CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the U.S. Provisional Patent Application No. 62/956,015 filed on Dec. 31, 2019, the entire contents of which are incorporated herein by reference.
FIELD OF INVENTION Automated staining system and reaction chamber.
BACKGROUND Field An automated staining system, in particular an automated staining system for processing biological specimens.
In various settings, processing and testing of biological specimens is required for diagnostic purposes. Generally speaking, pathologists and other diagnosticians collect and study samples from patients, and utilize microscopic examination, and other devices to assess the samples at cellular levels. Numerous steps typically are involved in pathology and other diagnostic processes, including the collection of biological samples such as blood and tissue, processing the samples, preparation of microscope slides, staining, examination, re-testing or re-staining, collecting additional samples, re-examination of the samples, and ultimately the offering of diagnostic findings.
Tissue processors can be operated with varying levels of automation to process human or animal tissue specimens for histology or pathology uses. Various types of chemical reagents can be used at various stages of tissue processing and various systems have been developed for delivering reagents to specimen containing slides. Examples of known reagent delivery systems include small quantity release dispensers, manual pouring into reagent vats, or via bulk containers connected with a processor via tubing.
There are various disadvantages of known systems. For example, manually pouring into, or draining, reagent vats is susceptible to cross contamination, time consuming and requires pouring accuracy, thereby decreasing the overall efficiency of the tissue processing system. Another disadvantage is that manually pouring and draining reagents can be sloppy, requiring clean-up of spills and consequential instrument down-time. A further disadvantage is that manually selecting and applying the correct reagent introduces significant risk of human error and increased possibility of reagent selection errors and application errors resulting in false positive or negative assay results, leading not only to a decrease in test accuracy and operational efficiency but also misdiagnosis.
BRIEF DESCRIPTION OF THE DRAWINGS The embodiments of the invention are illustrated by way of example and not by way of limitation in the figures of the accompanying drawings in which like references indicate similar elements. It should be noted that references to “an” or “one” embodiment in this disclosure are not necessarily to the same embodiment, and such references mean at least one.
FIG. 1 illustrates a perspective view of a sample processing system also referred to as a processor assembly.
FIG. 2 shows a top front side view of the processor assembly of FIG. 1 with a top exterior portion of the external housing of the core module and the staining module removed to expose the interior compartments of each module.
FIG. 3 shows a top front side magnified view of the core module of the processor assembly of FIG. 1 with a top exterior portion of the external housing removed to expose the interior compartment of the module.
FIG. 4 shows a top left side perspective view of a scanning and/or imaging apparatus that can be positioned in a slide identification station of the core module of the processor assembly of FIG. 1.
FIG. 5 shows a top left side perspective view of the scanning and/or imaging apparatus of FIG. 4 with the base, the support, the track and the pedestal removed.
FIG. 6 shows a top side perspective views of the scanning and/or imaging apparatus of FIG. 4 with the base, the support, the track and the pedestal removed and shows the lifting mechanism in a down or return position below a slide in the slide basket.
FIG. 7 shows a top side perspective views of the scanning and/or imaging apparatus of FIG. 4 with the base, the support, the track and the pedestal removed and shows the lifting mechanism in a up or advanced position below a slide in the slide basket.
FIG. 8 shows a top front side magnified view of a portion of the staining module of the processor assembly of FIG. 1 with a top exterior portion of the external housing removed to expose the interior compartment of the module, the magnified view showing a portion of staining module including the capped slide staging station.
FIG. 9 shows a top front side magnified view of a portion of the staining module of the processor assembly of FIG. 1 with a top exterior portion of the external housing removed to expose the interior compartment of the module, the magnified view showing a portion of the staining module that includes the antigen retrieval station.
FIG. 10 shows a magnified front side view of components of the printing station that is housed in the staining module of the processor assembly of FIG. 1 and includes a humidor and a cartridge cradle in a stacked orientation with the humidor disposed below the cartridge cradle and the cartridge cradle in a neutral position.
FIG. 11 shows a magnified front side view of a portion of the staining module of the processor assembly of FIG. 1, the magnified view showing a portion of the staining module including the printing station and the reagent storage cabinet with the cartridge cradle positioned in a rearward or back position for loading of printing cartridges in the cartridge cradle.
FIG. 12 shows a magnified front side view of an exterior of the staining module of the processor assembly of FIG. 1, the magnified view showing the reagent storage cabinet pulled outward so that its contents are in an accessible position.
FIG. 13 shows a magnified front side view of a portion of the staining module of the processor assembly of FIG. 1, the magnified view showing a portion of the staining module including the printing station and the cartridge cradle positioned in a forward position for printing a slide.
FIG. 14 shows a magnified front side view of a portion of the staining module of FIG. 1, the magnified view showing an operation involved in transporting a capped slide from the antigen retrieval station to the printing station following an antigen retrieval process or operation, specifically showing a robot mechanism retrieving a capped slide from the antigen retrieval station.
FIG. 15 shows an end effector of the robot mechanism or apparatus engaging a capped slide retrieved from the antigen retrieval station after the end effector and capped slide have been rotated 90 degrees to extend horizontally in an x-direction in alignment with a slot in the humidor of the printing station in the staining module of the processor assembly of FIG. 1.
FIG. 16 shows capped slides taken by the robot mechanism or apparatus shown in FIG. 14 and FIG. 15 from the antigen retrieval station and positioned in the humidor of the printing station lengthwise into slots in the humidor until a flange of each capped slide contacts the humidor forming a seal of the slot.
FIG. 17 shows a magnified front side view of a portion of the staining module of FIG. 1, the magnified view showing an operation involved in removing a capped slide from a slot in the humidor of the printing station by a robot mechanism or apparatus.
FIG. 18 shows a magnified front side view of a portion of the staining module of FIG. 1, the magnified view showing the automatic transfer of a capped slide from a slot in the humidor of the printing station to a wash station of the printing station by a robot mechanism or apparatus.
FIG. 19 shows a magnified front side view of a portion of the staining module of FIG. 1, the magnified view showing the automatic transfer of a capped slide into a wash station of the printing station by a robot mechanism or apparatus.
FIG. 20 shows a magnified front side view of a portion of the staining module of FIG. 1, the magnified view showing a capped slide automatically transferred from a wash station of the printing station to a printing position and the cradle of the printing station advanced to a printing position over a sample portion of the slide.
FIG. 21 shows a side view through line 21-21′ of FIG. 20 and shows a printhead of a cartridge in the cradle over the slide and an imager positioned to capture an image of a sample on a slide allowing the sample to be analyzed for placement of a reagent or antibody on the sample.
FIG. 22 shows a magnified front side view of a portion of the staining module of FIG. 1, the magnified view showing a capped slide automatically transferred from a printing station to a slide basket at a rear entrance of the staining module by a robot mechanism or apparatus and an end effector of the robot mechanism or apparatus automatically placing the capped slide into a slide basket.
FIG. 23 shows a top front side magnified view of the core module of the processor assembly of FIG. 1 with a top exterior portion of the external housing removed to expose the interior compartment of the module and shows a slide basket automatically transferred from the staining module to the core module and the slide basket engaged by an end effector of a robot mechanism or apparatus. FIG. 23 also shows a second slide basket engaged by a robot mechanism or apparatus above dehydration station.
FIG. 24 shows a top side view of an example of a printing cartridge that may be used in the staining module of the processor assembly of FIG. 1, the printing cartridge having a dedicated cap at its base, the cap in a closed or capped position.
FIG. 25 shows a top side view of the printing cartridge of FIG. 24 with the cap in an open position to expose the printhead of the cartridge.
FIG. 26 shows a top side view of another example of a printing cartridge that may be used in the staining module of the processor assembly of FIG. 1, the printing cartridge having a dedicated cap at its base that is attached to the cartridge by magnetism.
FIG. 27 shows a top side view of an example of a service station in the processor assembly of FIG. 1, with the service station having a cartridge decapping area and the figure showing the positioning of a cartridge in the decapping area for removal of its dedicated cap.
DETAILED DESCRIPTION In the following paragraphs, the invention will be described in detail by way of example with reference to the accompanying drawings. Throughout this description, the embodiments and examples shown should be considered as exemplars, rather than as limitations on the present invention. Furthermore, reference to various aspects of the embodiments disclosed herein does not mean that all claimed embodiments or methods must include the referenced aspects.
FIG. 1 illustrates a perspective view of a sample processing system also referred to as a processor assembly. Processor assembly 100 is a modular assembly including core module 110 connected with and in communication with staining module 120. Each module includes an external housing that contains interior compartments for enclosing and storing various components of processor assembly 100 to provide for the automatic processing of samples (biological samples) on respective slides. Core module 110 may serve to dewax and bake specimens (e.g., tissue samples) on slides from a microtomy unit. Staining module 120 may be, for example, an immunohistochemical staining unit. In general, immunohistochemical staining involves the process of selectively identifying antigens (e.g., proteins) in cells of a tissue section or cytology specimen by introducing antibodies that bind (e.g., specifically bind) to the antigens. Visualization of antibody-antigen interaction can be accomplished, for example, by conjugating an enzyme that can catalyze a color-producing reaction or a fluorophore that exhibits a fluorescence when viewed.
Referring to FIG. 1, the front side exterior view of core module 110 of processor assembly 100 includes shelf or landing 112 on which one or more baskets of specimen or microscope slides may be disposed and loaded into core module 110 through inlet opening 115 and discharged from core module 110 through outlet opening 125. A specimen or microscope slide is generally a thin flat piece of glass typically 75 millimeters long by 26 millimeters wide (e.g., 3 inches long by 1 inch wide) and of about one millimeter in thickness (0.04 inches thick). Representatively, a slide basket may be a 10-slide or 20-slide TISSUE-TEK PRISMA® slide basket commercially available from Sakura Finetek USA, Inc. In this view, core module also includes interface 135 positioned on a front side of core module 110 above shelf 112. Interface 135 is a computer interface including, for example, a graphic user interface, that is electronically linked to a controller or processor associated with the operation of processor assembly 100. An inset of FIG. 1 shows controller or processor 136 connected to interface 135 and memory 137 coupled to processor or computer 136. Interface 135 may serve to allow operation and control of core module 110 and core module 120 of processor assembly 100 from a human end as well as may provide feedback information about the operations of core module 110 and core module 120. Below shelf 112 of core module 110 is drawer or door 113 that provides access to a bottom portion of the module where bulk reagents and waste may be stored. Processor 136 may be electrically or wirelessly linked to a network, such as laboratory information system (LIS) that records, manages and stores data for clinical laboratories.
FIG. 1 shows staining module 120 connected to core module 110 in a side-by-side arrangement. Staining module 120 includes drawer 121 that provides access to a refrigerated storage area for inkjet reagent cartridges. Adjacent drawer 121 may be window or windows 122 providing visual access to the interior of staining module 120 (an interior compartment within which sample processing occurs). Window or windows 122 may be fixed to the body of the module so that the window(s) cannot be opened or may be fixed to the body in a way that the one or more windows may be opened (e.g., a hinged connection on one end or edge). Where window or windows 122 may be opened, window or windows 122 may be used to gain access to components within staining module 120. Below window or windows 122 and drawer 121 of staining module 120 is drawer or door 123 and drawer or door 124 that provide access to a bottom portion of the module where bulk reagents and waste containers may be stored. Bulk reagents may be dispensed into stations in core module 110 or staining module 120 via plumbing including a pump or pumps (not shown). Examples of bulk reagents that can be dispensed either alone or in combination with other bulk reagents include, without limitation, the following: Tris Buffered Saline (TBS), Saline Sodium Citrate (SSC), distilled water, dewaxing solution, alcohol or xylene. The pump or pumps may be connected to conduits that, for example, feed tanks in either module.
