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    • 专利摘要:
    invention patent: "apparatus and method for processing biological samples". the present invention relates to a method and an automated apparatus for processing at least one biological sample arranged on a slide. at least one capillary marking module has a blade tray retainer configured to detachably retain a blade tray configured to hold slides, and a cap retainer with capillary cover configured to detachably retain a capillary tray configured to retain capillary caps, the blade tray can be removed regardless of removing the capillary tray. a first fluid container has a first fluid. the apparatus is configured to automatically rotate one or more blades and to move the lids towards the blades to automatically form a capillary gap between each blade and each capillary cap, said capillary gap functioning as a capillary chamber; and to supply a quantity of the first fluid to the slide.
    公开号:BR112012013813B1
    申请号:R112012013813-8
    申请日:2010-12-09
    公开日:2020-03-17
    发明作者:Soren Damgaard Larsen；Peter Axel Valbjorn
    申请人:Dako Denmark A/S；
    IPC主号:
    专利说明:

    Invention Patent Descriptive Report for "AUTOMATED MARKING APPLIANCE FOR PROCESSING AT LEAST ONE BIOLOGICAL SAMPLE DISPLAYED ON A BLADE AND AUTOMATED METHOD FOR PROCESSING AT LEAST ONE BIOLOGICAL SAMPLE DISPLAYED ON A BLADE".
    PRIORITY CLAIM
    [0001] This application claims the benefit of Provisional Copending Patent Application No. US 61 / 267,906, entitled "AN APPARATUS AND METHOD FOR PROCESSING BIOLOGICAL SAMPLES", filed on December 9, 2009 and incorporated herein by reference in its wholeness.
    TECHNICAL FIELD
    [0002] The present invention relates to the processing of a biological sample for, for example, histological and cytological examination. In particular, the present invention relates to the processing of a biological sample, for example, a section of fine tissue, using a small amount of a processing fluid. BACKGROUND OF THE INVENTION
    [0003] Sample processing in immunohistochemical (IHC) applications, for example, and in other chemical and biological analyzes may involve one or more treatment processing protocols or sequences as part of an analysis of one or more samples. Typically, such treatment protocols are defined by organizations or individuals that require analysis, such as pathologists or histologists working in a hospital, and can be further defined by the results of a particular analysis to be developed.
    [0004] An in situ hybridization procedure (ISH), for example, a fluorescent in situ hybridization procedure (FISH), is traditionally a long two-day manual procedure. Attempts have been made to automate parts of the procedure in order to shorten the processing procedure and to reduce the number of manual steps. For example, the pre-treatment procedure for the first day was automated with a VP2000® instrument (Vysis, Abbott Molecular), and in such an instrument a robot moves blades from one jar to another.
    [0005] However, the problem, until then, was to combine the pre-treatment steps of the first day and the washing steps of the second day with the severe physical and environmental demands of the denaturation and hybridization steps in the meantime. In these steps, it is preferable to use small volumes of processing fluids and provide precise humidity control in the processing chamber surrounding the processed tissue section, and to provide controlled heating and cooling in order to obtain consistent FISH results.
    [0006] The automated IHC and ISH marking instruments were introduced by Ventana Medical Sistemas Inc. (BenchMark® and Discovery®) and VisionBiosistema (Bond®). A disadvantage of these instruments is that they provide only a fixed processing volume, that is, the processing chamber is of a fixed volume. The volume of the processing chamber in the instrument is at least 100 microliters.
    [0007] The BenchMark® instrument needs to cover the tissue section to be processed and the processing fluid applied with oil in order to reduce evaporation from the processing fluid. If not covered by oil, evaporation of processing fluid will deteriorate the processing result.
    [0008] The Bond® instrument has a small processing chamber that is manually attached over each section of tissue and over each carrier. By manually attaching the processing chamber to each carrier, an individual marking cavity is created.
    [0009] In the publication PCT WO 2009/086048 A1, by Ventana Medical Sistemas Inc., the application and removal of capillary range variation liquid are presented. A disadvantage of this system is that it requires a relatively complex mechanical device that includes an engine for each station and each station processes only one blade at a time.
    [00010] In PCT publication WO 2009/074154 A2, by Dako Denmark A / S, an apparatus for processing a biological sample arranged on a first flat surface of a carrier is presented. The apparatus comprises a second flat surface arranged substantially parallel to said first flat surface and at a first distance from said first flat surface, said first flat surface and said second flat surface being disposed at an angle greater than zero degrees of the horizontal plane; and supply means for supplying an amount of a liquid to be applied to said biological sample. The first flat surface and said second flat surface are configured to be disposed at a second distance from each other, wherein said second distance is such that said supplied quantity of liquid is distributed through said biological sample when said first flat surface and said second flat surface are led to said second distance from each other.
    [00011] The sample processing apparatus presented in 2009/074154 A2 is not configured to easily allow a slide tray to be automatically inserted, processed and removed.
    [00012] U.S. Patent No. 6,623,701 B1, to Max-Planck Gesellschaft zur Forderung der Wissenschaften e.V., discloses a specimen chamber for treating liquid from at least one specimen. The chamber comprises a base plate and a carrier plate, between which an accommodation space formed by a gap is formed for the specimen, through which the base plate and the carrier plate are held together with a retention device in a frame arrangement. , and, in order to form the accommodation chamber, they are separated from each other by spacer elements.
    [00013] A disadvantage of the specimen chamber of U.S. 6,623,701 B1 is that each specimen chamber must be manually assembled before processing of a specimen can begin. Manually assembling the chamber requires several steps and the associated time and work for each stage and requires some skills from the individual who assembles the chamber in order to position the parts of the chamber to be arranged in their correct position. This multi-step manual assembly process increases the opportunity for human error.
    [00014] PCT publication WO 2006/116037, by Celerus Diagnostics Inc., features a sample processing system that can be configured to achieve rapid sample processing, such as rapid histochemical processing. The processing system may involve a wave element that can use angular microscopic slide movements to cause repeated elimination and reapplication of a fluid substance perhaps through the action of capillary movement in order to renew a microenvironment adjacent to a sample, such as a biopsy or another sample. Through such renewal of a microenvironment, depletion of the microenvironment is avoided and the time required for blade processing can be shortened.
    [00015] Disadvantages of the sample processing system described in WO 2006/116037 refer to the fact that a fluid environment confined around a sample on one slide is achieved with the use of an opposite slide that, at one end, it is articulated to one end of the slide that holds the causative sample. As with other systems, multiple blades in a single tray cannot be automatically loaded and unloaded at the processing site. In addition, this system uses an absorption mechanism in the form of a large cartridge of absorbable material, thereby increasing the operating cost of the instrument.
    [00016] In addition, the mixing of the fluid within the confined fluid environment is accomplished by providing an angled movement of the opposite blade, that is, by rotating the opposite blade around the joint. Some of the disadvantages of prior art instruments are due to the fact that they require relatively large volumes, about 150 to 200 microliters, of processing fluid, do not provide results as good as manual processing, do not automatically provide a processing chamber and do not provide a variable volume of processing fluid to be used by providing a processing chamber that has a variable volume. In addition, many of the prior art instruments are relatively complex and require a large number of moving parts. In addition, prior art instruments often require manual assembly or fixation of a cover or lid to form a capillary gap or require evaporation that prevents the liquid from being applied to an accumulation of processing reagent during the incubation that typically results in a higher volume of reagent that needs to be applied.
    [00017] An objective of the present invention is to solve these and other problems and disadvantages of the prior art system. For example, an objective of the present invention is to overcome the disadvantage of having a complex mechanism that processes only one blade at a time.
    [00018] Another objective of the present invention is to overcome the disadvantages of horizontal carrier systems that require a vacuum to evacuate the capillary chamber.
