DE60224312T2 - Integrated system for fluid delivery and analysis - Google Patents

Description

Field of the invention

The The invention relates to a system for delivering and analyzing liquids, and in particular an integrated system for dispensing liquid and analysis.

Background of the invention

modern Laboratory techniques, such as a development of an investigation and screening with a high-performance run of candidates from Drug mixtures, can the dissecting and Analyze hundreds of thousands or millions of samples below Using techniques as diverse as luminescence, Absorption and diffusion are. Recently, the processing is such Samples by packing the samples in sample holders with high Density, such as microplates, for common analysis facilitated in an automated device.

Unfortunately have the known systems for processing multiple samples significant disadvantages. For example, the known systems not the flexibility for processing sample holders with different sample densities, or the sensitivity or have accuracy to sample holders with small sample volume to process. Furthermore, can known systems great base areas so that these significant areas in lab facilities, in which space is scarce, occupy. In addition, known systems can be applied to individual (Unit) processes limited so that, for example, spend these samples or analyze samples can, but do not do both. Therefore, the known systems different devices for require different applications, or too missed hits, limited Research skills, less run, and / or increased costs for blends, Conduct examinations and reagents.

Summary of the invention

The The invention provides an integrated system for liquid delivery and analysis before, the components to prepare and analyzing samples. The components can Transport module, a fluid technology module and include an analysis module among others. The invention includes Instruments and systems as described in the claims.

Brief description of the drawings

1 Figure 4 is a perspective view of an instrument system constructed in accordance with the aspects of the invention.

2A is a side view of a cross section of the instrument system of 1 , mainly along the line 2A-2A in the 1 runs, the sections of a fluid technology module, a material exchange module and a transport module shows.

2 B is an end view of a cross section of the instrument system of 1 Mainly along the line 2B-2B in the 1 which also shows sections of a fluid technology module, a material exchange module and a transport module.

3A and 3B FIG. 4 are complementary perspective views of a fluidics module constructed in accordance with the aspects of the invention. FIG.

4 FIG. 12 is a perspective view of portions of the fluidics module of FIG 3A and 3B showing a liquid dispensing system, a material exchange system, and a housing (in dashed lines).

5 FIG. 4 is an alternative perspective view of portions of the fluidics module of FIG 3A and 3B showing the system for dispensing liquid and the system for exchanging material.

6 is a perspective view of an output arrangement of the liquid dispensing system of 5 ,

7 is a partial exploded perspective view of the dispensing assembly of FIG 6 ,

8th is a perspective view of a means of transport of the station for the exchange of materials of 5 ,

9 is an exploded perspective view of the means of transport of 8th ,

10 Figure 13 is a schematic view of an analysis module constructed in accordance with the aspects of the invention.

11 Figure 3 is a perspective view of a transport module constructed in accordance with the aspects of the invention.

12 FIG. 13 is an exploded perspective view of a scanning optical section device for use with the analysis module of FIG 10 in combination with the transport module of the 11 ,

13 FIG. 16 is a perspective view of the optical section device of FIG 12 on the transport module of the 11 is attached.

14 is a perspective view of the other side of the transport module of 11 ,

15 is a perspective view of an air circulation housing for the underside of the transport module of 11 ,

16 is a perspective view of a variant of the transport module of 11 ,

17 FIG. 16 is a perspective view of the optical section device of FIG 12 attached to the transport module of the 16 is attached.

18 FIG. 12 is a perspective view of a portion of a temperature control system for use with the transport module of FIG 16 ,

Detailed description and best Mode of the invention

With particular reference to the 2A . 5 and 7 the drawings show an instrument for analyzing a sample, comprising: a detection device 1201 configured to detect light from a sample to an examination site, a sample output axis ( 2A ), which are substantially perpendicular to the examination site 1604 extends; and at least one station 1600 for exchanging material along the delivery axis for samples above the examination site.

Typically, the investigative body is an investigative site of several of examination sites located at an analysis station 1604 each inspection site having an output axis for samples that are perpendicular from the inspection site to the station 1600 extends to the exchange of material. Thus, the examination site can be one of several wells in a multiwell well. The instrument has a suitably fluid head 504 . 600 movable along the discharge axis for samples to convey liquid to the examination site.

The fluidic head 504 . 600 usually includes a number of channels 602 for dispensing liquid, in which case the station 1600 for exchanging material is preferably configured to pipette tips on the fluidic head 504 . 600 between the channels 602 to move liquid to and fro.

The instrument desirably has a delivery device 554A on that the material between the station 1600 for exchanging material in a direction that is substantially perpendicular to the sample dispensing axis. Another feature of preferred instruments is a second station 1602 to exchange material, each station 1600 . 1602 for exchanging material above the inspection site along the sample dispensing axis, in which case each station 1600 . 1602 for the exchange of material, preferably a conveying device 554A . 554B has, the material between the station for the exchange of material in a direction which is substantially perpendicular to the dispensing axis for samples, reciprocated.

The drawings also show a liquid dispensing system comprising: a liquid head assembly 504 . 600 containing an output device 602 ; a drive mechanism 506 that with the head assembly 504 . 600 connected to the head assembly 504 . 600 along a substantially vertical discharge axis for samples ( 2A ) to move; and at least two stations 1600 . 1602 for exchanging materials arranged along the sample dispensing axis, the head assembly 504 . 600 to every station 1600 . 1602 is movable to exchange materials to pick up or bring materials that are used to conduct an investigation.

The 1 is therefore a schematic view of an instrument system in accordance with aspects of the invention 100 for the preparation and / or analysis of samples. The system 100 includes a fluid technology module 102 , an analysis module 104 and a transport module 106 , The fluidics module participates in the sample preparation, for example by adding (and / or removing) a component of a sample and / or from a sample holder. The analysis module participates in sample analysis, for example, by performing an optical analysis of a sample based, inter alia, on photoluminescence, chemiluminescence, absorbance and / or diffusion. The transport module participates in sample transport, for example, by moving a sample or sample holder between an input / output (I / O) location, the fluidics module, and the analysis module.

The components of the system 100 may be partially or completely modular, potentially providing several advantages. First, a modular design allows non-functioning modules to be replaced by working modules, facilitating repair and reducing downtime. Second, a modular design allows outdated components to be replaced or expanded as operating requirements change or as improved modules become available to provide system growth.

The 2A is a cross-sectional view of the instrument 100 of the 1 , the details of the fluid technology module 102 , the analysis module 104 and the transport module 106 shows. The fluidics module includes an output system having an output assembly 504 for dispensing liquid, and a system for exchanging material that has multiple conveyors 554A . 554B for transporting materials to and from the dispensing assembly. The analysis module includes a light source, a detector, and optics adapted to receive light from the light source to a sample holder, such as a microplate 111 , which is positioned at an examination site, and to be directed from the sample holder to the detector. The analysis module may further include optics adapted to select the intensity, wavelength, and / or polarization of the light incident from the detector on the sample holder and from the sample holder on the detector. The transport module includes a holder for the sample holder or a conveyor 1101 for holding the sample holder, and a drive system for moving the sample holder holding device between loading / unloading positions and dispensing / inspecting positions. The replacement positions of the fluidics module and the analysis module inspection site can be separated by an integrated door that can be opened or closed to reduce or eliminate airflow and light leakage.

The Issuing arrangement and the means of transport for the exchange of material are movable between several positions, those caused by the work process or operations that performed at every position become, are distinguishable.

The dispensing assembly may be movable between two or more vertically separated positions including (1) an upper (shown) rest position, (2) a plurality of intermediate exchange positions, and (3) a lower dispensing position. The idle position can be used to accommodate the output device between the output operations. The replacement positions can be used to load and unload pipette tips, reagents, and other consumables during interactions with the materials handling equipment. The dispensing position may be used to dispense liquids into or onto a sample holder and / or to retrieve liquids from the sample holder. The dispensing position may be at or adjacent to an examination position ( 1600 . 1602 ) of the associated analysis module, so that liquid can be dispensed and samples can be analyzed simultaneously and / or sequentially without further movement of the sample holder.

The transport devices ( 554A . 554B ) to exchange material can be between two or more horizontally separated positions, including (1) an input / output position located just outside the module, (2) a rest position (shown) located exactly within the module, and (3) an exchange position ( 1600 . 1602 ) located further inside the module. The input / output position can be used to load consumables and other materials onto the conveyors for material exchange and to remove used consumables from the conveyances. A door may allow the conveyor to exit and retract the housing during movement to and from the entry / exit position. The rest position may be used to accommodate the conveyance between material exchange operations. The replacement positions may be used to transfer and receive pipette tips, reagents, and other consumables during interactions with the dispensing assembly. Thus, the replacement positions of the dispensing assembly and the conveying means for exchanging material should be partially or completely coincidental.

Further Aspects of the invention will become apparent without limitation in the following sections shown: (I) fluid technology module, (II) Analysis Module, (III) Transport Module and (IV) Examples.

I. Fluid technology module

The fluidics module generally includes any system or mechanism for automatically dispensing fluid into or onto a sample holder. The 3 to 9 show an exemplary fluidics module and its components constructed in accordance with aspects of the invention. The fluidics module may include a housing, an output system, and a material exchange system, among others, as described below. The housing may be used to surround and support portions of the module. The dispensing system can be used to dispense liquids, such as reagents, into a sample holder. The material exchange system may be used to supply the dispensing system with consumables such as pipette tips, reagents, and / or other materials.

A. Housing

The casing generally has any system or mechanism to Components of the output system and / or the system for the exchange of Material to surround and optionally support, and around the components, to protect the operator and the samples, if any.

The 3 shows complementary, perspective views of an exemplary fluidics module 300 that mimics exterior features of the module. These exterior features include a housing 302 , The housing may generally be shaped in any shape that allows the systems to be dispensed and / or exchanged for material and to interact with any associated auxiliary module, such as a transport module and / or an analysis module. Here, the housing comprises two substantially rectangular sections, in particular a larger output section 304 the housing components of the systems for dispensing and / or replacement of material and a smaller, adjacent input / output section 206 the housing components of the system for the exchange of material. The housing may generally be formed by any material that allows for interaction with the attached portions and / or a holder of the attached portions of the systems for dispensing and / or replacement of material and each auxiliary module. An exemplary housing includes a low cost, lightweight, rigid metal sheet chassis.

The housing may include handles, doors and / or removable panels. For example, handles 308 facilitate opening and / or carrying the modules. Removable plates 310 . 312 may facilitate maintenance access to interior portions of the module, such as those involved in fluid delivery. The doors 314a , b can facilitate the exchange of consumables within the module, such as pipette tips and reagents, and the removal of used consumables. In the module 300 can be an upper door 314a used to supply new pipette tips and remove used pipette tips, and a bottom door 314b can be used to deliver reagents. Here arrows indicate the general direction of movement of the movable / removable components.

The housing allows better control of environmental conditions within the module, including light level, temperature and humidity. The level of light can be reduced by using light-tight materials and connections and by closing the doors and the removable plat be checked during use. The temperature and humidity can be actively controlled, inter alia, by the use of a heater or a humidification system. Among other things, the temperature and humidity can be passively controlled by absorbing or releasing heat from drive components and moisture from evaporation. The fluid technology module 300 includes an active temperature control system that has separate, independently controlled heaters for the module as a whole and the fluid engineering system in detail, and a passive humidity control system that can still raise the humidity above the sample holder to at least 90%.