FIG. 2 shows a top front side view of processor assembly 100 with a top exterior portion of the external housing of core module 110 and staining module 120 removed to expose the interior compartments of each module. Referring to FIG. 2, core module 110 includes shelf 112 that transitions to generally horizontal processing platform 1101 that includes baking and dewaxing station 1110, slide identification station 1120 and dehydration station 1130. Representatively, when a basket of slides is introduced into core module 110 (e.g., through inlet opening 115 (see FIG. 1)), the basket is brought to slide identification station 1120 where a label of each slide in the basket is individually scanned, read and/or imaged. Each slide is returned to the basket after being scanned, read and/or imaged and the basket is transported to baking and dewaxing station 1110 where the slides are processed as a group to adhere a sample to a slide and then expose the sample. A basket may be transported from slide identification station 1120 to and through baking and dewaxing station 1110 by robotic mechanism 1140 that moves along rail 1145 that may be attached to a sidewall of the housing of core module 110 (e.g., a left sidewall). Following adherence and dewaxing of samples on slides in a basket, the basket is transported from core module 110 to staining module 120. A basket may be transported from slide identification station 1120 to and through baking and dewaxing station 1110 by robotic apparatus 1150 that moves along rail 1147 that may be attached to a sidewall of the housing of core module 110 (e.g., a rear sidewall). Each slide may then be stained in staining module 120 and then a basket containing the stained slides is returned to core module 110 and dehydration station 1130 for further processing. A basket may be transported through dehydration station 1130 by robotic apparatus 1137 that moves along rail 1135 that may be attached to a sidewall of the housing of core module 110 (e.g., a right sidewall).
Still referring to FIG. 2, staining module 120 includes generally horizontal processing platform 1201 that optionally includes cap station 1230, antigen retrieval station 1240 and printing station 1270. Representatively, a basket of slides is automatically introduced/transported into a rear entrance (as viewed) of staining module 120 (e.g., from core module 110) using robotic mechanism 1210 that moves along rail 1147. Once inside staining module 120, each slide in the basket may receive a cap. A cap may be attached to an end of a slide to aid in the individual grasping and movement of the slide by a robot mechanism or apparatus (e.g., by an end effector). In another example, a robot mechanism may include an end effector that can automatically grasp and move a slide without the use of a cap (e.g., grasp a slide lengthwise by opposite side edges or pinching on opposite sides (a pinch grip)). Where slides are capped to aid in individual grasping and movement (transport), the slides may be capped by using robot mechanism 1210 to individually retrieve a cap from cap storage station 1230 and attaching the cap on a slide in the basket. Once each slide in the basket is capped, the slides are individually transported to antigen retrieval station 1240. At antigen retrieval station 1240, the slides may be subjected to an antigen retrieval process at elevated temperature and pressure to expose antigenic sites in or on a sample. From antigen retrieval station 1240, slides are individually transported to printing station 1270. At printing station 1270, slides are individually washed and then an inkjet printing process is performed to print a reagent such as antibodies that bind to targeted exposed antigens on a sample and other enzymes and reagents which may provide colored appearance for identification and subsequent verification of proper application of the reagent to the specimen via the vision system. Slides may be printed one-by-one utilizing robotic mechanism 1255 that moves on rail 1252. Following a printing process at printing station 1270, slides are loaded into a basket and their cap is removed. The basket is then transported back to core module 110 and held in buffer or run through a dehydration process at dehydration station 1130. A buffering or dehydration process may be performed simultaneously on any slides in the basket. Following a dehydration process, the basket containing processed slides is discharged through outlet 125.
FIG. 3 shows a top front side magnified view of core module 110 of processor assembly 100 with a top exterior portion of the external housing removed to expose the interior compartment of the module. For illustration purposes, FIG. 3 shows six baskets containing slides (basket 210A, basket 210B, basket 210C, basket 210D, basket 210E and basket 210F). Baskets 210D and 210E are on shelf 112 outside of core module 110 (see FIG. 1) while baskets 210A, 210B, 210C and 210F are inside core module 110 indicating that the core module can process multiple slides (e.g., multiple baskets of slides) at different stations therein at the same or similar times. Basket 210C is positioned inside inlet 115 in first slide identification station 1120. First slide identification station 1120 representatively may include a scanning and/or imaging apparatus similar to that described in U.S. patent application Ser. No. 16/370,879, titled “Stand Alone Slide Identification Reader,” filed 29 Mar. 2019 and incorporated herein in its entirety. U.S. patent application Ser. No. 16/370,879 describes a device that accepts a basket of slides such as a 10-slide or 20-slide TISSUE-TEK PRISMA® slide basket commercially available from Sakura Finetek USA, Inc. and automatically individually lifts each slide in a basket to read and/or capture an image of a label on the slide.
FIG. 4 shows a top left side perspective view of a scanning and/or imaging apparatus that can be positioned in first slide identification station 1120. First slide identification station 1120 is situated adjacent input 115 of core module 110 and includes apparatus 300 that is similar to an apparatus described in U.S. patent application Ser. No. 16/370,879 with an exterior housing removed. Apparatus 300 includes track 324 onto which slide basket 210C may be placed either manually or robotically in core module 110. Inside core module 110 through input 115 is tray 310. FIG. 4 shows apparatus 300 includes base 302 that is representatively shown having a rectangular plate shape. Projecting perpendicularly from base 302 is support 304 that also has a rectangular plate shape. Disposed on support 304 is track 324 and tray 310 (shown in dashed lines). Projecting from support 304 above tray 310 at one end of tray 310 is pedestal 306. Sensor 401 is mounted on pedestal 170.
Tray 310 representatively is a relatively thin aluminum material. The sidewalls of tray 310 project perpendicularly from its base and are spaced to accommodate basket 210. Basket 210 includes sidewall support 235A and sidewall support 235B on opposite sides thereof. Sidewall supports 235A and 235B are arrow shaped with a tip of the arrow pointed outward (away from basket 210). The sidewalls of tray 310 have a shape to accommodate a shape of sidewall supports 235A and 235B so that basket 210 fits within tray 310.
FIG. 5 shows apparatus 300 of FIG. 4 with base 302, support 304, track 324 and pedestal 306 removed. As illustrated, a base of tray 310 has an opening through much of its length. Disposed within the opening is belt or track 320 such as a plastic belt. In one embodiment, belt 320 is disposed on roller 325A and roller 325B. Rollers 325A and 325B may be separated by a distance of approximately a length of tray 310. Each of roller 325A and roller 325B may have a number of equally spaced teeth defining their circumference. One side of belt 320 (the side facing rollers 325A and 325B) has similar spaced teeth operable to mate with the teeth on a roller. The spacing of the teeth on the roller and belt 320 may be similar to the spacing between notches 245 in basket 210 that separate one longitudinally positioned slide from another such that the belt can stop basket 210 notch 245-by-notch 245. In one embodiment, roller 325B is connected to motor 330 by way of a rod or axle 332. In one embodiment, motor 330 is an electrically powered step motor operable to rotate roller 325B. Roller 325A is disposed on axle 333 and is rotatable thereon.
FIG. 4 and FIG. 5 also show a motorized assembly for lifting the individual slides in basket 210. Apparatus includes, in this embodiment, U-shaped push bar 350 with one end of a vertical projection of push bar 350 being positioned to move vertically within an opening of a base of tray 310 and through an opening and in base 230 of basket 210. The other vertical projection of push bar 350 is positioned outside of tray 310. Connecting rod 360 is connected to push bar 350 at one end and at a second end to L-shape rotating arm 370. Rotating arm 370 is connected to motor 380 through rod 382. In one embodiment, motor 380 is an electrically operated motor operable to rotate rod 382. A rotation of rod 382 rotates rotating arm 370. Rotating arm 370 is pivotably connected to connecting rod 360 and a rotation of rotating arm 370 moves connecting rod 360 up and down. The up and down movements of connecting rod 360 are transferred to push bar 350 which itself moves up and down with rotation of motor 380. The upward movement advances the vertical arm of push bar 350 into and out of basket 210 (into and out of a base of the basket) to lift an individual slide (slide 290) in basket 210 vertically (a Y-direction) relative to a position where one end of the slide is seated at a base of basket 210. Upon lifting an individual slide (slide 290) from basket 210, an area 2901 of the slide is exposed and may be read and/or sensed (e.g., imaged) by sensor 401.
FIG. 6 and FIG. 7 show top side perspective views of apparatus 300 with base 302, support 304, track 324 and pedestal 306 removed and show the lifting and return of a slide in basket 210. Referring to FIG. 6 and FIG. 7, the figures show push bar 350 including vertical projection 3502 and vertical projection 3504 and separated by lateral projection 3503. In this embodiment, vertical projection 3502 of push bar 350 has a width that can be accommodated within basket 210 (e.g., through an opening in base 230 of basket 210) and a thickness approximately equivalent to a thickness of slide 290 and no thicker than a width of notch 245. FIG. 6 shows vertical portion 3502 of push bar 350 beneath basket 210 (beneath a base of the basket) and slide 290 resting in a slot at base 230 of basket 210. In FIG. 6, rotating arm 370 is in a down position. FIG. 7 shows rotating arm 370 in an up position. By moving rotating arm 370 from a down to an up position, connecting rod 360 lifts push bar 350 upward a representative distance on the order of 63 mm to 75 mm (2.5 inches to 3 inches). A slide in the basket may be lifted a sufficient distance to expose a section on the slide (a section being a sample embedded in and surrounded by embedding medium (e.g., paraffin)). Exposing the section may allow an image of the section to be captured by sensor 401. As push bar 350 is lifted, portion 3502 of push bar 350 enters basket 210 and pushes against an end of slide 290 and pushes slide 290 upward so that an end of slide 290 is no longer adjacent to or in contact with base 230 of basket 210. The vertical movement of push bar 350 is guided by linear guide 385. Slide 290 is in an up position with a greater length portion outside of basket 210 relative to other slides that might be nested in basket 210. Portion 2901 of the slide may be sensed (imaged) by a sensor as described above.
Once a slide basket (e.g., slide basket 210C) is placed on track 324 of apparatus 300 so that it is over a portion of belt 320 in slide identification station 1120, belt 320 engages teeth at the base of the basket (teeth 250) and detection sensor 345 detects the presence of the basket. Belt 320 may then be advanced by motor 330 automatically (e.g., in response to detection sensor 345 sending a signal to motor 330) and basket 210C is advanced in a direction toward sensor 401. As basket 210C is advanced, detection sensor 340 detects the presence of a slide in basket 210, motor 380 is activated and drives push bar 350 upward to lift a slide in basket 210. Detection sensor 330 senses the advancement of push bar 350. A signal from detection sensor 330 to sensor 401 will alert to a raised slide, allowing sensor 401 to then sense information on the raised slide (e.g., read, image). After sensing, the slide is lowered into basket 210 (block 470) and belt 320 is then advanced by motor 330 to advance basket 210 until detection sensor 340 detects another slide in basket 210. If a slide is detected the slide is raised and sensed.
