System and method for automated biological specimen preparation

Abstract

To provide an improved device and method for acquiring an aliquot from a liquid-based biological sample such as a Papanicolaou smear test sample, while minimizing the risk of secondary contamination.SOLUTION: An automated system for processing a sample contained in a liquid sample container includes an automated tool head configured to rotate about a first axis, and to translate along a second axis different than the first axis, an analytic element positioner having an analytic element holder configured to releasably hold an analytic element, and a specimen transfer device mounted on the tool head, where the tool head is configured to automatically position a working end of the specimen transfer device to obtain a specimen from a sample container held in the sample container holder, and to transfer the obtained specimen to an analytic element held by the analytic element holder, respectively, through one or both of rotation of the tool head about the first axis and translation of the tool head along the second axis.SELECTED DRAWING: Figure 10

Description

[Technical Field]

[0001] The present disclosure relates generally to biological specimen preparation, and more particularly to automated systems and methods for collecting biological specimens from liquid specimen containers and dispensing the specimens onto analytical elements such as specimen slides, as well as obtaining aliquots of the samples for further testing. [Background technology]

[0002] Cytology is a branch of biology that deals with the study of cell formation, structure, and function. As applied in the laboratory, cytologists, cytotechnologists, and other medical professionals make medical diagnoses of a patient's condition based on the visual examination of a sample of the patient's cells. A typical cytological procedure is a "cervical cytology," in which cells are scraped from a woman's cervix and analyzed to detect the presence of abnormal cells that may be a precursor to the development of cervical cancer. Cytological procedures are also used to detect abnormal cells and disease in other parts of the human body.

[0003] Cytological techniques are widely adopted because collecting cell samples for analysis is generally less invasive than traditional surgical pathology procedures such as biopsy. In this procedure, a solid tissue specimen is removed from a patient using a specialized biopsy needle with a spring-loaded, movable stylet or fixed cannula. Cell samples can be obtained from a patient by a variety of techniques, including, for example, scraping or swabbing an area, or by using a needle to aspirate bodily fluids from the thoracic cavity, bladder, spinal canal, or other suitable area. Once obtained, the cell sample is typically placed in a preservative solution, then removed and transferred to a glass slide. A fixative is applied to the cell sample to keep the cells in place on the slide and facilitate subsequent staining and examination.

[0004] It is generally desirable for cells on a slide to have a proper spatial distribution so that individual cells can be examined. A monolayer of cells is usually preferred. Therefore, preparing specimens from liquid samples containing many cells (e.g., tens of thousands) typically requires first separating the cells from each other by mechanical dispersion, liquid shearing, or other techniques to recover a thin monolayer of cells and place it on a slide. In this way, cytotechnologists can more easily identify the presence of abnormal cells in a patient sample. Cells can also be counted to confirm that an appropriate number of cells have been evaluated.

[0005] Specific methods and apparatus for producing a thin monolayer of cells from a liquid sample container and then transferring the thin layer to a "specimen slide" suitable for visual inspection are disclosed in U.S. Patent Nos. 5,143,627, 5,240,606, 5,269,918, 5,282,978, 6,562,299, 6,572,824, and 7,579,190, the disclosures of which are incorporated herein by reference in their entireties. According to one method disclosed in these patents, patient cells in a preservative solution within a sample container are dispersed using a rotating sample collector disposed therein. A controlled vacuum is applied to the sample collector to draw the liquid through a screen filter until the desired amount and spatial distribution of cells are collected on the filter. The sample collector is then removed from the sample container, and the filter portion is pressed against a glass slide, transferring the collected cells to the slide in substantially the same spatial distribution as when collected. Devices manufactured according to the teachings of one or more of these patents have been commercially successful, such as the ThinPrep® 2000 Processor (for processing single specimen slides from patient samples) and the ThinPrep® 5000 Processor (for processing batches of specimen slides from patient samples), manufactured and sold by Hologic, Inc. of Marlborough, Massachusetts. See also U.S. Patent Nos. 7,556,777 and 7,771,662, the disclosures of which are incorporated herein by reference in their entireties.

