Automated biological specimen preparation system and method

Abstract

The present invention provides an automated system and method for collecting biological samples from liquid sample containers and distributing those samples onto analytical elements such as sample slides, as well as an automated system and method for obtaining aliquots of samples for additional testing. [Solution] An automated system for processing a sample contained in a liquid sample container comprises an automated tool head configured to rotate around a first axis and move along a second axis different from the first axis; an analytical element positioner having an analytical element holder configured to hold an analytical element in a releasable manner; and a sample transfer device mounted on the tool head. The tool head is configured to automatically position the working end of the sample transfer device by either or both rotation of the tool head around the first axis and / or movement of the tool head along the second axis to acquire a sample from a sample container held in a sample container holder and transfer the acquired sample to an analytical element held in an analytical element holder.

Description

Technical Field

[0001] The present disclosure generally relates to the preparation of biological specimens, and more particularly to an automated system and method for collecting a biological specimen from a liquid specimen container and dispensing the specimen onto an analysis element such as a specimen slide, and an automated system and method for obtaining an aliquot of a sample for additional testing.

Background Art

[0002] Cytology is a branch of biology that deals with the study of the formation, structure, and function of cells. As applied in the laboratory, cytologists, cytotechnologists, and other medical professionals perform medical diagnoses of a patient's condition based on a visual examination of a specimen of the patient's cells. A typical cytological technique is "cervical cytology," in which cells are scraped from a woman's cervix and analyzed to detect the presence of abnormal cells that are precursors to cervical cancer. Cytological techniques are also used to detect abnormal cells and diseases in other parts of the human body.

[0003] The collection of cell samples for analysis is generally less invasive than conventional surgical pathology procedures such as biopsies. In this case, a solid tissue specimen is excised from a patient using a special biopsy needle having a spring-loaded movable stylet, a fixed cannula, or the like. Cell samples can be obtained from a patient by various techniques including, for example, rubbing or swabbing an area, or by aspirating body fluid from the chest cavity, bladder, spinal canal, or other appropriate area using a needle. The obtained cell sample is usually placed in a preservative solution and then removed from the solution and transferred to a slide glass. A fixative is applied to the cell sample to keep the cells in place on the slide glass and facilitate subsequent staining and examination.

[0004] Generally, it is desirable that the cells on the slide have an appropriate spatial distribution so that individual cells can be examined. Typically, a single layer of cells is preferred. Therefore, to prepare a sample from a liquid sample containing many cells (e.g., tens of thousands), it is usually necessary to first separate the cells from each other by mechanical dispersion, liquid shearing, or other techniques, collect a thin single layer of cells, and place it on the slide. In this way, the cytotechnologist can more easily identify the presence of abnormal cells in the patient's sample. They can also count the cells to confirm that the appropriate number of cells have been evaluated.

[0005] Specific methods and apparatus for generating a thin, monolayer of cells from a liquid sample container and then transferring this thin layer to a “sample slide” favorable for visual examination are disclosed in U.S. Patents 5,143,627, 5,240,606, 5,269,918, 5,282,978, 6,562,299, 6,572,824 and 7,579,190. These disclosures are incorporated herein by reference in their entirety. According to one method disclosed in these patents, patient cells in a preservation solution in a sample container are dispersed using a rotating sample collector positioned therein. A controlled vacuum is applied to the sample collector to draw the liquid through a screen filter until a desired amount of cells and spatial distribution are collected in the filter. The sample collector is then removed from the sample container, and the filter portion is pressed against a glass slide to transfer the collected cells to the slide in substantially the same spatial distribution as at the time of collection. Devices manufactured in accordance with one or more teachings of these patents, such as the ThinPrep® 2000 processor (for processing individual sample slides from patient samples) and the ThinPrep® 5000 processor (for processing sample slide batches from patient samples), manufactured and sold by Hologic, Inc. in Marlborough, Massachusetts, have been commercially successful. See also U.S. Patents 7,556,777 and 7,771,662. These disclosures are incorporated herein by reference in their entirety.

[0006] Once the specimen slide is prepared, the specimen is typically magnified and visually examined by a cytotechnologist, with or without various lighting sources. Additionally or alternatively, an automated slide imaging system may be used to assist the cytological examination process. For example, an automated slide imaging system can capture images of all or substantially all cells captured on the slide and use image processing techniques to perform a preliminary assessment of the cells, guiding the cytotechnologist to potentially the most relevant cells on the slide for further examination. Examples of such imaging systems are disclosed in U.S. Patents 7,587,078, 6,665,060, 7,006,674, and 7,590,492. These disclosures are incorporated herein by reference in their entirety. Whether examining the actual specimen slide magnified or examining magnified images of the specimen, the specimen is typically classified by the cytotechnologist as “normal” or “abnormal,” with abnormal specimens being classified into one of the major categories defined in the Bethesda System for Cervical / Vaginal Cytology Reporting. This category includes low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), squamous cell carcinoma, adenocarcinoma, atypical glandular cells of unknown significance (AGUS), adenocarcinoma in situ (AIS), and atypical squamous cells (ASC). Additional information regarding the classification of cell specimens is widely available.

[0007] In some cases, it is desirable to perform other types of diagnostic tests on the same patient sample, such as for human papillomavirus (HPV). Based on the strong correlation between HPV and cervical cancer, HPV DNA testing has been recommended as a severity assessment test for patients whose Papanicolaou smear results are classified as ASC-US. If liquid-based Papanicolaou smear analysis is performed, a “reflective” HPV DNA test can be performed using the same sample used for the Papanicolaou smear analysis, thereby eliminating the need for repeated hospital visits or a second Papanicolaou smear test. For example, if a sample is classified as ASC-US positive, an “aliquot” (e.g., 4 mL) of the liquid sample can be taken from the storage vial and sent to a molecular diagnostics laboratory for HPV DNA testing.

[0008] Importantly, laboratories performing HPV DNA testing are plagued by molecular contamination, a well-known problem in molecular diagnostics laboratories. Therefore, due to the risk of secondary contamination, molecular diagnostics laboratories may not accept aliquots taken from already processed liquid-based Papanicolaou smears, as this could lead to the creation of false HPV positives. Thus, to preserve a portion of the sample without exposure to secondary contamination, it is desirable to obtain and store aliquots of each patient sample before the sample slide preparation process. As an example, prescribed methods and apparatus for obtaining aliquots of patient samples before the sample slide preparation process are disclosed in U.S. Patents 7,674,434 and 8,137,289, which are incorporated herein by reference in their entirety. Further examples of generally obtaining sample aliquots, not necessarily related to sample slide preparation, are disclosed in U.S. Patents 9,335,336 and U.S. Patent Publication 2017 / 0052205, which are also incorporated herein by reference in their entirety.

[0009] In addition to being used for HPV DNA testing, aliquots from liquid-based Papanicolaou smears can also be used for DNA testing of other sexually transmitted infections (STIs), such as Chlamydia trachomatis and Neisseria gonorrhoeae. However, false positives are a particular concern when testing for Chlamydia trachomatis and Neisseria gonorrhoeae, as they can have a significant impact on families and society. Therefore, molecular diagnostic laboratories are even more reluctant to accept aliquots from liquid-based Papanicolaou smears that have already been processed. Testing for other STIs does not need to be limited to severity assessment of ASC-US specimens. In fact, such tests are intended to be performed in parallel with Papanicolaou smear testing at the request of a physician, and aliquots can be taken from Papanicolaou smears before processing, for example by manually pipetting the aliquots from the vial, thereby minimizing the risk of secondary contamination. However, this step may still not meet the stringent contamination prevention requirements imposed by molecular diagnostic laboratories.

[0010] In addition to contamination issues, pipetting aliquots from liquid-based Papanicolaou smear samples, whether done before or after sample processing, or for HPV or other sexually transmitted infection testing, involves not only pipetting the aliquots into additional vials but also manually labeling the vials, which increases costs.

[0011] Therefore, there is a need to provide improved apparatus and methods for obtaining aliquots from liquid-based biological samples, such as Papanicolaou smear samples, while minimizing the risk of secondary contamination. [Overview of the project] [Means for solving the problem]

[0012] Embodiments of this disclosure relate to improved automated systems and methods for processing samples (such as biological samples) contained in sample containers.