Apparatus 300 may be electrically connected to processor 136 that coordinates the movement of motor 330 and motor 380. Processor 136 may be operable to receive or retrieve signals from each of detection sensor 330, detection sensor 340 and detection sensor 345. Processor 136 contains non-transitory machine-readable instructions that when executed cause push bar 350 to be raised and sensor 401 to detect (e.g., read, image) a slide raised by push bar 350. The executable instructions also include instructions to lower push bar 350 and then step motor 380 a distance to position push bar 350 under another slide position in basket 210. The executable instructions further include instructions to eject basket 210 from slot 120 when all slides in the basket are individually sensed by sensor 401.
Sensor 401 may be connected to a memory of processor assembly 100 (e.g., memory 137) and/or a laboratory information system (LIS) that is a software system that records, manages and stores data for clinical laboratories. Where sensor 401 is, for example, bar code reader or scanner, sensor 401 is operable to read and optionally record one or a plurality of bar codes that is/are printed on a slide (e.g., on a slide label or frosted area of the slide). This information may include but is not limited to patient data (name, admitting physician, ordering department, specimen type, etc.) and a staining or other protocol for the specimen on the slide (e.g. accessioning number). The information that is read by sensor 401 may be transmitted to processor 136 or the LIS to allow the system to track the slide and also subsequently perform any required staining protocol or other preparation protocol for the specimen. It is appreciated that a bar code reader or scanner is one example of a sensor that is operable to sense information from a slide. In another embodiment, sensor 401 may be a camera or other reader (e.g., radio frequency identification (RFID) reader). Representatively, sensor 401 may include reader 4012 and scanner/imager 4014 as shown in FIG. 4. Reader 4012 may be a bar code reader or scanner (or other reader or scanner of identification information on a slide) and scanner/imager 4014 may be operable to capture (e.g., scan) an image of a sample on a slide. As a slide is initially introduced into core module 110, a sample on the slide may be disposed in and/or infiltrated with an embedding medium such as paraffin commonly referred to a section. The embedding medium typically occupies a larger area on a surface of a slide than the sample disposed in the embedding medium. The executable instructions in processor 136 may direct scanner/imager 4014 to capture an image of a portion of the section, including the entire portion so that a possible initial identification of the sample in the section can be determined. The captured image of the section may be stored or saved in memory 137. Often, with an embedding medium such as paraffin, a sample in the section may appear a different color (e.g., more opaque) than the surrounding embedding medium (e.g., paraffin). Processor 136 may use this difference in color to approximate a location of the sample on the slide. For example, the executable instructions in processor 136 may include instructions to overly a grid on the stored image captured by scanner/imager 4014 and detect the sample in the section by its color difference relative to a color of the embedding medium (e.g, using wavelength differences). Using Cartesian coordinates associated with the grid, an approximate location of the sample may be determined and this location stored or saved in member 137.
Once all the slides in a slide basket (e.g., slide basket 210C) are detected by sensor 401, the slide basket may be removed from slide identification station 1120. As illustrated, slide baskets such as a TISSUE-TEK PRISMA® slide basket have a handle that may be positioned over the basket. The handle of a slide basket may be supported and/or engaged and then moved within core module 110 by a robotic transfer assembly. FIG. 2 and FIG. 3 show a robotic transfer assembly including rail or track 1145 and robot apparatus 1140. Rail or track 1145 may be attached to an inside wall of core module 110 (e.g., a left wall as viewed) or be free standing adjacent an inside of a wall of the module or other location. Robot apparatus 1140 includes robot controller 1141 (see FIG. 3) that may control robot motion (e.g., movement of robot apparatus 1140 on track 1145 and processing tasks to be performed by robot apparatus 1140). Robot controller 1141 is linked either through hardwiring or wirelessly to processor 136. Machine readable program instructions are transmitted between processor 136 and robot controller 1141 (e.g., from processor 136 to direct robot controller 1141) to perform a desired protocol. Robot controller 1141 may transmit a signal or signals back to processor 136 confirming the instructions and/or after completing an action directed by processor 136. From slide identification station 1120, a protocol may be to transfer a slide basket (e.g., slide basket 210C) to baking and dewaxing station 1110. Rail or track 1145 may be positioned at a height sufficient to allow an end effector of robot apparatus 1140 (e.g., a hook or laterally extending bar at a distal end of robot apparatus) to be maneuvered under a handle of the slide basket and then ascend to raise the slide basket by the handle. The slide basket (e.g., slide basket 210C) may then be raised and then transferred to baking and dewaxing station 1110.
Prior to staining a sample (e.g., a tissue sample) on a slide, paraffin-embedded samples may be baked to affix the sample to the slide and then de-paraffinized (dewaxed) to allow aqueous solutions to penetrate the samples. At baking and dewaxing station 1110, a slide basket containing one or more slides each containing a paraffin-embedded sample may be subjected to a series of operations to bake and then dewax the sample. These operations are performed while the slide(s) are in a slide basket allowing multiple samples to be baked and dewaxed together. Representatively, baking and dewaxing station 1110 includes three tanks or compartments, each with a dedicated lid. Each lid may be connected to a hinge that may be automatically actuated via instructions from processor 136. Tank or compartment 1112 is operable to heat the slide(s) in a slide basket as part of a baking operation. The heat treatment should be sufficient to allow a sample on a slide to adhere or further adhere to a slide (a glass slide) and possibly to soften the embedding medium associated with a section on the slide. Representatively, tank or compartment 1112 may be lined on one or more sides of its exterior with resistive heating elements that are sufficient to bring a temperature inside a volume of tank or compartment 1112 to a temperature on the order of 55° C. to 70° C. Tank or compartment 1114 includes a volume of a dewaxing solution such as xylene sufficient to submerge the sample portion of slide(s) positioned lengthwise in a slide basket. Tank or compartment 1114 may be a series of tanks or compartments containing similar or different dewaxing solutions. One example of multiple tanks or compartments for tank or compartment 1114 is a first tank or compartment that contains a volume of xylene and a second tank or compartment that contains a volume of alcohol (e.g., ethyl alcohol). Tank or compartment 1116 includes a volume of a washing solution, such as water or other aqueous wash solution. Tank or compartment 1116 may also include an amount of stain such as eosin in the wash solution to stain a sample on a slide. Generally, following a dewaxing operation, an embedding material in the section is removed leaving the sample as a virtually colorless object on a slide. Adding an amount of a stain such as eosin in the wash solution may allow the presence and location of the sample on the slide to be detected.
A baking and dewaxing process may proceed automatically under the control of executable instructions in processor 136. Such instructions may include instructions to individually open one or more lids on the tanks or compartments, the placement of a slide basket into a tank or compartment, a time for an operation (e.g., baking, dewax, etc.), the removal of a slide basket from a tank or compartment and the closing of the one or more lids. As an example of a baking and dewaxing process to adhere and dewax samples on slide(s) in a slide basket, a lid on tank or compartment 1112 is automatically opened and then a slide basket (slide basket 210C) is placed by robot apparatus 1140 in tank or compartment 1112 and subject to a baking process sufficient to adhere the samples to individual slides and melt the paraffin on individual slides (e.g., 5-60 minutes). Robot apparatus 1140 may transfer the slide basket into tank or compartment 1112 and disengage with a handle of the slide basket. A door or lid may then be automatically closed over the top of the tank or compartment 1112 for the duration of a baking operation. Following a baking operation, a door or lid over tank or compartment 1112 may be automatically opened and robot apparatus 1140 may then engage the slide basket (e.g. slide basket 210B) and transfer the slide basket by the handle toward tank or compartment 1114. A door or lid over tank or compartment 1114 may be automatically actuated to open and the robot apparatus 1140 may transfer the slide basket into tank or compartment 1114 and disengage with the slide basket. Tank or compartment 1114 may contain an amount (a volume) of a dewaxing solution or solutions sufficient to submerge at least the sample on slide(s) in the slide basket in the dewaxing solution or solutions. Following the automatic transfer of the slide basket into tank or compartment 1114, the door or lid of the tank may be automatically closed. The slides in the basket may subjected to a representative dewaxing operation for 3-5 minutes. Tank or compartment 1114 may include an agitator (e.g., a magnetic stirrer) to agitate the dewaxing solution or solutions therein during the dewaxing operation. Alternatively, the door or lid of tank or compartment 1114 may be left open and rather than disengage the slide basket upon transfer of the slide basket into tank or compartment 1114, robot apparatus 1140 may lift and lower the slide basket during the dewaxing operation to agitate the dewaxing solution or solution in the tank or compartment. Following the dewaxing operation, robot apparatus 1140 automatically transfers the slide basket toward tank or compartment 1116. The door or lid over tank or compartment 1114 may then be automatically closed and a door or lid over tank or compartment 1116 may be automatically actuated to open and the robot apparatus 1140 may then transfer the slide basket into tank or compartment 1116. Tank or compartment 1116 may contain an amount (a volume) of a wash solution or solutions sufficient to submerge at least the sample on slide(s) in the slide basket in the washing solution or solutions. The slides in the basket may be subjected to a representative wash operation for 3-5 minutes. A door or lid associated with tank or compartment 1116 may be closed during the wash operation and the wash solution(s) therein may be agitated. Alternatively, robot apparatus 1140 may maintain engagement with the slide basket during the wash operation and repeatedly lift and lower the slide basket to agitate the wash solution(s).
As described above, a wash solution(s) in tank or compartment 1116 may contain a stain such as eosin that may at least temporarily color or stain a sample on a slide. Following baking and dewaxing at baking and dewaxing station 1110, the slides in a basket (e.g., basket 210F) may be automatically transferred to second slide identification station 1121. Second slide identification station 1121 may be similar to first slide identification station 1120 and may include a reader for scanning or reading slide identification information and a scanner/imager for capturing (e.g., scanning) an image of a sample on a slide. In an example where a stain is added to the wash solution at baking and dewaxing station 1110, a sample on a slide may be colored with a portion of that stain. A scanner/imager in second slide identification station 1121 may be able to capture an image of the sample so that a location of the sample on the slide may be determined. Executable instructions in processor 136 may direct a scanner/imager in second slide identification station 1121 to capture an image of a portion of the sample, including the entire portion. The captured image of the sample may be stored or saved in memory 137. Processor 136 may approximate a location of the sample on the slide from the stored or saved image. For example, the executable instructions in processor 136 may include instructions to overly a grid on the stored image and detect the sample by its color difference relative to a color of the slide (e.g, using wavelength differences). Using Cartesian coordinates associated with the grid, an approximate location of the sample may be determined and this location stored or saved in member 137. Alternatively, or additionally, the stored image of the sample captured at second slide identification station 1121 can be compared with the image captured and saved earlier from first slide identification station 1120. Based on this comparison, a location of a sample on a slide may be determined. This location information may be saved in memory 137 for use later in a printing operation to focus jetting of a printing medium on the sample and minimize waste associated with printing in areas where no sample is present. In situations where there is no stain added to a wash solution or the stain is not sufficient to allow an image to be accurately captured at second slide identification station 1121, the stored/saved location information of the sample from first slide identification station 1120 may later be used in a printing operation.
