Patent Description:
The present invention relates, in general, to an automated immunoassay analyzer system for use in a laboratory environment and, more particularly, to systems and methods for handling and performing testing on patient samples for in vitro diagnostics in a immunoassay analyzer.

In vitro diagnostics (IVD) allows labs to assist in the diagnosis of disease based on assays performed on patient fluid samples. IVD includes various types of analytical tests and assays related to patient diagnosis and therapy that can be performed by analysis of a liquid sample taken from a patient's bodily fluids, or abscesses. These assays are typically conducted with automated clinical chemistry analyzers (analyzers) onto which fluid containers, such as tubes containing patient samples have been loaded. The analyzer extracts a liquid sample from the tube and combines the sample with various reagents in special reaction cuvettes or tubes (referred to, generally, as reaction vessels or cuvettes).

A modular approach is often used for analyzers. Some larger systems include a lab automation system that can shuttle patient samples between one sample processing module and another module. These modules include one or more stations, including sample handling stations and testing stations. Testing stations are units that specialize in certain types of assays and provide predefined testing services to samples in the analyzer. Exemplary testing stations include immunoassay (IA) and clinical chemistry (CC) stations. In some laboratories, typically including smaller labs, these testing stations can be provided as independent/standalone analyzers or testing modules, allowing an operator to manually load and unload individual samples or trays of samples for CC or IA testing at each station in the lab.

A typical IA analyzer module is a clinical analyzer (integrated into a larger analyzer or standing alone) that automates heterogeneous immunoassays using magnetic separation and chemiluminescence readout. Immunoassays take advantage of the existence of either specific antibodies for the analytes being tested or specific antigens for the antibodies being tested. Such antibodies will bond with the analyte in the patient's sample to form an "immune complex. " In order to use antibodies in immunoassays, they are modified in specific ways to suit the needs of the assay. In heterogeneous immunoassays, one antibody (capture antibody) is bound to a solid phase, a fine suspension of magnetic particles for the IA module, to allow separation using a magnetic field followed by a wash process. This is exemplified in sandwich assays and competitive assays. An exemplary IA module menu can include additional variations on these formats.

In the typical sandwich assay format, two antibodies are used, each one selected to bind to a different binding site on the analyte's molecule, which is usually a protein. One antibody is conjugated to the magnetic particles. The other antibody is conjugated to an acridinium ester molecule (AE). During the assay, sample and the two modified antibody reagents are added to a cuvette. If the analyte is present in the patient's sample, the two modified antibodies will bind and "sandwich" the analyte molecule. Then, a magnetic field is applied which will attract the magnetic particles to the wall of the cuvette, and excess reagents are washed off. The only AE-tagged antibody left in the cuvette is one that formed an immune complex through the sandwich formation with the magnetic particles. Acid solution is then added to free up the AE into solution, which also includes hydrogen peroxide needed for the chemiluminescence reaction. A base is then added to cause it to decompose, emitting light (see reaction formulas below - a variety of AEs are used in various assays but the fundamental chemistry is substantially identical). Light is emitted as a flash lasting a few seconds and is collected and measured in a luminometer. The integrated light output is expressed as relative light units (RLU's). This is compared to a standard curve, which is generated by fitting a dose-response curve to RLU values generated by known standards of the same analyte over its clinical range. Sandwich assays produce a direct dose-response curve where higher analyte doses correspond to increased RLUs.

The competitive assay format applies to molecules for which only one antibody is used. This antibody is conjugated to the magnetic particles. A second assay reagent contains the analyte molecule conjugated to the AE. During the assay, the quantities of the reagents are chosen such that the analyte from the patient's sample and the AE-tagged analyte compete for a limited amount of the antibody. The more patient analyte there is, the less AE-tagged analyte will bind to the antibody. After magnetic separation and wash, the only source of AE in the cuvette is from AE-tagged analyte that has been bound to the magnetic particles through the antibody. Acid and base are added as before, and the dose analysis is as described for the sandwich assay. Competitive assays produce an inverse dose-response curve, where a higher signal corresponds to a lower amount of analyte in the patient sample.