The housing may also provide a framework to which, as desired, components of the module may be mounted for mounting to facilitate precision alignment between the components. For example, some module components may be mounted in the housing interior, as described below. Other module components, such as electronic control panels 316 , Drivers 318 and electrical connectors 320 , can be mounted on the outside of the housing to shield them from conditions within the housing (such as high temperature and humidity) and make them more accessible for repair and / or replacement. The electrical connectors may include power connectors for powering internal components of the module, such as drivers, sensors, etc. The electrical connectors may also include logic connectors for transmitting instructions and data between the components of the module and any associated analyzer and / or external processor.

The 4 shows a perspective view of a fluid technology module 400 that the relationship between a housing 402 (shown in dotted lines), an output system 404 (shown without its output device) and a material exchange system 406 represents. In particular, these figures show how the various guide shafts and drive motors of the systems for dispensing and exchanging material are disposed on the housing. These fixtures support the components during use and help maintain their proper orientation. Vertical guide shafts 408 from the dispensing system extend from the top to the bottom along a vertical extent of the housing, while horizontal guide shafts 410 from the system for exchanging material along a horizontal longitudinal extent of the housing. The drive motors, with a vertical drive motor 412 associated with the dispensing system mounted near the top of the housing and with two horizontal drive motors 414 belonging to the system for the exchange of material, which are fixed in the vicinity of the bottom of the housing, generally below the vertical drive motor, are mounted on the same side of the housing.

B. output system

The Output system generally includes any system or mechanism for dispensing liquids in a sample holder.

The 5 shows a perspective view of an exemplary fluidics module 500 that has an output device driver 506 to move an output device 504 for dispensing liquid and at various positions such as the rest position, the exchange position and the dispensing position as described above. The dispensing system may also include additional components that can reduce bubble formation and / or better adjust the reagent and sample temperature, such as a heat regulator, to control the temperature of the dispensed liquid.

The exemplary output system sees a compact, automatic plate to plate pipetting system for use with a variety of Investigations before. In particular, the system includes a compact, modularly folded pipetting head, which is for non-contact output down up to 2 μL using 200 μL Pipette tips with a fast acceleration / movement / deceleration is capable.

(1) issue order

The dispensing assembly generally includes any mechanism or system for automatically dispensing liquid into or onto a sample holder. The assembly may be capable of simultaneously and / or sequentially dispensing liquid at one or more sample sites in uniform and / or nonuniform aliquots. The output strategy may be coordinated with a suitable detection strategy, such as the time stamping strategy described in U.S. Patent Nos. 4,778,701 and 5,477,259 US Patent 6,236,456 , published May 22, 2001. The arrangement may also be suitable for automatically loading and / or removing dispensing elements, such as pipette tips.

The dispensing assembly may utilize non-contact dispensing mechanisms and / or touch-dispensing mechanisms, such as those disclosed in U.S. Pat WO 00/66269 , published November 9, 2000.

One non-contact Output mechanism generally has any mechanism for dispensing liquid in which the issuer does not normally take the sample or the Sample holder in which the liquid is spent, touched. An example of a manual, non-contact dispenser is an eye dropper that can deliver drops of a liquid without to touch a sample or sample holder. The eye dropper uses changes in air pressure, by pressing or releasing a balloon to be generated each liquid Pull into a dispensing tube and dispense liquid from a dispensing tube. Another example of a manual, non-contact dispenser is a syringe. The syringe uses a positive displacement piston (or an air displacement piston), which is slidably positioned in a syringe barrel to liquid suck in and deliver.

One Touch dispensing mechanism generally has any mechanism for dispensing liquid in which the dispenser normally receives the sample and / or the sample holder touched, into the liquid (s) is delivered. An example of a touch dispenser is a pen transfer device. This device uses a pen to handle small amounts of fluid to transfer between sample holders, by a tip of the pen touching a liquid to a drop of liquid record and then touched the tip of a sample or a sample holder to the drop in deliver the sample or to the sample holder.

Some Systems can between non-contact Output mechanisms and touch-dispensing mechanisms be interchangeable, depending on whether the liquid by air or by liquid to liquid Contact is made (eg ejected). For example, can a non-contact Dispensing mechanism, such as a pipette tip, in one Contact format can be used by the pipette tip a sample or touching a sample holder, around "one last drop of "liquid to remove.

The 6 and 7 show details of an exemplary output arrangement 600 showing portions of the dispensing assembly used to pick up and dispense liquids. This arrangement includes components for forming an automated multi-channel air displacement pipettor comprising pipetting elements, an ejection system, and an actuator.

The output arrangement 600 includes a plurality of pipetting elements, each having a tubular cylinder 602 with an internal bore and a cylindrical piston 606 which is so large that it fits exactly but slidably into the inner bore.

The cylinders generally include any mechanism having an opening configured to receive a piston for aspirating or dispensing fluid. The cylinders 602 can have different outside dimensions with a flared top end 608 that is designed to have a corresponding cylinder O-ring 610 take a substantially cylindrical central portion 612 and a conical or narrowed lower end 614 designed to receive a pipette tip (not shown). The cylinders can be held by appropriate openings 616 in a basic arrangement 618 be attached by placing the upper end of each cylinder and the corresponding cylinder O-ring between the base assembly and a cylinder receiving plate 620 , which is positioned above the base assembly, is inserted. The cylinders may also be through corresponding openings 622 in a base assembly attachment 624 are fixed by the base assembly attachment below the base assembly and positioned about the central portions of the cylinder so that only the lower ends of the cylinder are exposed. The cylinder receiving plate, the base assembly, and the base assembly attachment may be secured using suitable fasteners, including removable means such as screws 626 that facilitate repair by allowing easy disassembly and assembly to be interconnected.

The pistons generally include any component designed to fit within the aperture of a corresponding cylinder to aspirate or dispense liquid, including air displacement pistons and forced displacement pistons. The pistons 606 can have a different Außenabmes with a notched, upper end 627 that is designed to have a corresponding piston O-ring 628 and a locking E-ring 630 take a substantially cylindrical central portion 632 and a narrow, lower end 634 , The pistons can be held through corresponding openings 636 in a piston mounting plate 638 secured by the notched upper end of each piston and the corresponding O-ring and E-ring between the piston-mounting plate and a piston-receiving plate 640 , which is positioned above the piston support plate, are inserted. The plunger-receiving plate and the plunger-holding plate can be fixed using suitable fasteners such as screws 642 , which make the repair easier again, be connected to each other.

The output arrangement 600 Also includes an ejection system that generally includes any mechanism for removing pipette tips or other dispensing elements of the dispensing assembly, particularly after use. The ejection system can be a stripper plate 644 , a set of ejector pins 646 and a corresponding set of protrusions 648 the actuator include. The stripper plate generally includes any mechanism for catching and removing a pipette tip from a corresponding cylinder, preferably by contacting an upper portion of the pipette tip and ejecting it from the cylinder. Here is the stripper plate 644 an elongated plate that has several openings 650 Has. The plate is designed to be below the base attachment 624 so that the lower ends of the pipetting cylinders extend through the openings to receive the pipette tips. The ejector pins generally include any mechanism for engaging and moving the stripper plate. Here are the ejector pins 646 substantially cylindrical, similar to the pistons, with a notched upper end 652 which is designed to be an e-ring 654 and a narrow, lower end 656 that is designed to fit into a corresponding recess 658 to intervene in the stripper plate. The ejector pins pass through corresponding openings in the cylinder receiving plate 620 , the basic arrangement 618 and the base attachment 624 wherein the notched upper end and a biasing spring 660 , which is secured to the piston receiving plate by the E-ring, and the narrowed, lower end in contact (and preferably connected) with the stripper plate. The protrusions of the actuator generally include any mechanism to reversibly move the ejector pins, particularly by pressing on the upper ends of the ejector pins or adjacent to the upper ends of the ejector pins. Here are the projections of the actuator 648 down-facing components extending from a floor surface 662 extend the piston receiving plate.

The Ausgebanordnung 600 Also includes an actuator device that generally includes any mechanism for reversibly moving the pistons and / or ejector pins, for example, to respectively receive and / or dispense fluid, or to load and / or remove dispensing elements. The actuator may comprise a single system configured to move both the pistons and the ejector pins, as here, or comprise a plurality of systems configured to independently select either the pistons or the ejector pins or subsets or combinations thereof move. Suitable actuators may include, but are not limited to linear actuators, rotary actuators and combinations thereof, as described below in connection with the dispenser driver. Here, the actuator includes a rotary motor 664 , a pulley system 666 and a linear drive spindle 668 , The engine, the pulley system and a first end 670 the drive spindle are on the base assembly 618 adjacent to the cylinders 602 attached. A second end 672 The drive spindle is on the piston receiving plate 638 attached. In use, the motor rotates the pulley system, the pulley system rotates the drive spindle, and the drive spindle raises or lowers the piston receptacle depending on the direction of rotation of the motor. Over a first range of motion, the piston retainer moves only so far to raise and lower the pistons so that the pipetting elements can charge or dispense liquid. Over a second range of motion, corresponding to that which would be a negative displacement volume, the piston retainer moves so far that the projections of the actuator grip the ejector pins which push the stripper plate downwardly to remove the pipette tips. The biasing springs (or any other suitable biasing mechanism) ensure that the stripper plate returns to its disengaged position as the plunger retainer returns toward forced delivery.

The loading and unloading of the tip can be partially or fully automated. The pipette tips may be loaded onto a respective cylinder by moving the pipette tips and the dispensing assembly to a common replacement position and then lowering the dispensing assembly until the conical lower ends of the cylinders contact an appropriate set of pipette tips which then upwardly expose the ends move until they are firmly attached. The spacing, rate and / or force with which the dispensing assembly is lowered to load pipette tips can become constant or variable depending on the part of the type and the number of tips to be loaded. For example, the rate at which the dispensing assembly is lowered may be reduced as the number of spikes to be loaded is reduced. If the rate reduction is linear, an output device constructed to sustain eight peaks may be split from a first rate to receive eight peaks to a half of the first rate to receive four peaks, and a second rate Eighth of the first rate, to record a peak, be lowered. Such a reduction in the rate may result in a reduction in engagement force and may be accomplished through the use of various methods, such as a proportional reduction in the current for the output actuator. In particular, such a reduction in the exemplary embodiment may be performed by a current / speed reduction of the stepper motors connected to the output actuator. As described above, pipette tips may be unloaded by positioning the dispensing assembly in an appropriate position (eg, above an empty stacking position), and then moving the piston-receiving plate until the protrusions of the actuator grasp the ejection pins and the ejector pins Press the stripper plate until the pipette tips are pushed away from the cylinders. The dispensing assembly may be moved "back to baseline" after the pipette tips are loaded or unloaded, that is, the assembly is returned to its rest position prior to each subsequent operation.

The Dispensing arrangement may be a pipetting or multiple pipetting elements, z. B. the air displacement type or others, depending from the pipetting strategy. For example, the pipettor a linear array of 8, 16 or any other number of due comprise spaced-apart pipetting elements, each one a single Line of a 96-well microplate, a 384-well microplate or any other number of well microplates. The pipettor can also have a linear array of 12 or 24 comprise suitably spaced pipetting elements, each one column of a 96-well microplate or to correspond to a 384-well microplate. The pipettor can Also include a number and arrangement of pipetting elements, the a section of a row or a column, or two or more Rows or columns or another type of sample holder. The output arrangements can on the output device driver to be easily replaceable to microplates and other sample holders of different numbers and / or densities the shafts adapt.