    [00019] Yet another objective of the present invention is to solve the problem of having a fixed volume of processing fluid or requiring a relatively large amount of processing fluid for automated protocols when compared to the amount of fluid required for manual protocols of the same type.
    [00020] Another objective of the invention is to eliminate the problem of requiring separate complex mechanisms to mix a fluid in each single slide.
    SUMMARY OF THE INVENTION
    [00021] The present invention relates to molecular pathology, that is, the examination at a molecular level of DNA; mRNA and proteins that cause or are otherwise associated with disease. The present invention relates to the processing of a biological sample for, for example, histological and cytological examination. In particular, the present invention relates to the processing of a fine biological sample, for example, a section of tissue, with the use of a small amount of a processing fluid.
    [00022] In particular, the invention relates to the processing, for example, treatment and / or marking, of at least one biological sample, for example, a section of tissue, accommodated in a carrier, as well as the control of humidity and temperature during processing.
    [00023] It should be understood that the present invention can be used in the fields of cytology and histology, molecular biology, biochemistry, immunology, microbiology and cell biology. In particular, the invention relates to the fields of molecular cytogenetics and immunohistochemistry for the processing of biological samples in immunohistochemistry (IHC), in situ hybridization (ISH), fluorescent in situ hybridization (FISH), in situ chromogenic hybridization (CISH), special markings (SS), in situ silver hybridization (SISH), microarrays (tissue, protein, RNA, DNA, PNA, LNA, etc.), as well as other chemical and / or biological applications.
    [00024] Immunological applications, for example, may involve protocols or processing sequences that comprise steps, such as dewaxing, target recovery and tagging, especially for in situ hybridization (ISH) techniques.
    [00025] The marking procedure can be laborious and can use many different types of liquids, for example, reagents. The labeling protocol can include the following steps: dewaxing, washing, antigen recovery, endogenous biotin or enzyme blocking, incubation with immunological reagents, molecular probes, secondary visualization reagents and various chromogen reagents, washing and countermarking steps .
    [00026] The present invention relates to an automated marking apparatus for processing at least one biological sample arranged on a slide. The modalities of the automated marking apparatus comprise: at least one capillary marking module comprising: a blade tray retainer configured to detachably retain a blade tray configured to retain one or more blades, and a tray retainer with lid capillary configured to detachably retain a capillary tray configured to retain one or more capillary caps, where the blade tray can be removed regardless of the removal of the capillary tray, and a first fluid container comprising a first fluid , where the automated marking device is automatically configured to: control the blade tray retainer to rotate one or more blades from an insertion position to one or more inclined positions, and control the tray retainer with capillary cover to move the one or more capillary caps towards the one or more blades in order to form au a capillary gap between each slide and each capillary cap, in which said capillary gap functions as a capillary chamber; and to supply an amount of the first fluid from the fluid container to the blade when in said angled position.
    [00027] The present invention also relates to an automated method for processing at least one biological sample arranged on a slide, the method modalities of which comprise: providing at least one capillary marking module comprising: a tray retainer blade set detachable to hold a blade tray configured to hold one or more blades, and a cap retainer with capillary cover configured to detachable hold a capillary tray configured to hold one or more capillary caps, where the blade tray can be removed regardless of the capillary tray removal, provide a first fluid container comprising a first fluid, automatically control the blade tray retainer to rotate one or more blades from an insertion position to a or more inclined positions; automatically control the cap retainer with capillary cap to move the one or more capillary caps towards the one or more blades in order to automatically form a capillary gap between each blade and each capillary cap, in which said capillary cap functions as a chamber capillary; and automatically delivering a quantity of the first fluid from the fluid container to the blade when in said angled position.
    [00028] The preferred embodiments of the invention are defined in the dependent claims.
    DETAILED DESCRIPTION OF THE DRAWINGS
    [00029] The objectives, advantages and effects, as well as resources, of the present invention will be more readily understood from the following detailed description of modalities of the invention, when read in conjunction with the accompanying drawings, in which: Figure 1A is an illustration oblique schematic of an embodiment of an automated marking apparatus comprising an IHC automated capillary marking module and an ISH automated capillary marking module; Figure 1B schematically illustrates a biological sample arranged on a slide; Figure 1C is an oblique view of upper and intermediate sections of an embodiment of an automated marking apparatus comprising an automated capillary marking module; Figure 2A is an exploded oblique view of an automated capillary marking module modality showing a processing vessel, a capillary tray, a processing vessel lid and a blade tray; figure 2B is an exploded oblique view of an embodiment of an automated capillary marking module showing a processing container, a capillary tray, a processing container lid and a blade tray; Figure 3A schematically illustrates a cross-sectional view of an embodiment of the capillary marking module in which the insertion of the vertical blade tray followed by the rotation is shown; Figure 3B schematically illustrates a cross-sectional view of another embodiment of the capillary marking module in which the insertion of the rotating inclined blade tray is shown; Figure 4 schematically illustrates a cross-sectional view of an embodiment of the capillary marking module in which the initial fluid supply to a blade in an inclined position is shown; Figure 5 schematically illustrates a cross-sectional view of an embodiment of the capillary marking module in which the rotation of the capillary tray is shown; Figure 6 schematically illustrates a cross-sectional view of an embodiment of the capillary marking module in which a fluid-filled capillary gap is obtained between a capillary cap and a blade; Figure 7 schematically illustrates a cross-sectional view of an embodiment of the capillary marking module in which an amount of a reagent is supplied to the fluid filled capillary gap; Figure 8 schematically illustrates a cross-sectional view of a modality of the capillary marking module in which the capillary cap performs an oscillating movement; Figure 9 schematically illustrates a cross-sectional view of an embodiment of the capillary marking module in which the capillary gap between a capillary cap and a blade is removed during fluid supply; figure 10 schematically illustrates a cross-sectional view of a modality of the capillary marking module in which a capillary cap is cleaned by means of a wiper-type blade; figure 11 schematically illustrates a cross-sectional view of an embodiment of the capillary marking module in which a reagent is dispensed; figure 12 schematically illustrates a cross-sectional view of a modality of the capillary marking module comprising preventive means of condensation, in which a reagent is dispensed; figure 13 schematically illustrates an embodiment of a capillary tray comprising ten capillary caps; Figure 14A schematically illustrates the flow of fluid in a capillary gap between a blade and a capillary cap without a drip tip; Figure 14B schematically illustrates the flow of fluid in a capillary gap between a blade and a capillary cap with a drip tip; Figure 14C schematically illustrates the flow of fluid in a capillary gap between a blade and a capillary cap with a drip tip and a droplet captor; Figure 15A schematically illustrates an embodiment of a capillary cap comprising spacers, a central recess, a drip tip and a beveled top end; Figure 15B schematically illustrates an embodiment of a capillary cap comprising spacers, a central recess, a drip tip and an upper end beveled with a droplet drain; Figure 16A is an exploded oblique view of an embodiment of a bubble eliminator combined with an in-line fluid heater; and Figure 16B schematically illustrates an embodiment of a bubble eliminator and the flow of fluid and bubbles within the bubble eliminator.
    DETAILED DESCRIPTION OF THE INVENTION
    [00030] Although the invention encompasses several modifications and alternative methods, apparatus and systems, the modalities of the invention are shown in the drawings and will now be described in detail. However, it should be understood that the specific description and drawings are not intended to limit the invention to the specific forms presented. On the contrary, the scope of the claimed invention is intended to include all modifications and alternative constructions thereof that are within the spirit and scope of the invention, as expressed in the appended claims to the full extent of their equivalents. In the drawings, the same reference numeral is used for the same or a similar feature.