The IA analyzer module magnetic particle reagent is also referred to as the "solid phase" and the AE-tagged reagent is referred to as the "lite reagent. " The IA analyzer module provides the hardware and software to enable running multiple assays of various formats concurrently in random-access and with high throughput.

At the heart of a typical IA analyzer/module is an incubation ring. To perform the above-described assays, the reactions need to take place at a well-controlled temperature range, typically coinciding with nominal temperature of the human body. An incubation ring provides a regulated thermal body to ensure that cuvettes maintain this temperature range while the cuvettes move in the IA module. By providing a ring, random access to cuvettes can be provided. This allows assays of varying length to be performed in parallel, allowing some cuvettes to receive analytes/reagents, some receive sample aliquots, some to be analyzed, some to be washed, etc. simultaneously. The ring can then be moved at regular intervals under processor control to ensure that reactions take place at a controlled incubation temperature for a prescribed time interval before analysis of the reaction. The typical incubator ring rotates relative to a fixed base, typically driven by a motor affixed to the base that drives a gear ring or belt on the moving ring.

<FIG> shows a cutaway view of an exemplary prior art incubation ring. Incubation ring <NUM> includes two primary parts that generally move together, rings <NUM> and <NUM>. Inner magnetic ring <NUM> includes a plurality of arc-shaped magnets placed at specific locations along the circumference of ring <NUM>. Moving along with ring <NUM> is outer ring <NUM>, which includes a plurality of receptacles (called slots, but which can be any suitable shape) for cuvettes <NUM>. Generally, rings <NUM> and <NUM> are locked together as they move, allowing cuvettes and outer ring <NUM> to be exposed to magnetic fields for a predetermined amount of time. After a predetermined cycle time, ring <NUM> shifts angularly by a predetermined amount relative to ring <NUM>, indexing each cycle, such that cuvettes in ring <NUM> are exposed to the magnetic field for the predetermined amount of time, and each cuvette gets exposed to the field in succession. A drawback of this configuration is that the scheduling of the magnetic field exposure and wash cycle after a predetermined amount of time in the magnetic field can be complicated for a large number of samples in the ring <NUM>, especially if incubation times are intended to be varied for these cuvettes, which may be difficult or impossible with such an arrangement.

Incubation temperature control is provided by a stationary heating element <NUM> placed under ring <NUM>, allowing a uniform temperature to be applied to cuvettes <NUM>. As cuvettes <NUM> move along ring <NUM>, certain instruments interact with these cuvettes. Instruments <NUM> through <NUM> are spaced circumferentially from one another at predetermined locations. These instruments include a cuvette handler <NUM> that places fresh cuvettes into slots in the ring at a predetermined position. Once each cuvette is placed into the ring, the cuvette travels with the rotation of the ring until they reach the location of a reagent probe/pipette <NUM> that places an aspirated portion of a patient sample into the cuvette. After a sample portion is placed in a cuvette, the cuvettes travel with the motion of ring <NUM> to the location of reagent pipette <NUM>, which dispenses the appropriate reagents for a given immunoassay being performed on the given patient sample. The cuvette then travels along with ring <NUM>, where it is exposed to a magnetic field by the magnets in ring <NUM>, the content of the cuvette being washed by a washing pipette in the process. Typically, a cuvette is exposed to two magnetic field/wash cycles. Eventually, the cuvettes reach the location of elevator <NUM>, which pushes the cuvettes up out of ring <NUM> into position to be read by a luminometer <NUM>.

A drawback of ring <NUM> is that the magnets in ring <NUM> must be curved to match the curvature of ring <NUM>. This can be expensive to manufacture to the tolerances needed for medical testing. Furthermore, the throughput of the system is largely dictated by the radius of ring <NUM>. For a given size of ring <NUM>, the magnets of ring <NUM> must be designed specifically for that radius. Often it is desirable for a manufacturer to offer different models in a product family having different maximum throughputs to cater to customers having different needs. Because these systems require FDA approval, the radius of each ring <NUM> in a family of products must be independently certified, which can be time-consuming and expensive. Accordingly, a system such as that shown in <FIG> may not be a flexible design for family of products that have different throughput requirements for different models. A further drawback of this system is that this is only appropriate for a single-step immunoassay. The timing of the wash cycle directly affects the movement of all other cuvettes in the system, complicating scheduling.