It is appreciated that core module 1110 may contain multiple slide identification stations as illustrated with respect to FIG. 3 and the associated text where first slide identification station 1120 and second slide identification station 1121 are illustrated and described. In another example, following baking and dewaxing station, a basket of slides may be returned to first slide identification station 1120 and first slide identification station 1120 may capture images of samples after a dewaxing operation.
Following a capture of an image of each sample on a slide in a slide basket after a dewaxing operation, a slide basket may be transferred to staining module 120. A slide basket may be transferred using a robotic transfer assembly. FIG. 2 and FIG. 3 show a robotic transfer assembly including rail or track 1147 and robot apparatus 1150. Rail or track 1147 may be attached to an inside wall of core module 110 (e.g., a rear wall as viewed) or be free standing adjacent an inside of a wall of the module or other location. As illustrated in FIG. 2, rail or track 147 may extend from core module 110 into staining module 120. Robot apparatus 1150 may include robot controller 1151 (see FIG. 3) that may control robot motion (e.g., movement of robot apparatus 1150 on track 1147 and processing tasks to be performed by robot apparatus 1150). Robot controller 1151 may be linked either through hardwiring or wirelessly to processor 136. Machine readable program instructions are transmitted between processor 136 and robot controller 1151 (e.g., from processor 136 to direct robot controller 1151) to perform a desired protocol. Robot controller 1151 may transmit a signal or signals back to the computer 136 confirming the instructions and/or after completing an action directed by processor 136. From second slide identification station 1121, a protocol may be to transfer a slide basket (e.g., slide basket 210A in FIG. 3) to staining module 120. Rail or track 1147 may be positioned at a height sufficient to allow an end effector of robot apparatus 1150 (e.g., a hook or laterally extending bar at a distal end of robot apparatus) to be maneuvered under a handle of the slide basket and then ascend to raise the slide basket by the handle. The slide basket (e.g., slide basket 210A) may then be raised and transferred along rail or track 1147 to staining module 120.
Positioned at an entrance of staining module 120 from core module 110 on processing platform 1201 is tray 1206 including, in this example, two lanes in which a slide basket may be placed either manually or robotically. Lane 12061 of tray 1206 may be intended for slide baskets that are destined for staining module 120 from core module 110 while lane 12062 may be intended for slide baskets that are destined for core module 110 from staining module. Alternatively, each lane of tray 1206 may be intended to accommodate slide baskets destined for staining module 120 or destined for core module 110 (returning from staining module 120). Each lane of tray 1206 includes sidewalls (e.g., sidewall 1207) of representatively a relatively thin aluminum material that project perpendicularly from its base and are spaced to accommodate a slide basket in the lane. As noted above, for example, in FIG. 4, a slide basket such as a 10-slide or 20-slide TISSUE-TEK PRISMA® slide basket may include sidewall supports having a particular shape (e.g., sidewall supports 235A and 235B as shown in FIG. 4 are arrow shaped with a tip of the arrow pointed outward. The sidewalls of tray 1206 may have a shape to accommodate a shape of sidewall supports so that a slide basket fits within tray 310.
A base of tray 1206 in each lane may have an opening through a portion of its length in which a belt is disposed to transport a slide basket horizontally either into staining module 120 or into core module 110. A movable belt may be similar to belt or track 320 describe with reference to slide identification apparatus 300 (see FIG. 5) and be disposed on rollers where one roller is rotated by a motor. Each roller may have a number of equally spaced teeth defining their circumference with one side of the belt (the side facing the rollers) having similar spaced teeth operable to mate with the teeth on a roller. The spacing of the teeth on the roller and the belt may be similar to the spacing between notches in a slide basket that separate one longitudinally positioned slide from another.
Referring again to FIG. 3, robot apparatus 1150 may engage a slide basket (e.g., slide basket 210A) from second slide identification station 1121 and transport the slide basket (by moving horizontally along rail 1147 and deliver the slide basket to tray 1206. The slide basket may then be transported horizontally into staining module 120. As noted above with reference to FIG. 2 and the accompanying text, staining module 120 includes cap storage station 1230, antigen retrieval station 1240 and printing station 1270. FIG. 8 shows a magnified view of a portion of staining module including cap storage station 1230. FIG. 8 also shows tray 1206 and slide basket 210A in lane 12061 of tray 1206. Lane 12061 ends at an area adjacent cap storage station 1230. As previously noted, when a slide basket is introduced into staining module 120 (e.g., from core module 110), each slide in the slide basket may receive a cap that will aid in the transport of the slide by an end effector of a robot apparatus through stations in staining module 120. As also previously noted, the use of a cap is optional and slides may be transported individually by an end effector that may securely grasp a slide without a cap. FIG. 8 shows robot apparatus 1210 connected to rail 1147. Robot apparatus 1210 may include robot controller 1211 that may control robot motion (e.g., movement of robot apparatus 1210 on track 1147 and processing tasks to be performed by robot apparatus 1210). Robot controller 1211 is linked either through hardwiring or wirelessly to processor 136. Rail or track 1147 may be positioned at a height sufficient to allow end effector 1212 of robot apparatus 1210 to individually access unused caps from cap storage station 1230 and place a cap on each slide in slide basket 210A. The robot assembly including robot apparatus 1210 may provide at least three axes of movement. An x-direction of movement is provided through the lateral (e.g., horizontal) movement of robot apparatus 1210 on rail 1147. Robot apparatus 1210 has a rectangular body have a length, L, that projects from rail 1147 into staining module 120. Attached to a base of the rectangular body is end effector 1212. A y-direction of movement is provided by the ability of end effector 1212 to move along the length, L, of robot apparatus 1210. A base of robot apparatus 1210 may include a rail to which end effector is slidably attached. End effector 1212 can further move in a z-direction (up and down) to engage and move slides. Finally, end effector 1212 has joint 1213 that allows an arm of end effector 1212 to rotate (clockwise and/or counterclockwise).
Tray 1260 or each of lane 12601 and lane 12602 of tray 1260 may be open at a base and include a track and a motorized assembly for lifting individual slides in a slide basket similar to a scanning and/or imaging apparatus that can be positioned in first slide identification station 1120 described above with reference to FIGS. 4-7. According to this example, an individual slide in slide basket 210A may be raised or lifted to receive a cap. Robot apparatus 1210 may be directed by executable instructions from robot controller 1211 and/or processor 136 to move to cap storage station 1230 and retrieve a cap. A cap is engaged by end effector 1212 and then the cap is transferred to slide basket 210A where it is fitted on a raised or lifted slide (e.g., slide 160a).
An inset of FIG. 8 shows slide 160a having cap 1235 placed on one end. Cap 1235 is shown placed on an end of slide 160a that contains an identification label. As illustrated, cap 1235 may be a flexible polymer structure that includes rectangular body 12352 having an open rear end 12354 and an opposite front end 12353. Body 12352 may be hollow so that open rear end 12354 and front end 12353 are part of a continuous opening or a portion between the rear end and the front end may be closed. Cap 235 includes rectangular-shaped, solid flange 12356 having a first side and an opposite second side with the first side of flange 12356 connected to front end 12353 of body 12352. As illustrated, a cross-sectional area of flange 12356 is larger than a cross-sectional area of front end 12353 of body 12352. Cap 1235 further includes a pair of legs extending from a second side of flange 12356. Leg 12358a is separated from leg 12358b by a distance equivalent to a width of a slide (slide 160a), for example, 26 millimeters (1 inch). As illustrated, where cap 235 engages a top of a slide including a slide label, the legs are separated from one another a distance such that a face of a slide engaged by the pair of legs is visible. Each of leg 12358a and leg 12358b has a length dimension of, for example 10 millimeters to 25 millimeters. Each of leg 12358a and leg 12358b may have an inwardly facing groove that may extend a length of the leg. The groove may have a dimension to engage a side edge of a slide so that each leg contacts a slide at three surfaces (a top side surface, a bottom side surface and a side edge surface). The engagement of leg 12358a and leg 12358b with a slide (slide 160a) is such that once the cap is engaged with a slide, the capped slide may be lifted, moved and or transported at body 12352 and the slide will not disengage.
FIG. 8 shows robotic mechanism 1210 engaging capped slide 160a in slide basket 210A. Robotic mechanism 1210 includes end effector 1212 that has a spade end having dimensions (length, width and thickness) to be inserted in open rear end 12354 of cap 1235 and engage the cap by force fit. As noted, a protocol for robot mechanism 1210 may be to retrieve an unused cap from a cap storage station 1230 and then place the cap on an end of a slide (slide 160a) in slide basket 210A by pressing downward on the slide in the basket. Once the slide is capped, the capped slide (slide 160a) is lowered in slide basket 210A and the process is repeated until all the slides in the slide basket are capped.
Once any slides in slide basket 210A have been capped, the capped slides may be individually transferred to antigen retrieval station 1240. FIG. 9 shows a magnified view of a portion of staining module 120 that includes antigen retrieval station 1240. Antigen retrieval station 1240 may include one or more chambers for retrieval agents to be contained. Two or more chambers provide an opportunity to use the same or different retrieval reagents. FIG. 9 shows two chambers, chamber 1241 and chamber 1243 arranged side-by-side within processing platform 1201. Each chamber includes an insert across an upper portion. FIG. 9 shows insert 1242 having rectangular slots, with each slot having dimensions approximately equivalent or slightly greater than a width and thickness of a slide. As illustrated, insert 1242 has multiple slots allowing for multiple slides to be processed in chamber 1241 at one time. Pivotally connected to a side of each of chamber 1241 and chamber 1243 is a lid (lid 1245 and lid 1246, respectively) that can be automatically actuated open or closed by instructions from processor 136. FIG. 9 shows lid 1245 in an open position exposing the contents of chamber 1241 and lid 1246 in a closed position concealing the contents of chamber 1243. Lid 1245 and lid 1246 allow the respective chambers to be pressurized during an antigen retrieval process.
Capped slides in a slide basket (slide basket 210A) may be brought to antigen retrieval station 1240 by robot apparatus 1210. Robot apparatus 1210 may be directed by instructions from, for example, robot controller 1211 that may be linked computer 136. End effector 1212 of robot apparatus 1210 may be maneuvered over capped slide staging station 1230 and retrieve a capped slide and transfer the capped slide by way of the cap to antigen retrieval station 1240. The capped slide is then inserted lengthwise into a chamber in antigen retrieval station 1240. FIG. 9 shows end effector 1212 engaging capped slide 160a and inserting capped slide 160a into a slot in insert 1242 in chamber 1241. Capped slide 160a can be inserted through insert 1242 to a height of the flange on the cap (the flange on the cap has length and/or width dimensions greater than a length and/or width dimension of a slot). Once inserted, the capped slide is separated from end effector 1212. As seen in FIG. 9, chamber 1241 has several slots in insert 1242 allowing multiple slides (e.g., 6 slides) to be placed in a chamber for an antigen retrieval process. After loading one capped slide into chamber 1241, robot apparatus 1210 may return to the slide basket (slide basket 210A) and retrieve and transfer another capped slide to chamber 1241. The retrieval and transfer process may continue until all slots in insert 1242 in chamber 1241 are filled. When retrieval and transfer is complete, lid 1245 is closed and an antigen retrieval process may proceed. A lid may be opened and closed automatically by executable instructions from processor 136 (e.g., instructions may direct an electric motor associated with a hinge of a lid to open actuate the lid open or closed). With lid 1245 closed, a sealed chamber is created allowing an antigen retrieval process to be performed under an elevated pressure, such as a pressure of 1.0 to 1.06 bar (15 psi) above atmospheric. A representative antigen retrieval process may utilize a tris or citrate-based retrieval solution at temperatures of 100° C. to 121° C. and pressures up to 1.06 bar above atmospheric for 3 minutes to 15 minutes. Utilizing an elevated pressure allows an antigen retrieval process to be expedited to, for example, a process time of five minutes compared to prior process times of 45 minutes or more under atmospheric conditions in a similar bath. Chamber 1241 and chamber 1243 may be lined on one or more sides of its exterior with resistive heating elements that are sufficient to bring a temperature of the solution inside a volume of the chamber to a desired elevated temperature. The antigen retrieval solution may be agitated during an antigen retrieval process or operation with, for example, a magnetic stirrer in the solution.