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

[0007] It may be desirable to perform other types of diagnostic testing on the same patient sample, such as human papillomavirus (HPV). Based on the strong correlation between HPV and cervical cancer, HPV DNA testing has been recommended as a triage test for patients whose Pap smear results are classified as ASC-US. If a liquid-based Pap smear analysis is performed, a "reflex" HPV DNA test can be performed using the same sample used for the Pap smear analysis, thereby eliminating the need for a repeat clinic visit or a second Pap smear. For example, if the sample is classified as ASC-US positive, an "aliquot" (e.g., 4 mL) of the liquid sample can be removed 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 for molecular diagnostic laboratories. Therefore, due to the risk of cross-contamination, molecular diagnostic laboratories may not accept aliquots taken from already processed liquid-based Pap smear specimens, as this could unnecessarily produce false HPV positive results. Thus, to preserve a portion of the sample without exposure to cross-contamination, it is desirable to obtain and store an aliquot of each patient sample prior to the specimen slide preparation process. By way of example, certain methods and apparatus for obtaining aliquots of patient samples prior to the specimen slide preparation process are disclosed in U.S. Patent Nos. 7,674,434 and 8,137,289, the disclosures of which are incorporated herein by reference in their entireties. Further examples of obtaining sample aliquots generally, although not necessarily related to specimen slide preparation, are disclosed in U.S. Patent No. 9,335,336 and U.S. Patent Publication No. 2017 / 0052205, the disclosures of which are incorporated herein by reference in their entireties.

[0009] In addition to being used for HPV DNA testing, aliquots from liquid-based Pap smear specimens can also be used for DNA testing for other sexually transmitted diseases, such as Chlamydia trachomatis and Neisseria gonorrhea. However, false positives are a particular problem when testing for Chlamydia trachomatis and Neisseria gonorrhea, as they can have significant impacts on families and society. Therefore, molecular diagnostic laboratories are even more reluctant to accept aliquots from already processed liquid-based Pap smear specimens. Tests for other sexually transmitted diseases need not be used exclusively for triage of ASC-US specimens. In fact, such tests are intended to be performed in parallel with Pap smear testing at the physician's request. Aliquots can be taken from Pap smear specimens before processing, for example, by manually pipetting an aliquot from the vial, thereby minimizing the risk of cross-contamination. However, this step may not yet meet the strict contamination prevention requirements imposed by molecular diagnostic laboratories.

[0010] In addition to contamination issues, pipetting aliquots from liquid-based Pap smear specimens, whether done before or after the specimen is processed for HPV testing or other sexually transmitted infection testing, adds cost by including the manual steps of pipetting the aliquot into an additional vial as well as labeling the vial.

[0011] Therefore, there is a need to provide improved devices and methods for obtaining aliquots from liquid-based biological samples, such as Pap smear samples, while minimizing the risk of cross-contamination. Summary of the Invention

[0012] SUMMARY OF THE DISCLOSURE Embodiments of the present 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 samples contained in liquid sample containers includes a sample container holder configured to hold the sample container and an automated tool head configured to rotate about a first axis and move along a second axis different from the first axis. The system further includes a specimen transfer device mounted on the tool head, which automatically positions a working end of the specimen transfer device to acquire specimens from sample containers held in the sample container holder and then transfers the acquired specimens to analytical elements (e.g., slides) held in the analytical element holder via either or both of the rotation of the tool head about the first axis and the movement of the tool head along the second axis. Without limitation, the working end of the specimen transfer device is configured to receive a filter thereon, the filter including a tubular body that forms a seal with the working end of the specimen 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 includes an analytical element positioner having an analytical element holder configured to releasably grasp an analytical element. The analytical element positioner is configured to automatically place the analytical element loaded on the analytical element positioner into a fixed container held in the fixed container holder after transferring the sample to the analytical element. The system may also include an analytical element (e.g., slide) loading platform located on the tool head surface, the analytical element positioner operatively cooperating with the tool head to automatically engage and disengage the analytical element with the analytical element holder placed on the loading platform, and the analytical element positioner operatively cooperating with the tool head to automatically position the engaged analytical element with the working end of the specimen transport device to transfer the sample to the engaged analytical element.