Another exemplary prior art system <NUM> is shown in <FIG> in diagrammatic cutaway fashion. Rather than one ring <NUM> that holds cuvettes, such as that shown in <FIG>, system <NUM> uses two cuvette incubation rings <NUM> and <NUM>. These rings can move independently, providing random access to the contents of each ring. Meanwhile, an additional ring <NUM> is placed above concentric rings <NUM> and <NUM>. Ring <NUM> is non-concentric with these rings, allowing ring <NUM> two intersect rings <NUM> and <NUM> overhead at different locations along the travel of rings <NUM> and <NUM>. Ring <NUM> is used for the wash cycle, allowing cuvettes in this ring to be exposed to magnetic field for predetermined amount of time and washed, independently of the movement of rings <NUM> and <NUM>. This allows more flexible incubation cycle times for cuvettes in rings <NUM> and <NUM>. Piston elevators <NUM>, <NUM>, and <NUM> are actuators that facilitate movement of cuvettes starting in ring <NUM> into wash ring <NUM>, down into ring <NUM> if an additional incubation and wash cycle is required for an assay. Once all incubation and wash cycles are complete for cuvettes, elevator <NUM> can move the cuvettes up into the luminometer <NUM> for reading the results of the assay.

<FIG> shows an overhead view of system <NUM>. Rings <NUM> and <NUM> are concentric and allow for independent cuvette motion. Ring <NUM> interacts with instruments <NUM> through <NUM>, as discussed. Wash ring <NUM> is non-concentric, allowing ring <NUM> to intersect rings <NUM> and <NUM> at predetermined locations. Elevators are placed at these locations to move cuvettes up and down from rings <NUM> and <NUM> into and out of ring <NUM>. Elevator <NUM> at luminometer <NUM> allows the sample to be moved into the luminometer <NUM> for testing of the result of the immunoassay after prescribed incubation and wash times.

While the system provides more scheduling flexibility and a wider variety of immunoassays due to the potential for using rings of <NUM> and <NUM> for two stage assays, there are several drawbacks to system <NUM>. First, because wash ring <NUM> is a ring, the same issues relating to manufacturing and certifying curved magnets apply as in ring <NUM>. That is, ring <NUM> can be expensive to manufacture and ring <NUM> will be limited to a given diameter for all instances of analyzers to the product family unless additional certification testing is done for different diameter wash rings. Furthermore, multiple elevators can add additional expense and scheduling complexity.

Document <CIT> discloses an analyzer adapted to perform heterogeneous immunoassays. The analyzer comprises a conveyor system, which is divided into two sections, a cuvette preheater section and a cuvette dispense and incubation section. Each assay sample undergoes the same total incubation time of seven and one half minutes. When a cuvette reaches the end of this total incubation time, it enters a section of the process track or incubation section where separation and washing is accomplished.

<CIT> discloses an automated chemical analyzer wherein the analyzer includes an incubation station, a wash station and a read station. The incubation station includes an elongated, movable track to carry reaction vessels along an incubation path, the wash station includes a movable track to carry vessels along a washcycle path, and the read station is adapted to move vessels along a read path.

<CIT> discloses the incubation member may include one or more rings of receptacles and the washing member is a ring.

One or more of the shortcomings in the prior art can be addressed by providing a linear bridge wash system that transports the cuvettes along the linear track between portions of an incubation ring. This can include transport between portions of the same incubation ring or from one incubation ring to another.

The invention is disclosed in the independent claim <NUM>.

