into two respective vessels 10A, 10B in performance of two APPT tests at different stages respectively, followed by addition of a time-trigger reagent into a vessel <NUM> at the second static vessel holder <NUM>', such as into a vessel held by the gripper <NUM>' of the second movable vessel workstation <NUM>', in performance of a PT test, the PT test requiring only a time-trigger reagent. The same procedure may be repeated in a subsequent cycle for different test liquids and vessels <NUM> respectively. The system <NUM>' can be thus programmed to perform high-throughput analysis of two of the most frequently used tests in coagulation analysis.

Claim 1:
Automatic in-vitro diagnostic analysis method comprising adding in parallel with a single pipette head (<NUM>, <NUM>') comprising at least two pipetting nozzles (<NUM>, <NUM>, <NUM>', <NUM>') a time-trigger reagent and an incubation reagent to at least two test liquids respectively, wherein the time-trigger reagent is a reagent that triggers a time measurement from the moment that it has been added to the respective test liquid and wherein the incubation reagent is a reagent required for a first reaction to occur and that requires a time-trigger reagent for a test to be completed, characterized in that the method comprises adding the incubation reagent into a vessel (<NUM>, 10A) held by a static vessel holder (<NUM>, <NUM>') and adding the time-trigger reagent into a vessel (<NUM>, 10B) held by a gripper (<NUM>, <NUM>') of a vessel workstation (<NUM>, <NUM>'), wherein the method further comprises triggering a time measurement from the moment the time-trigger reagent has been added to the test liquid and transferring the vessel (<NUM>, 10B) held by the gripper (<NUM>, <NUM>') to at least one detection position (141B) of the static vessel holder (<NUM>, <NUM>') after the addition of the time-trigger reagent.