Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
  • G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
  • G01N1/31—Apparatus therefor
  • G01N1/312—Apparatus therefor for samples mounted on planar substrates
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
  • G01N1/2813—Producing thin layers of samples on a substrate, e.g. smearing, spinning-on
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
  • G01N1/36—Embedding or analogous mounting of samples
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations

Definitions

• Microscope slides bearing biological samples e.g., tissue sections or cells
• Samples can be prepared for analysis by manually immersing sample-bearing slides in containers of dyes or other reagents.
• This labor intensive process often results in inconsistent processing and carryover of liquids between containers. Carryover of liquids leads to contamination and degradation of the processing liquids.
• These types of manual processes often utilize excessive volumes of liquids resulting in relatively high processing costs, especially if the dyes or other reagents are expensive and are prone to degradation due to carryover.
• Conjugate biomolecules can be relatively large, ranging in size from a few kilo Daltons to several hundred kiloDaltons, which constrains them to diffuse slowly into solid tissue with typical times for sufficient diffusion being in the range of several minutes to a few hours. Typical incubation conditions are thirty minutes at 37 degrees centigrade.
• the diffusion rate is often driven by a concentration gradient so the diffusion rate can be increased by increasing the concentration of the conjugate in the reagent.
• conjugates are often very expensive, so increasing their concentration is wasteful and often not economically viable. Additionally, the excessive amount of conjugate that is driven into the tissue, when high
• a cover comprises one or more disposables or reusable membranes, films, coatings, tiles, or the like.
• the cover is a thin membrane that is made of a single material.
• a station for processing a slide carrying at least one sample includes a platen assembly and a slide retaining device.
• the slide retaining device is configured to move the slide along a curved portion of the platen assembly to apply a liquid to a sample on the slide when the liquid is between the platen assembly and the slide.
• a sample processing system in some embodiments, includes a roller unit, a slide retaining device, and an actuator.
• the roller unit has a curved portion that includes a liquid application region.
• the actuator is coupled to the slide retaining device.
• the actuator is configured to move a slide held by the slide retaining device along the curved portion to define a capillary gap between the slide and the curved portion such that the capillary gap has a varying height.
• a method may include delivering a slide to a slide retaining device.
• a first liquid is delivered to at least one of the slide and a curved portion of a roller unit.
• the slide held by the slide gripper device is moved along the curved portion of the roller unit to apply the first liquid to a sample between the slide and the roller unit.
• a second liquid is applied to at least one of the slide and the curved portion of the roller unit.
• the slide held is moved by the slide gripper device along the curved portion of the roller unit to apply the second liquid to the sample between the slide and the roller unit.
• the first plurality of gapping elements may extend along a first longitudinal side of the body and the second plurality of gapping elements may extend along a second longitudinal side of the body. The second longitudinal side opposes the first longitudinal side.
• the thickness of the body may be greater than a height of at least one of the first plurality of gapping elements.
• the first plurality of gapping elements may include linearly arranged dimples that are spaced apart from one another.
• the first plurality of gapping elements and the second plurality of gapping elements may be dimensioned to define a capillary gap between the microscope slide and the body when the microscope slide physically contacts at least one of the first plurality of gapping elements and at least one of the second plurality of gapping elements.
• the body may have a radius of curvature in a range of about 5 inches to about 40 inches.
• At least some embodiments of mixing fluids may includes dispensing a first fluid onto a slide, dispensing a second fluid onto the slide after dispensing the first fluid, and mixing the first fluid and the second fluid using a substrate that opposes the slide to produce a mixed fluid.
• the first fluid and second fluid can be at different temperatures when delivered onto the slide.
• a method comprises delivering a slide carrying a sample to a slide positioning device of an automated slide processing station.
• a liquid is delivered to at least one of the slide and a curved portion of a roller unit of the automated slide processing station.
• the curved portion of the roller unit is moved (e.g., rolled) relative to the slide held by the slide positioning device to apply the liquid to the sample on the slide.
• the liquid is applied while it is located in a varying height gap defined by the slide and the curved portion.
• Figure 26 is a detailed view of a gapping element.
• Figure 42 is an isometric view of the slide positioned to urge waste towards a waste port.
• Figure 1 shows a first substrate 80, a second substrate 82, and a substance 86 between the first and second substrates 80, 82.
• the first and second substrates 80, 82 can be moved with respect to one another to manage the substance 86, such as processing liquid.