[0013] In one embodiment, an automated system for processing a sample contained in a liquid sample container comprises a sample container holder configured to hold the sample container, and an automated tool head configured to rotate around a first axis and move along a second axis distinct from the first axis. The system further comprises a sample transfer device mounted on the tool head, which automatically positions the working end of the sample transfer device to acquire a sample from the sample container held in the sample container holder, and then transfers the acquired sample to an analytical element (e.g., a slide) held in an analytical element holder, respectively, via either or both rotation of the tool head about the first axis and / or movement of the tool head along the second axis. The working end of the sample transfer device is configured to receive a filter thereon, which comprises a tubular body that forms a seal with the working end of the sample transfer device, and a porous membrane end configured to allow liquid to pass through while retaining cellular material on its outer surface.

[0014] The system further comprises an analytical element positioner having an analytical element holder, the analytical element holder configured to releasably grip the analytical element. After transferring the sample to the analytical element, the analytical element positioner is configured to automatically position the analytical element mounted on the analytical element positioner into a fixed container held in a fixed container holder. The system may also comprise an analytical element (e.g., slide) loading platform located on the surface of the tool head, the analytical element positioner operably cooperating with the tool head to automatically engage and detach the analytical element placed on the loading platform by the analytical element holder, and the analytical element positioner operably cooperating with the tool head to automatically position the engaged analytical element at the working end of the sample transfer device and transfer the sample to the engaged analytical element.

[0015] The system further comprises a sample container capping device positioned on a tool head and configured to controllly grasp and release the cap of a sample container held in a sample container holder, wherein the tool head is configured to automatically position the sample container capping device near the sample container cap via either or both rotation of the tool head around a first axis and / or movement of the tool head along a second axis, and the sample container capping device operably cooperates with the sample container holder to remove or attach the sample container cap. The sample container holder is configured to automatically rotate in one of the clockwise and counterclockwise directions while engaging the sample container capping device with the sample container cap to remove the sample container cap from the sample container, and the sample container holder is configured to automatically rotate in the other of the clockwise and counterclockwise directions while engaging the sample container capping device with the sample container cap to attach the sample container cap to the sample container.

[0016] The system comprises a pipette tip dispenser and a pipette mounted by a tool head, the pipette having a pipette tip engaging member configured to releasably engage a pipette tip, the tool head being configured to automatically position the pipette tip engaging member near the pipette tip dispenser and to engage the pipette tip engaging member with a pipette tip held in the pipette tip dispenser via either or both rotation of the tool head around a first axis and / or movement of the tool head along a second axis. The pipette tip dispenser is mounted on a pipette tip dispenser transferr configured to move the pipette tip dispenser relative to the tool head, so that the pipette tip dispenser can be selectively moved to a position where the tool head engages the pipette tip away from the pipette tip dispenser. This system further includes a pipette tip dispenser isolation chamber, and the pipette tip dispenser transferr is configured to selectively move the pipette tip dispenser between a position where the tool head positions the pipette tip engagement member to engage the pipette tip and a second position within the separation chamber. A pipette tip waste bin can be mounted on the pipette tip dispenser transferr, and the pipette tip dispenser transferr is configured to selectively move the pipette tip waste bin to a position where the tool head positions the pipette tip engagement member to disengage the pipette tip and place it into the waste bin. For example, the pipette tip waste bin may be mounted on the pipette tip transferr relative to the pipette tip dispenser, and when the pipette tip waste bin moves to a position where the tool head positions the pipette tip engagement member to disengage the pipette tip and place it into the waste bin, the pipette tip dispenser may simultaneously move into the separation chamber.

[0017] In embodiments including a pipette, the system may further comprise an auxiliary container holder configured to hold an auxiliary container, wherein the tool head is configured to automatically position the first axis inserted into the sample container and the pipette tip engaging member, via either or both rotation of the tool head around a first axis and movement of the tool head along a second axis, to a position where a pipette tip engaged with the pipette tip engaging device is inserted into the sample container held in the sample container holder, and to a position where the pipette tip is engaged with the engaging member and inserted into the auxiliary container held in the auxiliary container holder. The auxiliary container may be an aliquot container, and the tool head and pipette cooperate operably to automatically engage a pipette tip from a pipette tip dispenser with the pipette tip engaging member, and the engaged pipette tip is used to take an aliquot of the sample from the sample container held in the sample container holder and dispense the obtained sample aliquots into aliquot containers, respectively. Alternatively, the auxiliary container may be a reagent container containing a reagent, and the tool head and pipette may work together to automatically engage a pipette tip engaging member from a pipette tip dispenser with the pipette tip, thereby using the engaged pipette tip to take an aliquot of the reagent from the reagent container and dispensing these reagent aliquots into the sample containers held in the sample container holder.

[0018] An auxiliary container capping device is positioned on a tool head and configured to controllly grip and release the cap of an auxiliary container held in an auxiliary container holder. The tool head is configured to automatically position the auxiliary container capping device near the auxiliary container cap via either or both rotation of the tool head around a first axis and / or movement of the tool head along a second axis. The auxiliary container capping device operates in cooperation with the auxiliary container holder to remove or attach the auxiliary container cap. For example, the auxiliary container holder is configured to automatically rotate in one of the clockwise and counterclockwise directions while the auxiliary container capping device is engaged with the auxiliary container cap to remove the auxiliary container cap from the auxiliary container, and is also configured to automatically rotate in the other of the clockwise and counterclockwise directions while the auxiliary container capping device is engaged with the auxiliary container cap to attach the auxiliary container cap to the auxiliary container cap. In some embodiments comprising both a sample container capping device and an auxiliary container capping device, the two capping devices are offset from each other on the tool head, so that when the sample container capping device is in a position to grasp and remove the sample, the auxiliary container capping device is in a position to grasp and remove the auxiliary container cap without further rotation of the head tool.

[0019] The system may further comprise an analytical element (e.g., slide) loading platform positioned on the surface of the tool head, the analytical element positioner operably cooperating with the tool head to automatically engage and disengage the analytical element holder with the analytical element positioned on the loading platform, and the analytical element positioner operably cooperating with the tool head to automatically position the engaged analytical element near the working end of the sample transfer device to transfer the sample onto the engaged analytical element.

[0020] The system may further include a reader (e.g., a barcode reader or scanner) positioned on the tool head and configured to read the markings on sample containers placed in the sample containers. An analytical element printer may be provided and configured to communicate with the reader to print, but not limited to, markings on analytical elements, such as slides, corresponding to the markings on the sample containers read by the reader. Alternatively, an aliquot container printer may be provided and configured to communicate with the reader to print markings on aliquot containers corresponding to the markings on the sample containers read by the reader. In various embodiments, the reader may further be configured to read markings on other system components and consumables, such as on slides or filters used to acquire sample specimens.

[0021] Embodiments of this system may include a controller that controls the operation of one or more tool heads, pipettes, capping devices, and analytical element positioners, as well as a user interface operably connected to the controller that displays the system status and / or an introduction to the system operator and receives user input as a response to the displayed system status and / or introduction.

[0022] In one embodiment, an automated system for processing a sample contained in a liquid sample container comprises: a sample container holder configured to hold the sample container; an automated tool head configured to rotate around a first axis and move along a second axis different from the first axis; a pipette tip dispenser; and a pipette mounted on the tool head, configured to releasably engage a pipette tip, wherein the tool head is configured to position a pipette tip engaging member near the pipette tip dispenser via either or both rotation of the tool head around the first axis and / or movement of the tool head along the second axis, such that the pipette tip engaging member engages a pipette tip held by the pipette tip dispenser; and the pipette tip dispenser is configured to... The pipette tip dispenser comprises a pipette, mounted on a pipette tip dispenser transfer device configured to move the pipette tip dispenser relative to a dot, and the pipette tip dispenser being selectively moved to a position where the tool head positions the pipette tip engaging member and engages with the pipette tip from the pipette tip dispenser; and a pipette tip dispenser isolation chamber configured to selectively move the pipette tip dispenser between a position where the tool head positions the pipette tip engaging member and engages with the pipette tip from the pipette tip dispenser and a second position within the isolation chamber.

