HK1214649B - In-vitro diagnostic analysis method and system - Google Patents

Description

In vitro diagnostic analysis methods and systems

Technical Field

The present invention relates to methods and systems for in vitro diagnostic assays involving pipetting reagents.

Background Art

In analytical laboratories, in particular in vitro diagnostic laboratories, analyses of biological samples are performed extensively in order to determine the patient's physiological and biochemical status, which may indicate disease, nutritional habits, drug efficacy, organ function, and the like.

Sample throughput, i.e. the number of biological samples analyzed per hour and the number of different tests that can be performed, is often very important. For laboratories processing thousands of samples per day, small delays in processing each individual sample can make a significant difference in overall laboratory efficiency.

In order to meet this demand, optimal hardware design and efficient workflow planning are required when developing automated systems for in vitro diagnostics. In particular, automated systems for in vitro diagnostic analysis may be required to repeatedly perform a large number of predetermined process operations at time intervals called cycles, and it is very important that the cycles of the same process operations are as short as possible in order to maximize processing capacity. In addition, it is common that different tests require different test conditions, such as different reaction times, different types of reagents, different volumes, different detection times, etc. Therefore, the system should also be able to dynamically adjust the predetermined workflow due to various test requirements and the variable order of test arrangements, and be able to quickly respond to anomalies, errors due to unexpected events, etc.

A method and system for in vitro diagnostic analysis are described herein that achieve higher throughput and workflow efficiency. This is achieved through programmable control of functional components that operate in parallel and collaboratively across different cycles on different samples, and is also expected to enable time savings in subsequent workflow operations.

Summary of the Invention

The present disclosure relates to automated in vitro diagnostic assay methods and systems for in vitro diagnostic assays.

" being used for in vitro diagnosis system " is a kind of analytical equipment, is specifically designed for analyzing test liquid for the laboratory automation instrument of in vitro diagnosis.The example of such analytical equipment is clinical chemistry analyzer, coagulation analyzer, immunochemical analyzer, hematology analyzer, urine analyzer and nucleic acid analyzer, and these instruments are used to the analyte being present in the test liquid and carries out qualitative and/or quantitative detection, so that the result of detection chemical or biological reaction and/or the progress of monitoring chemical or biological reaction.Analytical equipment can comprise the functional assembly for pipetting and/or mixing sample and/or reagent.Analytical equipment can comprise reagent holding assembly, is used to keep reagent to perform analysis.Reagent can be arranged according to the form of container or box in suitable receiver or position in storage chamber or conveying device, for example.It can comprise consumable supply assembly, for example supply reaction vessel.Analytical equipment can also comprise one or more mixing assemblies, and it comprises for example shaking the shaker containing test liquid, or the mixing paddle of mixing liquid in vessel or reagent container. Analytical devices may also include specific detection systems and follow specific workflows, such as performing multiple processing steps optimized for certain types of analysis (e.g., clinical chemistry, immunochemistry, coagulation, hematology, etc.).

Analytical equipment can have different configurations depending on needs and/or the desired laboratory workflow. Additional configurations can be achieved by connecting multiple devices together and/or adding modules. A "module" is a working unit that is typically smaller in size and weight than the entire analytical equipment and has functions that provide auxiliary functions to the analytical equipment's analytical functions and can operate solely in conjunction with the analytical equipment. In particular, a module can be configured to cooperate with one or more analytical equipment to perform specialized tasks in the sample processing workflow, such as performing one or more pre-analysis and/or post-analysis steps, which occur before or after sample analysis. Examples of such 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 cartridges, loading and/or unloading and/or transporting and/or storing and/or cleaning reaction vessels (e.g. test tubes), loading and/or unloading and/or transporting and/or storing pipette tips or pipette tip racks, reading and/or writing information-bearing labels (e.g. barcodes or RFID tags), cleaning pipette tips or needles or reaction vessels (e.g. test tubes, mixing paddles), mixing samples with other liquids (e.g. reagents, solvents, diluents, buffers), decapping, recapping, pipetting, aliquoting, centrifuging, etc. An example of such a module is a sample loading and/or unloading assembly for loading/unloading sample tubes.

According to some embodiments, a disclosed system for in vitro diagnostics includes a vessel handling area comprising at least one stationary vessel holder and at least one movable vessel workstation comprising a vessel gripper.

As used herein, the term "vessel" refers to a container comprising a body and an interior space suitable for receiving a liquid, for example, to enable a reaction between one or more samples and one or more reagents and/or to enable analysis of a test liquid contained therein. According to some embodiments, the vessel is a test tube, i.e., a container that is at least partially optically transparent and shaped to permit photometric measurements, such as, for example, measuring changes in light transmission, such as absorption and scattering, of a test liquid contained therein. In particular, the test tube can be used to perform absorption or scattering assays to detect the outcome of a chemical or biological reaction or to monitor the progress of a chemical or biological reaction, such as coagulation assays, hemostasis assays, and turbidimetric assays. According to one embodiment, the test tube body comprises sidewalls, a closed bottom, and an upper opening for allowing liquid to be introduced into the interior space formed by the sidewalls and the closed bottom. According to one embodiment, the test tube comprises at least one lip protruding outwardly from the test tube body adjacent the upper opening. This lip can be conveniently used to grip the test tube with a vessel clamp and/or to retain the test tube in a stationary test tube holder. Test tubes can have internal volumes in the milliliter or microliter range.

"Stationary vessel holder" is a holding device comprising one or more stationary vessel holding positions in the form of, for example, grooves, cavities, frames, bases, etc. The term "stationary" means motionless relative to the rest of the system. A stationary vessel holder can, for example, be implemented as a fixed assembly or component in a vessel processing area. In addition to the holding function, an assembly or component can have one or more other functions. A stationary vessel holder can, for example, be used as a cultivation station to keep one or more vessels at a certain temperature for a certain time, the time being long enough so that, for example, the reaction between a test liquid and a reagent is completed or reaches a degree of completion acceptable under reaction conditions, and wherein the time can last for more than one cycle. A stationary vessel holder can also, or alternatively, serve as a test station to allow the test liquid in the vessel to be detected, such as photometric measurement. In particular, according to some embodiments, a stationary vessel holder comprises at least one vessel holding position used as a cultivation position and/or at least one vessel holding position used as a detection position, wherein the stationary vessel holder can be divided into functional subassemblies on the same component or different components, for example, a subassembly for cultivating and a subassembly for detecting. According to some embodiments, the at least one stationary vessel holder comprises a plurality of linearly arranged vessel holding positions.