    [00031] In an embodiment of the invention and as schematically illustrated in figure 1A, an automated sample processing apparatus 1, in that description also referred to as an automated marking apparatus 1, comprises at least one capillary processing module 100, in that description description also called as a capillary marking module 100, to process at least one biological sample 3, as a biological tissue sample, arranged in a sample holder 10, see figure 1B.
    [00032] The biological sample can be presented in the sample holder in several ways and potentially in some form of preservation. As an example, a sample, such as a layer or piece of skin, tumor or other tissue, can be preserved in for-maldehyde and presented in a sample holder with one or more layers of paraffin or other chemical layers that overlap the sample. Samples preserved with paraffin may need to be dewaxed, a process by which the paraffin layers that overlap and / or infiltrate the sample are removed. In addition, the target or sample may need to be restored to a condition where it is suitable for marking operations - a process known as target retrieval.
    [00033] As used herein, automated is defined as a plurality of steps that are performed through substantially mechanical, computer and / or electronic means. It does not exclude some stages of human intervention, such as the manual replacement of one of the resources or steps described.
    [00034] Although, in this description, reference is made to a slide, it should be understood that the slide refers to a sample holder, and the sample holder is any means that supports a sample. Therefore, the sample holder includes any support, such as a carrier, test tube, chip, arrangement, disk or slide that can hold at least one sample.
    [00035] Furthermore, in this description, reference is also made to a blade tray. However, the blade tray must be understood to include any retainer suitable for a group of holders, such as a tray that supports a group of blades. The blade tray may additionally refer to a larger scale holder, such as a blade tray holder that holds at least one smaller holder, such as a plurality of blade trays, each tray containing a plurality of blades. A retainer may release reliably, retain securely and / or retain in such a way as to allow movement, such as vertical, horizontal or pivoting around one or more geometric axes.
    [00036] As schematically illustrated in figure 1A, the automated marking apparatus 1 comprises a first capillary marking module 100, a second capillary marking module 100 'and a third capillary marking module 100 ”, however, it should be understood that the number of capillary marking modules can be varied.
    [00037] In modalities, the first, second and third capillary marking modules, 100, 100 'and 100 ”can be configured for, for example, immunohistochemical (IHC) applications and in situ hybridization applications (ISH), respectively .
    [00038] As schematically illustrated in figure 1A, the marking apparatus 1 can comprise three levels; a first lower level I which comprises, for example, containers of fluid for bumps, refuse, valves and pumps; a second intermediate level II comprising, for example, several processing units, slide stores, robotics and reagent bottles; and a third upper level III comprising, for example, a cover slide and control units and communication interfaces. Certain elements, such as the control unit 151, can be positioned at level III to allow, roughly speaking, an eye level view of the display or at level I to leave the path when manually processing modules at level II .
    [00039] As illustrated, the automated marking apparatus 1 may comprise one or more processing units, such as one or more pretreatment modules 2, sometimes referred to as immersion tanks, blade storage units 6 and one or more capillary marking modules 100, 100 ', 100 ”.
    [00040] In modalities, a pre-treatment module 2 can be configured for dewaxing, that is, for removing paraffin from a biological sample embedded in paraffin. Pre-treatment module 2 can also be configured for target recovery (for example, antigen recovery or in situ hybridization), that is, to restore the sample target / antigen to a condition where it is suitable for marking operations .
    [00041] The automated marking apparatus 1 may include sample loading stations 17 for inserting slide trays with samples into the apparatus for processing. The automated marking apparatus 1 may additionally include accessory charging stations 21 for inserting accessories, such as covers for in situ hybridization protocols.
    [00042] The one or more blade storage units 6 are configured to store one or more blades 10 arranged in one or more blade trays 20 configured to hold several blades 10 mounted side by side. Blade 6 storage units are configured to store slides horizontally, vertically or in another suitable position.
    [00043] The automated marking apparatus 1 may additionally comprise several containers 8 of batch fluids 8a, such as washing solutions, buffer solutions, dewaxing solutions, target recovery solutions or aqueous solutions such as purified water, antibodies in solution, batch marking solutions, such as hematoxylin, eosin, cleaning solutions, such as DAB removal solution, etc. known to a person skilled in the art.
    [00044] The automated marking apparatus 1 may additionally comprise pipelines 9 connecting the batch fluid container (s) 8 to one or more 2,100, 100 ', 100 ”processing units, valves 7 for controlling the flow batch fluid 8a for one or more processing units 2, 100, 100 ', 100 ”from batch fluid container (s) 8, and one or more pumps 5 configured to provide a flow batch fluid from batch fluid container 8 to one or more processing units 2, 100, 100 ', 100 ”.
    [00045] Furthermore, the automated marking apparatus 1 may comprise a refuse container 11 configured to store refuse fluid that has been removed through pipes (not shown) from one or more processing units 2, 100, 100 ', 100 ''.
    [00046] As schematically illustrated in figure 1A, the automated marking apparatus 1 further comprises a blade robot 12 configured to transport one or more blades 10 or one or more blade trays 20 in X and Y directions (as well as Z), as indicated by arrows X and Y. Using a blade robot 12, the blades / blade tray can be transported between different processing units 2, 100, 100 ', 100' 'and storages 6 of the marking apparatus 100 so that the biological samples arranged on the slides can be processed as desired.
    [00047] In figure 1A, it is schematically illustrated how the blade robot 12 suspends, along the Y direction, a blade 10 or a blade tray 20 from a blade storage 6. In addition, as indicated by the arrow, the blade robot 12 can move to the left, along the X direction, for, for example, a first capillary marking module 100, 100 ', 100 ”.
    [00048] The blade robot 12 can hold a blade tray 20 from the sample drawer 17 and transport the blade tray 20 and blades 10 to any of the stations, such as cold plate 15, hot plate 4, heating station incubation 22, pretreatment modules 2, marking modules 100, 100 ', 100 ”, or wet / dry discharge modules 6, in order to process samples 3 on slides 10.
    [00049] When the blade robot 12 is arranged in a position above the blade tray position of the capillary marking module, the blade robot 12 can be configured to lower, along the Y direction, the blade or the hair tray. blade in the capillary marking module to insert the blade or the blade tray in a correct position inside the capillary marking module, as indicated by the downward arrow along the Y direction in figure 1A.
    [00050] In addition, blade robot 12 can be configured to position blade tray 20 horizontally, vertically or at an angle between horizontal and vertical. For example, blade robot 20 can hold or release blade tray 20 in a horizontal orientation over cold plate 15 or hot plate 4 or charging stations 17. As an additional example, blade robot 12 can hold or release blade tray 20 in a vertical orientation in pretreatment modules 2 or unloading stations 6. In yet another example, blade robot 12 can hold or release blade tray 20 in an angled horizontal orientation and vertical, such as 100, 100 'and 100' 'marking modules.
    [00051] In addition, the automated marking apparatus 1 comprises a fluid robot 14 for moving a probe 16 in the X and Y directions (as well as Z), as indicated by the arrows X and Y. The fluid robot 14 can position the probe 16 above one or more fluid containers 18, mixing stations, capillary marking modules 100,100 ', 100' ', cold plate 15 and hot plate 4.
    [00052] The fluid robot 14 can further operate the probe 16 to aspirate portions of reagent 18a contained in any of the reagent containers 18 in order to transfer the reagent portion 18a and apply it to one or more slides 10 arranged in one or more of the capillary marking modules 100, 100 ', 100' 'in order to provide a selected marking or sample treatment on the slide. As schematically illustrated in figure 1A, one or more fluid containers 18 can be arranged in a fluid container tray 19.