[0023] In yet another embodiment, an automated system for processing a sample contained in a liquid sample container comprises a sample container holder configured to hold the sample container, an automated tool head configured to rotate around a first axis and move along a second axis, a pipette tip dispenser, a pipette mounted on the tool head having a pipette tip engaging member configured to releasably engage with a pipette tip, and an auxiliary container holder for holding an auxiliary container, wherein the tool head is configured to automatically position the pipette tip engaging member near the pipette tip dispenser via either or both rotation of the tool head around the first axis and / or movement of the tool head along the second axis, causing the pipette tip engaging member to engage with the pipette tip held in the pipette tip dispenser, and the tool head is configured to automatically position the pipette tip engaging member so that the engaged pipette tip is inserted into the sample container held in the sample container holder and into the auxiliary container held in the auxiliary container holder, via either or both rotation of the tool head around the first axis and / or translation of the tool head along the second axis. While not limited to these, the auxiliary container may be either a reagent container or an aliquot container.

[0024] In yet another embodiment, a system for processing a sample contained in a liquid sample container comprises a sample container holder configured to hold a sample container, an auxiliary container holder configured to hold an auxiliary container, an automatic tool head configured to rotate around a first axis and move along a second axis different from the first axis, and a first capping device positioned on the tool head and configured to controllly grasp and release the cap of a sample container held in the sample container holder, wherein the first capping device is configured to automatically position itself near the sample container cap via either or both of the rotation of the tool head around the first axis and / or the movement of the tool head along the second axis, and the first capping device is configured to grasp and release the cap of the sample container A second capping device is configured to operate in cooperation with the tool head to remove or attach the sample container cap, to controllably grip and release the cap of an auxiliary container held in an auxiliary container holder, and the tool head is configured to controllably grip and release the cap of an auxiliary container held in an auxiliary container holder, and the tool head is configured to automatically position the second capping device near the auxiliary container cap via either or both rotation of the tool head around a first axis and / or movement of the tool head along a second axis, and the second capping device operates in cooperation with the auxiliary container holder to remove or attach the auxiliary container cap. The sample container holder can be configured to automatically rotate in one of the clockwise or counterclockwise directions while the first capping device is engaged with the sample container cap to remove the sample container cap from the sample container, and the sample container holder can also be configured to automatically rotate in the other of the clockwise or counterclockwise directions while the second capping device is engaged with the sample container cap to attach the sample container cap to the sample container.The auxiliary container holder is configured to automatically rotate in one of the clockwise and counterclockwise rotation directions while the second capping device is engaged with the auxiliary container cap to remove the auxiliary container cap from the auxiliary container, and the auxiliary container holder is also configured to automatically rotate in the other of the clockwise and counterclockwise rotation directions while the second capping device is engaged with the auxiliary container cap to attach the auxiliary container cap to the auxiliary container. The sample capping device and the auxiliary capping device are offset from each other on the tool head, and when the sample capping device is in a position to grasp and remove the sample container cap, the auxiliary capping device is in a position to grasp and remove the auxiliary container cap without further rotating the head tool. Without limitation, the auxiliary container may be either a reagent container or an aliquot container.

[0025] Other and further aspects and features of the disclosed embodiments will become apparent in view of the following detailed description in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0026] The foregoing and other aspects of the disclosed embodiments of the present disclosure will be described in more detail with reference to the accompanying drawings. Like reference numbers refer to like elements, and descriptions of like elements are applicable to all described embodiments in relation. [Figure 1] FIG. 1 is a right front perspective view showing an exemplary automated biological sample processing system according to one embodiment, comprising a sample processing cabinet, a slide printer, and an aliquot container printer. [Figure 2] FIG. 2 is a right front perspective view of the sample processing cabinet shown in FIG. 1, with the walls of the outer cabinet not shown to better illustrate the system components arranged therein. [Figure 3] FIG. 3 is a left front perspective view of the sample processing cabinet shown in FIG. 1, with the outer and inner walls and / or partitions not shown to better illustrate the system components arranged therein. [Figure 4]Figure 4 is a left, right, and front perspective view of the system components of the sample processing cabinet shown in Figure 1, showing various movements and operations performed by the system components during the sample processing procedure. [Figure 5] Figure 5 is a left, right, and front perspective view of the system components of the sample processing cabinet shown in Figure 1, showing various movements and operations performed by the system components during the sample processing procedure. [Figure 6] Figure 6 is a left, right, and front perspective view of the system components of the sample processing cabinet shown in Figure 1, showing various movements and operations performed by the system components during the sample processing procedure. [Figure 7] Figure 7 is a left, right, and front perspective view of the system components of the sample processing cabinet shown in Figure 1, showing various movements and operations performed by the system components during the sample processing procedure. [Figure 8] Figure 8 is a left, right, and front perspective view of the system components of the sample processing cabinet shown in Figure 1, showing various movements and operations performed by the system components during the sample processing procedure. [Figure 9] Figure 9 is a left, right, and front perspective view of the system components of the sample processing cabinet shown in Figure 1, showing various movements and operations performed by the system components during the sample processing procedure. [Figure 10] Figure 10 is a left, right, and front perspective view of the system components of the sample processing cabinet shown in Figure 1, showing various movements and operations performed by the system components during the sample processing procedure. [Figure 11] Figure 11 is a left, right, and front perspective view of the system components of the sample processing cabinet shown in Figure 1, showing various movements and operations performed by the system components during the sample processing procedure. [Figure 12]Figure 12 shows left, right, and front perspective views of the system components of the sample processing cabinet shown in Figure 1, illustrating the various movements and actions performed by the system components during the sample processing procedure. [Figure 13] Figure 13 shows left, right, and front perspective views of the system components of the sample processing cabinet shown in Figure 1, illustrating the various movements and actions performed by the system components during the sample processing procedure. [Figure 14] Figure 14 shows left, right, and front perspective views of the system components of the sample processing cabinet shown in Figure 1, illustrating the various movements and actions performed by the system components during the sample processing procedure. [Figure 15] Figure 15 is an elevation and side perspective view of the components mounted on the rotating tool head inside the sample processing cabinet shown in Figure 1, with the tool cover not shown. [Figure 16] Figure 16 is a perspective view of the bottom of the sample processing cabinet shown in Figure 1, with the bottom cover plate removed to reveal the system components. [Figure 17] Figure 17 is a perspective view of the rear of the sample processing cabinet shown in Figure 1, with the bottom cover plate removed to reveal the system components. [Modes for carrying out the invention]

[0027] For illustrative purposes, the systems and methods of use described herein and disclosed in the accompanying drawings concern the processing of patient samples that produce conventional cytological specimen slides, and the preparation of various types of biological specimens presented on various types of analytical elements (i.e., non-cytological and non-slide-based) is intended to be within the scope of the disclosed embodiments and claims. Furthermore, the systems and methods disclosed herein can be used for the processing of non-biological particulate matter and other types of liquid samples, including liquids. Therefore, it should be understood that the disclosed and illustrated embodiments are presented for illustrative purposes only, not limiting purposes.

[0028] In this specification, terms such as “specimen,” “specimen sample,” “biological sample,” “cytological sample,” “cell sample,” and “biological specimen” are interchangeable and should be understood and interpreted similarly unless the context of their use requires a more specific meaning. In addition, terms such as “aliquot” and “aliquot sample” may be interchangeable and should be understood and interpreted similarly. For example, but not limited to, the systems and methods disclosed herein can be used to process biological samples contained in liquid sample containers to produce specimens or specimen samples, as well as aliquots or aliquot samples. Furthermore, “aliquot” is another way of expressing “liquid sample” or “a portion of a liquid sample,” and the term “aliquot” should not be interpreted as limiting. In other words, obtaining an aliquot or aliquot sample of a biological sample means obtaining a portion of the original sample and storing it in a separate container for subsequent evaluation. Furthermore, terms such as “sample container,” “liquid sample container,” “patient container,” “sample vial,” “patient vial,” “tube,” and “auxiliary container,” and other variations thereof, are interchangeable and should be understood similarly, for example, based on the contents of the container described, unless the context of their use requires a more specific meaning.