Embodiments of an immunoanalyzer and incubation/wash system for use therein utilize a linear wash system that acts as a bridge between two points in one or more incubation rings. By utilizing a linear bridge wash system, this bridge can be used with different sizes of incubation rings without needing to redesign and recertify the wash components between models within a product family, as is a problem in some prior art systems. Furthermore, linear components, such as a rectilinear magnets, can be manufactured and engineered more cheaply than arc-shaped magnets used in traditional ring-based wash systems. This can result in an overall reduction in engineering, manufacturing, and certification costs for a product family utilizing the linear bridge wash system.

Embodiments generally fall into two types of configurations. In the first configuration, a single incubation ring can be used. The ring has slots along the inner circumference of the ring. Those slots are open towards the center of the ring. A linear bridge is placed as a chord between two positions in the ring. That chord is preferably a radial chord passing through the center of the ring (e.g., coextensive with the ring diameter). When each cuvette slot rotates to the position where the bridge intersects the ring, the cuvettes in that slot can be pushed out of the slot towards the center of the ring, into the bridge. A conveyor system within the wash bridge then transports that cuvette past two wash stations. Each wash station has one or more magnets to provide a magnetic field and a probe (e.g., pipette or nozzle) for rinsing the contents of the cuvettes while exposed to the magnetic field. After being washed by two wash stations on the linear bridge, each cuvette is moved by the conveyor system of the linear bridge into a slot in the ring on the output side of the bridge. In embodiments where the bridge is across the center point of the ring, the input and output interfaces are at directly opposite sides of the ring. (Note that the input and output slots will move during the wash cycle, so the input and output slots can have any angular relationship depending on how the ring moves during the wash cycle. ) The washed cuvette can then be elevated to a luminometer in a different location as the ring rotates. Washing and luminometer reading of test results can thereby be independently timed.

Another embodiment utilizes two non-concentric incubation rings, one inside another. By using nonconcentric rings, the wash bridge can be placed between the inner circumference of a larger ring and the outer circumference of a smaller ring. The outer ring has slots configured to hold cuvettes arranged along the inner circumference. The inner ring has slots configured to hold cuvettes arranged along the outer circumference of that ring. The wash bridge can transport cuvettes from the inner circumference of the larger ring to the outer circumference of the inner ring. This allows more slots for cuvette incubation than could be provided by a single ring. This can increase the throughput of the system without changing the wash bridge between embodiments having one ring and embodiments having two rings. Accordingly, the same wash bridge can be used for both single ring and double ring embodiments. Furthermore, in the multi-ring embodiment, the diameters of the two rings can be chosen to be any size, provided that the arrangement of the outer edge of the inner ring and inner edge of the outer ring is the same distance as the length of the wash bridge. In yet another embodiment that is less space efficient. The two-non-concentric rings can be placed beside one another, rather than using an inner and outer ring; slots are placed on the outside of each ring with the wash bridge between the rings. This can allow rings to be the same size or for rings to have any desired size relative to one another.

<FIG> shows a cutaway view of an exemplary embodiment of a single ring system <NUM> using a linear wash bridge <NUM>. System <NUM> includes a single incubation ring <NUM>, which includes a plurality of circumferential slots with openings toward the center of the ring. Cuvettes <NUM> are placed into these slots by cuvette loader <NUM>, and filled using a sample probe <NUM> and reagent probe <NUM>. The rotation of ring <NUM> is in accordance with the prescribed movement program that provides random-access to cuvettes, while exposing the cuvettes to the predetermined incubation cycle. In this embodiment, a ring-mounted heating element <NUM> is placed in thermal contact with the surface of ring <NUM>. This heating element <NUM> provides controlled thermal regulation to incubate cuvettes at a prescribed temperature, such as 37C. Power and control of heating element <NUM> can be provided by one or more slip rings <NUM>. Slip rings <NUM> can be part of a larger static element that provides axial constraint to the rotation to ring <NUM>. Additional information about the operation of heating element <NUM> and slip rings <NUM> can be found in <CIT>, entitled "System And Method For Thermal Control Of Incubation System In Diagnostic Analyzer,". In some embodiments, a static heating element that does not rotate with the incubation ring can be used.