Of the Pipettors can be built to work with a tray of output elements to interact, such as a tray of pipette tips, as described below. The distance between the output elements in the tray typically coincides with the distance between the Pipetting in the pipettor match.

(2) Driver for the output device

Of the Driver for the dispensing assembly generally includes any mechanism or any system for reversibly moving the dispensing assembly at least for a long time a single, preferably vertical axis, so that the Output arrangement between a rest position and an issue position can be moved. The driver can be a single, linear actuator or a combination of linear and / or rotary actuators lock in. Suitable linear actuation devices include, among other things, a positioning table, a rodless one Cylinder, a robot module, an electric pressure cylinder, one pneumatic cylinder, a linear motor, a linear voice coil and a solenoid. Suitable combinations include, among others a rotating actuator, like For example, a rotary motor, a stepper motor, a geared motor, a reduction gear, a hand crank or micrometer, and a mechanism for converting the rotary motion into a linear motion, such as, but not limited to, a belt drive, a ball screw, or a trapezoidal threaded spindle. The driver can be feedback mechanisms use the positioning and / or motion profile of the Increase output arrangement.

5 shows an exemplary output device driver 506 , which is a rotary motor 508 which is connected to the dispensing assembly by a series of pulleys and belts around the dispensing assembly along two vertical support guides 510 to move up and down. The engine is directly connected to a relatively narrow, first pulley 512 connected. The first pulley is through a horizontally oriented reduction belt 514 with a relatively large second pulley 516 connected at a first end 518 a tensioner block 520 is positioned. The second pulley is through a horizontally oriented idler pulley reduction shaft 522 , which is connected to the idler block, with a relatively small, third pulley 524 connected to the a second end 526 of the idler block is positioned. The third pulley is through a vertically oriented drive belt 528 is connected to a passive fourth (not shown) pulley, wherein the third and the fourth pulley are positioned approximately at opposite ends of the vertical guide shafts. Finally, the drive belt is with an output assembly holding member 530 connected, which holds the dispensing assembly and slidably to the vertical support guides using two openings 532 and two associated bearings 534 is attached. The support guides generally include any mechanism for aligning the movement of the dispensing assembly and may include one element, two or three or more elements, such as the two cylindrical shafts shown herein. The engine, the pulley block, the fourth pulley and the vertical bracket guides are as shown in the 4 is shown attached to portions of the housing so that the reduction belt, the idler gear reduction shaft, and the drive belt are aligned approximately at right angles to each other.

The output device driver can easily move the output device up or down by reversing the direction of rotation of the motor. The dispensing assembly is generally moved down to receive or dispense pipette tips and reagents and to position itself for dispensing above a sample holder. The dispensing assembly is generally moved upwardly after picking up or dispensing pipette tips and reagents and after dispensing into a sample holder. The dispensing assembly is generally oriented so that the pipetting elements remain aligned with the sample holder and the components of the stations for the exchange of materials. However, if desired, the dispensing assembly, sample holder, and / or components of the replacement stations may be realigned using, for example, the mechanisms disclosed in U.S. Pat WO 00/66269 , published November 9, 2000. This realignment mechanism, for example, allows the dispensing assembly to be offset along an axis determined by a linear array of the dispensing elements so that an 8-channel dispensing assembly for a 96-well microplate can be used to provide a 384-well microplate by outputting a combination of a first output into a first set of 8 bays, one offset, and a second output into the second set of 8 bays.

The Belts and pulleys on the output assembly driver can be selected and / or arranged to provide various benefits. First, the connecting the smaller, first pulley with the larger second pulley in the system with the reduction belt causes a mechanical Advantage, a reduction in the load on the engine, as a single Rotation of the small drive pulley only to a partial rotation the larger pulley leads. Second, the rotation for Turn connection of the larger second Pulley to the smaller third pulley through the idler gear reduction shaft elevated the accuracy of the engine, given a given movement of the engine and therefore the first pulley only to a reduced movement the third pulley leads, allowing a more accurate positioning and changes in positioning possible are. Third, the belt and pulleys may include locking recesses, or can through chains and gears be replaced to belt slippage and any associated error to reduce. If it is desirable is the tension in the reduction belt, the drive belt and / or other belts in the fluidics module the use of a tension spring to be maintained, the Example attached to one end of the respective belt. at the exemplary embodiment The peak load pressure is partly due to a very stiff and adjustable belt tensioning system which controls the Z-axis movement.

C. System for exchanging material

The System for exchanging material generally identifies each system or any mechanism for exchanging materials with an output system, such as pipette tips and reagents on.

The 5 shows a perspective view of an exemplary exchange system 552 , one or more means of transport 554 for holding a material holder or several material holders 556 and a vehicle driver 558 or more means of transport driver 558 for moving the conveyances to various positions, such as the entry / exit, resting and exchange positions described above. These means of transport and vehicle drivers may be the same or different depending on the part of their intended uses. For example, an upper conveyor may be larger and / or longer to accommodate a pipette tip shelf, and a lower conveyor may be smaller and / or shorter to adapt to a microplate for reagents.

Exemplary vehicles and vehicle drivers are described below. The exemplary system allows for intermediate plate transports with a minimum of movement, particularly two X-axis motions and one Z-axis motion. Suitable alternatives are in the U.S. Patent 6,159,425 , issued on December 12, 2000.

(1) means of transport

The means of transport generally includes any mechanism or system for supporting Materials on as the vehicle driver these to an exchange station and away from the exchange station emotional. The means of transport can for receiving and holding a material holder, such as a pipette tip tray, a liquid container or a microplate, be suitable. The means of transport can also be used to automatic attachment of the material holder within the means of transport in a defined and reproducible position and orientation, and capable of releasing the material holder prior to its removal be.

The 8th and 9 show details of an exemplary conveyance 800 , which is a means of transport housing 802 , a conveyor bracket 804 and an automatic material holder positioning mechanism 806 includes.

The carriage housing generally includes any mechanism for supporting a material holder. The conveyance housing 802 includes a filing structure 808 and an associated frame structure 810 for holding and fixing the material holder. The storage structure may be constructed to support a bottom of the material holder and the frame structure may be constructed to secure one or more sides of the material holder. The tray and / or frame structures may be continuous, as shown, or they may be discontinuous, including pins, staples, or other support mechanisms.

The Storage and frame structures can together form a transport cavity shaped and so is great to hold a special type of material holder, such as a standard pipette tip tray or microplate. Here the cavity is about rectangular, with a size that something bigger as the assumed outer dimension a microplate (for example having a larger dimension X of about 130 millimeters and a smaller dimension Y of about 90 millimeters). A slight oversizing can facilitate the arrangement by a robot and / or by hand.

The Carrier housing can along one Section of its bottom and / or its sides be open to the Reduce mass and / or the arrangement by a robot and / or to facilitate the removal of the material holder. In particular, can a material holder transfer device gently place a material holder on the conveyor housing, in which these are in or over the transport cavity moved to the open side and then down through the open Ground moves when at least a portion of the ground and one Side are open.

The conveyor mount generally includes any mechanism for supporting a carriage housing and attaching it to a conveyance driver. The conveyor bracket 804 includes two elongated components 812 which extend parallel to each other from adjacent corners of the conveyor housing. Each component comprises two circular openings 814 configured to slidably include a corresponding substantially cylindrical horizontal support guide as described below. The conveyor is preferably mounted so that the components extend away from the input / output position, for example, parallel to a major axis of the transporter housing. Every component can also have a bearing 816 include, for example, a linear bearing to facilitate the movement of the conveyor along the support guides. At least one component may also have a mounting structure 818 include, for example, a belt holder configured to connect the component and thus the conveyor to drive a mechanism or portion thereof.

The automatic material holder positioning mechanism generally includes any mechanism for automatically positioning and / or securing a material holder on a conveyor. The positioning mechanism 806 includes an elongated pusher 820 who had an engagement cut 822 that is inside a corner 824 the carriage housing is positioned adjacent to the elongated member, and an actuator portion 826 has positioned outside the corner inside or adjacent to the component. The engagement portion may comprise a surface, for example a bevelled engagement surface 828 , which is configured to touch and press a corner of the material holder. The actuator portion may include a surface, such as a flat actuator surface 830 configured to contact a portion of the housing and be pressed by a portion of the housing. A biasing element, such as a biasing spring 832 , can be positioned within or adjacent the pusher to bias the pusher toward the material holder. Here, the positioning mechanism and the mounting structure are positioned on opposite sides of the carriage housing; however, these mechanisms may also be positioned on the same side of the housing or on both sides of the housing when there are two or more of an existing mechanism.

Of the Positioning mechanism can be used to attach a material holder to attach and / or release. To attach a material holder, can the means of transport from an exchange position or rest position generally within of the fluid technology module to an input / output position, generally outside of the module are moved. When the conveyance housing of the Approaching input / output position, can a door the one with the case connected, open, and the actuator surface can a section of the housing touch and be stopped by a portion of the housing and the handle withdraw. A material holder may then generally be located somewhere in the transport cavity be positioned as long as the bottom of the material holder through the filing structure is held. After that, the means of transport from the input / output position back toward the rest position or replacement position. If the means of transport leaves the input / output position, the actuator surface is gradually the Contact with the housing lose, and thus becomes the pusher gradually grab the material holder. In particular, the beveled surface of the pusher capture one corner of the material holder and place it in an opposite one Corner of the transport cavity to press, in this precise and can be positioned reproducibly. To a material holder this process can be reversed.

(2) drivers for a means of transport

Of the Driver for a means of transport In general, any mechanism or system is reversible Moving the means of transport along at least a single, preferably horizontal axis, so that the means of transport between an input / output position and an exchange position can be moved. The driver can generally be any of the above described mechanisms for include the output array driver, including linear Actuators rotating actuators or a combination thereof.

The 5 shows an exemplary conveyance driver 558 , which is a rotary motor 560 Includes, by two pulleys and a single, horizontally oriented drive belt 562 is connected to the means of transport to the conveyor back and forward along the two horizontal support guides 564 to move. In particular, the engine is directly disc with a first belt 566 connected. The first pulley is through the drive belt with a passive second pulley 568 connected, wherein the first and the second pulley are positioned approximately at opposite ends of the horizontal support guides. Finally, the drive belt is with mounting portions of the conveyor via a mounting structure 570 attached, as related to the above 8th and 9 is described.

Of the Means of transport drivers can the means of transport simply by reversing the direction of rotation of the motor back and forth move. The means of transport Generally, this will be in the direction of the replacement position and the output arrangement moved to deliver new materials, such as clean Pipette tips and reagents, and used materials, such as used pipette tips. The means of transport will generally be in the direction of the input / output position and moved away from the dispensing assembly to new materials for transfer pick up the dispensing assembly and get back used materials to be able to.

In alternative embodiments, the conveyor (or a plurality of stacked conveyors) may move between an input / output position and an exchange position by alternative mechanisms, such as rotation rather than translation or a combination Rotation and translation. For example, in a pure rotary motion embodiment, the sample conveyor may include a portion of a disk configured to rotate about a central disk axis between input / output positions and replacement positions. A pure rotation is essentially a one-dimensional motion and may be done over any angle or arc length large enough to accommodate an input / output at the input / output station and a material exchange at the replacement station without interrupting the operation of the dispensing system or any other components of the systems for exchanging material.

II. Analysis module

The Analysis module generally has any mechanism or system to analyze a sample, including a qualitative analysis (to determine the nature of the sample and / or its components) and / or a quantitative analysis (by the amount, the relative proportions and / or the activity the sample and / or its components).