[0029] As used herein, the terms “automated” and “automated” mean that a system (device, process, and / or function) operates without user intervention (e.g., system operator) and is often, though not always, under the control of a programmed processor. In particular, the automated systems and methods disclosed herein favorably reduce the number of manual steps required to obtain aliquots of patient samples, such as the preparation of biological samples, e.g., the preparation of cytological specimen slides, and / or additional testing and / or additional sample processing, such as introducing reagents into the sample before further processing.

[0030] Figure 1 shows an exemplary automated biological sample processing system 10 that can be used to prepare cytological specimen slides and / or aliquot samples from biological samples contained in a liquid sample container (e.g., obtained from a Papanicolaou smear). As will be described in more detail below, system 10 can be used for additional types of sample processing, such as adding reagents to biological samples or other types of samples (but not limited to these).

[0031] System 10 generally comprises a sample processing cabinet 11, a slide printer 13, and an aliquot tube printer 19. In the embodiment shown in the figure, the main components of System 10 are housed (and / or mounted) in the sample processing cabinet 11. As will be further described below, the slide printer 13 and the aliquot tube printer 15 are operably connected to the sample processing cabinet via known wireless or wired communication connections (not shown) under the control of one or more processors located in the sample processing cabinet 11. For simplicity, one or more processors are collectively referred to as the “system controller 60” (further described below in relation to Figure 17), which controls the automated movement and other operations of the components of System 10 housed in the sample processing cabinet 11, as well as communication with the respective slide printer 13 and aliquot vial printer 19. For simplicity in describing System 10, the components of the sample processing cabinet 11, slide printer 13, and aliquot tube printer 19 are collectively referred to as “system” 10, regardless of where specific components are housed. It is obvious that in alternative embodiments, various components of system 10 can be accommodated or provided individually.

[0032] For illustrative purposes only, but not limited to them, System 10 can be configured to process sample containers such as Thin Prep® sample vials and aliquot containers such as Aptima® vials. These are available from Hologic, Inc. (www.hologic.com) in Marlborough, Massachusetts.

[0033] The sample processing cabinet 11 is preferably an environmentally enclosed housing (or "skin") to reduce potential contamination from the surrounding environment. In the illustrated embodiment, the sample processing cabinet 11 is provided with an openable front door 15 that provides access to the system components inside. The door 15 is hinged to open and swing and is equipped with a handle 29. In an alternative embodiment, the front door 15 may be a sliding door that opens and closes by sliding laterally, for example. In the embodiment shown in the figure, the front door 15 has a transparent or translucent panel so that the system components housed in the sample processing cabinet 11 are visible when the front door 15 is in the closed position, but this is not a requirement for carrying out the disclosed embodiment. Also, referring briefly to Figure 16, stabilizing legs 79 made of a material that minimizes cabinet vibration are provided at each of the four corners of the bottom, and the cabinet is usually placed on four legs on a laboratory table. The legs 79 are preferably sized and configured to provide some clearance from the table surface in addition to providing better stability.

[0034] The slide printer 13 may be a commercially available slide printer, such as the Signature Slide Printer (https: / / www.primera.com / signature-slide-printer) available from Primera Technologies, Inc. in Plymouth, Minnesota. A new slide is loaded into the slide printer 13, and the printed slide is output through the output slot 17, which is used to receive cytological specimens as part of the processing of each patient sample container. In particular, the printer 13 prints a mark (e.g., a barcode) on the portion of the slide to which the cytological specimen is applied. Here, the printed mark matches or corresponds to a mark read on the sample container during processing, as will be described in more detail below.

[0035] The aliquot container printer 19 is preferably the same as that taught in U.S. Patent No. 9,724,948 ('948 Patent). This disclosure is incorporated herein by reference in its entirety. As described in the '948 Patent, the aliquot container printer 19 is provided with an opening 21 into which a new (unprinted) aliquot is inserted. The printer 19 prints a mark (e.g., a barcode) on an aliquot container that matches or corresponds to a mark read on a sample container being processed, as will be described in more detail below. The printed container is then ejected from the opening 21 or retrieved from the opening 21 and made available for use.

[0036] Figures 2 and 3 show the components of the system 10 housed or mounted within the sample processing cabinet 11, with the cabinet housing walls removed for simplicity of explanation. The cabinet 11 comprises a chassis 14 having multiple floors, walls, and / or supports, providing a primary support structure for installing / mounting various system components.

[0037] As is most commonly seen in Figure 3, a cylindrical sample container holder 16 is located in the lower central portion of the chassis 14. As will be described in more detail below, the sample container holder 16 is fixedly mounted to a rotating platform configured to rotate the sample container 12 (shown in Figure 4) held in the sample container holder 16 around the central z-axis of the container 12, mixing the sample to uniformly disperse the cells or other specific material contained in the sample container 12 substantially before processing begins, and facilitating the uncapping and recapping of the container 12 during processing. In the embodiment shown in the figure, the sample container holder 16 is a cylindrical container configured to tightly receive and hold the sample container 12. The sample container holder 16 has an outer wall that extends to a height lower than the height of the sample container 12, so that the cap 43 of the sample container held in the sample container holder 16 is fully exposed, facilitating mixing, uncapping, and recapping. In an alternative embodiment, the sample container holder 16 is any suitable shape to receive the specific sample container to be used in the system 10, such as a rectangular box or other shape.

[0038] As is most commonly seen in Figure 3, the aliquot container holder 18 is located in the lower center of the chassis 14, directly in front of the sample container holder 16. As will be described in more detail below, the aliquot container holder 18 is fixedly mounted to a rotating platform configured to rotate the aliquot container 20 (shown in Figure 5) held in the aliquot container holder 18 around the z-axis of the center of the container 20, facilitating the uncapping and recapping of the container 20 during sample processing. The aliquot container holder 18 is configured to tightly receive and hold the aliquot container 20 and has an outer wall that extends to a height lower than the height of the aliquot container 20, so that the cap 45 of the aliquot container 20 held in the aliquot container holder 18 is fully exposed, facilitating mixing, uncapping, and recapping. In an alternative embodiment, the aliquot container holder 18 is sized and configured to hold a more tubular container than those held by the sample container holder 16. In alternative embodiments, the aliquot container holder is any suitable shape to receive a specific aliquot container used in System 10, such as a rectangular box or other shape. Furthermore, as described below, System 10 can be used for additional sample processing steps, such as introducing reagents into a sample container. Therefore, references to the aliquot container holder 18 and the aliquot container 20 themselves should be understood as illustrative and not limiting. For example, the terms “auxiliary container holder” and “auxiliary container” can be used interchangeably with those for the aliquot container holder and aliquot container.

[0039] More specifically, the sample container holder 16 and the aliquot container holder 18 are each mounted (or integrally formed) on a rotatable platform (not shown) below them, which is rotatably connected to or near the floor of the chassis 14. Each rotatable platform, and therefore the container holders 16 and 18, rotates selectively in a clockwise or counterclockwise direction about the central z-axis of each holder 16 and 18. Referring particularly to Figure 16, a sample dispersion drive assembly is provided which mixes the contents of the sample container 12 held in the sample container holder 16 at a relatively high speed to disperse cells and / or other particulate matter suspended in the liquid sample before further processing of the sample. The sample dispersion rotatable drive assembly comprises a sample dispersion motor (not shown) mounted in close proximity to the floor of the chassis 14, the sample dispersion motor having a rotary output shaft that passes through the floor of the chassis and rotates a drive wheel 81. The drive wheel 81 then rotates a larger diameter drive wheel 93 via a drive belt 88. The high-speed / low-speed clutch 82 is operably coupled to the drive wheel 93 and, via a rotary drive shaft (not shown) extending rearward through the chassis floor, selectively engages the drive wheel 93 with the respective rotating platform associated with the sample container holder 16, thereby also rotating the sample container holder 16 to disperse the particles contained in the sample container 12 at a relatively high speed before further processing of the sample.