    [00053] Therefore, fluid robot 14 is configured to move probe 16 between different positions within the automated marking apparatus 1. Fluid robot 14 can be, for example, configured to move probe 16 to, for example , an aspiration position in a reagent container 18 and to let the probe 16 suck in a quantity of a reagent 18a from the reagent container 18. In addition, as schematically illustrated by the arrow pointing left, along the X direction, and by the downward arrow, along the Y direction, through the fluid robot 14, the probe 16 can be moved to, for example, a dispensing position on a blade 10 arranged in a capillary marking module 100, 100 ', 100' ', and in such a dispensing position, a volume of the aspirated reagent 18a can be dispensed onto slide 10 in order to provide a selected marking or sample treatment on the slide.
    [00054] As schematically illustrated, for example, in figures 7, 11 and 12, the dispensing position can be defined by a first probe inlet 161 and / or a second probe inlet 163, respectively, arranged in a container lid processing 160.
    [00055] However, it should be understood that the number of first and second probe entries 161, 163 can be varied and that, in embodiments, the number of first and second probe entries 161, 163 is equal to the number of slides that can be processed in the capillary marking module. Thus, in embodiments, in the processing container lid 160, a first and a second probe inlet 161,163 are arranged for each slide that can be processed in the capillary marking module in order to provide an individual fluid supply for each slide.
    [00056] Furthermore, the capillary chamber automatically created as described here can be used in conjunction with fluid dispensing mechanisms, including robotic pipettes, probes, tubes, direct dispensing bottles, tubing and so on.
    [00057] Before aspirating a quantity of a different possible second fluid, probe 16 can be moved to a flushing fluid container 18 'and a flushing fluid amount can be aspirated in order to clean probe 16 before a quantity of a new possible fluid is aspirated by the probe 16.
    [00058] As schematically illustrated in figure 1A, the one or more reagent containers 18, 18 'can be arranged in a reagent container tray 19. A plurality of reagent container trays can be configured to be independently insertable and / or removable to accommodate the continuous workflow, that is, adding or removing reagents during ongoing slide processing.
    [00059] In addition, the automated marking apparatus 1 may additionally comprise a cover slide 13 configured to arrange a cover glass (not shown) on a processed biological sample arranged on a slide 10.
    [00060] As schematically illustrated in figure 1a, the automated marking apparatus 1 can also comprise a control unit 151 comprising processing control and an input / output interface. A suitable input may be a keyboard and a suitable output may be a monitor or the control unit 151 may comprise a touchscreen display.
    [00061] Figure 1C illustrates an orthographic view of the automated marking apparatus 1. As in Figure 1A, in the modalities of Figure 1C, the movement of samples on slides 10 in blade trays 20 is, in general, from the charging stations 17 , through the various processing stations and finally to the storage units 6 that function as unloading stations.
    [00062] For IHC slides, the sample processing workflow is one in which slides 10 in slide tray 20 are moved by robotic arm 12 to hot plate 4 if reinforcement is desired. The blade robot 12 moves and inserts blade tray 20 vertically into pretreatment module 2 for disengagement and, optionally, target recovery.
    [00063] After pre-treatment, the slide tray 20 is moved from one of the marking modules 100, 100 ', 100 ”, in which the reagents 18a are applied according to a desired HCI protocol, using a fluid 14.
    [00064] After marking, blade robot 12 moves blade tray 20 to blade storage units 6 that can be dried or can contain fluid to keep the blades moist. The blade storage units 6 can be accessed by a user to unload the blade tray 20.
    [00065] As schematically illustrated in figures 2A, 2B, 3A and 3B, a blade tray 20 configured to hold one or more blades 10 can be inserted into and removed from the capillary marking module 100, 100 ', 100 ”. In the embodiment shown in figure 2, the blade tray 20 is configured to hold several blades 10, for example, ten blades 10, however, it should be understood that the blade tray 20 can be configured to retain another suitable number of blades.
    [00066] In addition, a tray with capillary cap 40 configured to hold several capillary caps 30 can be inserted into and removed from the capillary marking module 100,100 ', 100' '. In the modality shown in figure 2, the capillary cap tray 40 is configured to hold several capillary caps 30, for example, ten capillary caps 30, however, it must be understood that the capillary tray 40 can be configured to retain another number capillary caps.
    [00067] The capillary marking module 100,100 ', 100' 'comprises a processing container 150 and a processing container lid 160. As illustrated in figure 3A and figure 3B, the container lid 160 is hinged in a hinge container lid 162 contained in processing container 150, through which container lid 160 can be rotated around container lid hinge 162 in order to open and close processing container 150. When processing container 150 is open, the capillary tray 40 with capillary caps 30 can be inserted into or removed from the processing container 150.
    [00068] Furthermore, figure 3A schematically illustrates a cross-sectional view of a modality of the capillary marking module 100,100 ', 100' 'in which the insertion and rotation of the blade tray are shown.
    [00069] As illustrated, one or more blade trays 20 comprising one or more blades 10 are inserted into the capillary marking module 100,100 ', 100 ”along a vertical direction, as indicated by the downward-pointing arrow, from a position above the capillary marking module to a position on the capillary marking module.
    [00070] Through the dotted lines in figure 3A, the blade tray 20 and a blade 10 are illustrated in a position above the capillary marking module, and in a first position inside the capillary marking module. In such a first position, the blade is arranged along the insertion direction, for example, the vertical direction. [00071] As additionally illustrated, the capillary marking module 100 comprises a blade tray retainer 102 configured to hold the blade tray 20 when inserted into the capillary marking module 100,100 ’, 100’ ’. In addition, blade tray retainer 102 is arranged on a blade tray retainer hinge 104, the blade tray retainer 102 is configured to rotate around that hinge 104.
    [00072] In embodiments, the blade tray retainer 102 is configured to rotate between an open position, in which a blade tray 20 in an insertion position, for example, a vertical position, can be inserted into or removed from the module capillary marking 100,100 ', and a closed position, in which a blade tray 20 is in an inclined position in which the blade tray 20 cannot be inserted or removed from the capillary marking module 100,100', 100 '', as schematically illustrated in figure 3A.
    [00073] Capillary marking modules 100,100 ', 100' 'can also comprise a moisture conduit 152 disposed in a lower part of the processing container 150 and configured to retain a volume of a fluid in order to provide a predefined humidity or predetermined inside the capillary marking module 100,100 ', 100' 'during the processing of biological samples. [00074] As previously described, the blade robot 12, see figure 1A, is configured to move a blade tray 20 inside the automated marking device 1 and to insert the blade tray 20 into a capillary marking module 100,100 ', 100' '. In addition, when the blade tray 20 is arranged on the capillary marking module 100,100 ', 100' ', the electronics of the automated marking apparatus 1 are configured to automatically rotate the blade tray 20 and the one or more blades 10 around of the blade tray retainer joint 104.
    [00075] In embodiments, the blade tray 20 is configured to rotate from the insertion position, for example, from the vertical position, to one or more inclined positions, for example, from an insertion position A to a first inclined position B, and from the first inclined position B to a second inclined position C.
    [00076] Furthermore, figure 3A schematically illustrates a cap retainer with capillary cap 106 that holds a cap retainer with capillary cap 40. The cap retainer with capillary cap 106 is configured to detachably retain a capillary cap 40. O capillary tray retainer 106 is arranged in a capillary tray retainer hinge 108, the capillary tray retainer 106 can rotate around hinge 108. In addition, the capillary tray retainer 106 it may comprise a lid lid tray 109 configured to detachably engage the lid lid 40.
    [00077] In embodiments, the capillary tray 40 comprises an upper cap bar 42 and an intermediate cap bar 44 configured to retain a capillary cap 30. Furthermore, the capillary tray 40 can comprise a lower bar 46 configured to detachably engage a slot 110 of the cap retainer with capillary cover 106.