The analysis module may include components for generating and / or detecting light and for transmitting light to and / or from a sample. These components may include (1) a portion for holding the sample at an analysis site or site or at multiple sites or sites, (2) one or more light sources for delivering light to the sample, (3) one or more detectors for receiving light transmitted from the sample and for converting the light into a signal, (4) first and second optical routing structures for relaying light between the light source, the sample and the detector, and / or (5) Processor for analyzing the signal from the detector. The module components can be selected to optimize the speed, sensitivity, and / or dynamic range for one or more examinations. For example, low intrinsic luminescence optical components can be used to increase sensitivity in luminescence studies by reducing the background. Module components can also be used together in different examinations or assigned to specific examinations. Suitable devices are disclosed in U.S. Patent Application 09 / 337,623, filed June 21, 1999; by doing U.S. Patent 6,097,025 , issued August 1, 2000, and in the article by Joseph R. Lakowicz, PRINCIPLES OF FLOURESCENCE SPECTROSCOPY (2nd Ed., 1999).

The Analysis module preferably comprises upper and lower optics, the enable a variety of measurement methods, including: (1) upper lighting and upper detection, or (2) upper lighting and lower detection or (3) lower illumination and upper detection or (4) lower illumination and lower detection. Lighting and Detection on the same page, (1) and (4), is referred to as "epi" and becomes in photoluminescence and diffusion studies prefers. Lighting and detection on opposite sides, (2) and (3), is called "trans" and becomes preferred in absorption studies. In general, upper Optics with any specimen holder that has an open top has to be used while lower optics can only be used with sample holders, the optically transparent floors have, for example, glass shelves or thin Plastic floors. Clear soil sample holders are particularly suitable for measurements, the cells and analytes that accumulate at the bottom of the holder and / or that connect to the bottom of the holder.

The analysis module may implement one or more methods, such as, but not limited to, spectroscopic methods and imaging methods, especially those useful for high throughput analysis of multiple samples. Spectroscopic methods generally include any method for studying the interaction of light with a sample, and in particular for monitoring and interpreting the properties of the light that are altered by the interaction. Suitable spectroscopic methods include, but are not limited to, luminescence (including photoluminescence, chemiluminescence, and electrochemiluminescence), absorption, light diffusion, circular dichroism, and optical rotation. Suitable photoluminescence methods include, but are not limited to, stationary and / or time resolved measurements of fluorescence intensity (FLINT), fluorescence polarization (FP), fluorescence resonance energy transfer (FREI), fluorescence lifetime (FLT), total internal fluorescence reflection (TIRF) , Fluorescence correlation spectroscopy (FCS), and fluorescence recovery after photobleaching (FRAP) and its phosphorescent analogues and higher-order transition analogs. Image methods generally include any method of visualizing a sample and / or its components, including, but not limited to, static imaging and real-time imaging. Suitable methods are described in the following documents: Publication WO 00/06991 , published on 10 February 2000; and Joseph. R. Lakowicz, PRINCIPLES OF FLOURESCENCE SPECTROSCOPY (2nd Ed. 1999).

The 10 schematically shows the main components of an analysis module 1000 , which is constructed in accordance with the aspects of the invention. The analysis module may be combined with other modules, such as fluid technology modules and / or transport modules, and may itself be constructed from assembly modules.

A light source assembly 1001 within the system 1000 generates illumination at a predetermined wavelength or a range of wavelengths. Preferably, the source is for the assembly 1001 a broadband source, such as a xenon flash lamp 1003 , The light from the lamp 1003 can through an opening or through multiple openings 1005 go through to condition the light before passing through an optical filter 1007 that goes in an opening of a filter wheel 1008 is attached. The wavelength of the light passing through the source assembly 1001 is emitted by a combination of the filter 1007 , a moving grid 1009 and openings defined by the entrance openings of the optical fibers 1019 be formed.

The light from the source assembly 1001 is used to a manhole 1025 a multiwell plate 1011 used in a multi-well chamber assembly 1013 contained, and / or a cuvette 1015 within a cuvette-chamber assembly 1017 to illuminate. The multiwell plate 1011 is held by a holding device. The light from the source assembly 1001 is through a selected fiber of the optical fibers 1019 to multi-well plate chamber assembly 1013 or to the cuvette-chamber assembly 1017 transfer. Further, the source light may be through either the open, upper sections 1024 the shafts 1025 or through the transparent, closed, lower sections 1026 the shafts 1025 be transmitted, with their selection by the special opti cal fiber 1019 which is selected to be the source assembly 1001 with the multiple shaft plate 1011 connect to. An optical aperture 1021 within the source assembly 1001 determines which of the fibers 1019 Light from the source 1003 receives. One or more focusing mirrors 1023 Focus the light through the fibers 1019 in the chamber that is of interest goes, for example, the multi-well slot 1025 or the cuvette 1015 ,

The light, either from the cuvette 1015 , the upper section 1024 of the shaft 1025 or the lower section 1026 of the shaft 1025 , is through the optics 1027 collected. The collected light may be, inter alia, emitted luminescence light for a luminescence measurement and / or transmitted light for an absorption measurement. The collected light passes through a selected optical fiber or through selected optical fibers 1029 to a detection module 1031 , When the transmitted light for an absorption measurement in wells 1025 in the preferred configuration, the light is first passed through the upper portion 1024 the shafts 1025 , then through the sample materials inside the manholes 1025 are included, and finally through the lower section 1026 the shafts 1025 walk. During absorption measurements, the transmitted light passes through the optics 1027 that under the multiwell plate 1011 are positioned, collected. The collected light is then onto a selected fiber 1029 for transmission to the detector 1035 in the detector assembly 1031 focused. In a first alternative configuration used for absorption measurements, as in the configuration described above, the light enters the well 1025 through the upper section 1024 one. After the light passes through the sample materials inside the shaft 1025 however, this is reflected back by a mirror below the sample well (not shown) and collected by optics positioned above the well (not shown). In a second alternative configuration, a detector, preferably a photodiode, is placed directly under the well (not shown) and collects the light passing through the well 1025 and the sample materials contained therein are transferred. In a third alternative configuration (not shown), the light enters the well 1025 through the lower section 1026 Enter, go through the sample materials, go through the top section 1024 and is then collected and focused on a detector. In this configuration, the detector can either be removed to the top section 1024 be attached or in close proximity to the upper section 1024 be attached. Other aspects of the upper and lower optics and their use are described below in connection with the transport module.

A panel 1033 determines which fiber 1029 through the assembly 1031 is monitored. The light from a selected fiber 1029 becomes a moving, focusing grid 1037 on a detector 1035 focused. Preferably, the detector is 1035 a photomultiplier tube (ie, PMT). The light can pass through one or more openings 1041 go to reduce stray light before applying this to the detector 1035 incident. The combination of the grid 1037 , the opening 1041 and a filter 1039 that is in an opening of the filter wheel 1040 fixed, determines the wavelength of light passing through the detector 1035 is detected.

The grid 1009 allows the excitation wavelength to be continuously varied over a relatively wide band of wavelengths. Similarly, it allows the grid 1037 in that the detection wavelength is continuously varied over a wide range of wavelengths. In a preferred embodiment, the grids 1009 and 1037 each have a focal length of about 100 millimeters and thus allow the excitation assembly 1001 and the detection assembly 1031 are relatively compact. Since the grids are preferably holographic gratings with 1200 Slits per millimeter, the dispersion of the gratings with this focal length provides a nominal transmission width of 10 nanometers. In a preferred embodiment, the illumination angle of the grid 500 Nanometers. However, illuminating the grids at different angles increases the decoupling of the excitation wavelengths and the fluorescence wavelengths. Preferably, the arc is the lamp source 1003 on the entrance opening of the fiber 1019 focused.

Additional aspects of the analysis module 1000 are described in U.S. Patent Application Serial No. 09 / 337,623 filed June 21, 1999.

III. transport module

A transport module generally includes any mechanism for holding a sample in a sample holder, inter alia, for liquid dispensing and / or analysis, and inter alia for moving the sample from an entry / exit position to an issue position and / or examination position. Suitable devices are disclosed in U.S. Patent Application Serial No. 09 / 337,623, filed June 21, 1999 / Patent Application Publication Number WO 00/66269 , published November 9, 2000; and the U.S. Patent 6,097,025 , issued on August 1, 2000.

The 11 to 15 show various aspects of a transport module constructed in accordance with the aspects of the invention; the 16 to 18 show aspects of a variant of the transport module of 11 to 15 , These aspects include interactions of the transport module with the dispensing head of the fluidics module and the upper and lower optical heads of the analytical module. Although in at least one embodiment the system may be used to read a cuvette using a cuvette port, the main application for this invention is the reading of multiple well plates. Further, the preferred embodiment of the invention is designed to be usable with multiple well plates of various configurations (ie, different number and sizes of sample wells, different plate sizes, etc.).

The 11 and 16 show a sample plate holding device (or means of transport) 1101 , which is intended to place multiple well plates of standard dimensions (for example, 86 to 129 millimeters). To place plates of other sizes, an adapter plate (not shown) is within the fixture 1101 attached so that the non-standard plate fits in the adapter plate.

The holding device 1101 holds the multi-well plate or adapter plate using a support frame 1103 along the edges. This leaves a surface 1105 open directly beneath the sample wells of the multiple well plate to enable a variety of sample measurements to be made requiring access to both the upper and lower surfaces of the sample wells. The holding device 1101 slides along a pair of railing poles 1107 attached to a base assembly 1109 are attached. A drive motor 1111 moved using a system 1113 with a belt and a pulley the holding device 1101 and thus the multiple well plate along a first axis, parallel to the railing rods 1107 ,

The 12 and 13 as well as the 17 show an optical, scanning arrangement 1200 in combination with the basic arrangement 1109 , The scanning arrangement 1200 allows an optics head 1201 along a second axis perpendicular to the handrails 1107 to be scanned. Thus, the scanning arrangement allows 1200 used in conjunction with the scanning fixture 1101 used that is an optics head 1201 in two dimensions, thereby providing an analysis means for each well of a two-dimensional array of wells in a multi-well plate.

In a preferred embodiment, the optics head comprises 1201 the optics required to illuminate the sample as well as the optics necessary to collect the emitted light. Optical fibers 119 and 129 although not shown in this illustration, they are with the optics head 1201 via a train-unloading bracket 1203 connected. The optics head 1201 slides along two railing poles 1205 that has two brackets 1209 on a lower assembly plate 1207 be are solidified. A drive motor 1211 and a system 1213 with a belt and a pulley move the optics head 1201 along a second axis orthogonal to the first axis.

In a preferred embodiment, the scanning engines are 1111 and 1211 both under the control of an internal processor. Typically, before use, the user enters the sample plate configuration (e.g., the number of wells, plate type, well size, etc.). The user then programs the internal processor to scan the intended sample plate using a scan mode from a variety of scan modes. For example, a flying scan mode can be used to minimize the amount of time needed to read a sample plate by eliminating the acceleration times and the delay times. In this mode, the holding device 1101 and the optical scanning head 1201 in a continuous manner, for example using a zigzag pattern. The source 1003 is flashed when the optics head assembly 1201 is moved over each slot, thus allowing a single measurement to be made for each slot. Alternatively, the internal processor can be programmed to head the optics 1201 to place over each well for a predetermined period of time such that a predetermined number of sample readings (initiated by the flashes emitted by the source 1003 emitted) can be made for each shaft.