[0040] Continuing to refer to Figure 15, the system 10 further comprises a capping drive assembly that rotates both the sample container holder and the aliquot container holders 16 and 18 simultaneously at a relatively low speed, removing and reattaching the respective caps 43, 45 on the sample containers and aliquot containers 12 and 20 held in the respective sample container holders and aliquot container holders 16 and 18, as will be described in more detail below. The capping drive assembly comprises a capper motor 39 (shown in Figure 3) mounted on or near the floor of the chassis 14 in the lower compartment 28 of the cabinet 11. This capper motor is reversible and provides rotational motion in clockwise and counterclockwise directions. The capper motor 39 has a rotating output shaft that passes through the floor of the chassis 14 and rotates a drive gear 84, which in turn rotates a larger drive gear 91 via a drive belt 85. A high-speed / low-speed clutch 82 is operably coupled to a drive gear 91, and via a rotating shaft (not shown) that returns from the drive gear 91 through the chassis floor, the drive gear 91 selectively engages with the rotating platforms associated with the sample container holder 16 and the aliquot container holder 18. In particular, one or more drive gears / wheels and belts (not shown) are further located under the chassis beneath the respective rotating platforms of the sample container holder 16 and the aliquot container holder 18, distributing the rotational motion of the wheel 91 to the respective rotating platforms simultaneously. In this way, the operation of the capping motor rotates the sample container holder 16 and the aliquot container holder 18 simultaneously at a relatively low speed, depending on the rotational direction of the motor's output shaft, to remove and reattach the caps 43 and 45.

[0041] Referring to Figure 4, the system 10 comprises an automatic tool head 30 rotatably mounted on a load-bearing shaft assembly 34, the tool head 30 configured to pivot or reciprocate around a rotation axis, as shown by the dashed line 33 in Figure 7. Preferably, the range of rotation of the tool head 30 is through an arc of at least 270 degrees around the rotation axis 33, but no specific minimum travel amount s beyond the amount of rotational travel required to perform the function of a particular system embodiment is required. In the embodiment shown in the figure, the tool head rotates at least 270 degrees around the rotation axis 33. The load-bearing shaft assembly 34 preferably comprises a spin bearing (not shown) to minimize friction between the tool head 30 and the mounting shaft (not shown) of the tool head 30. A tool head rotation actuator motor 36 is mounted on the load-bearing shaft assembly 34, and the output shaft (not shown) of the motor 36 is operably connected to a shaft in the tool head 30 or to rotate the tool head 30 via a drive belt 74. The rotary motor 36 is reversible and selectively provides rotational motion of the tool head 30 in both clockwise and counterclockwise directions.

[0042] Continuing to refer to Figure 4, the motor 36 (also referred to as item 36 in the figure) is housed in a block-type support housing, which is screwed onto a vertical lead screw 55 (best seen in Figure 15) located at the rear of the chassis 14. The lead screw 55 is actuated by a tool head linear actuator motor 32 mounted on the rear wall (near the top) of the chassis 14. The tool head linear actuator motor 32 is reversible and selectively provides rotational motion of the lead screw 55 in both clockwise and counterclockwise directions. In particular, the rotation of the lead screw 55 in either the clockwise or counterclockwise direction causes each load-bearing shaft assembly 34 of the motor block 36, and therefore the tool head 30, to move linearly upward relative to the chassis along the vertical (or "z") axis of movement, as shown by the dashed line 51 in Figure 14, and the rotation of the lead screw 55 in either the clockwise or counterclockwise direction causes each load-bearing shaft assembly 34 of the motor block 36, and therefore the tool head 30, to move linearly downward relative to the chassis 14 along the vertical axis 51. As will be further described below, this mechanical configuration allows the automatic tool head 30 to rotate selectively and controllly in both the clockwise and counterclockwise directions around the rotation axis 33, and to move selectively and independently up and down along the vertical axis 51, including simultaneous rotation and movement motions. The rotary actuation motor 36 controls the rotational position of the tool head 30 around the rotation axis 33, and the linear actuation motor 32 controls the vertical position of the tool head 30 along the vertical axis 51 inside the cabinet 11.

[0043] Many sample processing devices (or "tools") are arranged circumferentially around the tool head 30, and each device is configured such that the respective function achieved by each device is accomplished by either or both rotation of the tool head around its rotation axis 33 and / or movement of the tool head 30 along its vertical movement axis 51, without requiring the tool head 30 to be moved in the x-direction (i.e., laterally relative to the cabinet 11) or the y-direction (i.e., forward and backward relative to the cabinet 11). In the embodiments shown in the figures, these devices comprise: a mark reader 31 configured to read markings such as barcodes on a sample container 12; a first capping device 42 having a pneumatically controlled gripper configured to releasably grip the cap 43 of the sample container 12 during processing; a second capping device 44 having a pneumatically controlled gripper configured to releasably grip the cap 45 of an auxiliary container 20 (e.g., an aliquot tube or a container containing reagents); a pipette 37 (most commonly shown in Figure 15) having a pipette tip engaging member 38 extending outward from the tool head 30 and configured to releasably engage a pipette tip; a sample collection and transfer device (hereinafter, "sample transfer device") 40 having a working end extending outward from the tool head 30 and configured to collect a sample from the sample container; and a slide loading bed or "platform" 46 (described in more detail below) configured to receive slides 50 that are fed by the tool head 30 into the slide holder 57 of the slide positioner assembly 56.

[0044] Devices 31, 42, 44, 37 / 38, 40, and 46 are each positioned on the tool head 30 in various circumferential and / or angular positions and orientations around the rotation axis 33, and each of these devices rotates with the tool head 30 as the tool head rotates around the rotation axis 33 under the control of the rotary actuation motor 34, and as the tool head moves vertically up and down within the cabinet 11 along the vertical axis 51 under the control of the movable actuation motor 32. Thus, the rotation and / or vertical movement of the tool head 30 positions each device in a relative rotational and vertical position within the cabinet 11 to perform its respective function, as will be further described herein. It is obvious that the specific devices or tools provided on the tool head 30 in the embodiments shown in the figures are neither essential nor limiting. For example, in alternative embodiments, more or fewer devices / tools may be mounted on the tool head 30. For example, only a single capping device (e.g., 42 or 44) and / or the leader 31 may be provided at a location away from the tool head 30, including not being inside the cabinet 11. As a further example, the slide loading platform 46 may be omitted in some embodiments, in which case the system operator loads the slides directly into a slide holder such as a slide holder 57. These and / or other variations and substitutions of temporary devices / tools on the tool head 30 are also intended to be within the scope of this disclosure.

[0045] As seen in Figures 3 and 4, a pump 47 with a pump head 49 supplies pressurized air stored in a high-pressure tank 71 that supplies pressurized air to operate various pneumatic devices within the cabinet 11 via a manifold of solenoid valves 68 and connectors 67. A slightly higher-pressure tank 72 and a slightly lower-pressure tank 73 are also provided, respectively, to operate the sample transfer device 40 (described in more detail below). For clarity, the pressurized air transmission paths, such as solid and / or flexible tubular lines connecting the pump 47 to the tank 71 and the tank 71 to the various pneumatic devices, are not shown to more clearly illustrate the system components located within the cabinet 11 without obstruction by tubing. However, flexible conduits 23, on which various pneumatic piping and electrical conductions are connected to the tool head 30 and to devices on it such as cappers 42, 44, pipettes 37 and the sample transfer device, are shown (only) in Figure 2. By bundling various tubes and wires through a single conduit 23, the possibility of tubes or wires getting caught or dislodged from connectors during operation of the tool arm 30 is reduced. In particular, the length of the tubes and electrical connections through the conduit 23 is long enough so that the conduit 23 moves with the tool head 30 as the tool head 30 moves linearly along its vertical axis 51 and rotates around its rotation axis 33.