A "movable vessel station" is a functional component that is operably connected to a stationary vessel holder and is movable relative to the stationary vessel holder. According to some embodiments, the at least one vessel station is capable of translating relative to the at least one stationary vessel holder to transfer vessels between different vessel holding positions of the at least one stationary vessel holder. In particular, the movable vessel station comprises a clamp for clamping vessels, such as one vessel at a time, whereby vessels can be placed into a vessel holding position, removed from a vessel holding position, and moved between vessel holding positions. In particular, the clamp can be embodied as a movable element of the movable vessel station, which movable element is capable of translating at least in a vertical direction and comprises jaws that can be opened and closed to clamp or release a vessel.

According to some embodiments, the movable vessel workstation includes a shaking mechanism for shaking the vessel held by the clamp at least partially during the transfer of the vessel between different vessel holding positions of the stationary vessel holder. According to one embodiment, the shaking mechanism is an eccentric rotating mechanism driven by a motor and coupled to the clamp for eccentrically shaking the clamp and thereby the vessel held by the clamp, thereby causing the liquid contained therein to be mixed.

According to some embodiments, the vessel handling area further comprises a vessel input station for supplying at least one vessel to at least one static vessel holder at a time. In particular, a "vessel input station" is a functional component operably coupled to the at least one static vessel holder for supplying a new vessel to the at least one static vessel holder, for example placing at least one new vessel in at least one vessel holding position of the at least one static vessel holder at a time. According to one embodiment, the vessel input station is common to at least two static vessel holders. The vessel input station can be operably coupled to a vessel dispensing assembly for supplying individual vessels to the vessel input station starting from a bulk supply. In particular, the vessel input station can be implemented as a workstation with a vessel fixture that translates and/or rotates.

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

A "pipettor" is a functional component of the system for pipetting test liquids and/or reagents and, for this purpose, comprises at least one dispensing nozzle which can also serve as an aspiration nozzle. The nozzle can be implemented as a reusable washable needle (e.g. a steel hollow needle) or as a pipetting tip (e.g. a disposable pipetting tip suitable for regular replacement, e.g. before pipetting different test liquids or reagents). At least two pipetting devices are mounted to the pipetting head. According to some embodiments, the pipetting head can be moved by a head translation mechanism, e.g. using guide rails, in one or two directions of travel in a plane and can be moved, e.g. using a spindle drive, in a third direction of travel perpendicular to the plane. According to one 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 device can be moved alone in a vertical direction of travel perpendicular to the plane. In this document, the term "mounted to" is used in a broad sense to refer to a connection to, a combination to or the like, without referring to a specific position.

The system for in vitro diagnosis also includes a controller. A "controller" is a programmable logic controller that runs a computer-readable program provided with instructions for performing operations according to an operating protocol. In particular, the controller is programmed to control the at least one vessel workstation, the at least one pipetting head, and the at least two pipetting devices to perform a plurality of predetermined process operations. The predetermined process operations include adding a first reagent type and a second reagent type to a first test liquid during a first and second cycle, respectively, adding the first reagent type to the first test liquid includes adding the second reagent type to the second test liquid in parallel during the first cycle, and adding the second reagent type to the first test liquid includes adding the first reagent type to a third test liquid in parallel during the second cycle.

However, the operation plan may further include other operations, such as drawing test liquid, distributing test liquid, drawing first and second types of reagents, cleaning the absorption/distribution nozzle and/or replacing disposable pipette tips, and moving the pipette head to the absorption, distribution, terminal or cleaning position. The operation plan may also include other operations except those related to pipetting and moving the pipette device. For example, the operation plan may include one or more of the following: moving the test liquid container, opening and/or closing the test liquid container, piercing the cap of the test liquid container, moving the vessel, mixing the test liquid, and in particular the result of the detection reaction. In particular, the controller may include a scheduler for executing a series of steps within a predetermined cycle for multiple cycles. The controller may further determine the arrangement of the in vitro diagnostic test based on the type of assay, urgency, etc. The controller may further dynamically change the operation plan based on the occurrence of an abnormality or a newly occurring test arrangement or event.

As used herein, the term "test liquid" is used to indicate a sample or a mixture or solution of one or more samples and one or more reagents, the subject of a test (i.e., an in vitro diagnostic assay). As used herein, the term "sample" refers to a liquid material suitable for being pipetted and subjected to an in vitro diagnostic assay, for example, to detect one or more analytes of interest suspected of being present therein, or to measure a physical parameter of the sample itself, such as pH, color, turbidity, viscosity, clotting time, and the like. Examples of in vitro diagnostic assays are clinical chemistry assays, immunoassays, coagulation assays, blood assays, nucleic acid tests, and the like. In some embodiments, the disclosed system is particularly suitable for in vitro testing of coagulation.

The sample can be obtained from any biological source (e.g., physiological fluids, including blood, saliva, lens fluid, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, joint fluid, peritoneal fluid, amniotic fluid, tissue, cells, etc.). The sample can be pretreated before use, such as preparing plasma from blood, diluting viscous liquids, lysing bacteria, etc.; treatment methods can include filtration, centrifugation, distillation, concentration, inactivation of interfering components and addition of reagents. The sample is used directly as obtained from the source, or is first pretreated to change the characteristics of the sample, such as after dilution with another solution, or after mixing with a reagent, for example, to perform one or more in vitro diagnostic tests. Therefore, the term "sample" as used herein is not only used for the original sample, but also refers to samples that have been processed (pipetted, diluted, mixed with reagents, enriched, purified, amplified, etc.). According to one embodiment, the sample is a blood sample treated with citric acid.