Lots Fluorescence measurements, luminescence measurements and absorption measurements are based on external environmental factors, such as the temperature, extremely sensitive. This effect may even be a bigger problem because of the number of sample wells per multi-well plate that is about to change over the Plate leads.

One Approach to overcome the environmental problem is simply the Check the temperature of the reading chamber. This approach can but little to the effects of a temperature drop minimized, which is caused by evaporating coolant. One second approach is to control the temperature with the use to combine a multiple bay cover. Although the Cover evaporating coolant minimized and the control of the temperature allows light, this typically leads to a decrease in instrument sensitivity as a result of lid effects on the optical system (i.e., increased stray light due to Scattering by the cover, absorption by the lid, etc.).

The present invention overcomes these problems through the use of a virtual lid in conjunction with a temperature control system. In the preferred embodiment, the retainer moves 1101 between the system readings the multi-well plate 1011 to a surface 1115 , A lid 1401 ( 18 ) is directly above this area. Additional components made, for example, of foam may also be used to surround the multi-well plate when in the surface 1115 is. The bottom plate 1207 of the optics head 1201 resting on the top of the lid 1401 (ie, opposite to the reading chamber 202 ; 16 ). An opening 1208 ( 17 ) exists both in the plate 1207 as well as in the lid 1401 , and thus allows excitation light and emission light from the optics head to pass to the specimens housed in the multiple well plates within the chamber 202 are included. Preferably, the dimensions of the opening are 1208 approximately at 1.2 millimeters to 104 millimeters. When the holding device 1101 the multi-well plate 1011 below the lid 1401 moved, the top surface is about 10 millimeters above the surface of the multi-well plate and the sides of the multi-well plate are firmly enclosed. When the multi-well plate once so in the rest position 1115 is moved, and the access door 1116 closed, the moisture above the plate increases by more than 90 percent, so that the cooling is reduced by evaporation. This system reduces deviations from a sample well to a sample well within a multi-well plate, preferably less than about ± 0.2 ° C, and generally less than about ± 0.5 ° C.

In the embodiment shown, variations in the size of the multiple well plate are made possible by the use of different adapter plates. The adapter plates not only ensure that the multi-well plate is resting on the support frame 1103 These can also be used to ensure that the top of the multi-well plate is sufficiently close to the surface of the lid 1401 is to minimize the temperature variations between the wells. In an alternative embodiment, the relative distance between the lid 1401 and the upper end of a multi-well plate in the fixture 1101 by adjusting either the vertical position of the lid or the conveyor assembly which the multi-well plate 1011 carries, be optimized. In this embodiment, either the lid or conveyor assembly is a motor connected, the engine is under the control of the internal processor. Preferably, a sensor (eg, an optical sensor, a mechanical position sensor, etc.) is used in conjunction with this motor and the internal processor to control the separation between the multi-well plate and the lid 1401 to control. Alternatively, the user may enter the type of multiwell plate in use and the internal processor may use a lookup table to determine the amount of adjustment necessary for the type of multiwell plate in use.

The 18 is an illustration of a portion of a temperature control system. To the temperature of the area 1115 as well as the circulation of the reading room 202 to control one or more heaters 1403 attached to different sections of the reading chamber. The heaters 1403 are preferably so on the lid 1401 attached as shown. One temperature monitor or several temperature monitors (eg Thermistore) 1405 are used to monitor the temperature of the reading chamber. An outer cover 1407 is with the lid 1401 connected to allow the control of the temperature within this area. Other covers, such as an internal cover 1409 and an outer cover 1411 , surround the remaining upper portion of the reading chamber and thus further assist in controlling the temperature of the system. The embodiment of the 11 to 15 usually has essentially the same construction.

The 15 is a perspective view of an air circulation housing 1501 at the bottom of the base assembly 1109 is appropriate. A fan 1503 drives air through the housing 1501 , The air goes through perforations 1117 within the raised sections 1118 the basic structure 1109 like this in the 11 is shown. The air circulation system, including the perforations 1117 Ensures uniformity of temperature throughout the reading chamber without causing exaggerated air movement above the multiwell plate.

IV. Timestamp

Of the Term "time marking", like this one used refers to methods of assignment of a series measurements based on the collection of time-dependent experimental data, where both the values of the collected data and the time The collection can be recorded and used. Time marking methods are helpful in a variety of applications, but are special useful for the collection of time-sensitive data, for example, in monitoring the progression a reaction, collecting a kinetic analysis or if the material or composition being studied relative unstable. For example, time stamping typically provides in a test for determining the absorption properties of a Range of materials with a slightly different composition, in which the absorption properties of the materials are not change with time, little advantages. In a luminescence examination, however, in the the luminescence of a material by the addition of one or more reactants triggered it is typically very helpful to take the time, in which the luminescence was measured with respect to the time in which Added the reactants were. Furthermore, a valid Comparison requires that the time sequence for each individual composition is recorded when the luminescence properties of a series of compositions. If the number of the samples to be compared is increased, for example by the use of a multiple examination plate with a large number from sample shafts, will be monitoring The reaction kinetics as a function of time increasingly important. Of particular importance is the amount of time that elapses between the preparation and the characterization of each sample has passed. Also the sequential repetition of the characterization process allows the kinetic analysis of the process involved in the one sample or at several samples in the manholes the multiple-assay plate is or is included occurs.

The device system of the invention may preferably be operated in a plurality of different time stamping modes with associated processing and / or presentation of the data made using a processor. The processor may be internal or external, and may be dedicated (ie, separate) or shared (for example, with an analytical and / or fluidics module). In an exemplary embodiment, a single, internal processor is used to control both the output system and the analysis module; however, a multiple processor may also be used as long as certain timing functions are programmable, as described in more detail below. Typically, the internal processor is connected to a clock. The associated clock is optionally an internal or an external clock. In some embodiments, the clock connected to the processor provides a current time (for example, 2:32 PM); in other ways forms the clock provides a past or a continuous time. In the latter mode, the timepiece simply provides the amount of time that elapsed between timestamps. Preferably, the clock sets time units that are substantially smaller than the time increments needed to dispense a reagent into a well or perform a luminescence measurement, so that the absolute error in the recorded time tag is relatively unimportant when used with other sources of uncertainty in the measured data. Preferably, the internal clock uses time units of the order of milliseconds, if possible in microseconds.

Of the Internal process may involve a memory and / or a data presentation system or more data presentation systems be connected. The memory system, in terms of the processor internal or external, takes the time stamps with connected to each sample. The memory system can either be volatile or permanent and any kind of a known medium use (for example, electronic random access dynamic memory, magnetic media, capacitive and charge storage systems, optical Storage systems, etc.). The system for presentation Data may include a printer, a plotter or drawing device and / or to be a monitor.

The Device, Using the time stamping methods can use both analysis modules as well as fluid technology modules include as described above. The analysis module may preferably measure both luminescence and absorption. The fluid technology module may preferably be the desired Concentrations of each of the multiple components in the individual sample wells the multiple examination plate output. The device system may also include means for mixing the components within the sample wells and Means to change the environment of the multiple assay plate (for example, temperature, Pressure, etc.).

The Device becomes typically used with a sample plate inserted into the fluidics module added can be. The internal processor can with the type, the size and the Shaft configuration of the selected Plate can be programmed. This programming supplies the system with sufficient information to the positions of each of the sample wells to be determined in the plate. Alternatively, the system can be sensors or use other means to adjust the positions of the sample wells Find. The processor will then compare with the amount of each of the individual Components to be dispensed into the individual sample wells programmed to the desired To produce compositions.

at some embodiments Timestamp mode sets a single point in time for a whole Sample series. This means, a first time is recorded which is representative of the initiation of the experiment. This time can be, for example, the addition of a reactant to each material in the sample series. A second time is recorded when the sample series is characterized (for example, by measuring luminescence or absorption). If the sample series is over the time is repeatedly characterized, can be recorded at any time in which the series is characterized with a time that associated with the characterization. Thus, any of the materials be characterized in the series as a function of time. Although this mode of time marking is adequate for many examinations, considered these are not variations that occur at the beginning of the experiment, for example due to the addition of the reactants rather in a sequential manner as in a simultaneous way. Also, this mode does not take into account any Time Delay, which is connected to the measuring process. This time delay can essential for be a multiple assay plate with a large number of sample wells (For example, 364 or 1500 sample wells).

typically, can the triggering each reaction within each sample well to a single, be assigned to a controllable event, such as the introduction a reactant. If the reaction by introducing several Raised reactants it is often possible to simultaneously introduce the reactants, so that results in a single reaction-release time. Although that present example a single, critical reaction trigger point the present embodiment can also be used in more complicated, multiple critical event reactions are used. In this However, case will be an accurate time stamp at each critical time Phase applied.

An exemplary time stamping operation of a multiple well may be performed as follows. A reaction in a first sample well of the multiple assay plate is triggered at a time equal to x. The time x is recorded by the processor. A reaction in a second sample well is triggered at a second time equal to x + Δ, where Δ is a known time interval. Similarly, a reaction in a third sample well is triggered at a third time equal to x + 2 Δ. By spacing the reaction triggers in known, regelmäßi At the time intervals, only the first time x has to be recorded. After the preparation of the sample multiple assay plate is completed, the multiple assay plate is transported to the analysis module. The composition in the first sample well is then characterized at a time equal to y, with the time y taken by the processor. The second composition is characterized at a second time equal to y + Δ, the third composition is characterized at a third time equal to y + 2 Δ, and any subsequent composition is determined using the same, known, regular Time intervals characterized. Therefore, this methodology requires that only two times, a sample preparation start time and a sample characterization start time, be included along with the time interval used during the experiment, assuming that the same procedure for the samples Preparation and the sample characterization is used. This same methodology can easily be used in multiple characterization runs by recording the start time of each characterization run and maintaining the same run and time intervals.

at a specific example of this embodiment of the invention a series of two main component blends first in one Multiple assay plate prepared with 364 sample wells. A single reactant (i.e., a third component) is then added to each of the sample wells. Of the first sample shaft is prepared at 8:00 am, the following one Samples are then periodically Prepared for 30 seconds. Thus, the 121st sample is prepared at 9:00 am (i.e., 60 minutes for 120 samples, at a first rehearsal at 8:00 am). When using the Present methodology will be the 121st sample at 2:00 pm be characterized when testing starts at 1:00 pm. As a consequence, although only two times, 10:00 am and 1:00 pm, were recorded All samples in the multiple assay plate were compared directly because the time intervals between the preparation of the individual Samples and the time intervals between the characterization for the individual samples is identical. Furthermore, the preparation time and / or the Characterization time for every special sample using the known start time and the known time interval are easily calculated. Obviously can much shorter Time intervals for fast analyzes (for example 0.1 seconds or less) are used become.

In an alternative embodiment use the fluidics module and the analysis module has two separate and different processors. This embodiment offers the same advantages as the previous embodiments as long as the same time interval, Δ, used by both processors will and the trigger times for the both processors can be correlated.

The device system The invention can also according to a alternative embodiment used to apply time marks to individual samples. Preferably, a time stamp becomes at each critical sequence step for every Sample applied in the multiple assay plate. For example can be a time marker at each preparation step as well be applied to each characterization step. In addition, can the time stamps are applied when outer variables, such as Temperature, humidity, gas pressure, gas type, etc., to be changed.