[0015] The system further includes a sample vessel capping device disposed on the tool head and configured to controllably grasp and release a cap of a sample vessel held by the sample vessel holder, wherein the tool head is configured to automatically position the sample vessel capping device adjacent to the sample vessel cap via one or both of rotation of the tool head about a first axis and / or movement of the tool head along a second axis, and the sample vessel capping device operatively cooperates with the sample vessel holder to remove or attach the sample vessel cap. Without limitation, the sample vessel holder is configured to automatically rotate in one of a clockwise and counterclockwise direction while engaging the sample vessel capping device with the sample vessel cap to remove the sample vessel cap from the sample vessel, and the sample vessel holder is configured to automatically rotate in the other of a clockwise and counterclockwise direction while engaging the sample vessel cap device with the sample vessel cap to attach the sample vessel cap to the sample vessel.

[0016] The system includes a pipette tip dispenser and a pipettor carried by a tool head, the pipetter having a pipette tip engaging member configured to releasably engage a pipette tip, the tool head configured to automatically position the pipette tip engaging member adjacent the pipette tip dispenser and engage the pipette tip engaging member with a pipette tip held in the pipette tip dispenser via either or both of rotation of the tool head about a first axis and movement of the tool head along a second axis.

[0004] Without limitation, the pipette tip dispenser is mounted on a pipette tip dispenser transporter configured to move the pipette tip dispenser relative to the tool head, allowing the pipette tip dispenser to be selectively moved to a position where the tool head engages a pipette tip from the pipette tip dispenser. The system further includes a pipette tip dispenser isolation chamber, and the pipette tip dispenser transporter is configured to selectively move the pipette tip dispenser between a position where the tool head positions the pipette tip engaging member to engage a pipette tip from a pipette tip and a second position within the separation chamber. The pipette tip waste bin can be mounted on the pipette tip dispenser transporter, and the pipette tip dispenser transporter is configured to selectively move the pipette tip waste bin to a position where the tool head positions the pipette tip engaging member to disengage the pipette tip and place it in the waste bin. For example, the pipette tip waste bin may be mounted on the pipette tip transporter relative to the pipette tip dispenser so that the pipette tip dispenser moves into the separation chamber simultaneously when the tool head positions the pipette tip engaging member to disengage the pipette tip and place it in the pipette tip waste bin.

[0017] In embodiments including a pipettor, the system may further include an auxiliary container holder configured to hold an auxiliary container, wherein the tool head is configured to automatically position, via one or both of rotation of the tool head about a first axis and movement of the tool head along a second axis, the first shaft inserted into the sample container and the pipette tip engaging member to a position where a pipette tip engaged with the pipette tip engaging member is inserted into a sample container held in the sample container holder, and a position where the pipette tip is engaged with the engaging member and inserted into an auxiliary container held in the auxiliary container holder, respectively. The auxiliary container may be an aliquot container, and the tool head and the pipettor operatively cooperate to automatically engage pipette tips from the pipette tip dispenser with the pipette tip engaging member to remove aliquots of sample from sample containers held in the sample container holder using the engaged pipette tips and dispense the retrieved sample aliquots into the aliquot containers. Alternatively, but not by way of limitation, the auxiliary container may be a reagent container containing a reagent, and the tool head and pipetter may operatively cooperate to automatically engage a pipette tip engagement member with a pipette tip from the pipette tip dispenser, and use the engaged pipette tip to extract an aliquot of reagent from the reagent container and dispense the reagent aliquot into each sample container held in the sample container holder.

[0018] The auxiliary container capping device is disposed on the tool head and configured to controllably grasp and release a cap of an auxiliary container held in the auxiliary container holder, the tool head is configured to automatically position the auxiliary container capping device adjacent to the auxiliary container cap via one or both of tool head rotation about a first axis and tool head movement along a second axis, and the auxiliary container cap device operatively cooperates 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 a clockwise and counterclockwise direction while the auxiliary container cap device is engaged with the auxiliary container cap to remove the auxiliary container cap from the auxiliary container, and the auxiliary container holder is configured to automatically rotate in the other of the clockwise and counterclockwise direction while the auxiliary container cap 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 vessel capping device and an auxiliary vessel capping device, the two capping devices are offset from one another on the tool head so that when the sample vessel capping device is in a position to grasp and remove the sample, the auxiliary vessel capping device is in a position to grasp and remove the auxiliary vessel cap without further rotation of the head tool.