The term "reagent" is usually used to indicate the liquid or material needed for processing a sample. Reagent can be any liquid (for example, a solvent or a chemical solution), which can be mixed with sample and/or other reagents so that, for example, reaction or detection can be carried out. Reagent can be, for example, a diluent, comprises water, it can include an organic solvent, it can include a detergent, it can be a buffer. In a more stringent sense, reagent can be a liquid solution containing a reactant, and a reactant is generally a compound or reagent that can, for example, bond or chemically transform one or more analytes present in the sample. The example of a reactant is an enzyme, an enzyme substrate, a conjugated dye, a protein bonding molecule, a nucleic acid bonding molecule, an antibody, a chelating agent, a promoter, an inhibitor, an epi-position, an antigen and the like.

" first reagent type " or " reagent of the first type " are reagents required for the first reaction that occur in the early stage of sample processing workflow, and usually need the reagent of the second reagent type or the second type, for completing the test. According to one embodiment, the first reagent type is a cultivation reagent, such as should keep in contact with the sample under certain conditions (such as certain time, and at a certain temperature), so that the reaction is completed or reaches an acceptable degree of completion. Single test may need one or more reagents of the first type that are added successively at the different times of reaction. The example of the reagent of the first type is the reagent for determining coagulation factors and other coagulation parameters (such as activated partial thromboplastin time (APTT)).

A "second reagent type" or "reagent of the second type" is a reagent that is required to complete a test at a later stage in the sample processing workflow by a test liquid that has reacted with one or more reagents of the first type, or a reagent that is sufficient in itself to complete a test without the need to add a reagent of the first type. Thus, the second reagent type can have the function of continuing the reaction of the first reagent type or stopping the reaction of the first reagent type or being able to detect the reaction of a sample with the first reagent type. The second reagent type can be the only or last reagent used in a test before or during a test. According to one embodiment, the second reagent type is a time-initiating reagent, also referred to as a starting reagent, i.e., a reagent that initiates the time measurement from the moment the second reagent type has been added to the test liquid. An example of a time-initiating reagent is a coagulation initiator, such as a saline solution, such as a sodium chloride or calcium chloride solution.

A "cycle" is a recurring time window, usually of fixed length, during which a certain number of process operations (also called "tasks" or "work packages") are repeatedly performed in a controlled sequence, which is called a "cycle". However, this does not necessarily mean that all process operations performed in one cycle will be repeated in another cycle. In particular, certain process operations may be repeated in each cycle, while others may occur every two or more cycles. In addition, new process operations can be introduced within the cycle based on newly added test arrangements and/or new situations that arise, so that the cycle can adapt dynamically. In addition, in response to abnormal conditions, such as when the pipetting device is blocked, when an error is detected in the pipetting or liquid level, when an error occurs in the operating vessel, or similar situations, abnormal cycles or changes in the cycle process may occur. Typically, of all the process operations that occur within a single cycle, only certain process operations are dedicated to performing a test. This means that within a single cycle, usually at least two tests are carried out simultaneously, although usually at different stages, that is, in a single cycle, different process operations are dedicated to different tests. Thus, the test is typically performed in multiple (eg, two or more) cycles, wherein different process operations for performing the test occur in different cycles and there may be time intervals between cycles, such as time intervals during which the test fluid is incubated.

When referring to a "first cycle", it means any cycle; when referring to a "second cycle", it means any cycle coming after the first cycle, where "after" refers to the next cycle or two or more cycles after the first cycle.

The terms "adding to the test liquid" or "adding to the test liquid" are not necessarily limited in time relative to the presence of the test liquid. In particular, the addition of the first reagent type may occur before or after the addition of the test liquid, as long as the test liquid and one or more reagents are brought together by the addition.

"Added in parallel" or "parallel addition" means that the first and second reagent types are added to the two corresponding test liquids at the same time. However, the term "simultaneously" does not necessarily mean starting and ending at the same time, as this can depend on various factors, such as the volumes added, which may be different. Therefore, the term includes at least partial overlap, or one being included in the other.

The term "dispensing" more particularly refers to a pipetting operation which is typically preceded by an aspiration action of the liquid to be dispensed. Parallel dispensing does not necessarily mean parallel aspiration.

According to certain embodiments, the controller is programmed to control the at least two pipetting devices and the at least one vessel workstation to add a first reagent type to vessels held by the stationary vessel holder and a second reagent type to vessels held by the clamps of the movable vessel workstation.

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

In accordance with certain embodiments, the controller is further programmed to control the vessel workstation to move the clamp to a dispensing position for dispensing a second reagent type into a vessel held by the clamp, wherein the dispensing position is defined based on the position of a vessel held by a stationary vessel holder that requires the first reagent type within the same cycle, and based on the distance between corresponding pipetting devices on the same pipetting head.

According to certain embodiments wherein the at least one stationary vessel holder comprises at least one testing location, after adding the second reagent type, the controller is further programmed to control the vessel station for transferring the vessel held by the gripper to the at least one testing location.

According to certain embodiments wherein the vessel workstation includes a rocking mechanism, the controller is further programmed to control the rocking mechanism for rocking the vessel held by the gripper at least partially during transfer of the vessel between different vessel positions in the stationary vessel holder.

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

According to one embodiment, a system comprises at least two stationary vessel holders, a reagent pipetting head comprising at least three reagent pipetting devices, and a sample pipetting head comprising at least two sample pipetting devices.