• Managing the substance 86 may include agitating the substance 86, spreading the substance 86 along an upper surface 90 of the first substrate 80, moving the substance 86, or otherwise manipulating the substance 86 to process a biological sample 88 on the upper surface 90.
• FIG. 1 shows ends 94a, 94b (collectively "94") of the gap 91 that can be filled with the liquid 86 by reducing the gap height, by changing the gap height profile, and/or by adding liquid to the gap 91 .
• Processing protocols may require different liquid volumes in order to meet various processing criteria (e.g., chemical requirements, uptake
• the varying height gap 91 can accommodate a wider range of liquid volumes than a uniform height gap because the narrowed region of the gap 91 can accommodate a small liquid volume, while the widened gap end 94 can accommodate a large liquid volume.
• the widened gap end 94 can also provide convenient access to deliver liquid to the gap 91.
• a substrate can be a flat or substantially flat substrate.
• substantially flat substrate refers, without limitation, to any object having at least one substantially flat surface, but more typically to any object having two substantially flat surfaces on opposite sides of the object, and even more typically to any object having opposed substantially flat surfaces, which opposed surfaces are generally equal in size but larger than any other surfaces on the object.
• a substantially flat substrate can comprise any suitable material, including plastics, rubber, ceramics, glass, silicon, semiconductor materials, metals, combinations thereof, or the like.
• the processing liquid 160 can be efficiently applied to the sample 187 to minimize or limit the cost of processing liquid(s) and to minimize or limit the amount of waste liquid produced.
• the substrate 140 can be manipulated (e.g., translated, rotated, vibrated, or combinations thereof) to move the liquid 160.
• the substrate 140 can be rolled along slide 120.
• the substrate 140 in a curved configuration can rotate due to physical contact with the slide 120.
• the substrate 140 can slide along the slide 120.
• Cell conditioning can make cross-linked antigenic sites more accessible by large biomolecules such as antibodies and nucleic acid probes.
• the slide processing apparatus 100 can perform cell conditioning protocols.
• the processing apparatus 100 can have different modes of operation.
• the apparatus 100 has a static mode and a dynamic mode.
• the substrate 140 can be moved to agitate the liquid 160.
• a rolling motion can provide generally even liquid coverage along the sample 187.
• the substrate 140 can be rolled back and forth across the sample 187 any number of times. If the liquid 160 has a relatively low viscosity, the substrate 140 can be moved at a relatively high speed. If the liquid 160 has a relatively high viscosity, the substrate 140 may be moved at a relatively low speed.
• the speed of the substrate 140 can be increased or decreased to increase or decrease agitation of the liquid 160. Agitation may effect fluid uptake rates, settling of constituents in the liquid 160, mixing of constituents,
• Figure 15 shows the gap 214 filled with the substance 213.
• the lower end 192 of the substrate 140 can be moved towards the slide 120 to further spread the substance 213.
• the slide 120 and substrate 140 can be rotated together counterclockwise (indicated by an arrow 220 in Figure 14) or clockwise (indicated by an arrow 224).
• the slide 120 may be moved to a generally horizontal orientation, and the substrate 140 can assume a substantially flat configuration.
• the slide 120 can be moved to an inclined or vertical orientation.
• the orientation of the slide 120 can be selected based on the processing to be performed, such as immunohistochemical processes (e.g., deparaffinization, antigen retrieval, and detection (cell conditioning)).
• the slide 120 can be at the inclined orientation to promote removal of the paraffin and/or any solvents, such as xylene or limonene.
• the volume of captivated fluid is kept in a range of about 15 microliters to about 25 microliters. In certain protocols, the volume of fluid is about 15 microliters. Any number of times during processing, a volume of reagent, reagent buffer, or water can be pipetted onto the slide 120 to restore fluid volume.
• the row 450 can include about 5 gapping elements to about 60 gapping elements with an average distance between adjacent gapping elements in a range of about 0.05 inch (1.27 mm) to about 0.6 inch (15.24 mm). In some embodiments, including the illustrated embodiment of Figures 23 and 24, the row 450 includes 19 gapping elements that protrude outwardly from a surface 460, illustrated as a specimen facing surface. In other embodiments, the row 450 includes about 10 gapping elements to about 40 gapping elements. As viewed from above (see Figure 24), the row 450 has a generally linear configuration. In other embodiments, the row 450 has a zigzag configuration, serpentine
• the cover 350 is in the shape of a complex arc (e.g., an elliptical arc), compound arc, or the like. In yet other embodiments, the cover 350 can be substantially planar.