    [00078] As schematically illustrated in figure 3A, the capillary cap 30 comprises a surface facing the upper and intermediate cap bars 42, 44, and fasteners 32, 34 by means of which the capillary cap 30 can be removably disposed on the capillary cap 40 tray. Preferably, fasteners 32, 34 are configured to provide flexible capillary cap 30 fixing to capillary cap 40 so that the distances d1 and d2 between the top cap bar 42 and the cap surface capillary facing the upper lid bar 42 and between the intermediate lid bar 44 and the capillary lid surface facing the intermediate lid bar 44, respectively, can be varied.
    [00079] In embodiments, the upper clamp 32 and the lower clamp 34 of the lid 30 are made as hooks configured to detachably engage the upper lid bar 42 and the intermediate lid bar 44, respectively, of the capillary tray 40 .
    [00080] As schematically illustrated in figure 3A, in modalities, the upper fastener 32 of the lid 30 comprises a pair of hooks and the lower fastener 34 of the lid 30 comprises a single hook. However, in other embodiments, the upper fastener 32 may comprise a single hook and the lower fastener 34 may comprise a pair of hooks, or the upper and lower fasteners 32, 34 may comprise the same number of hooks. Any type of fastener, such as sliding brackets, columns and hangers, can be used. Fasteners that are not rigidly and fixedly attached to the upper cover bar 42 and intermediate cover bar 44 are beneficial as they move smoothly and evenly over the blades.
    [00081] As schematically illustrated in Figure 3B, the illustrated mode works in substantially the same way as the Figure 3A mode, with the exception that, in the Figure 3B mode, the blade tray 20 does not rotate, however, it is inserted, otherwise, at an angle Θ to the horizontal HP plane through the blade robot 12.
    [00082] The angle Θ can be in the range of approximately 15 to 90 degrees in relation to the horizontal HP plane. By orienting the blade tray at an angle Θ, a desired flow through time for fluid in the capillary chamber can be achieved by adjusting the relationship between gravitational forces and the capillary forces acting on the fluid.
    [00083] As schematically illustrated, for example, in figures 3A to 6, the capillary cap 30 is arranged in the capillary cap tray 40 such that the distances d1, d2 between the capillary cap 30 surface facing the capped cap capillary 40 and the upper and intermediate capillary bars 42, 44 can be varied between a maximum distance, see figure 3A, and a minimum distance, see figure 6.
    [00084] However, it must be understood that the distances d1, d2 do not need to be the same or changed at the same time or need not be changed at the same rate. Therefore, distance d1 can be different from distance d2 and, for example, distance d1 can have a maximum value while distance d2 has a minimum value, or vice versa.
    [00085] In modalities, fluids 8a, 18a are supplied to a blade 10 when the blade is in an inclined position, for example, when the blade 10 is in an inclined position, see figures 4, 5, 6, 7, 9 and 11.
    [00086] Figure 4 schematically illustrates a cross-sectional view of an embodiment of the capillary marking module 100, 100 ', 100 ”in which a quantity of fluid 8a, through the nozzle 9c, which is supplied for a blade 10 in an inclined position is shown.
    [00087] In modalities, the nozzle 9c is configured with a chamfered distal end 9c ', see, for example, figure 3A, configured to provide an immersion-free nozzle through which the fluid 8a is not poured into the blade 10, however, it flows over slide 10.
    [00088] As schematically illustrated by pipes 9, 9a and 9b, fluid 8a is supplied from a fluid container (8, see figure 1A, not shown in figure 4) to a preheater 120 configured to heat the fluid that it passes through the heater 120 to a predetermined temperature before the fluid is supplied to the blade through a nozzle 9c disposed in a distal part of the tubing 9b.
    [00089] It should be understood that the capillary marking module modalities comprise several pipes 9b and nozzles 9c, preferably a pipe 9b and a nozzle 9c for each blade that can be processed in the capillary marking module in order to provide a supply individual fluid for each of the slides arranged in the capillary marking module.
    [00090] It should be understood that the modalities may comprise one or more pipes that deviate from a possible preheater and a possible bubble eliminator so that the fluid can be supplied directly from the fluid container to the lamina (s) (s) without going through a possible preheater and a possible bubble eliminator.
    [00091] Therefore, in modalities, the automated marking device 1 is configured to individually control the fluid supply for slides arranged in the capillary marking module. For example, fluid can be delivered to the slide (s) as a continuous fluid flow for a predetermined period of time. [00092] The preheater 120 can be realized as an inline resistive heater, an inductive heater or any type of heater that includes a microwave heater. By means of such a preheater, no heater disposed below the sample carrier is necessary to heat the fluid to a desired temperature.
    [00093] Alternatively, a preheater 120 can be integrated with a bubble eliminator 130 or even a plurality of bubble eliminators 130, as illustrated and described below in relation to figures 16A and 16B.
    [00094] For some applications, for example, as immunohistochemical marking, the predetermined temperature of the fluid can be set to be approximately 30 degrees Celsius in order to prevent the slide from being cooled by a relatively cold rinse plug. By keeping the blade temperature relatively constant, even during rinses, the immunoincubation reaction rate can be made relatively consistent, thereby providing more consistent staining results. However, it should be understood that, for other applications, such as in situ hybridization, which can occur at 37 degrees Celsius or 50 degrees Celsius, the predetermined temperature may be different and may also be different for different fluids used for the application.
    [00095] Capillary marking module modalities 100, 100 ', 100 ”can also comprise a bubble eliminator 130, see figures 3A to 12. The bubble eliminator 130 can be arranged together with the preheater 120 by means of a tubing 9a or may be contained in the preheater 120. The bubble eliminator 130 can be configured to remove bubbles from the preheated fluid before the preheated fluid is supplied to one or more blades 10 via a tubing 9b and the nozzle 9c.
    [00096] As schematically illustrated in figures 3 to 12, the bubble eliminator 130 may comprise, in some embodiments, an upper compartment 132 to which the heated fluid is supplied and a lower compartment 134 through which the heated fluid which has possible bubbles removed comes out of the bubble eliminator 130. Possible bubbles, such as air bubbles, will move to the upper compartment 132 from which air bubbles can be removed via the gas outlet (not shown). A more detailed illustration and description of a bubble eliminator modality 130 is described below in a section referring to figures 16A and 16B.
    [00097] As schematically illustrated, for example, in figures 4 and 5, when an amount of a first fluid 8a has been supplied to the blade 10, the automated marking apparatus 1 is configured to control the cap retainer tray 106 to move the capillary tray 40 so that a first end 36, sometimes referred to as a lower end, of a capillary cap 30 is moved towards the corresponding blade 10 to a position where protrusions 33 (see figures 15A and 15B) of first end 36 of capillary cap 30 are adjacent to blade 10, see figure 5.
    [00098] Furthermore, when the protuberances 33 of the first end 36 of the capillary cap 30 adjoin the blade 10, the automated marking apparatus 1 is configured to control the capillary tray retainer 106 to move the capillary cap 40 to that a second end 38, sometimes referred to as an upper end, of the capillary cap 30 is moved towards the corresponding blade 10 to a position where the protrusions 33 (see figures 15A and 15B) of the second end 38 of the capillary cap 30 contiguous with the blade, see figure 6.
    [00099] Through the movements of the first and second ends 36, 38 of the capillary cap 30, a capillary gap 31 is formed between a central recess 35 of the capillary cap 30 and a central part of the blade 10, see figures 6, 14B and 15 The capillary compartment can function as a capillary chamber or a hybridization chamber. Capillary gap 31 can be in the range of 10 to 300 micrometers. In some modalities, the span will preferably be approximately 140 micrometers. Several modalities can be configured to provide the desired flow through the rate, that is, the rate at which an amount of fluid 8a dispensed near a higher end of the blade 10 will cause a corresponding amount of fluid 8a to flow down the lower end of the blade 10. The span dimension can be adjusted to accommodate fluids that have higher or lower viscosity, and to accommodate the inclination or angle at which blade 10 is positioned in relation to the horizontal plane.