Also disclosed herein is a further system for in vitro diagnostic analysis, wherein the controller is programmed to control the at least one vessel workstation, the at least one pipetting head, and the at least two pipetting devices to perform a plurality of predetermined process operations, including adding at least two reagents in parallel to at least two corresponding vessels, at least one of which is held by a stationary vessel holder and at least one of which is held by a clamp of a movable vessel workstation. According to certain embodiments, the controller is programmed to control the at least two pipetting devices to add an incubation reagent to the vessel held by the stationary vessel holder and to add a time triggering reagent to the vessel held by the clamp of the movable vessel workstation. According to certain embodiments, the controller is further programmed to control the movable vessel workstation to hold the vessel by the clamp at a different height than the vessel held by the stationary vessel holder. According to some embodiments, the at least two pipetting devices are mounted to a single pipetting head, and the controller is further programmed to control the movable vessel workstation to move the vessel held by the fixture to a dispensing position for dispensing a time-triggered reagent into the vessel, wherein the dispensing position is defined based on the position of vessels held by the stationary vessel holder that require incubation of the reagent within the same cycle and based on the distance between the corresponding pipetting devices on the single pipetting head. According to some embodiments, the method further includes shaking the vessel held by the fixture while moving the vessel toward the detection position.

Also disclosed herein is a further system for in vitro diagnostic analysis, wherein the controller is programmed to control the at least one vessel workstation, the at least one pipetting head, and the at least two pipetting devices to perform a plurality of predetermined process operations, including adding a time triggering reagent and an incubation reagent in parallel to at least two test liquids in at least two corresponding vessels. According to certain embodiments, the controller is programmed to control the at least two pipetting devices to add the incubation reagent to the vessel held by the stationary vessel holder and to add the time triggering reagent to the vessel held by the clamp of the movable vessel workstation. According to certain embodiments, the controller is further programmed to control the movable vessel workstation to hold the vessel by the clamp at a different height than the vessel held by the stationary vessel holder. According to some embodiments, the at least two pipetting devices are mounted to a single pipetting head, and the controller is further programmed to control the vessel workstation to move the vessel held by the fixture to a dispensing position for dispensing a reaction-initiating reagent into the vessel, wherein the dispensing position is defined based on the position of vessels held by the stationary vessel holder that require incubation of the reagent within the same cycle and based on the distance between the corresponding pipetting devices on the single pipetting head. According to some embodiments, the method further includes shaking the vessel held by the fixture while moving the vessel toward the detection position.

Also disclosed herein is a further system for in vitro diagnostic analysis, the system comprising a vessel handling area comprising two stationary vessel holders and a common vessel input station for feeding containers to the stationary vessel holders, the vessel handling area further comprising two movable vessel workstations, each movable vessel workstation comprising a vessel clamp and being capable of translating relative to a respective stationary vessel holder to transfer the vessel between different vessel holding positions of the respective stationary vessel holders, the system further comprising: a reagent pipetting head comprising at least three reagent pipetting devices, and a sample pipetting head comprising at least two sample pipetting devices. Utilizing this system, the total sample processing capacity (number of tests per hour) is nearly doubled, without doubling the number of functional components, compared to a system having a single stationary vessel holder and a single sample/reagent pipetting head. In particular, this configuration is optimized for high throughput tests of two of the most frequently scheduled coagulation tests, such as the prothrombin time (PT) test and the activated partial thromboplastin time (APTT) test. The PT test only requires a time-priming reagent, while the APTT test requires an incubation reagent in the first phase and a time-priming reagent in the second phase. Higher throughput can be achieved if the tests are performed alternately according to the order in which the tests are scheduled. The two stationary vessel holders can advantageously be dedicated to different tests.

Also disclosed herein is an automated in vitro diagnostic assay method comprising adding a first reagent type and a second reagent type to a first test fluid in first and second cycles, respectively. Specifically, adding the first reagent type to the first test fluid comprises adding the second reagent type to the second test fluid in parallel during the first cycle, and adding the second reagent type to the first test fluid comprises adding the first reagent type to a third test fluid in parallel during the second cycle, respectively.

According to certain embodiments, the parallel addition of the first reagent type and the second reagent type is performed using a single pipetting head comprising at least two pipetting devices. According to one embodiment, the at least two pipetting devices are independently drivable in a vertical direction.

According to certain embodiments, adding the first reagent type includes dispensing the first reagent type into a vessel held by a stationary vessel holder, and adding the second reagent type includes dispensing the second reagent type into a vessel held by a gripper of a movable vessel station.

According to one embodiment, the first reagent type is an incubation reagent and the second reagent type is a time-priming reagent.

According to certain embodiments, the method includes holding a vessel held by a gripper and a vessel held by a stationary vessel holder at different heights during the parallel addition of the first reagent type and the second reagent type, respectively.

According to certain embodiments, the method includes moving a fixture to a dispensing position for dispensing a second reagent type into a vessel held by the fixture, wherein the dispensing position is defined based on the position of a vessel held by a stationary vessel holder that requires a first reagent type within the same cycle, and based on a distance between corresponding pipetting devices on a single pipetting head.

According to some embodiments, the method further comprises shaking the vessel held by the clamp while moving the vessel toward the testing position.

Also disclosed herein is a method for a further automated in vitro diagnostic analysis. The method comprises dispensing at least two reagents in parallel into at least two corresponding vessels using at least two pipetting devices, at least one of which is held by a stationary vessel holder and at least one of which is held by a fixture of a movable vessel workstation. According to certain embodiments, the reagent dispensed into the vessel held by the stationary vessel holder is an incubation reagent, and the reagent dispensed into the vessel held by the fixture of the movable vessel workstation is a time-triggered reagent. According to certain embodiments, the method further comprises maintaining the vessel held by the fixture and the vessel held by the stationary vessel holder at different heights during the parallel dispensing. According to certain embodiments, the at least two pipetting devices are mounted to a single pipetting head, and the method comprises moving the fixture to a dispensing position for dispensing the reagents into the vessels held by the fixture, wherein the dispensing position is defined based on the position of the vessels held by the stationary vessel holder that require a reagent in the same cycle, and based on the distance between the corresponding pipetting devices on the single pipetting head. According to some embodiments, the method further comprises shaking the vessel held by the clamp while moving the vessel toward the testing position.