This embodiment can be explained as follows using an example. Here, a time t _{1 is} taken when a reaction of a sample 1 is triggered. If necessary, multiple times may be taken for the preparation of each sample, with each step or critical step of the process being marked for each sample. For example, although it is only necessary to mark the introduction of a reactant, it may be desirable to mark the introduction of each component of the composition, the start times and stop times of a composition mixing process, and so on. After the sample 1 has been marked, a time t ₂ for the sample 2 is recorded. This process continues until all samples to be prepared have been completed and marked. The same process is then used to include a time stamp, t ₀ , for each characterization run made for each sample.

This embodiment offers greater flexibility than the previously described embodiment, since it is not necessary to maintain a constant time interval between steps. Thus, if some compositions in the series are more complex than others and therefore take longer to prepare, the time interval can be varied to accommodate the differences in preparation time. In addition, repetitive characterization runs can be made on selected samples of the series rather than having to cling to the same sequence throughout the experiment. For example, if the user 100 various compositions test, a preliminary characterization check shows that 90% of the samples are not important for further consideration. However, the remaining ten samples can then be selected individually and a more thorough characterization can be performed on each of them. When an experimental run is complete, the data can either be stored for later retrieval or displayed immediately in a user-defined graphical or tabular format (e.g., absorbance versus time, fluorescence vs. composition and versus time, etc.) ,

In a further embodiment The invention uses a processor in conjunction with a clock timestamps on individual samples, each critical sequence step for every Sample, and more typically the luminescence or absorbance of the Sample over represent a certain period of time. In contrast to the examples, the top available are collected in this embodiment, the collected Data presented as continuous data or refer to a single, common time. This data representation is typically done by performing a mathematical operation achieved with the collected data to a calculated data value or to determine multiple calculated data values between two measured data points (interpolation) intervening or in order a calculated data value or multiple calculated data values determine before or after the measured data points (extrapolation) lie. Interpolation is typically used to make a continuous Curve of discrete data or calculated data values to compare between samples at a fixed time. extrapolation is typically used to compute data at a starting point in fact, before any but can also be used to To determine endpoint data values.

This Type of data representation is particularly useful as it allows that data from individual samples are compared directly, regardless of the exact time recording of data collection operations. In addition are most users are used to see kinetic data presented as continuous data are. Although the mathematical processing that is required to interpolate / extrapolate the collected data points by performed the internal processor Typically, the time tagged data becomes an outer processor exported, such as a dedicated computer system, to the requested data processing and optionally the requested Perform data representation.

Everyone mathematical algorithm that has sufficient interpolation or Extrapolation is a suitable algorithm for the purposes of the invention. Examples of useful algorithms include linear or polynomial compensation algorithms, in particular square, cubic and biquadratic polynomial balancing algorithms. Especially good results are obtained by polynomial spline functions, preferably obtained cubic or biquadratic spline functions. Even though the use of a biquadratic spline algorithm is a more accurate one Adaptation to the experimental data will produce some Aspects of the invention include the use of a cubic spline algorithm preferred, since the calculated data typically faster through the processor can be determined. In another embodiment In the invention, the algorithm used is a Savitsky Golay polynomial algorithm.

V. Examples

This Section shows examples, without limitation, hardware and software for use in operating a preferred embodiment a device system and its components, as described above, for preparation and / or for analyzing samples, especially in automatic modes, describes. The preferred embodiment includes a fluid technology module for preparation of samples, an analysis module for analyzing samples and a Transport module for moving samples into and out of a dispensing position / examination position.

example 1

This Example describes customer characteristics necessary for a device system, as described above Prepare and / or analyzing samples is provided.

The instrument includes a fully automated 8/16 channel pipettor to add reagents and / or other materials to a sample holder for analysis using the analysis module. The reagents may be obtained from the sample plate and / or from an additional reagent plate or reservoir plate located in the fluidics module. In fact, the fluidics module may have two or more plates / reservoirs / tip trays, similar to the plate carrier in the down reading chamber of the device to provide materials such as pipette tips and reagents.

The device may use a variety of output strategies and / or analysis strategies, independently or in conjunction with one another. The fluidics module may output fluid in an automated manner before, during, and / or after the analysis module analyzes a sample to, among other things, perform rapid kinetic studies, such as for a well or wells at one time or a row or column or more To allow rows or columns at a time. The output can be a direct disk to disk transfer, for example one column at a time. This output may be from the same reagent from a reservoir of the same format as a microplate for all wells in the sample holder or even multiple reagents at different times. Appropriate strategies for coordinating fluid delivery and sample analysis, such as time tagging, are known in the art U.S. Patent 6,236,456 , published May 22, 2001.

The Device and especially the fluid technology module can perform a variety of fluid transfers. The Module can deliver between the plates, for example, from a reagent holder to a sample holder or from a sample holder to a reagent holder or from a Reagent holder to another reagent holder. The module can also a handover perform inside the plate, for example, from a manhole or from several manholes in a given plate to the same wells and / or a different one Shaft or several different shafts in the same plate, both within the sample holder and within a reagent holder, so a lot of pipetting functions that are performed should, including Mixing and serial dilutions, to enable.

The Device can recognize or allow a user the tips and reagents each in the appropriate tip trays and reagent holders are. The tip tray and reagent holders may be full or less as a complete one assembly containing materials, for example a diagonal sentence, to output a well-by-well issue in addition to column-by-column output enable. A diagonal set may be a column-by-column thinning and maybe more important a fast, kinetic well-by-well reading without time stamping.

Example 2

This Example describes recommended protocols for defining a pipetting procedure for a Device system, as described above to prepare and / or analyze samples. These Logs include a plate at the starting point and a plate at the target, a reagent holder and a sample holder for a handover between plates or the same reagent holder or sample holder to handovers can be inside the plate. The device may include software that it allows a user to determine a specially prepared pipetting protocol and / or from a set of standard protocols, such as pipetting of a single reagent into all the wells without at a time to manually determine the process of a column or a complete handover of Plate-to-plate reading with a column-by-column reading Disk is synchronized.

The The following abstracts describe methods for the determination of Formats (A) and to determine a series of pipetting events or operations (B).

A. Define formats (automated over the Plates choice menu)

• (1) Define the tip storage format (for example 96, 384). An 8-channel head or 16-channel head is installed.
• (2) Define the reagent (or drug) plate format (for example, microplate, tub, etc.)
• (3) Define the top-column format, if less than the complete assembly is. The loading pressure is based on the number of installed Tips set.
• (4) Define the disk tray floor height Z and the cross section of the Shaft (to allow determination of the amount of expenditure).

B. Define a series of pipetting events Pn at designated times Tn, setting the properties of a every pipetting event

• (1) Define the time for pipetting (after the Reading starts).
• (2) Define the intake volume.
• (3) Define the suction / discharge rate.
• (4) Define the suction height.
• (5) Define the output height.
• (6) Define the plate and the column at the starting point.
• (7) Define the destination plate and the column.
• (8) Define the top column.

Example 3

This Example describes hardware features of a fluid technology module for a device system, as described above, for preparation and / or analysis of samples. The fluid technology module is an 8- / 16-channel pipetting system, (1) the pipette tips of can receive a tip tray on an upper carrier, (2) the from a well or a column and into a well or a column in a plate or pan in either the lower carrier in one Fluidics module or the plate carrier can aspirate and dispense in one analysis module at a time, and (3) the used pipette tips to the same tip tray, from which they were taken. The components of the system are using stepper motors that intermittently with opto-breakers be switched, operated.

The following tables describe preferred values of various parameters. parameter Step calibration Opto position Area speed Pipettor volume V 0.05 μL / step 0 μL -30 to 250 μL 1 to 200 μL / s Pipettor Z axis 615 microsteps / mm 00 mm Tip carrier Xa axis 210 microsteps / mm open closed Plate carrier Xb axis 210 microsteps / mm open closed function Z-position Comments Loading the tip, load-free (Z starting position) 0 mm Loading the top -46 mm Reagent plate free -56 mm Aspirate the reagent plate -107 mm + Height of the shaft bottom + suction height volume / cross section (shaft) Examination plate free -166 mm Examination plate output -191 mm + Shaft bottom height volume / cross section (shaft)

A. Control of temperature / control the moisture

The temperature and humidity of the fluid technology module can be controlled through the use of various mechanisms. The temperature can be controlled by the use of two control loops, one of which heats the structure of the fluidics module independently of the analysis module and one heats the pipetting head. The motors can be supplied with reduced power when not in use to reduce heat build-up. The moisture can pass through Limitation of evaporation in the fluid technology module are maintained to at least over 90% above the plate.

B. Identification of the channel head

Of the Pipetting head can be selected be that among other things the number and the distance of the pipette channels of the number and the distance of the shafts in a single line of a 96-well microplate or one 384-well microplate ent speaks. Thus, a pipetting head, the eight channels has separated by 9 millimeters, including one 96-well plate, and a pipetting head, the 16th channels has separated by 4.5 millimeters, among other things be used with a 384-well plate. The identity of the pipetting head can by a connecting device of the pipetting head to a Control device are signaled, z. B. using an additional one Wire connecting the pipetting head to the control device. The control device may be the wrong association between the Configuration of the pipetting head and the configuration of the sample holder as an error condition, for example by sending an error message if a 384 shaft plate with one installed 8 channel head selected becomes.

C. Calibration of the positions of the fluid technology module

The Fluidics module is designed to be from device to device without recalibration is interchangeable. The carriers and the Z axis have three offset options, which are determined manually and be divided by a mounting flange of the module or automatically using a tool and firmware hooks (firmware hooks) are determined. The shaft bottoms in a bottom plate, the can have an unknown format can be found as follows: (1) separate the current from the Z axis ab, (2) allow the head, which is loaded with tips, to lay down on the examination plate, (3) turn the motor back on and (4) count the steps to the opto-break, which form a new Z-axis offset within limits.

Example 4

This Example describes operational features for coordinating the fluidics module and the analysis module for a device system, as described above, for preparation and / or analysis of samples. The modules can with each other and / or with a central processor using any suitable mechanism, including a serial port, be connected. To reduce communication during the analysis, all pipetting events are specified and transferred to the fluid technology module, before reading to be started. The fluid technology module checks the status of the device and ensures that the correct pipetting head is in place before pipetting.

• (1) Mach eine Abfrage, um die Zeit zu synchronisieren. Der Zeitpunkt für das Pipettierereignis ist spezifiziert auf die Zeit bezogen, nachdem ein kinetisches Lesen beginnt.
• (2) Während einem kinetischen Lesen, besteht eine geringe Möglichkeit, wenn es eine einzelne Spalte ist, die gelesen wird, dass die inkorrekte Spalte der Untersuchungsplatte am Platz sein wird, überprüfe jedoch vor dem Pipettieren zuerst den STATUS und die SÄULE und erstelle einen HALT.
• (3) Wenn mehrere Spalten gelesen werden sollen und mehrere Spalten ausgegeben werden sollen, müssen die Ausgabeereignisse sorgfältig koordiniert werden. In diesem Fall wird eine SPALTE XX ANFRAGE an das Gerät gesendet, und das Gerät zeigt dann dem Flüssigkeitstechnikmodul mit einem SPALTE XX VERFÜGBAR an, wenn diese Spalte während des Lesens erreicht wird. Die exakte Zeit des Pipettierens wird zur Verwendung während einer nachfolgenden Analyse aufgenommen.

The following summary describes a series of coordinated output and read steps. The first two steps cover the minimum requirements for a single column operation. The third step begins when the beeping log is issued while the device is not operating.