[0046] Referring back to Figures 2 and 3, the reader 31 is configured to read identification indicators such as (but not limited to) the patient identifier and / or medical record identifier, date, or medical facility from which a sample was taken on any of the sample container 12, aliquot container 20, slide 50, and / or filter 54. The reader 31 may be an optical camera that takes an image of a label that is read and / or identified using barcodes, QR codes, machine-readable alphanumeric text and / or optical character recognition (OCR) software, or an electronic reader configured to read NFC chips, RFID or other electronic tags, or other readers configured to read readable markings. Examples of such alternative marking storage technologies for slides are described in U.S. Patent No. 7,083,106 and U.S. Patent Publication No. 20070148041, the entire disclosure of which is incorporated herein by reference. In the embodiments shown in the figures, the reader 31 is configured to read markings in the form of barcodes, among other things. The mark on the sample container 12 is read by the reader 31 and transmitted via the system controller 60 (described in more detail below) to the slide printer 13 and the aliquot container printer 19, respectively, to print the matched or otherwise corresponding mark on the slide 50 and / or aliquot container 20 used in the sample processing procedure.

[0047] Referring (primarily) to Figures 2 to 5, the pipette tip dispenser gantry or "transfer unit" 22 is connected to the chassis 14 in front of the aliquot container holder 18. The pipette tip dispenser transfer unit 22 comprises a pipette tip dispenser holder 24 configured to permanently mount a pipette tip dispenser 26 on it. This pipette tip dispenser is configured to hold a plurality of pipette tips 48, for example, eight pipette tips in the illustrated embodiment, and this dispenser may be supplied as a pipette tip cartridge. The pipette tip dispenser 26 is removablely attached to the holder 24 in one of several ways. In the embodiment shown in the figure, the pipette tip dispenser 26 is magnetically coupled to the pipette tip dispenser holder 24 to ensure accurate and predictable positioning of the dispenser 26 relative to the holder 24, and to allow the system controller 60 to verify via a sensor circuit that the dispenser 26 is properly mounted and positioned relative to the holder 24. This is important for the pipette tip engaging member 38 mounted on the tool head 30 to be precisely aligned and thereby engage with the pipette tip 48 held in each slot of the dispenser during the sample processing procedure.

[0048] Referring briefly to Figure 16, the lateral movement of the pipette tip dispenser transfer unit 22 is performed by an electric drive belt 87 that rotates back and forth on drive wheels 80a and 80b located beneath the bottom surface of the chassis 14. The drive wheels extend backward through the floor of the chassis and rotate their respective shafts (not shown) that are mechanically connected to the transfer unit 22, thereby moving the pipette tip holder 24 and the pipette tip dispenser 26 mounted on it laterally between a storage position where the pipette tip dispenser is located in the isolation chamber 28, as shown in Figure 4, and a loading position where the slots of the pipette tip holder 26 with available pipette tips 48 are aligned with the pipette tip engaging members 38 on the tool head 30, as shown in Figure 7. In particular, the loading position depends on which slots of the dispenser 26 are occupied by pipette tips. In storage, each pipette tip holder 24 and the pipette tip dispenser 26 attached thereto are placed in a separation chamber 28 located within the sample processing cabinet 11, reducing the possibility of contamination of unused tips from sample processing operations performed in the main internal area of ​​the cabinet 11.

[0049] As can be seen by comparing Figure 4 and Figure 5, panel 52 (Figure 4) is mounted on the side of the pipette tip dispenser 26, and the holder 24 and dispenser 26 are sized and shaped to close the opening into which the pipette tip enters through the isolation chamber. As shown in Figure 3, a pipette tip sensor 35 located in the isolation chamber 28 tracks the pipette tip 48 held in the dispenser 26 and notifies the system controller 60 to move the pipette tip dispenser transferr 22 precisely to a position where the tip 48 held in the dispenser 26 aligns with the pipette tip engaging member 38 of the tool head 30, ensuring that there is a suitable pipette tip available in the dispenser 26. If the dispenser 26 is empty or otherwise holds an insufficient amount of pipette tips 48 to perform a particular sample processing procedure, the system 10 pauses and does not perform any further sample procedures until a new pipette tip 48 is loaded into the dispenser 26.

[0050] The used pipette tip waste bin 25 is mounted on a separate platform / holder 27 attached to the pipette tip transferr 22, and the pipette tip dispenser transferr is configured to selectively move the pipette tip waste bin 25 to a position where the tool head 30 disengages the pipette tip 48, which has been engaged with the pipette tip engaging member 38, into the waste container 25. Similar to the pipette tip dispenser 26 and holder 24, the waste bin 25 is preferably magnetically coupled to the holder 27 to provide stability and allow the system 10 to verify via a detection circuit that the waste bin is properly mounted. In particular, the pipette tip waste bin holder 27 is mounted on the pipette tip transferr 22 relative to the pipette tip dispenser holder 24, and when the pipette tip dispenser 26 is moved to the isolation chamber 28, the pipette tip waste bin 25 simultaneously moves to a position where the tool head 30 positions the pipette tip engaging member 38, disengaging the engaged / used pipette tip 48 into the waste bin 25.

[0051] Referring also to Figure 15, the pipette 37 has a pipette tip engaging member 38 positioned at a slight angle to the tool head relative to the pipette tip dispenser 26, and similarly, the tool head 30 is angled such that it coincides with engaging with a pipette tip 48 held in one slot by either or both of the rotational and / or movement of the tool head 30. The pipette 37 may be, but is not limited to, a CAVRO® air displacement pipette (ADP) (www.tecan.com / components) sold by Tecan Group Ltd., which has a spring-biased engaging tip 53 (Figure 15) that engages each pipette tip 48 when inserted into the bore of each pipette tip 48 by compression fitting of the release engaging tip 53 or the like. The pipette 37 is configured such that when the pipette tip 48 engages with (or is placed on) the pipette tip engaging member 38, it selectively draws liquid from the sample container 12 into the pipette tip 48 and then distributes the liquid contained within the drawn-in pipette tip 48.

[0052] In this way, during the sample processing procedure, the pipette 37 engages the pipette tip 48 from the pipette tip dispenser 26. The pipette is then repositioned by the tool head 30 to place the engaged tip into an open container (e.g., an open sample container 12). In known methods, the pipette tip 48 is made of a conductive material (such as a conductive polymer), and a vacuum is supplied into the bore of the pipette tip 48 to draw a certain amount of sample into the pipette tip 48, for example, an aliquot from a sample container. The impedance sensing circuit of the pipette 37 is used to confirm that the pipette tip 48 is submerged in the liquid. The pipette 37 then releases the vacuum to allow the sample to be distributed from the pipette tip 48, for example, into an open aliquot container 20. The pipette 37 is configured and operates so that only the pipette tip 48 is in contact with the sample material, and the pipette tip engaging member 38 of the pipette 37 is not contaminated by the sample material. The pipette tip engaging member 38 is configured to release the pipette tip 48 from the waste container 25 after use by a movable displacement sleeve that pushes the tip 48 out of the tip 53 of the pipette tip engaging member 38.

[0053] The sample transfer device 40 is transported by the tool head 30 and is configured to collect a sample from the sample container 12 and transfer the collected sample to the slide 50. In the embodiments described above, the sample transfer device 40 comprises a cylindrical working end extending from the tool head 30 and is configured to form a pressure-resistant seal around it, together with a filter 54 that sits on it before the sample processing procedure begins, as shown in Figure 4. The filter 54 comprises a hollow cylinder having an open proximal end and a membrane having pores of a size selected to capture desired cells for the sample and to allow smaller cells and non-cellular particles and liquids to pass through to the distal end. Embodiments of the filter 54, as well as sample collection and transfer devices and techniques suitable for use in the illustrated system 10, are disclosed and further described in U.S. Patent No. 8,119,399, U.S. Patent Publication No. 20050100483, and U.S. Patent Publication No. 20080145887, the entirety of which these disclosures are incorporated herein by reference. When positioned at the working end of the sample transfer device 40, the filter 54 extends from the tool head 30 far enough to insert the filter into the sample container 12 and collect the sample onto the filter membrane, so that only the filter comes into contact with the sample solution, without any part of the sample transfer device 40 coming into contact with the sample solution. This ensures that the sample transfer device 40 is not contaminated with the sample material when it collects the sample from the sample container 12. Once the sample transfer device 40 has collected the sample into the sample collector 54, it is operated to transfer the sample from the filter 54 to the slide 50, as will be described in more detail below.