In the above example, slides were removed from a slide basket and placed individually in chamber 1241 and chamber 1243 for an antigen retrieval process or operation. In another example, a slide basket containing one or more slides may be placed in chamber 1241 or chamber 1243 and the one or more slides may undergo an antigen retrieval process or operation while present in the slide basket. Executable instructions from processor 136 may direct robot apparatus to transfer a slide basket into one of chamber 1241 or chamber 1243. In such an example, inserts (e.g., insert 1242) that hold individual slides in an upright position in chamber 1241 or chamber 1243 would not be present.
Once an antigen retrieval process is completed, slides may be transferred to wash tank 1247. Wash tank 1247 may contain an amount (volume) of a wash buffer such as TBS or phosphate-buffered saline containing a surfactant. Executable instructions from processor 136 may direct robot apparatus to transfer individual slides or a slide basket from one of chamber 1241 or chamber 1243 into wash tank 1247 depending, for example, whether slides were individually placed in chamber 1241 or chamber 1243 or placed in the chamber in a slide basket. Where capped slides are transferred individually into wash tank 1247, wash tank 1247 may include an insert having slots for slides similar to insert 1242 in chamber 1241. Alternatively, a slide basket may be placed in wash tank 1247 and slides that were individually placed in chamber 1241 or chamber 1243 may be placed in the slide basket within wash tank 1247. FIG. 9 shows one wash tank. In another example, there may be two or more wash tanks that each may have similar or different wash buffers and/or may be designated for certain slides.
To monitor the progress of slides in staining module 120, staining module may include a slide identification station similar to first or second slide identification station in core module 110. Such a slide identification station may be placed adjacent antigen retrieval station 1240. An identifier such as a bar code on a slide may be read at such a slide identification station before or after a slide or basket of slides is introduced into wash tank 1247. The information may be stored in memory 1237 and displayed on interface 1235.
In certain situations, an individual slide or slides may need priority over other slides. Wash tank 1247 containing a wash buffer provides an environment for slide retention prior to a printing operation. Such retention includes retention due to scheduling as in the situation where a slide or slides having higher priority need to be brought to printing station over other slides that were perhaps loaded and processed in staining module 120 ahead of the high priority slide(s).
From wash tank 1247 of antigen retrieval station 1240, slides may be transferred to printing station 1270. Slides may be individually transported to printing station 1270 leaving other slides in wash tank 1247. At printing station 1270, an inkjet printing process is performed to print a reagent such as a primary antibody that binds to targeted exposed antigens on a sample or a detection agent (e.g., secondary antibody, peroxidase conjugate, substrate) that may react or otherwise link to the primary antibody. FIG. 2 shows printing station 1270 adjacent to antigen retrieval station 1240 on processing platform 1201 (e.g., printing station 1270 is forward of antigen retrieval station 1240 in FIG. 2). FIG. 10 shows a magnified front side view of components of printing station 1270. FIG. 10 shows printing station 1270 including humidor 1272 and cartridge cradle 1275 in a stacked orientation with humidor 1272 disposed below cartridge cradle 1275. Humidor 1272 is operable to create a humidity-controlled environment for slides following a printing process to reduce evaporation of the staining reagents at the samples on the respective slides. Representatively, humid air may be introduced into or circulated through an interior of humidor 1272 by a control valve to maintain a certain humidity level that may be monitored by a monitor linked to processor 136 (e.g., processor 136 may contain executable instructions to control the rate of humid air through the control valve). In one example, a conduit and valve assembly may be connected to a water supply (possibly heated) below processing platform 1201. The conduit may extend into a side of humidor 1272. A fan or blower may introduce air and water into the conduit and into humidor 1272. Humidor 1272 includes a number of slots 1273 arranged in a row along a side of the humidor. Each slot 1273 defines a cavity having dimensions to accept a portion of a slide lengthwise in a plane parallel to platform 1201 (horizontal). FIG. 10 shows several capped slides in slots 1273 as well as several open slots. Capped slides are inserted into slots 1273 up to a flange on the capped slides. The flange has dimensions greater than a dimension of a slot so that when a flange of a capped slide comes in contact with an outer sidewall of humidor 1272, the flange forms a seal with the slot. Alternatively, if no cap is used to transfer slides, the humidor slots may each have a cover/door available that can be automatically opened and closed to maintain humidity levels within the humidor by remaining closed during times when the slide is not being inserted or retrieved.
At a side end of humidor 1272 is wash station 1274. Wash station 1274 includes a cavity having dimensions into which a slide may be inserted lengthwise. Slides are inserted one-by one into the cavity of wash station 1274. Inside the cavity may be a spray nozzle or mister operable to spray a solution such as an aqueous solution containing defined concentrations of one or more salts, one or more buffers, a surfactant, a preservative, and other excipients as required. A mode of action is expected to be flooding of the surface of a slide as required before and/or possibly after a reagent is printed on the sample. In one example, a conduit and valve assembly may be connected to an aqueous solution supply tank below processing platform 1201. The conduit may extend to a nozzle or nozzles within wash station 1274. Wash station 1274 may include a motion sensor therein to detect a presence of an object such as a slide in the wash station. The motion sensor may be connected to processor 136. When the motion detector detects the presence of a slide in wash station 1274, processor 136 may signal a valve associated with the conduit and valve assembly to actuate the valve to open to spray an aqueous solution inside the wash station. A second signal from the motion detector may signal that a slide has been removed, triggering processor to actuate a valve shut to stop the aqueous solution flow. Wash station 1274 may also include a fluid removal device, such as an air knife therein. An air knife may direct pressurized air or inert gas at a slide surface to remove excess aqueous solution on a slide if desired. A valve and conduit system may provide the air to wash station 1274 from a pressurized air tank below processing platform 1201. A valve may be controlled by instructions from processor 136.
Many detection assays such as immunohistochemical (IHC) assays for which printing station 1270 may be employed may be performed at ambient or near ambient temperatures. Some assays, such as some in situ hybridization (ISH) assays often require individual steps to be performed at higher temperatures. Printing station 1270 may accommodate different temperature assays through the inclusion of a temperature-controlled humidor. FIG. 10 shows temperature-controlled humidor 1372 in dashed lines positioned adjacent humidor 1272. Temperature-controlled humidor 1372 may be operated at a non-ambient temperature (either above or below ambient). A representative range of hybridization temperatures above ambient may be, for example, 45-70° C. for an ISH process. Temperature-controlled humidor 1372 may be otherwise similar to humidor 1272 and include slots 1373 (with optional individual doors) and temperature-controlled wash station 1374. An alternative or addition to a temperature-controlled humidor may be a dedicated tank that is operable to contain a heated solution (e.g., a buffer solution). For example, a DNA melting protocol may require that a sample on a slide be heated to a temperature of 90° C. or more. A dedicated tank adjacent, for example, humidor 1372 may contain a solution heated to the desired temperature and controlled by instructions from processor 136. Such a tank would allow for relatively high temperature processing protocols such as DNA melting.
Overlying humidor 1272 in FIG. 10 is cartridge cradle 1275. As illustrated, cartridge cradle contains a number of rows of slots for ink jet cartridges (e.g., two rows shown). FIG. 10 shows first row 12752 and second row 12754 of cartridges. Cartridges in first row 12752 are, for example, primary antibodies and cartridges in second row 12754 may be similar or may be of different size and are, for example, detection agents such as secondary antibodies, enzymes, conjugates, etc. The cartridges may be drop on demand-type cartridges, preferably thermal drop on demand-type cartridges with each cartridge including an individual printhead. Cradle 1275 is the printer. Each of cartridges in rows 12752 and 12754 may contain a printhead at their base, so that when inserted into cradle 1275, the ejection of contents in a cartridge occurs through a base of the cradle.
Cradle 1275 may be slidably positioned in frame 1276 so that cradle 1275 can move forward or backward. Siderails or grooves support the forward and backward movement of cradle 1275 in frame 1276. FIG. 10 shows cradle 1276 in frame 1276 in a neutral position. Cradle 1275 may be automatically moved backward of the neutral position as part of a cartridge loading operation and moved forward of the neutral position as part of a cartridge printing operation. Such movement may be controlled by processor 136 or a separate controller associated with cradle 1275 (an ink jet printer controller). Machine readable program instructions to perform a cartridge loading, unloading or replacement protocol in cradle 1275 may cause cradle 1275 to move backward of the neutral position. A backward position of cradle 1275 is shown in FIG. 11. Machine readable program instructions to perform a printing protocol may cause cradle 1275 to move forward of a neutral position. A forward position of cradle 1275 is shown in FIG. 13. Alternatively, cradle 1275 may be fixedly positioned in frame 1276 and a slide carrying mechanism may move a slide underneath cradle 1275 to apply reagents onto a sample on the slide (e.g., robot apparatus 1210 illustrated in FIG. 15 may be configured to position a slide in a printing position under cradle 1275).
Referring to FIG. 11, disposed behind printing station 1270 is reagent storage cabinet 1250. Reagent storage cabinet 1250 may be a refrigerated cabinet having slots to store a number of printing cartridges therein. Each cartridge may contain a volume of a reagent and have a dedicated printhead and may be stored in storage cabinet 1250 with a cap on or over its respective printhead. Each cartridge may be a single use cartridge. A single use cartridge in this context means that once the volume of the reagent in the cartridge is dispensed or used, the cartridge including its printhead is to be discarded or disposed of as opposed to being resupplied with a volume of reagent. An example of a single use cartridge is a thermal inkjet cartridge.
Referring to storage cabinet 1250 in FIG. 11, the slots in the storage cabinet may be arranged in a series of rows and columns with each slot being addressed by its row and column. Addresses may be stored in processor 136. Each cartridge may include an identifier such as a machine-readable identifier (e.g., one dimensional or two-dimensional bar code). The identifier may include a lot number and a unique serial number. The identifier may be read (e.g., read by a barcode reader or scanner) prior to being stored in storage cabinet 1250 (e.g., read by a barcode reader or scanner outside processor assembly 100. The reading may be transmitted and stored in processor 136. The identifier may also provide information such as an expiration date of a reagent and/or a number of operations (prints) that can be performed with the cartridge. Processor 136 may assign the cartridge an address (row and column address) of a slot in storage cabinet 1250. A display screen on interface 135 may depict the slots and the cartridges therein. An alarm or display indicator on interface 135 may provide an alert when a cartridge is not in an assigned slot.