• the cover 350 can be formed by injection molding processes, compression molding processes, extrusion process, machining processes, or combinations thereof.
• an injection molding process can be used to fabricate the main body 459 and gapping elements 450, 452.
• the waste port 374 can then be machined in the main body 440.
• the cover 350 can be a mono-layer membrane, multi-membrane, film, or coating.
• An underlying component can have one or more gapping elements to which the cover 350 can conform to form corresponding gapping elements (e.g., bulges, protrusions, or the like).
• gapping elements can be positioned on the face 359 of the base 360 of Figure 18. When the cover 350 overlays the base 360, the cover 350 can conform to the gapping elements. As such, the cover 350 can be permissive to gapping elements.
• the film can include an adhesive layer.
• the adhesive layer can comprise, without limitation, one or more pressure sensitive adhesives, adhesive gels, binding agents, or the like.
• the film is a sheet that is dispensed from a roll. Each slide can be processed with a different section of the sheet to prevent carryover contamination.
• individual sheets with an adhesive layer are applied to platen assemblies. In some non-adhering embodiments, a sheet is held against the platen assembly via a vacuum. In other embodiments, a sheet is securely held against the platen assembly by both an adhesive layer and by applying a vacuum.
• the processing station 300 can also include a dispenser assembly 540 for outputting processing fluids.
• the dispenser assembly 540 includes a pair of units 544, 546, each capable of dispensing a fluid. Outlet ports 554, 556 of the units 544, 546, respectively, can be aimed at a gap between an end 558 of the slide 340 and the cover 350.
• the illustrated outlet ports 554, 556 are in the form of conduits through which substances can flow.
• a waste manifold member 600 To remove the fluid 560, a waste manifold member 600 from a standby position shown in Figure 27 to a waste removal position shown in Figure 29. As the waste manifold member 600 reaches the waste removal position, an entrance 609 of a passage 610 of the manifold member 600 is mated with an outlet 618. The waste manifold member 600 moves the arm actuator 580, which in turn moves the slide 340 to a waste removal position, as shown in Figure 29. The end 558 of the slide 340 of Figures 29 and 30 overlays the waste port 374, such that the fluid 560 can be removed via the waste port 374. Gravity, a vacuum, wicking materials, or the like can be used to draw the fluid into and through the waste port 374.
• an absorbent member e.g., a pad or a sheet
• the absorbent member is adhered directly to the bottom surface of the cover 350.
• the absorbent member can be at any other suitable location, if needed or desired.
• substantially no residual liquid 560 remains in the gap 570 after the vacuum has been applied for a sufficient length of time.
• Appropriate surface finishes e.g., surface smoothness
• surface energy e.g., the energy determined by the surface chemistry of the cover 350
• a higher level of smoothness and a lower surface energy will favor migration along the gap 570, whereas more surface imperfections and higher surface energy will tend to retain the liquid 560 in the gap 570.
• Figure 31 shows a staining system 700 with an array of slide processing stations.
• the staining system 700 is shown with slides loaded into each of the processing stations.
• Some of the slide processing stations include fluid dispensers for automatically processing specimens.
• An operator, or an external fluid delivery system can deliver fluids onto the slides at the processing stations without fluid dispensers.
• the external fluid delivery system can be a robotic pipette system.
• all of the processing stations can include fluid dispensers such that each processing station can perform an individual protocol. Readers can be incorporated into the processing stations and can acquire information from the slide to determine an appropriate protocol.
• each processing station can be connected to an independently operable drive mechanism. Different protocols can be performed at different stations.
• the fluid handling system 1 1 10 can also include one or more pumps, filters, fixed nozzles (e.g., fixed nozzle fluid dispensers), pipette systems, or other types of fluid dispensers.
• Fixed nozzle fluid dispensers are especially well suited to delivery H&E fluids, bulk advanced stain fluids, or the like.
• Pipette systems are especially well suited to output non- bulk advanced stain fluids.
• the slide system 1 1 16 can provide slides carrying samples ready for processing.
• the slide system 1 1 16 can include, without limitation, heaters or slide dryers (e.g., conductive dryers, convection dryers, ovens, etc.), as well as other types of components or devices used to prepare samples.