[0054] In particular, the sample transfer device 40 and system 10 insert the filter membrane into the sample in the sample container via either or both of the moving and rotational motions of the tool head 30, forcing the sample to move back and forth through this membrane, collecting the sample onto the membrane in a “suction” manner, and depositing a thin layer of cells in the liquid sample onto the outer surface of the membrane. The sample transfer device 40 may be configured to circulate a vacuum (and pressure) within the working end of the sample transfer device to move the sample back and forth through the membrane. In addition, or alternatively, the sample transfer device 40 and system 10 may be configured to move the membrane up and down within the sample to reciprocate the sample through the membrane and collect the sample onto the membrane. A method and apparatus for determining whether a sufficient but not excessive amount of cells has been collected on the filter membrane using this same “shipping process” is disclosed and described in U.S. Patent No. 8,119,399 above. Further details of the general sample collection process and the design and operation of the sample transfer device 40 (and filter 54) can be found in U.S. Patent No. 8,137,642, which, like several other patents mentioned above, is incorporated herein by reference in whole. Briefly referring to Figure 17, waste liquid from the sample collection process is removed through port 95 on the rear of cabinet 11.

[0055] The sample container capping device 42 comprises a movable pneumatic prong or “gripper” configured to grip and hold the cap 43 of the sample container 12. As can be seen in Figure 15, the gripper is actuated by air pressure supplied to the actuator 77 to provide a tweezers-like radially inward gripping motion or a radially outward release motion. Preferably, two or more grippers are arranged substantially evenly around the sample container cap 43 and can be positioned in a “capping” or “uncapping” position by one or more moving and rotational movements of the tool head 30. When removing the cap 43, the cappers 42 grip the cap 43 while the container holder 16 rotates in either a clockwise or counterclockwise direction, and the tool head 30 rises slightly and steadily, moving the cap 43 upward as it rotates on the threads of the container 12. When attaching the cap 43, held by the gripper, to the container 12, the tool head 30 positions the capper 42 over the open container, and as the holder 16 rotates clockwise and counterclockwise, the tool head 30 moves slightly steadily, while as the container holder 16 rotates the container relative to the cap 43, the tool head 30 moves the cap 43 downward over the container 12. The grippers used for the sample container capping device 42 and the aliquot container capping device 44 described below are parallel-style air grippers / 2-finger, 3-finger, and 4-finger series grippers available from SMC Pneumatics.com.

[0056] The aliquot container capping device 44 operates substantially the same as the sample container capper, and includes the step of using two or more protrusions or grippers to releasely grip the cap 45 of the aliquot container 20 while the aliquot container holder rotates clockwise or counterclockwise to remove the cap 45 from the container 20 or to attach the cap 45 to the container 20. In this case as well, the tool head 30 moves steadily up and down to accommodate the movement of the cap relative to the container 20 during processing. In particular, as shown in Figure 15, since the torque required to remove and cap the aliquot container 20 is small, power is supplied to the aliquot container gripper using direct pneumatic pressure supplied via the hose attachment 75.

[0057] The sample container capping device 42 and the aliquot container capping device 44 are preferably positioned and oriented on the tool head 30 so that both capping devices 42 and 44 are in the appropriate position and can be removed without removing their respective caps 43 and 45.

[0058] In an alternative embodiment, the cappers 42 and 44 are each rotatable, and the capping process in that case comprises the steps of the capper 42 gripping the cap 43, the sample holder rotating while remaining stationary, and the capper 44 gripping the grip cap 45, the aliquot holder 18 rotating while remaining stationary, as is taught, for example, in U.S. Patent No. 9,335,336 and U.S. Patent Publication No. 2017 / 0052205 incorporated above.

[0059] The slide loading platform 46 is preferably positioned on the tool head 30 at a location convenient for the system operator to load the slide 50 before the sample processing procedure, and is configured to receive and hold the slide 50 once it is loaded. While the loading platform 46 in this described embodiment is configured to receive and hold a microscope slide as the slide 50, it should be understood that the loading platform 46 may also be configured to receive and hold other types of analytical elements other than slides, depending on the type of sample specimen output by the system 10.

[0060] As described above, the slide positioner 56 comprises a slide holder 57 having a pneumatic gripper 59 configured to grasp the slide 50 and remove it from the loading platform 46 (this movement is shown in Figure 5), and then position the slide to receive the sample acquired by the sample transfer device 40. The slide positioner is also movable with at least two degrees of freedom provided by a slide positioner motor 63 and various hinge arms and is supported by a counterweight 64. After the membrane of the filter 54 is pressed against the slide 50 to move the sample (Figure 12), the slide positioner moves the slide 50 and rotates the slide 50 90 degrees near the open container of the fixative 58 fixed in the fixative container holder 61, and the slide positioner 56 is configured to grasp and move the slide 50. As a result, the slide positioner 56 includes a pneumatically controlled gripper 59 configured to grip the slide 50 and remove the slide 50 from the loading platform 46, as shown in Figure 5. The slide positioner 56 then moves the slide to a transfer position, as shown in Figure 11, where the sample transfer device 40 can transfer the sample from the filter 54 to the slide 50, and then moves to a fixing position, where the analytical positioner 50 can place the sample into a fixative container 58 containing a fixative that fixes the sample to the slide 50. The system 10 includes a fixative container holder 61.

[0061] Referring to Figure 17, System 10 also comprises one or more processors collectively called Controller 60, located on the rear panel of the cabinet. Controller 60 is operably connected to, communicates with, and controls the automatic operation of various components of System 10, including the tool head 30, tool head actuator 32, pipette 37, sample transfer device 40, first capping device 42, second capping device 44, slide positioner 56, and reader 31. Controller 60 comprises a computer processor, input / output interfaces, and other support electronics that communicate with and control the operation of the system components. Controller 60 comprises a user input device that allows a system operator to input commands, data, etc., into Controller 60. The user input device may be a touchscreen / display 62, as described below. Controller 60 also comprises system software that programs and communicates with System 10, and controls it to perform procedures for preparing sample specimens and / or aliquots from biological or other samples contained in sample containers 12, as described herein. In the embodiment shown in the figure, the touchscreen / display 62 is mounted on the chassis, preferably incorporated into the cabinet housing, and preferably integrated with the cabinet housing, and is positioned to allow the system operator to input instructions (for example, when prompted by the system 10) and to check the status of items being handled during sample handling procedures. The touchscreen / display 62 is configured to display graphics generated by the controller 60, including information about the operation of the system 10, such as operating status and data. The touchscreen / display 62 may be a suitable display such as a liquid crystal display (LCD), LED display, or AMOLED.

[0062] Herein, an exemplary sample preparation procedure will be described with reference to Figures 1 to 14 in order to illustrate the various elements and components of System 10. In particular, the exemplary sample preparation step comprises the step of first obtaining an aliquot of the sample and then processing the sample to prepare a biological specimen slide. This process is described for illustrative purposes only and not limitation, and it should be understood that other types of sample preparation can be performed using the disclosed and described system and its variations, while still within the scope of this disclosure. For illustrative purposes only and without limitation, each method using the automated system for processing samples contained in the sample containers described in the appended claims should be considered an additional exemplary sample preparation procedure that can be performed using the illustrated System 10.

[0063] To begin processing a predetermined patient sample container 12, the system operator inputs an instruction, for example, by touching the “start button” or a similar symbol on the user interface 62. The system controller 60 causes the tool head 30 to assume the “start” position (if the tool head 30 is not inside the cabinet 11), in which case the tool head 30 rotates to a position inside the cabinet 11, positioning the reader 31 in a location convenient for the system operator to view the sample vial 12, as shown in Figure 4.