    [000100] In modalities, the cap that forms the capillary gap is floating in the fluid dispensed on the blade, through which blade alignment problems can be avoided.
    [000101] In modalities, for example, of an ISH capillary marking module, the automated marking apparatus 1 is configured to control the blade tray retainer 102 to automatically rotate the blade tray 20 and one or more blades 10 from the insertion position A, for example, vertical, to a first inclined position B, in which, an amount of a fluid, for example, a reagent, is dispensed on the slide or the biological sample by means of of probe 16 disposed in the first probe entry 161. The automated marking apparatus 1 is additionally configured to control the blade tray retainer 102 to automatically rotate the blade tray 20 and one or more blades 10 from the first inclined position B for a second inclined position C. In addition, when blade (s) 10 is in the second inclined position C, the automated marking device 1 is configured for control release the capillary tray retainer 106 to automatically move the capillary tray 40 and capillary cap 30 so that the first end 36 of capillary 30 is moved towards the corresponding blade 10 to a position where the first end 36 adjoins the blade 10 and to automatically move the second end 38 of the capillary cap 30 towards the corresponding blade 10 to a position where the second end 38 is contiguous to the blade 10, through which the capillary cap 30 is arranged parallel to the slide 10 and through which a capillary gap 31 is formed between a central recess 35 of capillary cap 30 and a central portion of blade 10. Capillary gap 31 comprises the reagent supplied for the biological sample and, due to capillary gap 31, the biological sample can be processed with a small volume of reagent, for example, a volume in the range of 10 to 100 microliters. For example, in some embodiments, it may be desirable to use a capillary gap to process slides using 10 microliters to 20 microliters, or 20 microliters to 50 microliters in other embodiments, or 50 microliters to 100 microliters in still other embodiments, as desired . Figure 11 schematically illustrates a dispensing of reagent from probe 16 on a slide 10, when slide 10 is arranged in a B position, for example, at an angle greater than approximately 45 degrees from the horizontal plane. However, the blade could be arranged at another desired angle. By arranging the slide at a desired angle to the horizontal plane, probe 16 can be, via the first probe entry 161, located above a desired location on the slide and, through it, a desired volume of a reagent can be dispensed at the desired location of the slide 10, for example, directly on the biological sample arranged on the slide 10 if the sample is arranged directly below the probe 16. In addition, by arranging the slide at a plurality of different angles, the probe 16 can dispense a conductor for a plurality of locations on the slide or sample.
    [000102] However, as schematically illustrated in figure 12, it should be understood that in other modalities of, for example, an ISH capillary marking module, the reagent can be dispensed to the same location on slide 10 as that illustrated in figure 11, for example, directly in the biological sample, also when the slide is disposed at an angle less than the horizontal plane, as shown in figure 12, if the processing cover 160 is provided with a second probe input 163 for the probe 16 in a position directly on the biological sample.
    [000103] In yet other modalities of an ISH capillary marking module, certain steps, such as dispensing a probe on slide 10, can occur outside the marking module, for example, an ISH reagent can be dispensed on a blade in an open horizontal station before or after inserting the blade in the ISH capillary marking module.
    [000104] In modalities, for example, of an IHC capillary marking module, the automated marking apparatus 1 is configured to control the blade tray retainer 102 to automatically rotate the blade tray 20 and one or more blades 10 from vertical position A to the second inclined position C, in which position an amount of a fluid 8a, for example a buffer solution, is dispensed on the slide or the biological sample via the nozzle 9c, see Figure 4. Furthermore, the automated marking apparatus 1 is configured to control the capillary tray holder 106 to automatically move the capillary tray 40 and capillary cover 30 so that the first end 36 of capillary cover 30 is moved towards the corresponding blade 10 to a position where the first end 36 is contiguous to the blade 10, see figure 5, and to automatically move the second end 3 8 of the capillary cap 30 towards the corresponding blade 10 to a position where the second end 38 adjoins the blade 10, see figure 6, through which the capillary cap 30 is arranged in parallel with the blade 10 and through which a capillary gap 31 is formed between a central recess 35 of the capillary cap 30 and a central part of the blade 10, in which the capillary gap is filled with the fluid 8a provided. Capillary gap 31 functions as a capillary chamber.
    [000105] As schematically illustrated in figure 7, a second fluid, for example, a reagent 18a, is supplied to the slide 10 in a position above the fluid filled capillary gap 31, through which the amount of the second fluid, due to the gravity, flows into the capillary gap 31 causing the fluid in the capillary gap 31 to be removed from the bottom of the capillary gap 31 and the second fluid to be pulled into the capillary gap 31 and flowing downwardly into the capillary gap 31 to cover biological sample 3 disposed on slide 10, causing the biological sample to be processed by the reagent.
    [000106] In modalities, when in the first inclined position B, the one or more slides 10 are arranged at an angle Θ in the range of approximately 20 to 90 degrees in relation to the horizontal HP plane which allows a quantity of reagent to be dispensed directly in a small specimen (not shown) positioned on the open face of slide 10 and approximately centered on slide 10. Therefore, the reagent can be dispensed directly without using capillary flow through, for example, an ISH probe, where it can be desired dispense the probe directly, instead of dispersing it in a fluid-filled capillary. In addition, when in the second inclined position C, the one or more blades 10 are arranged at an angle Θ in the range of approximately 10 to 40 degrees in relation to the horizontal plane HP, preferably in the range of approximately 15 to 30 degrees in relation to to the horizontal HP plane and, with maximum preference, approximately 20 degrees in relation to the horizontal HP plane, see figure 3. An additional description of modalities suitable for direct dispensing applications, such as ISH, is shown in figure 11 and figure 12 and described below in the detailed descriptions of figure 11 and figure 12. In certain applications, for example, in ISH applications, the formed capillary gap is configured to function as a hybridization chamber.
    [000107] As schematically illustrated in figure 8, the automated marking apparatus 1 can be configured to control the cap retainer with capillary cap 106 to automatically move the cap capillary tray 40 and one or more capillary caps 30 forward and back in a direction parallel to one or more slides 10, as indicated by the arrow in figure 8, through which local depletion of fluid or reagent in the capillary gap 31 can be avoided and through which the fluid or reagent in the capillary gap 31 can be mixed. By avoiding depletion of fluid / reagent and / or mixture of fluid / reagent in the capillary gap 31, the processing, for example, marking, of the biological sample exposed to the fluid / reagent in the capillary gap 31 can be improved.
    [000108] Furthermore, the automated marking apparatus 1 can be configured to control the capillary tray retainer 106 to move the capillary tray tray 40 and one or more capillary caps 30 along the geometric axis, in the direction of blade 10 length, and in some embodiments the movement can be approximately 1 to 5 mm and can have a speed of approximately 0 to 25 mm / s. The movement can be paused with capillary caps 30 at each end position. Other modalities may include lateral movements instead of lengthwise axial movements. Circular motions can also be used.
    [000109] It should be noted that, after the incubation steps, a rinse with washing buffer can be performed substantially, as illustrated in figure 6. In this way, with a rinse, the incubation step and corresponding reactions can be stopped and the slide may be ready to receive additional reagents, for example, a second antibody, a visualization reagent, etc. Alternatively, when a slide has been rinsed with wash buffer, it can be "paused" or remain under buffer, as long as desired, with capillary forces retaining the rinse buffer.