When a cuvette is rotated to a predetermined position corresponding to the input side of wash bridge <NUM>, a pushing element, such as a pusher <NUM>, (e.g., a pneumatic/hydraulic piston, a linear actuator, a lead screw/rack and pinion device) provides a radial force on the cuvette to push the cuvette out of the slot in ring <NUM> and into the transport mechanism of wash bridge <NUM>. Wash bridge <NUM> then transports the cuvettes linearly past a plurality of washing stations that include one or more linear magnets and a probe that uses aspirations and dispensing of a washing agent to wash the contents of the cuvette while exposed to a magnetic field of the magnets. After the washing steps are complete, cuvettes are delivered by the motion system that provides linear motive force on each cuvette across linear bridge to a slot on the other side of ring <NUM>. Ring <NUM> is then rotated with the cuvette in that new slot until that cuvette reaches an elevator <NUM> (e.g., a pneumatic/hydraulic piston, a linear actuator, a lead screw/rack and pinion device) that lifts the cuvette into luminometer <NUM> for a luminosity reading to detect the results of the immunoassay. Rotational motive force can be provided to move the incubation ring by motor <NUM>, via timing belts/chains or direct/gear drive. This allows ring <NUM> to rotate under computer control.

<FIG> is a perspective view of example embodiment <NUM>. Incubation ring <NUM> includes a plurality of slots <NUM> configured to hold cuvettes on the inner circumference. When each slot aligns with the opening for wash bridge <NUM>, a pusher pushes the cuvette into the motion system of wash bridge <NUM>, where wash stations perform washing steps. After passing through the washing stations, the motion system of wash bridge <NUM> places the cuvette into an open slot on the opposite side of ring <NUM>. This transfer can utilize another pusher device to place the cuvette into the receiving output slot of the incubation ring.

<FIG> is a cutaway view of a system <NUM> where two incubation rings are used, joined by a wash bridge. Incubation ring 52a is a larger diameter incubation ring having the same configuration as incubation ring <NUM> in <FIG>. A static slip ring is not shown, for visual clarity. Incubation ring <NUM> is thermally regulated by heating element <NUM> as previously discussed. In this embodiment, wash bridge <NUM> goes between the inner circumference of ring 52a and the outer circumference of smaller incubator ring <NUM>. This allows a greater number of slots for cuvettes in these two rings. Ring <NUM> is also thermally regulated by a heating element (not shown). Cuvette slot are placed circumferentially around ring <NUM>, oriented outwardly, allowing the slots to be exposed to bridge <NUM>. Incubated cuvettes are pushed from ring 52a by piston <NUM> to wash bridge <NUM>. Cuvettes exit wash bridge <NUM> via the motion mechanism of wash bridge <NUM> into an open slot in ring <NUM>. Upon reaching the position <NUM> coincident with elevator <NUM>, each cuvette is raised into luminometer <NUM> for reading the results of the assay.

<FIG> is a perspective view of a two-ring system <NUM>. Outer ring 52a is thermally regulated and includes a plurality of internal facing slots 53a configured to hold cuvettes. As each of these slots 53a reaches the position coincident with the entrance to bridge <NUM>, that cuvette is moved out of the slot of ring 52a into the motion system of bridge <NUM> for washing. After washing is completed by washing stations on wash bridge <NUM>, the linear motion system positions the cuvette into a corresponding open slot on internal ring <NUM>. Ring <NUM> has a plurality of outward facing slots <NUM> configured to receive and hold cuvettes until the luminometer <NUM> (<FIG>) is available for reading the result of the immunoassay. An elevator (not shown) raises the cuvette up for a reading.