• the slide system 1 1 16 can also include any number of racks, trays, cartridges, or other structures suitable for holding a desired number of slides.
• One or more slide transporters can move slides between components of the slide system 1 1 16 and can load and unload the staining system 1 105.
• the processing may be optimized by determining, for example, an optimum schedule to increase processing speeds, to increase throughput (e.g., a number of slides processed in a length of time), or the like.
• Such optimum schedule can be a schedule of preparing and delivering slides to the staining system 1 105.
• the control system 1 120 determines loading sequences to reduce processing wait times.
• the control system 1120 can also be programmed such that loading of the pipettes, nozzles, or fluid dispensers for the next specimen can start during processing of the currently loaded specimen. This saves time because fluids can be dispensed onto the next specimen as soon as the current specimen is removed from the station.
• the processing system 1100 can include any number of the transporters.
• Transporters can include, without limitation, one or more robotic handlers or arms, X-Y-Z transport systems, conveyors, combinations thereof, or other automated mechanisms capable carrying items between locations.
• Transporters can have end effectors to carry items.
• End effectors may include, without limitation, grippers, suction devices, holders, clamps, or the like.
• the end effectors can have temperature sensors, vacuum sensors, surface sensors, position sensors, or the like.
• vacuum sensors of an end effector are capable of detecting the presence of an item, or other characteristics of the covers, slides, specimens, or the like.
• End effectors can load both slides and covers into the staining system 1 105. After processing, the end effectors can retrieve the slides and covers.
• a drive mechanism 1260 can translate the upper platen assembly 1220 along a rail apparatus 1290 from a standby position (shown in Figure 33) to a processing position (see Figure 38) directly above the lower platen assembly 1210. The slide 1242 is then lowered onto the upper platen assembly 1220.
• the rail apparatus 1290 includes a pair of rails 1292a, 1292b (collectively "1292") and a support 1294 extending between the rails 1292a, 1292b.
• the rail 1292a retains one side of a cover holder 1266
• the other rail 1292b retains the other side of the cover holder 1266.
• the cover holder 1266 can slide along slots in the respective rails 1292 between the standby position and the processing position.
• the sizes, configurations (e.g., straight configuration, curved configuration, or the like), and features (e.g., slots, tracks, stops, or the like) of the rails 1292 can be selected based on the desired motion of the upper platen assembly 1220.
• the upper platen assembly 1220 includes the cover holder 1266 and a cover 1268.
• the cover 1268 includes a substantially flat surface 1270 and two rows of gapping elements 1280, 1282.
• the cover holder 1266 includes thermal elements 1281 that can provide heating and copling capabilities.
• the thermal elements 1281 can be cooling devices including channels through which chilled liquid flows.
• the holder 1266 includes a plate with embedded thermal elements 1281.
• the plate can be made of metal or other thermally conductive material to provide rapid heat transfer to the cover 1268.
• temperature sensors can be positioned between the cover holder 1266 and the cover 1268. In yet other embodiments, one or more sensors are incorporated into the cover 1268.
• the roller mechanism 244 includes a cam device 1250 and connectors 1252a, 1252b.
• the cam device 1250 includes a motor 1251 and a roller 1257 eccentrically mounted on a rotatable output shaft 1259 of the motor 1251 , as shown in Figure 34.
• the motor 1251 can rotate the roller 1257 about an axis of rotation 1253 to push a follower 1254 of the slide retaining device 1240.
• the motor 1251 can include, without limitation, a stepper motor, a drive motor, or other type of electrical motor.
• the slide positioning device 1230 lifts an end on the slide 1242 to move the waste (e.g., unused liquid) towards a waste port 1330.
• the roller 1257 can be rotated to move a slide end 1334 upwardly.
• Figure 36 shows the slide 1242 in an angled orientation to urge the waste towards the waste port 1330.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Physics & Mathematics (AREA)
• Chemical & Material Sciences (AREA)
• Analytical Chemistry (AREA)
• Biochemistry (AREA)
• General Physics & Mathematics (AREA)
• Immunology (AREA)
• Pathology (AREA)
• Biomedical Technology (AREA)
• Molecular Biology (AREA)
• Engineering & Computer Science (AREA)
• Sampling And Sample Adjustment (AREA)
• Automatic Analysis And Handling Materials Therefor (AREA)

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• 2010
  • 2010-11-15 IN IN3245DEN2012 patent/IN2012DN03245A/en unknown
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