    [000110] In modalities, as schematically illustrated in figure 9, the marking apparatus 1 is additionally configured to supply a quantity of fluid, for example, a washing fluid, to the blade 10 when the capillary cap 30 is removed from the blade after sample processing, thereby ensuring that the cap 30, due to the suction effects, does not tear the biological sample, removing it from the blade 10, when the capillary cap 30 is removed. [000111] As schematically illustrated in figure 10, one or more cleaning blades 10a disposed in a blade tray 20 can be inserted in the capillary marking module 100, 100 ', 100 ”. The cleaning blade 10a comprises several ribs or bristles or cleaning surface 10b configured to clean a capillary cap 30 when, in use, capillary cap 30, by means of capillary tray retainer 106, is moved back and forth in a direction parallel to the cleaning blade 10a, as illustrated by the arrows in figure 10.
    [000112] In some embodiments, a cleaning solution, such as a DAB remover or any desired cover cleaning solution, can be combined with cleaning blade 10a in order to optimize the cleaning of the cover.
    [000113] In modalities, the capillary marking module 100, 100 ', 100 ”can be additionally configured to prevent condensation on the module during processing. In embodiments, the processing container lid 160 can be configured to prevent condensation on the capillary marking module 100, 100 ', 100 ”and thereby configured to prevent the formation of water droplets on the capillary marking module 100, 100 ', 100 ”, such droplets of water can cause a fluid, for example, a reagent, dispensed to a biological sample, to be diluted during sample processing.
    [000114] As schematically illustrated in figure 12, the processing container lid 160 can be provided with a condensation preventive layer 164 disposed on an internal surface of the processing container lid 160 facing blades 10 and capillary caps 30, and configured to prevent condensation on the 100, 100 ', 100 ”capillary marking module. For example, the condensation preventive layer 164 may comprise aluminum or other heat conductive material or a fluid absorbing material.
    [000115] In embodiments, the processing vessel lid 160 may comprise a heating element 168 disposed, for example, on the outer side of the processing vessel lid 160. Heating element 168 may be configured to supply heat to the lid processing container 160 in order to prevent condensation on the capillary marking module.
    [000116] Figure 13 schematically illustrates a perspective view of an embodiment of a capillary tray 40 comprising ten capillary caps 30. However, it should be understood that the capillary tray can be configured for any number of caps capillaries.
    [000117] In modalities and as schematically illustrated in figure 15A and figure 15B, the capillary cap 30 comprises, on a surface facing a biological sample, a central surface 35 and two distal projecting surfaces 33 (sometimes referred to as lumps 33) .
    [000118] The distal projecting surfaces 33 are disposed distally from the central surface 35 and on opposite sides of the central surface 35. In addition, the distal projecting surfaces 33 are configured to form spacers when in contact with a blade 10, forming thus, the aforementioned capillary gap 31 between the central surface 35 of the capillary cap 30 and the blade 10, see, for example, figure 14B.
    [000119] In the embodiment of figure 14C, the inlet reservoir 39 'is arranged in a fork shape that can penetrate the surface of any droplet that can accumulate on the surface, for example, of a blade label, thereby preventing any sudden build-up and release of fluid from a droplet. One embodiment of a droplet capture form for an inlet reservoir is illustrated in figure 15B.
    [000120] The capillary cap 30 may comprise glass and the distal projecting surfaces / spacers 33 may comprise one or more layers of paint or other suitable material having a predefined thickness in order to provide an accurate distance between the central surface 35 of the cap. capillary 30 and blade 10.
    [000121] However, it should be understood that the capillary cap 30 can be molded in a plastic material, such as polycarbonate, or another suitable material.
    [000122] As schematically illustrated in figures 15A and 15B, the capillary cap 30 is provided with a chamfered surface 39 in an upper central part. The chamfered surface 39 is configured to function as an inlet reservoir 39 in the capillary gap 31, when in use, the capillary cap 30 is arranged in the blade 10. The inlet reservoir 39 is configured to retain a volume of fluid / reagent preset volume of up to approximately 300 microliters.
    [000123] In embodiments and as schematically illustrated in figures 15A and 15B, capillary cap 30 is provided with a drip tip 37 in a lower central part of capillary cap 30. Drip tip 37 is configured to provide controlled removal of fluid from the bottom of the capillary gap 31. Through the drip tip 37, a uniform fluid front of fluid / reagent supplied to the top of the capillary gap is performed, see figure 14B, as compared to the uneven fluid front in a gap capillary created between a blade 10 and a cap 30 without a drip tip, as shown in figure 14A.
    [000124] Figure 16A is an exploded view of an embodiment of a double fluid heater / bubble eliminator combination 130 '. A heater 120 includes a heating element 121 and a temperature sensor 122 to control the temperature. The heater 120 can be produced from aluminum or other materials with desired heat conducting properties. Non-reactive plates 123.125 can be arranged on both sides of heater 120 so that the fluid is heated by heater 120, however, does not come into direct contact with heater 120. Suitable materials for non-reactive plates may include stainless steel or other thermally conductive materials, such as thermally conductive polymers, which are non-reactive with the fluids that can be heated by heater 120.
    [000125] In one embodiment, a first bubble eliminator 139 and a second bubble eliminator 139 'can be included in combination with the fluid heater / bubble eliminator 130'. This allows the bubble eliminator 139 to be used to heat and remove bubbles from a first fluid, for example, distilled water, and the second bubble eliminator 139 'to be used to heat and remove bubbles from a second fluid, for example. example, a wash buffer.
    [000126] As schematically illustrated in figure 16B, the bubble eliminators 139 and 139 'shown in figure 16A work as follows. A fluid 140 enters the bubble eliminator 139 through inlet 134 and flows through deflector 133 to exit through outlets 135 and 137. Any bubbles 131 that may have formed inside the fluid will rise to the upper half 136 of the elimination. bubble miner and travel a path to the bubble outlet 132. The outlet 132 can be closed by a valve so that the pressure of the closed air prevents the fluid from flowing out through the outlet 132. Then, at a desired time, outlet 132 can be opened to allow accumulated bubbles 131 to be vented.
    权利要求:
    Claims (17)
    [1]
    1. Automated marking apparatus (1) for processing at least one biological sample arranged on a slide, the apparatus characterized by the fact that it comprises: at least one capillary marking module (100, 100 ', 100 ”) comprising: a blade tray retainer (102) configured to detachably retain a blade tray (20) configured to retain one or more blades (10), and a capillary tray retainer (106) configured to detachably retain a capillary cap tray (40) configured to hold one or more capillary caps (30), where the blade tray (20) can be removed regardless of removing the capillary cap (40), and a first fluid container (8) comprising a first fluid (8a), in which the automated marking apparatus (1) is configured to automatically: control the blade tray retainer (102) to rotate one or more blades (10) from one position from inse to one or more inclined positions, and control the capillary tray retainer (106) to move the one or more capillary caps (30) towards one or more blades (10) in order to automatically form a capillary gap ( 31) between each slide and each capillary cap, in which said capillary gap (31) functions as a capillary chamber; and to automatically deliver a quantity of the first fluid (8a) from the fluid container (8) to the blade (10) when in said angled position.
    [2]
    2. Apparatus according to claim 1, characterized by the fact that the automated marking apparatus (1) is further configured to automatically: control the cap retainer with capillary cover (106) to move a first end (36 ) of a capillary cap (30) towards a corresponding blade (10) so that the first end (36) of the capillary cap (30) adjoins the blade (10), and to move a second end (38) of the cap capillary (30) towards the corresponding blade (10) so that the second end of the capillary cap is contiguous to the blade (10), through which a capillary gap (31) is formed between a central recess of the capillary cap and a central part of the blade, the capillary gap (31) being configured to comprise the first fluid supplied (8a).
    [3]
    3. Apparatus according to claim 1 or 2, characterized by the fact that the automated marking apparatus (1) is further configured for: using a reagent probe (16), to directly supply a quantity of a reagent ( 18a), as the first fluid (8a), for the biological sample (3) disposed on the slide (10), through which the formed capillary gap (31) can function as a hybridization chamber.