Behind the slots in storage cabinet 1250 may be refrigeration equipment such as a compressor that constricts a refrigerant vapor and pushes the vapor through coils where it liquefies and cools the cabinet slots. The refrigerated cabinet may be disposed on a rail or rails 1251 at its base to allow the cabinet to be slid outward from a front face of staining module 120 of processor assembly 100 so that cartridges or storage cabinet 1250 may be accessed away from processing platform 1201 inside the module. FIG. 12 shows storage cabinet 1250 pulled outward so that its contents are in an accessible position.
Referring again to FIG. 11, the figure shows cradle 1275 having an open slot in row 12752. The figure also shows robot apparatus 1220 mounted on processing platform 1201 adjacent storage cabinet 1250. Robot apparatus 1220 may be a robotic arm that includes end effector 1222 and robot controller 1221 that may control robot motion (e.g., movement of robot apparatus 1220 and end effector 1222 and processing tasks to be performed by robot apparatus 1220). Robot controller 1221 is linked either through hardwiring or wirelessly to processor 136. Machine readable program instructions are transmitted between processor 136 and robot controller 1221 (e.g., from processor 136 to direct robot controller 1221) to perform a desired protocol. Robot controller 1221 may transmit a signal or signals back to processor 136 confirming the instructions and/or after completing an action directed by processor 136. One protocol may be to retrieve a cartridge from storage cabinet 1250 and place that cartridge in a particular open slot in cradle 1275. Robot controller 1221 may be provided an address of a cartridge in storage cabinet 1250 (e.g., row and column information of a slot) and proceed to direct end effector 1222 to that address to retrieve the cartridge. Robot controller 1221 may receive another address in cradle 1275 where the retrieved cartridge is to be placed and subsequently direct end effector 1222 to that address to deposit the retrieved cartridge in cradle 1275. Prior to depositing the retrieved cartridge in cradle 1275, the protocol may direct that the cartridge be brought to service station 1203. Service station 1203 may include spittoon 1204 and wiping area 1205. The retrieved cartridge can eject a small amount of reagent therefrom in spittoon 1204 and then a printhead may be wiped with, for example, an absorbent material in wiping area 1205. Service station 1203 may also include reader 1202 (e.g., a barcode reader or scanner) to mad an identifier on the retrieved cartridge. Reader 1202 may provide the read information to processor 136 and processor 136 may include protocol instructions to confirm that the retrieved cartridge is the desired cartridge. The retrieved cartridge may then be placed in cradle 1275. Another protocol may be to retrieve a cartridge from cradle 1275 and place the retrieved cartridge in a particular slot in storage cabinet 1250. The cartridge retrieved from cradle 1275 may initially be brought to cradle 1275 and reader 1202 may read an identifier thereon and provide that information to processor. Processor 136 may confirm that the cartridge has been correctly retrieved from cradle 1275. Robot apparatus 1220 may include reader 1224 (e.g., a barcode reader or scanner) that may read an identifier once a cartridge is placed in a slot and provide that information to processor 136. Based on the cartridge identifier, its assigned slot address and its actual slot address, machine-readable instructions in processor 136 may than compare the assigned slot address and the actual address to confirm that a cartridge is in a correct slot. The instructions may include notification of confirmation of a correct slot address or an incorrect slot address (e.g., alarm) at interface 135 to a user of processor assembly 100. Interface may also include a user accessible screen that displays some or all the slots in storage cabinet 1250 and the cartridges in each slot. A location of a cartridge in a slot in storage cabinet 1250 and in cradle 1275 may be stored in a log in memory 137. Such log can later be utilized to verify that a sample on a slide was printed with a particular reagent in a cartridge.
Each cartridge may include a chip that may store information such as an expiration date and a print or operation count. The print or operation count may be used to estimate a volume of reagent in a cartridge. The print operation count may be changed each time a print operation is performed using a cartridge. Adjacent each slot in storage cabinet 1250 may be a light array 12502 (e.g., red, yellow, green light emitting diodes) that provides an indication of a volume of reagent in a cartridge based on the print or operation count. For example, a chip associated with a cartridge may be electronically connected to a light array adjacent to a slot in storage cabinet when the cartridge is seated in the slot. A cartridge may contain, for example, a volume of reagent suitable for 30 standard print operations (30 jettings). The chip may be programmed to trigger a green light in a RYG array when the count of the print operations performed using the cartridge are zero to 10; yellow when the print operations performed are 11-20; and red when the count of the print operations performed are 21-30. A chip in a cartridge may be read, for example, when a cartridge is in storage cabinet 1250 and provided to processor 136 and the count stored in memory 137. The print count for each cartridge in storage cabinet 1250 may also be provided on a screen on interface 135 by processor 136. Alternatively or additionally, array 12502 may be used to warn of an approaching reagent expiration date (e.g., a red light might be triggered within one month of the expiration).
FIGS. 14-16 illustrate operations involved in transporting a capped slide from antigen retrieval station 1240 to printing station 1270. Capped slides in antigen retrieval station 1240 may be brought to printing station 1270 by robot apparatus 1210. FIG. 14 shows slide 160a being removed by robot mechanism 1210 from wash tank 1247 following an antigen retrieval process or operation. Robot apparatus 1210 may be directed by instructions from, for example, robot controller 1211 that may be linked to processor 136 that maneuver end effector 1212 of robot apparatus 1210 over capped slide 160a and engage/retrieve the capped slide and transfer the capped slide to printing station 1270. FIG. 14 shows capped slide 160a engaged through a top of its cap by end effector 1212 and being removed by robot apparatus 1210 through a slot in an insert in wash tank 1247. In this example, slides are individually positioned in wash tank 1247. In another example, slides may be grouped in a slide basket that is in wash tank 1247. Where slides are contained in a slide basket in wash tank 1247, executable instructions may direct robot apparatus 1210 to remove the slide basket from the wash tank and then individually retrieve a slide (e.g., slide 160a) 1210 from the removed basket. In a further example, the executable instructions may direct robot apparatus 1210 to individually retrieve a slide (e.g., slide 160a) from a slide basket while the slide basket remains in wash tank 1247.
When a slide (e.g., slide 160a) is removed from wash tank 1247 or a slide basket in antigen retrieval station 1240, the slide is removed lengthwise so that it extends vertically in a z-direction. Following removal, instructions from, for example, robot controller 1211 direct end effector 1212 to rotate 90 degrees so that the slide extends lengthwise in an x-direction (horizontally). A sample on the rotated slide faces upward or toward the top of staining module 120. FIG. 15 shows end effector 1212 engaging slide 160a through a cap on the slide and slide 160a extending horizontally in an x-direction. Further instructions from, for example, robot controller 1211 direct robot mechanism 1210 to transport slide 160a to printing station 1270 and align the slide with a slot (slot 1273) in humidor 1272. FIG. 15 shows capped slide 160a adjacent to humidor 1272 with a distal end of the slide aligned with a slot in the humidor. FIG. 16 shows slide 160a positioned in humidor 1272. A capped slide is advanced lengthwise by robot mechanism 1210 into a slot (slot 1273) in humidor 1272 until a flange of the cap on the slide contacts the humidor forming a seal of the slot. FIG. 16 shows slide 160a along with other slides in humidor 1272. Prior to positioning of a slide (e.g., slide 160a) in humidor 1272, executable instructions may direct that the slide be transferred to wash station 1274 where the slide may be rinsed.
In one example, slots 1273 are assigned addresses and the addresses are stored in memory 137. Executable instructions associated with processor 136 include instructions that associate a slide by its identifier with a slot in humidor and store the associated information. Processor 136 may also display the associated slide and humidor slot on display 135 so that an operator can visualize a printing operation.
Referring to FIG. 2, slides may be printed one-by-one utilizing robot mechanism 1255 that moves on rail 1252. FIG. 2 shows rail 1252 oriented horizontally in a plane above processing platform 1201 in printing module 120. Rail 1252 is positioned to the left of printing station 1270 between tray 1206 and a front of printing module 120. Rail 1252 is attached to posts at opposite ends and is operable to move vertically (in a z-direction) on the posts. FIG. 17 shows a magnified top side view of a portion of printing station 1270 and robot mechanism 1255 on rail 1252. Referring to FIG. 17, FIG. 17 shows robot apparatus 1255 including sleeve 1259, arm 1257 and end effector 1258 that has a spade end. Sleeve 1259 has an opening from one side to an opposite side with dimensions to accommodate rail 1252 therethrough so that sleeve 1259 is moveable on rail 1252. Arm 1257 and end effector 1258 are connected to sleeve 1259 and positioned below rail 1252. Arm 1257 and end effector 1258 are oriented horizontally, perpendicular to rail 1252.
Robot apparatus 1255 may be directed by instructions from, for example, robot controller 1256 that may be linked to processor 136. The instructions may include removing a slide from humidor and transferring the slide to wash station 1274. Following a wash at wash station 1274, the instructions may also include transferring the slide to a printing region for deposition of, for example, a primary antibody or a detection agent. Referring to FIG. 17, based on instructions, end effector 1258 of robot apparatus 1255 is initially aligned along its z-axis and y-axis with a targeted slide in humidor 1272 (e.g., slide 160d). Z-axis alignment is achieved by automatically moving rail 1252 up or down in its posts. Y-axis alignment is achieved by the automatic movement of sleeve 1259 along rail 1252. Once aligned along a y-axis with a targeted slide in humidor 1272, end effector 1258 is advanced into the cap of the targeted slide by the automatic movement of arm 1257 in an x-direction. FIG. 17 shows end effector 1258 being directed into the cap of slide 160d. Once slide 160d is engaged by end effector 1258, the slide is automatically removed from humidor 1272 by reversing the x-direction travel of arm 1257 and end effector 1258.
FIG. 18 shows the automatic transfer of a slide from humidor 1272 to wash station 1274. Following the removal of the slide from humidor 1272, sleeve 1259 of robot mechanism 1255 is moved in a y-direction along rail 1252 from a humidor area to wash station 1274 until a slide (e.g., slide 160d) is aligned along a y-axis with wash station 1274. Following y-axis alignment, arm 1257 of robot mechanism 1255 is automatically moved in an x-direction to position the slide (e.g., slide 160d) into wash station 1274 as shown in FIG. 19. Engagement of end effector 1258 with the slide (e.g., slide 160d) may remain during a wash operation in wash station 1274. A wash operation may include spraying an aqueous solution (e.g., buffer) on the sample portion of a slide or on an entire length of the slide. Following a wash operation, excess reagent may be removed by air or an inert gas spray from a fluid removal device in wash station 1274. The slide may then be removed from wash station 1274 by reversing the x-direction travel of arm 1257 and end effector 1258.