A further method for automated in vitro diagnostic analysis is described herein. The method includes adding a time-initiating reagent and an incubation reagent, respectively, to at least two test fluids in parallel using a single pipetting head comprising at least two pipetting devices. According to certain embodiments, the method includes adding the incubation reagent to a vessel held by a stationary vessel holder and adding the time-initiating reagent to a vessel held by a fixture of a movable vessel workstation. According to certain embodiments, the method further includes maintaining the vessel held by the fixture and the vessel held by the stationary vessel holder at different heights during the parallel dispensing. According to certain embodiments, the method includes moving the fixture to a dispensing position for dispensing the time-initiating reagent into the vessel held by the fixture, wherein the dispensing position is defined based on the position of vessels held by the stationary vessel holder that require incubation reagent during the same cycle and based on the distance between corresponding pipetting devices on the single pipetting head. According to certain embodiments, the method also includes shaking the vessel held by the fixture while moving the vessel toward a testing position.

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

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a partial top view of a system for in vitro diagnostics.

FIG2 shows a variation of the system of FIG1 .

3A is a partial top view of a vessel processing area according to the embodiment of FIG. 2 .

3B is a fragmentary top view identical to FIG. 3A , except for the location of the vessel holder.

FIG4 shows some components of the system of FIG2 in more detail.

FIG5 shows some components of the system of FIG1 in more detail.

FIG. 6A illustrates a method of operation of the system of FIG. 2 , which is also applicable to the system of FIG. 1 .

FIG. 6B is an enlarged view of a detail of FIG. 6A .

Specific embodiments

Fig. 1 illustrates an example of the system 100 for in vitro diagnostic analysis, particularly coagulation analyzer.System 100 comprises reagent and holds assembly 110, is used to keep the reagent of first type and second type to carry out different coagulation tests.Reagent assembly 110 is embodied as the storage compartment of sealing and regulation, and it comprises the access hole 111 that is used to make the pipette mouth enter the compartment and retrieve aliquot reagent.This system 100 also comprises the sample loading/unloading assembly 120 that is used to load/unload and comprises the sample tube rack 121 of sample tube.This system also comprises the vessel handling area 130 (illustrated and described in more detail with reference to Figure 5) of central government.Vessel handling area 130 comprises a linear static vessel holder 140, and static vessel holder 140 comprises a plurality of vessel holding positions 141.Vessel handling area 130 also comprises vessel input station 150, is used for each vessel being supplied to in static vessel holder 140. The vessel handling area 130 also includes a movable vessel workstation 160 that is linearly translatable relative to and functionally coupled to the stationary vessel holders 140 for transferring vessels between the vessel holding positions 141 of the stationary vessel holders 140 .

System 100 also comprises pipetting head 170, and pipetting head 170 comprises three pipetting devices (shown in Fig. 5).Particularly, pipetting head 170 can be installed on horizontal arm 171 translationally, and arm 171 can be coupled to orthogonal guide rail 172 translationally.Like this, pipetting head 170 can move in the space above reagent assembly 110, above vessel treatment zone 130 and above sample loading/unloading assembly 120.In addition, each of pipetting device can be translated individually in the vertical direction, so that can approach the reagent container in reagent assembly 110, the sample tube in sample loading/unloading assembly 120 and the vessel in vessel treatment zone 130 via hole 111.Particularly, utilize identical pipetting head 170, can draw test liquid from the sample tube in sample loading/unloading assembly 120, can draw reagent from the reagent container in reagent assembly 110, and test liquid and reagent can be all assigned to the vessel in vessel treatment zone 130.

The system 100 also includes a controller 180 that is programmed to control the execution of a plurality of predetermined process operations, including operation of the movable vessel workstation 160, operation of the pipetting head 170, and operation of the pipetting device (described in detail with reference to Figures 5 and 6A).

FIG2 shows another system 100′, which is a variation of the system 100 of FIG1 . One difference between system 100 and system 100′ is that system 100′ includes a vessel handling area 130′ that, compared to the vessel handling area 130 of the vessel handling system 100, also includes a second linear stationary vessel holder 140′ and a second movable vessel workstation 160′ that is capable of linear translation relative to the second stationary vessel holder 140′ and is functionally coupled to the stationary vessel holder 140′ for transferring vessels between a plurality of vessel holding positions 141′ of the second stationary vessel holder 140′. Another difference between system 100′ and system 100 is that system 100′ includes two pipetting heads 170′, 173 that are translationally mounted on two respective horizontal arms 171, 174. As better shown in Figure 5, the first pipetting head 170' includes three reagent pipetting devices, which are suitable for drawing reagents from the reagent assembly 110 and distributing the reagents into the vessels in the vessel processing area 130'. The second pipetting head 173 includes two sample pipetting devices, which are suitable for drawing test liquids from the sample tubes in the sample loading/unloading assembly 120 and distributing the test liquids into the vessels in the vessel processing area 130'. The arms 171, 174 are translationally coupled to the same orthogonal guide rail 172. The two stationary vessel holders 140, 140' are arranged parallel to each other, and the vessel input station 150, which is the same as the vessel input station 150 in Figure 1, is symmetrically arranged between the two stationary vessel holders so that the vessels are supplied to the two stationary vessel holders 140, 140'. Another difference between system 100' and system 100 is that system 100' further includes a sample rack tray assembly 122, which is functionally coupled to the sample loading/unloading assembly 120 as a module for loading and unloading sample racks 121 into and from the sample loading/unloading assembly 120.

The system 100' also includes a controller 180', which is programmed to control the execution of multiple predetermined process operations, including the operation of the movable vessel workstations 160 and 160', the operation of the pipetting heads 170' and 173, and the operation of the pipetting device (described in detail with reference to Figures 4 and 6A-6B).

Fig. 3 A and 3B are the local top views of the vessel processing area 130 ' (without pipetting device) according to the embodiment of Fig. 2. Particularly, Fig. 3 A and Fig. 3B show two static vessel holders 140, 140 ' and two corresponding movable vessel workstations 160, 160 ' relative to each other and relative to the arrangement of vessel input station 150 from the top. The first static vessel holder 140 and the second static vessel holder 140 ' are identical, and are arranged one before and one after and are parallel to each other along the longitudinal direction. However, their orientation is opposite, wherein, the second static vessel holder 140 ' rotates 180 degrees around itself relative to the first static vessel holder 140. The first and second static vessel holders 140, 140 ' are embodied as linear components, and each component comprises the vessel holding position 141, 141 ' array of linear arrangement respectively, wherein a part is used as cultivating position, and a part is used as detection position (as described in more detail with reference to Fig. 6 A).