    [4]
    4. Apparatus according to any one of claims 1 to 3, characterized in that the automated marking apparatus (1) is further configured to: supply, via a probe inlet or a nozzle, a quantity of one second fluid from a second fluid container for the blade (10) in a position above the capillary gap (31) filled with fluid, through which the amount of the second fluid, due to gravity, flows into the capillary gap (31), causing an amount of the first fluid in the capillary gap to be removed from the bottom of the capillary gap (31) and the second fluid to be pulled into the capillary gap (31) and flowing downwardly into the capillary gap to cover the biological sample (3) arranged on the slide (10).
    [5]
    5. Apparatus according to claim 4, characterized by the fact that the one or more sample slides (10), when tilted, are arranged at an angle in the range of approximately 10 to 40 degrees in relation to the horizontal plane .
    [6]
    Apparatus according to any one of claims 1 to 5, characterized by the fact that it still comprises one or more pipes (9, 9a, 9b) connected to one or more fluid containers (8), the pipes ( 9, 9a, 9b) comprise, in a distal part, one or more nozzles (9c) for dispensing a fluid to the one or more blades (10), in which the nozzle is configured with a chamfered distal end opening (9c ' ) to provide an immersion-free nozzle (9c) through which the fluid (8a) is not dripped onto the blade (10), however, it flows over the blade (10).
    [7]
    Apparatus according to any one of claims 1 to 6, characterized by the fact that it also comprises a fluid robot (14) configured to operate a probe (16): to aspirate a portion of a reagent contained in a container of reagent (18); to transfer the aspirated portion of the reagent (18a) to a position above a slide (10) or a biological sample (3); to dispense an amount of the aspirated portion of the reagent (18a) to the slide (10) or the biological sample (3).
    [8]
    Apparatus according to any one of claims 1 to 7, characterized in that the automated marking apparatus (1) is configured to control the cap retainer with capillary cover (106) to automatically move one or more capillary covers (30) back and forth in a parallel direction along the blade length axis (10), through which local depletion of the fluid in the capillary gap (31) is avoided and / or the fluid in the capillary gap (31 ) is mixed.
    [9]
    Apparatus according to any one of claims 1 to 8, characterized in that the automated marking apparatus (1) is configured to: supply an amount of fluid to the blade (10) when the capillary cap (30) is removed from the slide after sample processing, thereby ensuring that the lid (30) does not tear, due to the suction effects, the biological sample (3), removing that from the slide (10) when the capillary lid ( 30) is removed.
    [10]
    10. Apparatus according to any one of claims 1 to 9, characterized in that it further comprises a preheater (120) configured to heat the fluid (8a) to a predetermined temperature before the fluid is dispensed to the blade (10).
    [11]
    11. Apparatus according to any one of claims 1 to 10, characterized in that the capillary cap (30) on a surface facing a biological sample (3) comprises a central surface (35) and two distal projecting surfaces (33) , the distal projecting surfaces being disposed distally from the central surface (35) and on the opposite sides of the central surface (35), where the distal projecting surfaces (33) are configured to form spacers when in contact with a slide sample. (10), the distal projecting surfaces (33) having a predefined thickness in order to provide an exact distance between the central surface (35) of the capillary cap (30) and the blade (10) when the distal projecting surfaces of the cap (30) adjoins the blade (10), thereby forming the well-defined capillary gap (31) between the central surface (35) of the capillary cap (30) and the blade (10).
    [12]
    12. Apparatus according to claim 11, characterized by the fact that the capillary cap (30) in an upper central part is provided with a beveled surface (39) that functions as an inlet reservoir (39 ') in the capillary gap ( 31), when in use, the distal projecting surfaces (33) of the capillary cap (30) are adjacent to the blade (10).
    [13]
    13. Apparatus, according to claim 11, characterized by the fact that the capillary cap (30) in a lower central part is provided with a drip tip (37), the drip tip (37) being configured to provide a controlled removal of fluid from the bottom of the capillary gap (31), through which a uniform fluid front of fluid supplied to the top of the capillary gap (31) can be performed.
    [14]
    14. Apparatus according to any one of claims 1 to 13, characterized in that the capillary marking module (100, 100 ', 100 ") comprises a moisture conduit (152) arranged in a lower part of a processing container (150) of the capillary marking module (100, 100 ', 100 ”), the moisture conduit (152) is configured to retain a volume of liquid and thereby preventing the evaporation of fluid in the capillary marking module (100, 100 ', 100 ").
    [15]
    15. Apparatus according to any one of claims 1 to 14, characterized in that the capillary marking module (100, 100 ', 100 ”) further comprises a processing container lid (160) configured to prevent condensation inside capillary marking module (100, 100 ', 100 ”) and thus configured to prevent the formation of water droplets in the capillary marking module (100, 100', 100”), and such water droplets can cause a fluid dispensed into a biological sample (3) to be diluted during sample processing.
    [16]
    16. Apparatus according to claim 15, characterized in that the processing container lid (160) is provided with a heating element (168) disposed on the outside of the processing container lid (160) and configured to supply heat to the processing vessel lid (160) to prevent condensation on the capillary marking module (100, 100 ', 100 ”).
    [17]
    17. Automated method for processing at least one biological sample (3) arranged on a slide (10), characterized by the fact that it comprises the steps of: providing at least one capillary marking module (100, 100 ', 100 ") comprising : a blade tray retainer (102) configured to detachably retain a blade tray (20) configured to retain one or more blades (10), and a capillary tray retainer (106) configured to retain so detachable a capillary tray (40) configured to hold one or more capillary caps (30), in which the blade tray (20) can be removed regardless of the removal of the capillary tray (40), providing a first container of fluid (8) comprising a first fluid (8a), automatically controlling the blade tray retainer (102) to rotate one or more blades (10) from an insertion position to one or more inclined positions; and automatically control the capillary tray retainer (106) to move the one or more capillary caps (30) towards one or more blades (10) to automatically form a capillary gap (31) between each blade (10 ) and each capillary cap (30), wherein said capillary gap (31) functions as a capillary chamber; and automatically supplying a quantity of the first fluid (8a) from the fluid container (8) to the blade (10) when in said inclined position.
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    同族专利:
    公开号 | 公开日
    EP2510329B1|2020-01-22|
    CA2782892A1|2011-06-16|
    AU2010330454A1|2013-03-28|
    US20110136135A1|2011-06-09|
    CA2782892C|2018-09-04|
    US10018542B2|2018-07-10|
    CN102770746A|2012-11-07|
    BR112012013813A2|2017-09-26|
    US8877485B2|2014-11-04|
    JP2013513782A|2013-04-22|
    AU2010330454B2|2014-10-23|
    RU2012126082A|2014-01-20|
    US20150079592A1|2015-03-19|
    EP3591374A1|2020-01-08|
    EP2510329A1|2012-10-17|
    WO2011069507A1|2011-06-16|
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    法律状态:
    2019-01-08| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2019-08-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|
    2020-01-28| B09A| Decision: intention to grant|
    2020-03-17| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/12/2010, OBSERVADAS AS CONDICOES LEGAIS. |
    2020-09-29| B25D| Requested change of name of applicant approved|Owner name: DAKO DENMARK APS (DK) |
    2020-10-20| B25A| Requested transfer of rights approved|Owner name: AGILENT TECHNOLOGIES, INC. (US) |
    优先权:
    申请号 | 申请日 | 专利标题
    US26790609P| true| 2009-12-09|2009-12-09|
    US61/267,906|2009-12-09|
    PCT/DK2010/000169|WO2011069507A1|2009-12-09|2010-12-09|An apparatus and method for processing biological samples|
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