Once a slide is removed from wash station 1274, rail is automatically moved in a z-direction on post 12524 and post 12525 downward so that a z-position of the capped slide on end effector 1258 is lower than a z-position of a base of cradle 1275. Sleeve 1259 of robot apparatus 1255 is then automatically moved in a y-direction along rail 1252 from wash station to a location of a desired cartridge in cradle 1275. Cradle 1275 is then automatically moved in an x-direction to align a printhead of the desired cartridge with a sample on the slide. FIG. 20 shows slide 160d having sample portion 1610 of the slide positioned under cradle 1275. FIG. 21 shows a side view through line 21-21′ of FIG. 20 and shows printhead 1279 over slide 160d. The slides or cartridges may be arranged or carried such that a long side of a nozzle plate of a printhead may be perpendicular to a long side of a slide such that a width of the printhead may cover the entire, or most of, the width of the slide with a minimum number of passes. FIG. 21 also shows imager 1278 positioned at a base of cradle 1275. Imager 1278 such as a digital camera may be used to capture an image of a sample on a slide allowing the sample to be analyzed for placement of an amount of a reagent (e.g., a primary antibody or a detection agent) on the sample or to view whether an amount of reagent was actually discharged from a cartridge. Imager 1278 may be slidably connected to a base of cradle 1275 so that it may be automatically positioned in a y-direction near a slide that is to be printed based on instructions implemented by computer 136. An image captured by imager 1278 may be transmitted to processor 136 and analyzed, such as by overlying a grid on the image followed by identifying the sample in the grid by, for example, a refractive index change to determine a location of a sample and such analysis may form the basis of a decision where printhead 1279 is to print. In another example, a location of the sample may be obtained from the image of the sample taken at first slide identification station 1120 or the image of the sample taken at second slide identification station 1121 as described above. Once a sample location is established, a sample area on to which a reagent will be applied is determined and instructions associated with processor 136 limit application (jetting) to that sample area. In this manner, reagent application (jetting) may be limited to an area where the sample is present rather a much larger area that would result in a waste of the reagent.
A drop-on-demand-type printhead such as printhead 1279 may dispense a reagent, such as a detection agent or antibody, in droplets having a volume of 1 picoliter (pL) to 10 nanoliters (nL), or 1 pL to 5 nL, or 1 pL to 1 nL, or 1 pL to 500 pL, or 1 pL to 250 pL or 1 pL to 100 pL, or 1 pL to 50 pL. The small volume allows for targeted dispensing of a reagent onto identified area(s) of a sample on a slide (identified previously by imaging or other technique). For example, an area of a sample such as a tissue section may be identified that may contain particular antigens in cells. Such antigens may be selectively identified by introducing antibodies in the targeted area by a drop-on-demand technique that bind (e.g., specifically bind) to the particular antigens if present. Visualization of antibody-antigen interaction can be accomplished, for example, by conjugating an enzyme that can catalyze a color-producing reaction or a fluorophore that exhibits a fluorescence when viewed. The enzyme may be dispensed with the antibody or subsequently by a drop-on-demand type printhead. Target dispensing of reagents such as antibodies or enzymes results in a reduction in utilization of the antibody, reagent carryover and associated waste compared to prior art techniques that covered an entire area of a sample on a slide with the reagent.
In one example, a colorant or stain may be added to a reagent to allow a visual indication that the reagent was applied as directed. The colorant or stain may be unique for a particular reagent. For example, a colorant or stain could be added to a primary antibody solution in a print cartridge. Following dispensing of the primary antibody solution onto a sample on a slide, the color of the primary antibody solution could be detected and captured (e.g., captured by imager 1287) and transmitted to memory 137. The detection/capture of a reagent actually being applied to a sample on a slide provides a quality control that (1) the reagent was applied and (2) the correct reagent was applied (due to its unique color characteristic).
Following a printing process at printing station 1270, printed slides may be returned to slots 1273 in humidor 1272 for an incubation time period (to, for example, allow a primary antibody to bind to any targeted antigen). Following any incubation period, the slide may be transported by robot apparatus 1255 via executable instructions from processor 136 to wash station 1274. At wash station 1274, the slide may be rinsed one or more times with an aqueous solution and the rinse fluid removed. The rinse may remove any non-reacted/non-conjugated reagent as well as the colorant or stain that was added to the reagent. If the sample on the slide is to receive an additional reagent(s), the executable instructions may direct robot apparatus 1255 to return the slide to a printing position under cartridge 1275 and the printing process repeated. Following each printing operation, the slide may be rinsed at wash station 1274. A printed and rinsed slide may also be stored in a slot in humidor 1272.
Once all printing operations are finished for a slide, the slide may be loaded into a basket and any cap removed utilizing robot apparatus 1210. When capped slides are removed from humidor 1272, the slides are removed lengthwise so that each slide extends horizontally in an x-direction. Following removal, instructions from, for example, robot controller 1211 direct end effector 1212 to rotate 90 degrees so that capped slide 160a extends vertically in a z-direction. FIG. 22 shows end effector 1212 engaging capped slide 160a and capped slide 160a extending vertically in a z-direction. In FIG. 22, end effector 1212 is shown placing slide 160a into slide basket 210A. Once slide 160a is in basket 210A, end effector 1212 will remove cap 1235, by for example exerting an outward force on sidewalls of body portion 12352 then moving upward in a z-direction. Once cap 1235 is removed, instructions may direct end effector to transfer cap 1235 to capped slide staging station 1230. The process may be repeated for all the slides in humidor 1272 that have been through a printing process.
FIG. 22 shows basket 210A positioned on tray 1206 (in lane 12061) at an entrance of staining module 120. Once basket 210A is loaded with one or more printed slides from staining module 120, basket 210A is transported from staining module 120 to core module 110. Processor 136 may track (e.g., count) the number of slides that are delivered to staining module 120, removed from basket 210A, printed and reloaded into basket 210A. Once it is confirmed that all slides are reloaded into basket 210A, instructions from processor 136 may direct a transport mechanism such as a movable belt under a base of tray 1206 to transport basket 210A to an area that allows basket 210A to be engaged by an end effector of robot apparatus 1150 (see FIG. 3) such as an area in core module 110.
FIG. 23 shows a top front side magnified view of core module 110 of processor assembly 100 with a top exterior portion of the external housing removed to expose the interior compartment of the module and with slide basket 210A in core module and engaged by an end effector of robot apparatus 1150. Following a return of slide basket 210A to core module and containing printed slides, the printed slides may be subject to a dehydration process at dehydration station 1130. Dehydration station, in this example, contains multiple tanks each recessed below processing platform 1101. Each tank may have an electrically actuatable lid with its operation directed by executable instructions in processor 136. Each tank may also contain an agitator (e.g., a magnetic stirrer) FIG. 23 shows tank 1133, tank 1134 and tank 1136 each operable to contain a volume of liquid reagent and each having a dimension to receive a slide basket therein (e.g., a TISSUE-TEK PRISMA® slide basket). Each of tank 1133, tank 1134 and tank 1136 may contain a dehydration reagent such as alcohol (e.g., 100 percent ethanol) or xylene. Representatively, tank 1133 contains ethanol, tank 1134 contains ethanol and tank 1136 contains xylene. A dehydration process may involve transferring a slide basket such as slide basket 210A containing one or more printed slides into each of tank 1133, tank 1134 and tank 1136 sequentially.
To begin a dehydration process or protocol at dehydration station 1130, machine readable instructions executed by robot controller 1141 direct robot apparatus 1145 to transfer a slide basket (slide basket 210A) to tank 1133.
In addition to robot apparatus 1145, FIG. 23 shows a robotic transfer assembly including rail or track 1135 and robot apparatus 1137. Rail or track 1135 may be attached to an inside wall of core module 110 (e.g., a right wall as viewed) or be free standing adjacent an inside of a wall of the module or other location. Robot apparatus 1137 includes robot controller 1131 that may control robot motion (e.g., movement of robot apparatus 1137 on track 1135 and processing tasks to be performed by robot apparatus 1137). Robot controller 1131 is linked either through hardwiring or wirelessly to computer 136. Machine readable program instructions are transmitted between computer 136 and robot controller 1131 (e.g., from computer 136 to direct robot controller 1131) to automatically perform a desired protocol. Robot controller 1131 may transmit a signal or signals back to the computer 136 confirming the instructions and/or after completing an action directed by computer 136. From a dehydration process, a protocol may be to transfer a slide basket (e.g., slide basket 210A) from tank 1133 to tank 1134 and then to tank 1136. Rail or track 1135 may be positioned at a height sufficient to allow an end effector of robot apparatus 1137 (e.g., a hook or laterally extending bar at a distal end of robot apparatus) to be maneuvered under a handle of the slide basket and then ascend to raise the slide basket by the handle from a tank (e.g., tank 1133). The robot apparatus may raise and lower the slide rack into and out of the dehydration tank to increase agitation and speed up the dehydration process. The slide basket may then be raised and then transferred to a subsequent tank. As one example, a slide basket may remain in tank 1133 of 100 percent ethanol for 30 seconds, tank 1134 of 100 percent ethanol for one minute and then tank 1136 of xylene for two minutes. Following the dehydration protocol, the program instructions may direct robot apparatus 1137 to transfer a slide basket to drip platform 1139 on processing platform 1101. From drip platform 1139, the program instructions may further direct that robot apparatus to transfer a slide basket to outlet opening 125 in core module 110.
It is appreciated that some tissue samples that have a printed reagent present may not be suitable for a dehydration process utilizing xylene and alcohol. FIG. 23 shows tank 1138 in dehydration station 1130. Tank 1138 may contain an aqueous buffer solution. A slide basket containing slides that are not suitable for a xylene and alcohol dehydration process may be transferred by robot apparatus 1137 to tank 1138.
As described above in reference to FIG. 11, printing cartridges may be stored in reagent storage cabinet 1250 until needed. Each cartridge 1260 is stored in reagent storage cabinet 1250 with its printhead capped so that the reagent therein does not evaporate or dry out. A base of a slot in storage cabinet 1250 where a cartridge is stored may serve as the “cap” of the printhead with the printhead of a cartridge placed in contact with the base or an absorbent material between the base of the slot and the printhead (an absorbent material may also serve to wipe or otherwise clear the printhead of reagent). Alternatively, a cartridge may have a dedicated cap.
FIG. 24 and FIG. 25 show a top side view of one example of a cartridge assembly with a dedicated cap. In this example, the assembly includes cartridge 1260 that includes printhead 1262 at its base and body 1263 operable to contain a reagent therein. Body may be generally rectangular or other suitable shape to contain a sufficient volume of reagent and be compatible with slots in reagent storage cabinet 1250 and cradle 1275 (see FIG. 11). FIG. 24 and FIG. 25 illustrate a body having a generally rectangular shape with a base of the body cut out near the printhead. An identifier containing machine and/or human readable information about the reagent may be disposed on one side of body or multiple identifiers may be disposed on the body, possible containing similar information. Representative identifiers may include, but are not limited to, visually readable, optically readable, magnetically readable, tactilely readable, etc. identifiers. FIG. 24 and FIG. 25 show identifier 1261A on a top side of body 1263 and identifier 1261B on one vertical sidewall of the body.