The vessel input station 150 comprises a vessel gripper 151 and is arranged symmetrically between the first stationary vessel holder 140 and the second stationary vessel holder 140′ so that when the vessel gripper 151 is rotated 180 degrees, the vessel 10 can be placed in the vessel holding position 141 of the first stationary vessel holder 140 or in the vessel holding position 141′ of the second stationary vessel holder 140′ by the same vessel gripper 151. The first movable vessel workstation 160 and the second movable vessel workstation 160′ are identical and are arranged parallel to the respective stationary vessel holder 140, 140′ on the outer side of the respective stationary vessel holder 140 and opposite the central vessel input station 150. In particular, the first movable vessel station 160 is capable of translating relative to the first stationary vessel holder 140 along the guide rails 162, while the second movable vessel station 160′ is capable of translating relative to the second stationary vessel holder 140′ along the guide rails 162′ independently of the first movable station 160. Thus, the first movable vessel station 160 is functionally coupled to the first stationary vessel holder 140 for transferring vessels between the plurality of vessel holding positions 141 of the first stationary vessel holder 140, and the second movable vessel station is functionally coupled to the second stationary vessel holder 140′ for transferring vessels between the plurality of vessel holding positions 141′ of the second stationary vessel holder 140′.

The vessel input station 150 is spatially fixed relative to the stationary vessel holders 140, 140', so that only the vessel clamp 151 can be translated vertically and can be turned toward either of the stationary vessel holders 140, 140'. Thus, the vessel input station 150 can place a new vessel 10 at a time into only one input vessel holding position 141 of the first stationary vessel holder 140 (Figure 3B) and into only one input vessel holding position 141' of the second stationary vessel holder 140' (Figure 3A). These two input vessel holding positions 141, 141' are dedicated detection positions for performing photometric blank measurements for each new vessel 10 placed in each stationary vessel holder 140, 140'. The two corresponding movable vessel workstations 160 , 160 ′ can then transfer vessels 10 from the two input vessel holding positions 141 , 141 ′ to any other vessel holding position 141 , 141 ′ according to a predetermined process.

FIG4 perspectively illustrates the vessel handling area 130 ' of FIG3B , in addition having two pipetting heads 170 ', 173 above the vessel handling area 130 '. The vessel input station 150 is implemented as a vessel elevator comprising a vessel fixture 151, which can translate vertically along guide rails 152 and can rotate in a horizontal plane. In particular, the vessel fixture 151 can be operably coupled to a vessel dispensing assembly (not shown) for supplying a separate vessel 10 to the fixture 151 at a position lower than the guide rails 152. Thus, the vessel fixture 151 can transport one vessel 10 at a time from the vessel dispensing assembly in a lower position to one of the vessel holding positions 141, 141 ' of the stationary vessel holder 140, 140 ' in a higher position.

The movable vessel workstations 160, 160' are capable of linear translation along guide rails 162, 162', respectively, parallel to the stationary vessel holders 140, 140'. In addition, each movable vessel workstation 160, 160' comprises a vessel clamp 161, 161', respectively, which is capable of translation in the vertical direction. Therefore, the movable vessel workstations 160, 160' can be independently moved along the corresponding stationary vessel holders 140, 140' to introduce the vessel clamps 161, 161' corresponding to any vessel holding position 141, 141', and by vertically translating the vessel clamps 161, 161', they can clamp the vessel 10 and pull the vessel 10 out from any vessel holding position 141, 141', or place the vessel 10 into any empty vessel holding position 141, 141' of the corresponding stationary vessel holders 140, 140'. Thus, via the movable vessel workstations 160 , 160 ′, vessels 10 can be easily transferred between different vessel holding positions 141 , 141 ′ of the same stationary vessel holder 140 , 140 ′, respectively, for example between an incubation position and a testing position.

The first pipetting head 170' is a reagent pipetting head comprising three reagent pipetting devices, in particular two reagent pipetting devices 175' suitable for pipetting a reagent of the second type and one reagent pipetting device 176' suitable for pipetting a reagent of the first type. In particular, each reagent pipetting device 175' comprises a heating element 177' for heating the reagent of the second type to an optimal temperature between reagent aspiration and reagent dispensing. The second pipetting head 173 is a sample pipetting head comprising two sample pipetting devices 178' suitable for pipetting a sample from a sample tube, for example, including pipetting through a closure by piercing the closure.

Compared to the embodiment of Fig. 5, the embodiment of Fig. 4 can realize doubled sample processing capacity for at least some tests, yet does not need to make the number of functional components doubled.In particular, can save at least one reagent needle and can use a common vessel input station 150.

Fig. 5 perspective view illustrates the vessel handling area of the system 100 of Fig. 1, and this vessel handling area comprises only a static vessel holder 140, only a movable vessel workstation 160 and only a pipetting head 170.Particularly, static vessel holder 140, movable vessel workstation 160 and vessel input station 150 and their functional relationship are identical with those in Fig. 4.Pipette head 170 is a sample/reagent pipetting head, and it comprises first reagent pipetting device 175, second reagent pipetting device 176 and sample pipetting device 178.Particularly, first reagent pipetting device 175 is suitable for pipetting the reagent of the first type, and second reagent pipetting device 176 is suitable for pipetting the reagent of the second type.Particularly, second reagent pipetting device 176 comprises a heating element 177 that is used for heating the reagent of the second type to optimal temperature between reagent absorption and reagent distribution.Sample pipetting device 178 is suitable for pipetting test liquid from sample tube, for example comprises the absorption that carries out through this closure by piercing closure.