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

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

[0021] Embodiments of this system may include a controller that controls the operation of one or more of the tool head, pipettor, capping device, and analytical element positioner, and a user interface operatively connected to the controller that displays system status and / or prompts to a system operator and receives user input in response to the displayed system status and / or prompts.

[0022] In one embodiment, an automated system for processing a sample contained in a liquid sample container includes: a sample container holder configured to hold the sample container; an automated tool head configured to rotate about a first axis and move along a second axis different from the first axis; a pipette tip dispenser; a pipettor mounted on the tool head configured to releasably engage a pipette tip, the tool head configured to position a pipette tip engaging member adjacent to the pipette tip dispenser via one or both of the rotation of the tool head about the first axis and the 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 engage the pipette tip held by the pipette tip dispenser. a pipette tip dispenser transporter configured to move the pipette tip dispenser relative to the pipetter, such that the pipette tip dispenser can be selectively moved to a position where the tool head positions a pipette tip engaging member to engage pipette tips 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 to engage pipette tips 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 includes a sample container holder configured to hold the sample container, an automated tool head configured to rotate about a first axis and move along a second axis, a pipette tip dispenser, a pipettor mounted on the tool head, the pipette tip engaging member configured to releasably engage 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 adjacent the pipette tip dispenser via one or both of rotation of the tool head about the first axis and translation of the tool head along the second axis, so that the pipette tip engaging member engages a pipette tip held in the pipette tip dispenser, and to automatically position the pipette tip engaging member via one or both of rotation of the tool head about the first axis and translation of the tool head along the second axis, to a position where the engaged pipette tip is inserted into a sample container held in the sample container holder and an auxiliary container held in the auxiliary container holder. The auxiliary container may be, but is not limited to, 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 includes a sample container holder configured to hold a sample container, an auxiliary container holder configured to hold an auxiliary container, an automated tool head configured to rotate about a first axis and move along a second axis different from the first axis, and a first capping device disposed on the tool head and configured to controllably grasp and release a cap of a sample container held in the sample container holder, wherein the first capping device is configured to automatically position the first capping device adjacent to the sample container cap via one or both of the rotation of the tool head about the first axis and the movement of the tool head along the second axis, and the first capping device is configured to automatically position the first capping device adjacent to the sample container cap. a second capping device disposed on the tool head and configured to controllably grip and release the cap of an auxiliary container held in the auxiliary container holder; the sample container holder and a second capping device disposed on the tool head are configured to controllably grip and release the cap of an auxiliary container held in the auxiliary container holder; the tool head is configured to automatically position the second capping device adjacent to the auxiliary container cap via one or both of rotation of the tool head about the first axis and movement of the tool head along the second axis; and the second capping device is operatively associated with the auxiliary container holder to remove or install the auxiliary container cap. The sample vessel holder can be configured to automatically rotate in one of a clockwise and counterclockwise direction to remove the sample vessel cap from the sample vessel while the first capping device is engaged with the sample vessel cap, and the sample vessel holder can be configured to automatically rotate in the other of the clockwise and counterclockwise direction to attach the sample vessel cap to the sample vessel while the second capping device is engaged with the sample vessel cap.The auxiliary container holder is configured to automatically rotate in one of a clockwise and counterclockwise direction 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 configured to automatically rotate in the other of a clockwise and counterclockwise direction 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, so that 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 rotation of the head tool. The auxiliary container may be, but is not limited to, a reagent container or an aliquot container.