• (1) Make a query to synchronize the time. The timing of the pipetting event is specified relative to the time after a kinetic reading begins.
• (2) During kinetic reading, if there is a single column read that the incorrect column of the assay plate will be in place, there is little possibility, but first check the STATUS and COLUMN before pipetting and make a STOP ,
• (3) If multiple columns are to be read and more columns are to be output, the output events must be carefully coordinated. In this case, a COLUMN XX REQUEST is sent to the device and the device will then display to the fluidics module with a COLUMN AVAILABLE if this column is reached during reading. The exact time of pipetting is recorded for use during a subsequent analysis.

Example 5

This example describes programming features of a fluidics module for a device system, as described above, for preparing and / or analyzing samples. These features may be used inter alia using software and / or firmware. Here, software refers to programs, utilities, and symbolic programming languages that control the functioning of the hardware and perform its operation, and firmware refers to programming instructions that are stored in a ROM unit rather than being implemented by software. The programming features allow the fluidics module to be controlled in a simple, flexible and independent manner.

The The following abstracts describe and define a series of Pipetting events, where A-D is parent Commands include and E-I include subordinate commands.

A. Install the format equal for all pipetting events for a experiment

• (1) gap reagent plate column (Rxpos)
• (2) distance peak column (Txpos)
• (3) height Reagent plate shaft bottom
• (4) height Examination plate shaft bottom
• (5) Number of peaks in each column
• (6) shaft cross section

B. Pipetting Event Specification

• (1) event number
• (2) event time (after the scheduled start event)
• (3) starting point plate (for example, reagent or assay plate)
• (4) target plate (for example, reagent or assay plate)
• (5) Starting point column
• (6) destination column
• (7) volume to carry that is
• (8) suction height
• (9) Output height
• (10) mixed periods
• (11) mixing volume

C. Additional Commands equal for all pipetting events

• (1) Intake rate
• (2) issue rate
• (3) Air gap of the pipettor
• (4) Ineffectiveness of the pipettor
• (5) Volume calibration of the pipettor
• (6) temperature adjustment
• (7) lace bearer open closed
• (8) reagent carrier open closed
• (9) Shake (eg reagent or assay plate)

D. Coordinate commands for the device

• (1) time
• (2) status
• (3) Column
• (4) Hold the column (new)
• (5) columns request (new)
• (6) Column available (New)
• (7) Find the shaft bottom

E. Commands for the intermediate positioning

• (1) Move the pipetter to the carrier (T, R or A) (free or discharge / intake) position
• (2) Move lacy beams to the column (X)
• (3) Move reagent carrier to the column (X)
• (4) Output
• (5) aspiration
• (6) Move the Z-axis to the starting position
• (7) Move the piston of the pipettor to the starting position
• (8) Load the tips
• (9) Unload the tips

F. Position and Calibration Commands

• (1) Set the Z axis position of the pipetter on offset
• (2) Set the position of the tip carrier at offset
• (3) Set the position of the reagent carrier to offset

G. Commands for positioning the deepest levels

• (1) Set the Z position of the pipettor one
• (2) Set the X position of the tip carrier
• (3) Set the X position of the reagent plate
• (4) Set the position of the piston of the pipetter

H. Prohibited Actions Preferred Embodiment

• (1) The pipettor must be in one at all times tip-free position when the tip tray is moved.
• (2) The pipettor must load tips in the same column and discharged from the same column peaks.
• (3) The lace wearer can not open if not all tips are unloaded.
• (4) During a reading may not affect the tip carrier and the reagent carrier be accessed.
• (5) The lace wearer and the reagent carrier can not be open at the same time.
• (6) The pipettor must be on or above the reagent plate be free before the reagent carrier is moved.
• (7) The pipettor must be dispensed before the tips be discharged.
• (8) The sum of the aspirations / outputs must be in the range -30 to 225 μL lie.
• (9) The volume setting of the pipettor must be in the starting position before it goes to the 0 Z position.

I. Sequence of startup

• (1) When switching on, the status of the installed spikes and unissued volumes.
• (2) If there is unissued volume, do not do any further action and generate an error message "Unissued volume".
• (3) If there is no unissued volume, move the Pipet to the starting position and move Z to the starting position.
• (4) If Z does not want to go to the home position, open the tip puller and move Z to the starting position.
• (5) If Z still does not want to get to the starting position, generate an error message "Z Axis does not want to return to its starting position ".
• (6) When the tips are installed, unload the tips.
• (7) If the tips are not installed, move the pipettor to the starting position.

J. Execution of the firmware pipetting event

One Pipetting event, as defined above, can be a series of intermediate commands. For example, the following event command At a time T used to be A microliter from the column B in the reagent plate to column C in the examination plate below Using tips from column D in the tip tray with Mixed periods of E and a volume F are used.

PIPETTES T A BR CA D E F

A Series of events is previously loaded into the fluidics module, before reading starts. The command "Events" asks all stored Events and the command "delete the Events "deletes them.

Of the The following pseudo code describes a possible sequence for performing this Working process.

Example 6

This Example describes alternative mechanisms to deliver excitation light and to collect emissions and / or transmitted light that uses can be to improve performance and / or additional Provide functions and features. It is believed that the place where it is appropriate, reading at a repetition rate R for some time before, during or after dispensing multiple pipettes begins. The sampling settles for a rate R for an entire period T of sampling continues. The pipettes can be one after the other, all at once or in any desired Output sequence relative to each other.

Exemplary embodiment:

• (1) 8 or 16 simultaneous pipettors, single channel scanning reading head:
• (2) flash lamp → monochromator → fiber → scanning, bottom reading, achromatic, optical head → optical fiber → monochromator → PMT

Alternative embodiment (s):

• (1) The detection architecture for a higher Throughput and / or higher Read rate (for example, readings per second), R, would be one Simultaneously use excitation / detection of the multiple wells, for example n = 8 or 16. General 1 <n ≤ 3456 shafts.
• (2) flash lamp, arc lamp or laser → monochromator or filter → n optical Fibers → n bottom reading, achromatic, optical heads → n optical fibers monochromator of the filter → n PMTs or n photodiodes, photodiode array, photodiodes Arrangement or shock-discharge diodes Arrangement or a suitable CCD (rectangular or square, chilled to a saturating temperature, an adequate one Signal to the background ratio to secure).

The efficiency of the optical head can be improved by the use of a dichroic filter which could be changed either manually or automatically as often as the logger wavelength has been changed. Suitable dichroic filters are described in the following patent application: Publication Number WO 00/55372 , published on September 21, 2000. Alternatively or additionally, the system could also be used to read fluorescence polarization when the optical head provided means for separating and detecting changes in sample emission polarization in response to polarized excitation light, such as For example, a polarizing light divider, a set of switchable polarizers and / or a fixed and a rotating polarizer comprises. Suitable polarizers are described in the following patents and patent applications:
U.S. Patent 6,097,025 issued on 1 August 2000; and publication number WO 99/23466 , published May 14, 1999.

Example 7

This Example describes additional Embodiments, which can be used to measure fast movements, such as fluorescent reactions, which take place in milliseconds to seconds. This ability is especially for the monitoring faster reactions in biological cells, such as at potential changes a cell membrane, useful. Many common ones equipment can Fluorescence values only at about Measure 1 Hz, this being for many applications is too slow.

Exemplary embodiment:

The exemplary embodiment As described above, an 8-channel pipettor (which can be divided into eight different types) is included shafts a microplate simultaneously) and a fluorescence read head, the The fluorescence in each of the eight wells reads by being sequential following the output step. The problem is that the time interval quite a bit longer between repeat readings on each well can be, since all eight shafts have to be read before the reading head returns to the first slot. To the process too have to accelerate The pipette tips are specially loaded by hand, so only a pipette tip is loaded (in each of 8 lines), and after that must the device be instructed to read only those shafts in which the Pipette tips are loaded. This can become a significant, manual Lead effort and means that only one-eighth of a plate can be monitored before the tips again in yet another, special pattern manually have to be loaded.

Alternative embodiment (s):

The alternative embodiment would be back have eight pipettors arranged in one line. The Improvement indicates that each pipettor can be activated independently is. In this way could an entire well plate with 96 cells, a sample plate with 96 shafts and a 96-well slot tray is loaded in the device. A shaft could at a time for monitoring the fluorescence selected become. The entire line of eight pipette tips could be simultaneously loaded as described above. In the alternative Version would only the selected one Well (i.e., one well at a time) liquid received from the issuer, and this shaft could subsequently be attached be monitored at a very high repetition rate. The repetition rates could every rate between about 10 Hz and about Be 1 mega heart. In particular, would Repetition rates of about 1 Hz to about 1 kilohertz for the excitation by a flash lamp are preferred.

The alternative embodiment could thereby analyzing each well at a very high repetition rate (i.e., where the intervals between measurements are very much are less than 1 second). The number of repetitions (and the entire time length, in which each slot is analyzed) could be selected by the user. Every shaft could for the same predetermined length of time monitored become. Alternatively, could different shafts in a microplate different lengths of the total time for analysis or have different interval times for the analysis.

Physical Embodiments:

Everyone Pipettor could mechanically, electrically (for example by an electrically driven magnet), or by other mechanical or hydraulic means, such as through the use of air pressure or other fluid pressure or a gas pressure, operated separately become. additionally could each separately activated pipettor also provided with a means Be sure to let each pipettor move up and down separately can drive. That way only one of the (for example eight) pipette tips in a cell to be lowered for dispensing. (Sometimes it is desirable the tip below the liquid surface in the Lower the receiving shaft to trigger a droplet, or around the liquid to sputter in a blending manner, so as to sample and that Completely mix medium in the well).

Example 8

This Example describes selected Aspects of the Exemplary Embodiments of the device system of the invention using a time tag as above is described.

The device system The invention may be a system for characterizing the time tag include a system for dissection several samples for preparation of multiple samples in a multi-well microplate; one first processor connected to the system for the preparation of multiple samples wherein the first processor is the preparation of each of the plurality Samples controlled, with the first processor at least one time marker a first type for determining each of the plurality of samples, wherein the first type of timestamp with a step to dissection matches a sample; a first time recorder, which is connected to the first processor, wherein the first time recorder records each time stamp of the first type of time marker; a system for characterization several samples to determine at least one character characteristic each of the multiple samples, the character feature being the group selected which consists of fluorescence, luminescence and absorption; a second processor working with the characterization system multiple samples, the second processor is the characterization controls each of the multiple samples, the second processor at least one time stamp of a second type for each of determined several samples, and wherein the second type of time marking coincides with a step of characterizing a sample; and a second time recorder which is connected to the second processor, wherein the second time recording device record each time marker of the second type of time marker.

The time stamp characterization system may use a time stamping scheme wherein a first time stamp of the first type of time stamp matches a first time and each time stamp of the first type thereafter matches the first time plus an increasing time period, the time period being predetermined Increment for each successive time stamp of the first type, and wherein a first time stamp of the second type of time stamp matches a second time, and each time stamp of the second type subsequently coincides with the second time corresponds to an increasing period of time, with the time period increasing at a predetermined increment for each subsequent time stamp of the second type.

The System for characterizing the timestamp can also be a scheme use to timestamp, with each timestamp of the first Type and each time stamp of the second type with a current, chronological time coincides.

The A system for characterizing the time marker may further include a Clock include those with the first processor and with the second processor connected is.

The A system for characterizing the time marker may further include System for presentation of data associated with the first and second processors connected, the system for the presentation of data from the Group selected which consists of monitors, plotters or drawing devices and printers.