Fig. 6 A and Fig. 6 B (having amplified the details of Fig. 6 A) have shown during operation, under the control of controller 180 ', the further details of the part of the embodiment of Fig. 4. Particularly, for the sake of clarity, only a static vessel holder 140 with corresponding movable vessel workstation 160 and only a pipetting head 170 ' are shown. Particularly, the process of adding the first reagent type and the second reagent type in parallel is shown. Same process also applies to the embodiment of Fig. 5, except using different pipetting heads.

The stationary vessel holder 140 includes a plurality of vessel holding positions 141 for holding a plurality of vessels 10. In particular, the stationary vessel holder 140 includes an incubation subassembly 140A including a plurality of incubation positions 141A (twenty in this example), which are implemented as cavities in an aluminum component that are complementary in shape to the vessels 10. In particular, the incubation subassembly 140A includes a temperature regulation assembly (not shown) for regulating the temperature of the vessels 10 accommodated in the incubation positions 141A, for example, for maintaining the vessels 10 at an optimal reaction temperature.

The stationary vessel holder 140 also includes a detection subassembly 140B, which includes a plurality of detection positions 141B (13 in this example). In particular, the detection subassembly 140B includes a photometric assembly 142, which includes a light source 143 located on one side of the detection position 141B and an optical detector (not shown) arranged inside the detection subassembly 140B on the other side of the detection position 141B. In particular, for each detection position 141B, there is an optical fiber 144 and an optical detector, the optical fiber 144 being used to guide light from the light source 143 through the vessel 10 set at the detection position 141B, and the optical detector being placed on the opposite side of the detection position so as to detect light passing through the vessel 10 at the detection position 141B. Therefore, each detection position 141B is arranged in the light path between the optical fiber 144 and the optical detector. Therefore, the vessel 10 can be conveniently implemented as a test tube that can be placed in the light path and includes two parallel and transparent walls. Light of different wavelengths can be guided through different optical fibers 144, and/or light of different wavelengths can be alternately guided in the same optical fiber 144. In particular, the light source 143 can be common to all optical fibers 144 and comprise a multi-wavelength light source, such as a broad spectrum light source or a plurality of light emitting elements having separate wavelengths or wavelength ranges.

One of the detection positions 141B′ is a blank measurement position for obtaining a blank measurement value for each new vessel 10. The blank measurement position 141B′ is an input vessel holding position where a new vessel 10 is placed each time by the vessel gripper 151 of the vessel input station 150.

The stationary vessel holder 140 also includes a waste port 145, which is implemented as a hole passing through the stationary vessel holder 140 located between the incubation subassembly 140A and the detection subassembly 140B. The hole 145 leads to a vessel waste box (not shown) located below the stationary vessel holder 140 for discarding used vessels 10 through the vessel clamp 161.

Now describe a part of exemplary process with reference to all embodiments.In particular, the process below describes some process operations that may occur in a cycle.Each time the vessel input station 150 places a new vessel 10 into the input vessel holding position 141B' of the static vessel holder 140 and/or into the input vessel holding position 141' of the second static vessel holder 140', depending on whether one static vessel holder 140 or two static vessel holders 140, 140' are used. Subsequently, first a photometric blank measurement is performed on each new vessel 10 in each static vessel holder 140, 140'.After obtaining the photometric blank measurement value of the vessel 10, the corresponding movable vessel workstation 160, 160' transfers the vessel 10 to the empty incubation position 141A, 141' of the corresponding static vessel holder 140, 140'.

2, 4, 6A and 6B, the sample pipetting head 173 moves to the sample loading/unloading assembly 120 and uses two corresponding pipetting devices 178' to draw two test liquids from two sample tubes, or draw two equal portions from the same sample tube. The sample pipetting head 173 then moves to the first stationary vessel holder 140 to dispense the test liquid to the vessel 10 in the incubation position 141A, and to the second stationary vessel holder 140' to dispense another test liquid to another vessel 10 in the incubation position 141' of the second stationary vessel holder 140', or to another vessel 10 in the other incubation position 141A of the first stationary vessel holder 140. The reagent pipetting head 170' moves to the reagent assembly 110 and uses reagent pipetting devices 176' and 175' to draw one reagent of the first type and two reagents of the second type, respectively.

The clamp 161 of the first movable vessel workstation 160 clamps the vessel 10B from the incubation position 141A. The first movable vessel workstation 160 then moves to a dispensing position for dispensing the second reagent type into the vessel 10B held by the clamp 161. The dispensing positions shown in Figures 6A and 6B are defined based on the position of the vessel 10A (requiring the first reagent type in the same cycle) held in the incubation position 141A of the stationary vessel holder 140 and based on the distance between the corresponding reagent pipetting devices 175', 176' on the reagent pipetting head 170'.

In particular, the reagent pipetting head 170' is moved relative to the first stationary vessel holder 140 so that the reagent pipetting device 176' containing the first type of reagent is positioned above the vessel 10A requiring the first type of reagent, and the reagent pipetting device 175' containing the second type of reagent is placed above the vessel 10B held by the vessel clamp 161 and requiring the second type of reagent. The reagent pipetting devices 176', 175' are then lowered to different heights into the corresponding vessels 10A, 10B for adding the first and second reagent types in parallel, respectively. The reagent pipetting devices 175', 176' are then raised, and the vessel 10B held by the clamp 161 is transported to the empty detection position 141B of the detection subassembly 140B for detection by the linear translation movable vessel workstation 160. When moving movable vessel workstation 160 between distribution position and detection position 141B, fixture shakes vessel 10B, is used for mixing the test liquid that wherein holds and the reagent of the second type.By utilizing identical pipetting head to add cultivation reagent and time initiation reagent in parallel, and by the coordinated cooperation of movable vessel workstation, can optimize the use to functional resource, and can increase the efficiency of work flow, significantly save time, save space and reduce cost.By being kept vessel 10B by fixture 161 and in the vessel 10B that is kept by fixture, pipetting time initiation reagent, can make to add time initiation reagent and detect the time minimization between beginning.By shaking vessel 10B during transportation, the time used for mixing is also minimized, thereby helps to make to add time initiation reagent and detect the time minimization between beginning.