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

[0026] The foregoing and other aspects of the disclosed embodiments will be described in further detail with reference to the accompanying drawings, in which like reference numerals refer to like elements and the description of like elements shall apply to all relevant described embodiments. [Figure 1] FIG. 1 is a right front perspective view illustrating an exemplary automated biological sample processing system according to one embodiment, including 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 outer cabinet walls not shown to better show the system components in place. [Figure 3] FIG. 3 is a left front perspective view of the sample processing cabinet shown in FIG. 1, with exterior and interior walls and / or partitions not shown to better illustrate the system components in place. [Figure 4]4A-4C are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 5] 5A-5C are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 6] 6A-6C are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 7] 7A-7C are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 8] 8 are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 9] 9A-9C are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 10] 10 are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 11] 11 are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 12]12 are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 13] 13 are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 14] 14A-14C are left, right, and front perspective views, respectively, of the system components of the sample processing cabinet shown in FIG. 1, illustrating the various movements and actions performed by the system components during a sample processing procedure. [Figure 15] FIG. 15 is an elevated side perspective view of the components mounted on the rotating tool head in the sample processing cabinet of FIG. 1, with the tool cover not shown. [Figure 16] FIG. 16 is a perspective view of the bottom of the sample processing cabinet of FIG. 1 with the bottom cover plate removed to reveal the system components. [Figure 17] FIG. 17 is a rear perspective view of the sample processing cabinet of FIG. 1 with the bottom cover plate removed to reveal the system components. DETAILED DESCRIPTION OF THE INVENTION

[0027] For purposes of illustration, the systems and methods of use described herein and disclosed in the accompanying drawings are directed to the processing of patient samples to produce conventional cytological specimen slides; however, the preparation of various types of biological specimens (i.e., non-cytological and non-on-slide) presented on various types of analytical elements is intended to be within the scope of the disclosed embodiments and claims. Additionally, the systems and methods disclosed herein can be used to process other types of liquid samples, including non-biological particulates and liquids. Accordingly, it should be understood that the disclosed and illustrated embodiments are presented by way of example and not limitation.

[0028] As used herein, terms such as "specimen," "specimen sample," "biological sample," "cytological specimen," "cell sample," and "biological specimen" may be used interchangeably and should be understood and interpreted similarly unless the context of their use requires a more specific meaning. Additionally, terms such as "aliquot" and "aliquot sample" may be used interchangeably and should be understood and interpreted similarly. For example, but not by way of limitation, the systems and methods disclosed herein can be used to process a biological sample contained in a liquid sample container to produce a specimen or specimen sample, as well as an aliquot or aliquot sample. Furthermore, "aliquot" is another way of expressing a "liquid sample" or "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," "auxiliary container," and other variations thereof may be used interchangeably and should be understood similarly unless the context of their use requires a more specific meaning, for example, based on the contents of the described container.

[0029] As used herein, the terms "automatic" and "automated" mean that a system (device, process, and / or function) runs without user (e.g., system operator) intervention, often, but not necessarily, under the control of a programmed processor. In particular, the automated systems and methods disclosed herein advantageously reduce the number of manual steps required to obtain an aliquot of a patient sample, such as biological sample preparation, e.g., preparation of a cytology specimen slide, and / or additional testing and / or additional sample processing, such as introducing reagents into the sample prior to further processing.

[0030] 1 illustrates an exemplary automated biological sample processing system 10 that can be used to prepare cytology specimen slides and / or aliquot samples from biological samples (e.g., obtained from Pap smears) contained in liquid sample containers. As described in more detail below, system 10 can be used for additional types of sample processing, such as, but not limited to, adding reagents to biological samples or other types of samples.

[0031] System 10 generally includes a sample processing cabinet 11, a slide printer 13, and an aliquot tube printer 19. In the illustrated embodiment, the major components of system 10 are housed in (and / or attached to) sample processing cabinet 11. As described further below, slide printer 13 and aliquot tube printer 15 are operably connected to the sample processing cabinet 11 via known wireless or wired communications connections (not shown) under the control of one or more processors located in the sample processing cabinet 11. For simplicity, the one or more processors are collectively referred to as a "system controller 60" (further described below in connection with FIG. 17), which controls the automated movement and other operations of the components of system 10 housed within the sample processing cabinet 11, as well as communications with each of the slide printers 13 and aliquot vial printers 19. To more easily describe system 10, the components of sample processing cabinet 11, slide printer 13, and aliquot tube printer 19 will be collectively referred to as "system" 10, regardless of where the particular components are housed. It will be appreciated that in alternative embodiments, the various components of system 10 may be housed or provided separately.