Pivotally connected to the opposite sides of body 1263 of the printhead assembly shown in FIG. 24 and FIG. 25 are arms 1265A and 1265B. Arms 1265A and 1265B are connected to body 1263 at a first end (near their apex, as viewed) by pins (pin 1266 shown with a similar pin being on the opposite side). The pins (pin 1266) are positioned in a channel (pin 1266 in channel 1267) and are operable to move in the channel. A second end of arms 1265A and 1265B are connected to opposite sides of cap 1264. Cap 1264 is shown as a plate-like rectangular structure. Optionally disposed (e.g., glued) on a surface of cap 1264 facing printhead 1262 is absorbent material 1268 such as a sponge or cloth material. The size and shape of cap 1264 (rectangular, circular, oblong) are selected to cover printhead 1264 of cartridge 1260 when arms 1265A and 1265B extend vertically downward from their connection point defined by the pin (e.g., pin 1266) as in FIG. 24. The pin (e.g., pin 1266) in this “capped” configuration is at or near the top or one end of channel 1267. This “capped” configuration of printhead 1262 may be the configuration of the assembly when it is stored in reagent storage cabinet 1250. FIG. 25 shows an “uncapped” configuration of the printhead assembly. In this configuration, arms 1265A and 1265B and cap 1264 have moved (swung) counterclockwise exposing printhead 1262. FIG. 25 shows pin at a bottom end of channel 1266. This “uncapped” configuration of printhead 1262 may be the configuration of the assembly when it is removed from reagent storage cabinet 1250 and positioned in cradle 1275. The transition from a “capped” configuration to an “uncapped” configuration may be achieved by end effector 1222 of robot controller 1221 (see FIG. 11). As end effector 1222 engages a cartridge assembly in reagent storage cabinet 1250 and pulls the cartridge assembly out, the pulling force and engagement of cap 1264 with a base of a slot may cause cap 1264 to trail the removal of the body. This trailing of cap 1264 may be sufficient to move arms 1265A and 1265 in a counterclockwise position to the uncapped position. The cartridge assembly in the “uncapped” configuration may then be placed in cradle 1275. The opposite procedure may be followed to transition the cartridge assembly from an “uncapped” configuration to a “capped” configuration. For example, end effector 1222 engages the cartridge assembly in cradle 1275 in the “uncapped” configuration. As end effector 1222 seeks to place the cartridge assembly in a slot in reagent storage cabinet 1250, cap 1264 displaced from a base of the cartridge will lead the body of the cartridge and engage the slot first. As end effector 1222 applies a force to push the cartridge assembly into the slot, cap 1264 and arms 1265A and 1265B will rotate clockwise to a “capped” configuration as the assembly is seated in the slot.
FIG. 26 shows a top side view of another example of a cartridge assembly with a dedicated cap. In this example, the assembly includes cartridge 2260 that includes printhead 2262 at its base and body 2263 operable to contain a reagent therein. On one more sides of body 2263 near its base may be magnetic strip 2265. Cap 2264 is a separate component of the cartridge assembly—separate from cartridge 2260. Cap 2264 in this example is a rectangular structure having a base and sidewalls extending from the base. The base has dimensions similar or slightly larger than an area of printhead 2262. The sidewalls have a length dimension to extend to or slightly beyond (to cover) magnetic strip 2265. The sidewalls of cap 2264 may made of a material ferromagnetic or paramagnetic material that is magnetically attracted to magnetic strip 2265. The magnetic attraction is sufficient to secure cap 2264 to cartridge 2260 when cartridge 2260 is in storage cabinet 1250 or otherwise not in use.
Cap 2264 may be removed from cartridge 2260 after the cartridge is removed (robotically) removed from storage cabinet 1250 and before it is placed (robotically) in cradle 1275. In one example, cap 2264 may be removed by placing the capped end of cartridge 2260 (cartridge 2260 with cap 2264) in an area containing a reversed magnetizing field that opposes the magnetism of magnetic strip 2265. One way this may be done is by applying an alternating current through magnetic strip 2265. FIG. 27 shows an example of service station 1203 in staining module. Service station 1203, in this example, includes spittoon 1203 and wiping area 1205 and also decapping area 1208. Spittoon 1203 may be a container where an amount of a reagent from a cartridge may be discharged. Wiping area 1205 may include material 12052, such as an absorbent material, that is extended between roller 12053A and roller 12053B. One or both of rollers 12053A and 12053B may be controlled by processor 136 to rotate periodically to move material 12052.
As noted, service station 1203 in FIG. 27 includes decapping area 1208. Decapping area 1208 includes a number of slots 1209 (e.g., a number corresponding to the number of openings in cradle 1275). The slots may have an address (a row and column address) stored in memory 137 and accessible by processor 136. Each slot 1209 has a dimension to contain a cartridge cap (cap 2265) therein. A base of each slot (e.g., below processing platform 1201) may be connected through electrical wires to power source 12092 that produces an alternating current controlled by processor 136. When a capped cartridge is placed in slot 1209, instructions from processor 136 may direct that power source 12092 apply a current to the particular slot to overcome the attraction of the one or more sidewalls of cap 2264 to the one or more magnetic strips 2265. Once overcome, the cartridge (cartridge 2260) may be removed from slot 1209 without its cap (cap 2264). The cartridge may then be placed in cradle 1275. When a cartridge is removed from cradle 1275, the cartridge may be returned to its slot in decapping area 1208 based on a recorded address assigned to a cap for the cartridge. When returned to a slot (slot 1209), the power source is turned off and the one or more sidewalls of cap 2264 will be attracted to one or magnetic strips 2265 on the cartridge to connect the cap to the cartridge. The capped cartridge may then be robotically returned to storage cabinet 1250.
The following numbered clauses summarize some aspects of the invention:
1. A processor assembly comprising:
a core module operable to expose a sample on a slide;
a staining module operable to apply a stain to the exposed sample; and
a robotic transfer mechanism to transfer the slide from the core module to the staining module.
2. The processor assembly of clause 1, wherein the staining module comprises:
a reagent cartridge comprising a reagent and a thermal inkjet print head; and
a processor including non-transitory machine-readable instructions that when executed cause the processor to direct application of the reagent from the thermal inkjet print head in a staining area in the staining module.
3. The processor assembly of clause 2, wherein the core module or the staining module comprises an imager operable to capture an image of the sample and the processor includes non-transitory machine-readable instructions that when executed cause the processor to determine a target location on the sample based on the captured image for application of the reagent from the thermal inkjet printhead of the cartridge.
4. The processor assembly of clause 2 or clause 3, wherein the cartridge is positioned in a staining area and the staining module comprises a storage station operable to store a plurality of cartridges, wherein prior to directing application of the reagent from the thermal inkjet print head, the instructions cause the cartridge to be retrieved from the storage station and coupled to a printing assembly.
5. The processor assembly of any of the preceding clauses, further comprising a humidor station in the staining module operable to store the slide, wherein the processor includes non-transitory machine-readable instructions that when executed caused the slide to be removed from the humidor and aligned with the thermal inkjet print head of the cartridge.
6. The processor assembly of any of the preceding clauses, further comprising an antigen retrieval station in the staining module operable to expose antigenic sites on the sample utilizing pressure, wherein the processor includes non-transitory machine-readable instructions that when executed caused the slide to be transported to the antigen retrieval station and, after an antigen retrieval process, transported to the staining area.
7. The processor assembly of any of the preceding clauses, wherein the core module comprises a dehydration station, wherein, after staining, the processor includes non-transitory machine-readable instructions that when executed caused the slide to be transported to the dehydration station.
8. The processor assembly of any of the preceding clauses, wherein the core module comprises a baking station and a dewaxing station.
9. The processor assembly of any of the preceding clauses, wherein the core module comprises an identification station comprising an identifier operable to identify label information on the slide.
10. The processor assembly of any of the preceding clauses, wherein in the core module, the slide is in a basket operable to contain a plurality of slides and the robotic transfer mechanism is operable to transfer the basket from the core module to the staining module and the processor assembly further comprises a processor including non-transitory machine-readable instructions that when executed cause the slide to be removed from the basket for a printing operation in the staining module.
11. The processor assembly of any of clauses 2-10, wherein the cartridge is a single use cartridge.
12. An apparatus comprising:
a rectangular body having an open rear end and an opposite front end;
a flange having a first side and a second side, wherein the first side of the flange is coupled to the front end of the body; and
a pair of legs extending from second side of the flange,
wherein the pair of legs are operable to engage opposite side edges of a slide.
13. The apparatus of clause 12, wherein each of the pair of legs has an inwardly facing groove comprising a dimension to engage a side edge of a slide in the groove.
14. The apparatus of clause 12 or clause 13, wherein the pair of legs are separated from one another a distance such that a face of a slide engaged by the pair of legs is visible.
15. A method comprising:
exposing a sample on a slide in a core module of a processor assembly;
robotically transferring the slide from the core module of the processor assembly to a staining module of the processor assembly;
applying a reagent to the exposed sample in the staining module by a thermal inkjet printing process; and
after applying the reagent, robotically transferring the slide back to the core module.
16. The method of clause 15, wherein prior to applying the reagent, the method comprises exposing antigenic sites of the exposed sample in the staining module.
17. The method of clause 15 or clause 16, wherein exposing a sample on a slide in the core module comprises placing a basket containing the slide in at least one of a baking station and a dewaxing station.
18. The method of any of clauses 15-17, wherein robotically transferring the slide from the core module to the staining module comprises robotically transferring a basket containing the slide, the basket having a volume to contain a plurality of slide.
19. The method of clause 18, wherein prior to applying the reagent to the exposed sample, the method comprises removing the slide from the basket.
20. The method of clause 19, wherein removing the slide from the basket comprises placing a cap on the slide and removing comprises removing the slide by the cap.
21. The method of clause 19 or clause 20, wherein prior to applying the reagent to the exposed sample, the method comprises placing the slide in a humidor.
22. The method of any of clauses 15-21, wherein after robotically transferring the slide back to the core module, the method further comprises dehydrating the sample.
23. The method of any of clauses 15-21, wherein prior to robotically transferring the slide to the staining module, the method comprises capturing identification information from the slide in the core module.
The algorithms and displays presented herein are not inherently related to any particular computer or other apparatus. Various general-purpose systems may be used with programs in accordance with the teachings herein or it may prove convenient to construct a more specialized device to perform the described method. In addition, the invention is not described with reference to any particular programming language. It will be appreciated that a variety of programming languages may be used to implement the teachings of the invention as described herein.
A computer readable medium includes any mechanism for storing information in a form readable by a computer. For example, a computer readable medium includes read only memory (“ROM”), random access memory (“RAM”), magnetic disk storage media, optical storage media, flash memory devices or other type of machine-accessible storage media.
It should also be appreciated that reference throughout this specification to “one embodiment”, “an embodiment”, or “one or more embodiments”, for example, means that a particular feature may be included in the practice of the invention. Similarly, it should be appreciated that in the description various features are sometimes grouped together in a single embodiment, Figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects may lie in less than all features of a single disclosed embodiment. Thus, the claims following the Detailed Description are hereby expressly incorporated into this Detailed Description, with each claim standing on its own as a separate embodiment of the invention.
In the foregoing specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes can be made thereto without departing from the broader spirit and scope of the invention as set forth in the appended claims. For example, a reagent cartridge as disclosed herein (e.g. reagent cartridge 408) may contain solvent or water instead of a reagent and used for purposes other than, for example, staining a sample on an underlying slide. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.