After the first type of reagent and the second type of reagent are added in parallel to the two vessels 10A, 10B at the first stationary vessel holder 140, the reagent pipetting head 170' moves to the second stationary vessel holder 140' for dispensing the second reagent of the second type into the vessel 10 held by the vessel clamp 161' of the second stationary vessel holder 140'.

Vessels 10, 10A that have received a reagent of the first type remain incubated for one or more cycles until receiving a reagent of the second type in a subsequent cycle.

In one embodiment, the first stationary vessel holder 140 is at least temporarily dedicated to one test type, such as performing an APTT test, while the second stationary vessel holder 140' is dedicated to a different test type, such as performing a PT test. Thus, in one cycle, at the first stationary vessel holder 140, incubation reagents and time triggering reagents are added in parallel to two corresponding vessels 10A, 10B that are performing two APTT tests at different stages, followed by the addition of time triggering reagents to the vessel 10 performing the PT test at the second stationary vessel holder 140', such as the vessel held by the clamp 161 of the second movable vessel workstation 160', which only requires time triggering reagents. In subsequent cycles, the same process can be repeated separately for different test liquids and vessels 10. Thus, the system 100' can be programmed to perform high-throughput analysis of the two most commonly used tests in coagulation analysis.

1 and 5 , the process is similar, except that on the same sample/reagent pipetting head 170, there is one sample pipetting device 178 and two reagent pipetting devices 175 and 176 for the first and second types of reagents, respectively, but only one stationary vessel holder 140. Apart from this, the process of parallel addition and transport of the vessels 10B held by the fixture 161 is the same.

Obviously, modifications and variations can be made to the disclosed embodiments in light of the above description. It is therefore to be understood that within the scope of the appended claims, the present invention may be practiced otherwise than as specifically designed in the foregoing examples.

Claims (17)

1. An automated in vitro diagnostic analysis method, comprising: adding a first reagent type and a second reagent type to a first test liquid during a first cycle and a second cycle, respectively; wherein adding the first reagent type to the first test liquid includes adding the second reagent type in parallel to a second test liquid during the first cycle, and adding the second reagent type to the first test liquid includes adding the first reagent type in parallel to a third test liquid during the second cycle, wherein the parallel addition of the first reagent type and the second reagent type is performed using a single aspiration head, the single aspiration head including at least two aspiration devices. 2. The method of claim 1, wherein adding the first reagent type comprises dispensing the first reagent type into a vessel held by a stationary vessel holder, wherein adding the second reagent type comprises dispensing the second reagent type into a vessel held by a clamp of a movable vessel workstation. 3. The method according to claim 1, wherein the first reagent type is a culture reagent, and the second reagent type is a time-initiating reagent. 4. The method of claim 2, wherein the first reagent type is a culture reagent, and the second reagent type is a time-initiating reagent. 5. The method according to any one of claims 2 to 4, comprising holding a vessel held by a clamp and a vessel held by a stationary vessel holder at different heights, respectively, during the parallel addition of a first reagent type and a second reagent type. 6. The method according to any one of claims 2 to 4, comprising moving a clamp to a dispensing position for dispensing a second reagent type into a vessel held by the clamp, wherein the dispensing position is defined based on the position of a vessel held by a stationary vessel holder that requires a first reagent type within the same period, and based on the distance between corresponding suction devices on a single suction head. 7. The method according to any one of claims 2 to 4, further comprising shaking the vessel held by the clamp while moving the vessel toward the detection position. 8. A system for in vitro diagnostic analysis, the system comprising: The vessel handling area includes at least one stationary vessel holder and at least one movable vessel workstation including vessel clamps. The system also includes: The system includes a controller and at least one suction head, the suction head comprising at least two suction devices movable in the space above the vessel handling area. The controller is programmed to control the at least one vessel workstation, the at least one suction head, and the at least two suction devices to perform a plurality of predetermined process operations, the predetermined process operations including: The first reagent type and the second reagent type are added to the first test liquid during the first cycle and the second cycle, respectively. Adding the first reagent type to the first test liquid includes adding the second reagent type to the second test liquid in parallel during the first cycle, and adding the second reagent type to the first test liquid includes adding the first reagent type to the third test liquid in parallel during the second cycle. 9. The system of claim 8, wherein the controller is programmed to control the at least two suction devices and the at least one vessel workstation to add a first reagent type to a vessel held by a stationary vessel holder and to add a second reagent type to a vessel held by a clamp of a movable vessel workstation. 10. The system of claim 8, wherein, during the parallel addition of the first reagent type and the second reagent type, the clamp is controlled to hold the vessel at a different height than the vessel held by the stationary vessel holder. 11. The system of claim 9, wherein, during the parallel addition of the first reagent type and the second reagent type, the clamp is controlled to hold the vessel at a different height than the vessel held by the stationary vessel holder. 12. The system according to any one of claims 9 to 11, wherein the controller is further programmed to control the dish workstation to move the fixture to a dispensing position for dispensing a second reagent type into a dish held by the fixture, wherein the dispensing position is defined based on the position of the dish held by the stationary dish holder that requires the first reagent type within the same cycle, and based on the distance between corresponding suction devices on the same suction head. 13. The system according to any one of claims 8 to 11, wherein the vessel processing area further includes a vessel input station for supplying at least one vessel to the at least one stationary vessel holder at a time. 14. The system according to any one of claims 8 to 11, wherein the at least one vessel workstation is capable of translating relative to at least one corresponding stationary vessel holder to transfer vessels between different vessel holding positions of the at least one stationary vessel holder. 15. The system according to any one of claims 8 to 11, wherein the at least one stationary vessel holder includes at least one detection position, and upon addition of a second reagent type, the controller is further programmed to control the vessel workstation for transferring the vessel held by the clamp to the at least one detection position. 16. The system of claim 14, wherein the vessel workstation includes a shaking mechanism for shaking the vessel held by the clamp at least in part during the transfer of the vessel between different positions of the stationary vessel holder. 17. The system of claim 15, wherein the vessel workstation includes a shaking mechanism for shaking the vessel held by the clamp at least in part during the transfer of the vessel between different positions of the stationary vessel holder.