The System for characterizing the time marking can be used to a method of characterization of a variety of samples perform, in a variety of sample wells of a multiwell microplate are included, the method comprising the steps of: a sequential Prepare the plurality of samples within the plurality of sample wells, wherein a first, constant time interval between the preparation the successive samples of the plurality of samples is not required; recording a first plurality of timestamps, each one the first variety of time marks with the preparation which matches one of the plurality of samples; measuring the Luminescence from each sample of the plurality of samples, with a second, constant time interval between successive measurements the luminescence is not required; and the inclusion of a second Plurality of time stamps, each of the second plurality of Timestamps with the step of measuring the luminescence of one of the plurality of samples matches.

The Time stamping method may include a scheme in which each the first variety of timestamps with a specific one Step of the preparation corresponds to each of the plurality of samples, the specific Step is selected from the group of steps that consist Add a component of a sample, adding a reactant, the setting a temperature of a sample, setting a temperature, the coincides with the plurality of sample wells, adjusting a humidity of a sample, adjusting a Humidity, which coincides with the plurality of sample wells, adjusting a gas pressure of a sample, adjusting a gas pressure with matches the variety of sample wells, the selection of a gas type for a sample and the selection of a type of gas with the variety of Sample wells matches.

The Timing method may further include the step of determining a plurality of time intervals, each of the plurality the time intervals with a separation of the time between one of the mentioned, first plurality of time marks and one of said, second plurality of time marks coincide, wherein the plurality the time intervals coincide with the plurality of samples.

The Timing method may further include the steps: the Measurement of luminescence from each sample of at least one section said plurality of samples; and the inclusion of a third Variety of time stamps, each of said, third Variety of time marks with the step of measuring the luminescence of one of the sections of said plurality of samples.

The Timing method may further include the step of determining a plurality of time intervals, each of said Variety of time intervals with a separation of time between one said first plurality of time stamps and one of said, third plurality of time stamps, wherein the plurality of time intervals with said section matches said plurality of samples.

The time-mark characterization system may be used to perform a method of characterizing a plurality of samples contained in a plurality of sample wells of a multi-well microplate, the method comprising the steps of: sequentially preparing said plurality of samples in FIG said plurality of sample wells, wherein a first, constant time interval between the preparation of the successive samples of the plurality of samples is not required; the inclusion of a first plurality of time stamps, each of said, ers the plurality of time markers of the preparation corresponds to one of the said plurality of samples; measuring the fluorescence of each sample of said plurality of samples, wherein a second, constant time interval between successive measurements of fluorescence is not required; and receiving a second plurality of time stamps, each of said second plurality of time stamps coinciding with the step of measuring the fluorescence of one of said plurality of samples.

The Time stamping method may include a scheme in which each said, first variety of timestamps with a specific one Step of the preparation corresponds to each of said plurality of samples, wherein the specific Step is selected from the group of steps that results from adding a Component of a sample, the addition of a reactant, the adjustment a temperature of a sample, setting a temperature, the matches the variety of sample wells that Adjusting a humidity of a sample, setting a Moisture that matches said plurality of sample wells, adjusting a gas pressure of a sample, adjusting a gas pressure, which coincides with said plurality of sample wells, the selection of a Gas type of a sample, and the selection of a type of gas with the match said plurality of sample wells, consist.

Of the Step to measure the fluorescence of the time-marking method can also be the step of irradiating each sample of the mentioned Include variety of samples with an excitation light.

The Timing method can also be the step of determination a plurality of time intervals, each of said Variety of time intervals of a separation of time between one of mentioned, first plurality of time marks and one of said, second plurality of time stamps, said Variety of time intervals of said plurality of samples corresponds.

The Timing method may also include the steps: the Measuring the form of fluorescence of each sample of at least one section said plurality of samples; and the inclusion of a third Variety of time stamps, each of said, third Variety of time marks the step of measuring the fluorescence from one of said sections of the plurality of samples.

The Timing method can also be the step of determination a plurality of time intervals, each of said Variety of time intervals of a separation of time between one of said first plurality of time stamps and one of said, third plurality of time marks corresponds, wherein the plurality the time intervals the portion of said plurality of samples equivalent.

alternative For this purpose, the method of the invention for time marking a method to characterize a variety of samples that are included in a variety of sample wells a multichannel microplate are included, the method the steps comprises: sequentially preparing said plurality the samples in the plurality of sample wells, wherein a first, constant Time interval between the preparation the successive samples of said plurality of samples is not required; recording a first plurality of timestamps, wherein each of said first plurality of time stamps is the preparation one of said plurality of samples corresponds; the measurement the absorption of each sample of said plurality of samples, wherein a second, constant time interval between successive Measurements of absorption is not required; and the recording a second plurality of time stamps, each of said, second plurality of time marks with the step of measurement matches the absorption of one of said plurality of samples.

Of the Step of measuring the absorption can be the step of irradiation of each sample of said plurality of samples with light from a light source.

The Timing method may further include the step of determining a plurality of time intervals, each of said Variety of time intervals of a separation of time between one of mentioned, first plurality of time marks and one of said, second plurality of time stamps, said Variety of time intervals of said plurality of samples corresponds.

The time stamping method may further include the steps of: measuring the absorption of a each sample of at least a portion of said plurality of samples; and receiving a third plurality of timing marks, each of said third plurality of timing marks corresponding to the step of measuring the absorption of one of said portions of said plurality of samples.

The Timing method can also be the step of determination a plurality of time intervals, each of said Variety of time intervals of a separation of time between one of mentioned, first plurality of time marks and one of said, third plurality of time stamps, said Variety of time intervals the said section of said Variety of samples corresponds.

Claims (27)

An instrument for analyzing a sample, comprising: a detection device ( 1201 ) configured to receive light from a sample in an examination site ( 1604 ), a sample transfer axis extending substantially vertically from the examination site ( 1604 ), a dispenser assembly ( 504 . 600 ) movable along the sample transfer axis for transporting liquid to the examination site; and at least one material exchange station ( 1600 ) disposed along the sample transfer axis over the inspection site, the material exchange station being adapted to exchange materials such as pipettes and reagents with the donor system. The instrument of claim 1, wherein the inspection body ( 1604 ) is one of a plurality of examination sites located at an analysis station ( 104 ), each of the examination sites having a sample transfer axis extending vertically from the examination sites to the material exchange station (FIG. 1600 ). The instrument according to one of claims 1 or 2, further comprising a conveying device ( 554A ), material to and from the material exchange station ( 1600 ) in a direction substantially perpendicular to the sample transfer axis. The instrument of any of claims 1 to 3, further comprising a second material exchange station (10). 1602 ), each of the material exchange stations ( 1600 . 1602 ) is located above the examination site along the sample transfer axis. The instrument of claim 4, wherein each material exchange station ( 1600 . 1602 ) a conveying device ( 554A . 554B ) adapted to move material substantially perpendicular to the sample transfer axis. The instrument according to claim 5, wherein the transport devices ( 554A . 554B ) are arranged to move substantially perpendicular to each other. The instrument according to any one of claims 4 to 6, wherein one of the material exchange stations is set up as an analysis station to be used in a light detection instrument. The instrument of any one of claims 1 to 7, wherein the dispenser assembly ( 504 . 600 ) a matrix of liquid transport channels ( 602 ) includes. The instrument according to claim 8, wherein the liquid transport channels ( 602 ) Have pipette channels. The instrument of claim 8 or 9, wherein the material exchange station ( 1600 ) is adapted to pipette tips between the liquid transport channels ( 602 ) and the dispenser assembly ( 504 . 600 ) to transport back and forth. The instrument of any one of claims 7 to 10, further comprising a drive mechanism ( 506 ), which controls the donor arrangement ( 504 . 600 ) exert a force on the pipette tips that are at the material exchange station ( 1600 ) available. The instrument according to claim 11, wherein the amount of force exerted by the dispenser assembly ( 504 . 600 ) is variable, depending on the number of pipette tips at the station ( 1600 ) available. The instrument according to one of claims 1 to 12, further comprising a tip receiving station, arranged along the sample transfer axis, in which disposable tips briefly removed from the dispenser assembly and can be attached to them; one Tip support arrangement along a sample transfer axis vertical direction from the tip receiving station every now and then is movable away; and where one along the sample transfer axis arranged examination site, the dispenser arrangement set up for it is, along the sample transfer axis to be moved to pick up tips at the charging station and liquid to transport to the investigation site. The instrument according to any one of claims 10 to 13, wherein the dispenser assembly includes a tip removal mechanism Has. The instrument according to one of claims 1 to 14, comprising at least two material exchange stations ( 1600 . 1602 ) arranged along the sample transfer axis and the dispenser assembly ( 504 . 600 ) to each material exchange station ( 1600 . 1602 ) to pick up or bring materials to perform an investigation. The instrument of claim 15, wherein a first material exchange station ( 1600 ) is adapted to exchange pipette tips and the second material exchange station ( 1602 ) is adapted to exchange liquid using the pipette tips obtained at the first material exchange station. The instrument of claim 16, wherein the first material exchange station (16) 1600 ) over the second material exchange station ( 1602 ) is located along the sample transfer axis. The instrument of any one of claims 15 to 17, wherein the dispenser assembly ( 504 . 600 ) to an analysis station ( 1604 ), which is below the material exchange stations ( 1600 . 1602 ) are arranged along the sample transfer axis, wherein the material exchange and analysis stations are arranged so that when the dispenser assembly ( 504 . 600 moved down the transfer axis, first a material exchange station ( 1600 ), which transfers pipette tips, and then a material exchange station ( 1602 ), which transfers liquid and then the examination site ( 1604 ). The instrument according to one of claims 1 to 18, further comprising a first processor associated with the Dispenser assembly is coupled, wherein the first processor, the preparation a variety of samples controlled and at least one timestamp for each Sample preparation step for every determined the variety of samples. The instrument according to one of claims 1 to 19, further comprising an analysis chamber with an opening above the examination center; and the dispenser assembly is so in the relationship to the opening dimensioned that light incidence is substantially suppressed by the opening, when the dispenser assembly is liquid to the investigatory body. The instrument according to one of claims 2 to 20, wherein the analysis station includes upper and lower optical heads and each of the optical heads is laterally movable to light from the variety of examination sites to detect. The instrument of claim 21, wherein the upper optical head is movable out of the way of the pipette assembly, though liquid is delivered. A method of performing an analysis of a sample using the instrument of any one of claims 1 to 20, comprising: robotically guided (ie, by automated apparatus) a dispenser assembly along a sample transfer axis to a liquid transfer station; Aspirating fluid at the fluid transfer station into the dispenser assembly for further transport along the sample transfer axis; robotically guided transport of the dispenser assembly further along the sample transfer axis to a Investigative body; Dispensing liquid from the pipette tips to a sample container at the examination site; and detecting light from the fluid at the examination site. The method of claim 23, further comprising: robot-bound Transporting the dispenser assembly along the sample transfer axis to a pipette tip loading station; and Loading one or more Pipette tips on the dispenser assembly before transporting the dispenser assembly to the liquid transfer station. The method according to any one of claims 23 or 24, where all steps are generally along a single linear Processing path lie. The method according to any one of claims 23 to 25, wherein the step of dispensing liquid from the pipette tip further comprising receiving a plurality of time stamps, with the addition of liquid correlated to each of the variety of samples. The method according to any one of claims 23 to 26, wherein the step of detecting light from the liquid further, in the examination site, recording a variety of timestamps involved in detecting light from each of the variety of samples correlates.