[0064] After receiving visual confirmation from the system controller 60 on the user interface display 62, the system operator presents the sample container 12 to the reader 31, so that the patient and / or other markings on the sample container 12 are within the reader 31's field of view. The reader 31 reads the markings on the sample container 12 and communicates (via the controller 60) to the respective slide printer 13 and aliquot container printer 19. The slide printer prints and outputs a new (i.e., unused) slide 50, where a mark matching or corresponding to the marking on the sample container 12 is printed on the slide 50. The system operator inserts a new (i.e., unused) aliquot container 20 into the aliquot container printer and prints a mark on the aliquot container 20, which also matches or corresponds to the marking on the sample container 12.

[0065] The pipette tip dispenser transfer unit 22 moves to a loading position (Figure 2) to expose the pipette tip dispenser 26 when additional tips 48 need to be added. Loading the sample container 12, aliquot container 20, slide 50, and pipette tip dispenser 26 into the system 10 can be automated using a robot or the like, or it can be done manually by a system operator. The latter is assumed as an example of simplification. In particular, the system operator loads the (capped) sample container 12 into the sample container holder 16 and the (capped) aliquot container 20 into the aliquot container holder 18, and in each case, after reading the reader 31, verifies that the markings on each sample and aliquot container match. The system operator loads the slide 50 face down onto the slide mounting platform 46, that is, the slide has a mark and a "sample spot" area printed on its side and receives the sample face down onto the platform 46. The system operator loads a new filter 54 into the working end of the sample transfer device 40, verifies that there is an appropriate number of unused pipette tips 48 in the pipette tip dispenser 26 (at least one), and that the pipette tip waste bin is empty. Once all consumables are loaded, the system operator closes the cabinet door 15 of the cabinet 11 and indicates via the user interface that all system validations are complete and that the sample processing procedure can be initiated.

[0066] In particular, system 10 will not initiate the sample processing procedure unless the sensor 35 indicates that there is at least one sufficient number of pipette tips 48 in the dispenser 26, and unless the pipette tip dispenser 26 and the waste bottle 25 are mounted in the correct position and magnetically coupled to their respective mounting platforms 24 and 27 on the pipette tip dispenser transfer unit 22. The sample transfer device 40 performs a "dry" test to verify the integrity of the filter 54, in particular checking that the distal end membrane is not perforated (indicating that the filter 54 has already been used), not blocked, or torn. In particular, once it is confirmed that there are appropriate pipette tips 48, the pipette tip dispenser transfer unit is moved by the system and the pipette tip dispenser is placed in the isolation chamber 28. From that point until the sample processing procedure is completed, the involvement of the system operator is usually not required.

[0067] As shown in Figures 4 to 6, at the start of the sample processing procedure, the pipette tip dispenser transferr 22 moves the pipette tip dispenser to its storage position in the isolation chamber 28 (Figure 3), and the tool head 30 rotates slightly upward and moves linearly upward so that the slide 50 is grasped by the gripper 59 of the slide holder 57. The tool head 30 then moves linearly downward and rotates so that the reader 31 reads the mark on the side 50 and confirms that this mark matches the mark on the sample container 12 and the aliquot container 20, respectively. Assuming that a match has been confirmed, the system 10 continues to perform the automated process to prepare the sample and aliquot samples in each component of the system 10 which is operated and controlled by the controller 60.

[0068] As shown in Figure 6, the tool head 30 is rotated by the tool head actuator 34 and moves vertically downward, positioning the sample container capping device 42 on the cap 43 of the sample container 42 and the aliquot container capping device 44. The respective capping devices 42 and 44 work in cooperation with the rotation of their respective container holders 156 and 18 to remove and grip the caps 43 and 45.

[0069] As shown in Figure 7, the pipette tip dispenser transfer unit 22 moves to the loading position to position the pipette tip 48 contained in the pipette tip dispenser 26 and attach it to the pipette tip engaging member 38 of the pipette 37. As shown in Figure 7, the tool head 30 rotates to position the pipette tip engaging member 38, and the rotation and movement of the tool head 30 attaches the pipette tip 48 and pushes the pipette tip engaging member onto the pipette tip 48.

[0070] As shown in Figure 8, the pipette tip dispenser transfer unit 22 returns to its storage position. The tool head 30 rotates and moves vertically to place the pipette tip 48 on the pipette 37 into the sample in the sample container 12. The pipette 37 creates a vacuum inside the pipette tip 48 and draws a certain amount of sample (aliquot sample) into the pipette tip 48.

[0071] As shown in Figure 9, the tool head 30 rotates and moves vertically to position the pipette tip 48 into the aliquot container 20. The pipette 37 releases the vacuum and dispenses the aliquot sample from the pipette tip 48 into the aliquot container 20. After dispensing the aliquot sample into the aliquot container 20, the tool head 30 rotates and moves to position the aliquot container capping device 44 in place and returns the cap 45 to the aliquot container 20 (to the same position as shown in Figure 6).

[0072] As shown in Figure 10, the tool head 30 is rotated and moved vertically to position the pipette tip 48 on or inside the waste container 25. The pipette tip engaging member 38 then detaches (discharges) the used pipette tip 48 into the waste bottle.

[0073] As shown in Figure 11, the tool head 30 is rotated and moved to position the filter 54 installed in the sample transfer device 40, and the sample is collected from the sample container 20 onto the filter membrane according to the process described above, namely by moving the filter up and down by cycling vacuum and / or moving the tool head 30 via the tool head actuator 34, thereby causing the sample to reciprocate through the membrane. This process allows for the collection of a thin or monolayer of cells onto the thin film.

[0074] As shown in Figure 12, the tool head 30 rotates and moves to position the filter membrane and transfer the sample to the slide 50, which is held by the gripper 59 of the slide holder 57. Next, the sample transfer device 40 and / or slide positioner 56 are operated to bring the membrane with the sample onto the slide 50. The tool head 30 moves by the tool head actuator 34 and operates the sample transfer device 40. In order to transfer the sample (e.g., a thin layer of cells) onto the slide 50 without disturbing its spatial distribution, it is generally desirable that the membrane of the filter 54 first contacts the slide 50 at a single location, forming a predetermined small preliminary contact angle between the membrane and the deposition surface of the slide 50, and then gently and gradually bring it into full contact with the slide 50. This is achieved by operating the sample transfer device 40 and the slide positioner 56 in coordination.

[0075] As shown in Figure 13, the tool head 30 can also move downward to provide space for the slide positioner 56, on which the slide 50 with the sample can be placed in the fixative container 58 containing the fixative that secures the sample to the slide 50. After the sample has been transferred to the slide 50, the tool head 30 moves and / or rotates to push the filter membrane into the pin 41 (Figure 4), preventing the filter membrane from being destroyed and reused. As also shown in Figure 13, the slide positioner 56 is activated to place the slide 50 with the sample into the fixative container 58. Once the sample processing procedure is complete, the system operator can remove the sample slide 50 from the fixative solution in the container 58, or remove the fixative container containing the sample slide 50 and replace (or place a new) the fixative container 58 in the holder 61 before starting a new sample processing procedure.

[0076] Rotate the tool head 30 downwards to position the sample container capping device 42 correctly, and reattach the cap 43 to the sample container 12 (to the same position as shown in Figure 4).

[0077] This completes the automated process for preparing specimen samples and aliquot samples. The slide 56, with the specimen sample fixed with the fixative, is then removed from the fixative container 58 and ready for testing. The sample container 12 and aliquot container 20 are also removed from the system 10 and stored appropriately. The waste container 25 is removed from the system 10 and discarded in the waste bottle to dispose of the used pipette tips 48. The waste container 25 is then returned to the waste container platform 27.

[0078] The process described herein can be repeated for additional sample containers containing each sample, as needed.

[0079] While specific embodiments have been described, it should be understood that the above description is not intended to limit the scope of these embodiments. Although many variations of the embodiments disclosed herein have been disclosed and described, it should be understood that the foregoing disclosures are provided for illustrative and illustrative purposes only, and various changes and modifications may be made to the disclosed embodiments without exception. The following claims deviate from the scope of the claims. For example, not all components shown and described in the embodiments are necessary, and alternative embodiments may include any suitable combination of the described components, and the general shape and relative size of the components may be modified.

Claims

[Claim 1] The invention described herein.

Images