<FIG> is an isometric view of wash bridge <NUM>. <FIG> is a bottom review of wash bridge <NUM>. Wash bridge <NUM> includes a linear wash bridge track <NUM> that can be made out of a suitable rigid material, such as machine aluminum, hard plastic, or fiber-reinforced plastic. This provides a rigid linear constraint on the motion of cuvettes crossing the bridge. Cuvettes are moved along wash bridge track <NUM> via a motorized belt, such as timing belt <NUM>, which is driven by stepper motor <NUM>. The term motorized belt in this context is a generalized term to describe a flexible belt made of continuous material, such as a rubber timing belt with or without teeth to engage a gear, or a chain made of rigid plastic or metal links. The belt includes features configured to engage the cuvettes, such as a high friction surface or mechanical elements that secure the cuvettes to the moving belt to move the cuvettes in the direction of travel. The motorized belt provides a motive force to transport the cuvettes along the linear wash bridge track <NUM> of the wash bridge <NUM>.

In some embodiments, timing belt <NUM> is arranged as a serpentine belt driven by motor <NUM> and tensioned and positioned by idler pulley's <NUM>. Serpentine belt <NUM> includes a plurality of ribs that interface corresponding structural features on cuvettes that cross linear wash bridge track <NUM>. Cuvettes pass to wash stations 90a and 90b. Each wash station includes a linearly actuated pipette (92a and 92b) that is driven up and down by a stepper motor (<NUM>). Pressure inside the probes can be driven by suitable means, such as by pneumatic or hydraulic pumps or pistons, to provide aspiration and dispense pressures to sip and spit to remove extraneous components of the contents of the cuvettes during a washing process. Prior to interacting with these pipettes, cuvettes <NUM> passed by linear magnets 94a and 94b. These linear magnets provide a magnetic field that interacts with magnetic particles in the reaction fluid, pulling these particles against the wall of the cuvette. This prevents those particles from being washed by the pipettes during the sip and spit washing process. The remaining particles then luminesce later during a luminosity reading. In this embodiment, two wash stations are provided on linear bridge <NUM>, which is typical for a washing process in the art. This is typical where the washing process at each station is not sufficient to be completed using a single wash cycle. However, it should be appreciated that some embodiments use a single wash station that provides a sufficiently complete wash of the contents of the cuvette in a single washing operation, and that additional wash stations can be provided as part of bridge <NUM> if the immunoassays being used would benefit from additional washing processes. The number of washing stations used can be chosen based on the overall washing efficiency of a station, which can be affected by such factors as the rinsing agent, the pressure/velocity/volume of the rinsing agent, the volume of the analyte being washed, the magnetic field strength, the needed test accuracy, the cycle time, the number of wash cycles performed at a station, etc..

In some embodiments the serpentine belt <NUM> is not entirely planar, as shown in <FIG> and <FIG>. Rather, in some embodiments, serpentine belt <NUM> can be twisted, such that motor <NUM> need not be mounted in the same plane as wash stations 90a and 90b (e.g., the motor can be mounted underneath with the drive shaft placed horizontally). This can be done for more efficient packaging if necessary.

Claim 1:
An immunoanalyzer comprising:
a first cuvette incubation ring (52a) having a plurality of slots on an inner circumference, each slot being configured to hold a sample cuvette (<NUM>) and a drive mechanism to rotate the first ring (52a);
a second cuvette incubation ring (<NUM>) having a plurality of slots on an outer circumference, each slot being configured to hold a sample cuvette (<NUM>) and a drive mechanism to rotate the second ring (<NUM>);
a plurality of pipettes configured to interact with cuvettes (<NUM>) in the first cuvette incubation ring (52a) at predetermined locations;
a linear wash bridge (<NUM>) configured to receive cuvettes (<NUM>) from a first location of the first cuvette incubation ring (52a), wash the contents of each cuvette, and to deliver each cuvette (<NUM>) to a second location of the second cuvette incubation ring (<NUM>); and
a luminometer (<NUM>) configured to analyze the contents of each cuvette (<NUM>) subsequent to each cuvette (<NUM>) traveling along the linear wash bridge (<NUM>),
wherein the second cuvette incubation ring (<NUM>) is configured to receive and hold cuvettes (<NUM>) until the luminometer (<NUM>) is available.