[0032] By way of example, and not limitation, system 10 can be configured to process sample containers such as Thin Prep® sample vials and aliquot containers such as Aptima® vials, available from Hologic, Inc. of Marlborough, Massachusetts (www.hologic.com).

[0033] The sample processing cabinet 11 is preferably an environmentally enclosed housing (or "skin") to reduce potential contamination introduced from the surrounding environment. In the illustrated embodiment, the sample processing cabinet 11 is provided with an openable front door 15 to provide access to the system components therein. The door 15 is hinged so that it swings open and closed, and includes a handle 29. In alternative embodiments, the front door 15 may be a sliding door, for example, one that slides open and closed laterally. In the illustrated embodiment, the front door 15 has a transparent or translucent panel, allowing the system components housed in the sample processing cabinet 11 to be visible when the front door 15 is in the closed position, although this is not a requirement for practicing the disclosed embodiments. Also, with brief reference to FIG. 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 typically rests on four legs on a laboratory table. The legs 79 are preferably sized and configured to provide better stability as well as allow some clearance from the table surface.

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

[0035] Aliquot receptacle printer 19 is preferably the same as that taught in U.S. Pat. No. 9,724,948 (the '948 patent), the disclosure of which is incorporated herein by reference in its entirety. As described in the '948 patent, aliquot receptacle printer 19 is provided with an opening 21 into which a new (unprinted) aliquot is inserted. Printer 19 prints indicia (e.g., a bar code) on the aliquot receptacle that match or correspond to the read indicia on the sample container being processed, as described in more detail below. The printed receptacle is then ejected through opening 21 or is available for retrieval therefrom.

[0036] 2 and 3 show the components of system 10 housed or mounted within a sample processing cabinet 11, with the walls of the cabinet housing removed for ease of illustration. Cabinet 11 comprises a chassis 14 having a number of floors, walls, and / or supports, providing the primary support structure for mounting / attaching the various system components.

[0037] As best seen in FIG. 3 , a cylindrical sample container holder 16 is located in a lower, central portion of chassis 14. As described in more detail below, sample container holder 16 is fixedly mounted to a rotational platform configured to rotate sample containers 12 (shown in FIG. 4 ) held in sample container holder 16 about the central z-axis of the containers 12 to mix the samples, uniformly distribute cells or other specific material contained in the sample containers 12 substantially prior to the start of processing, and to facilitate uncapping and re-capping of the containers 12 during processing. In the illustrated embodiment, sample container holder 16 is a cylindrical container configured to snugly receive and hold sample containers 12. Sample container holder 16 has an outer wall that extends to a height less than the height of the sample containers 12, fully exposing the caps 43 of sample containers held in sample container holder 16 to facilitate mixing, uncapping, and recapping. In alternative embodiments, sample container holder 16 is any suitable shape to receive the particular sample containers utilized in system 10, such as a rectangular box or other shape.

[0038] Also best seen in FIG. 3 , aliquot container holder 18 is centrally located on the underside of chassis 14, immediately preceding sample container holder 16. As described in more detail below, aliquot container holder 18 is fixedly mounted to a rotational platform configured to rotate aliquot containers 20 (shown in FIG. 5 ) held in aliquot container holder 18 about the central z-axis of the containers 20 to facilitate uncapping and recapping of the containers 20 during sample processing. Aliquot container holder 18 is configured to closely receive and hold aliquot containers 20 and has outer walls that extend to a height less than the height of the aliquot containers 20, fully exposing the caps 45 of aliquot containers 20 held in aliquot container holder 18 to facilitate mixing, uncapping, and capping. In an alternative embodiment, aliquot container holder 18 is sized and configured to hold containers that are more tubular than those held by sample container holder 16. In alternative embodiments, the aliquot container holder is any suitable shape to receive the particular aliquot container utilized in system 10, such as a rectangular box or other shape. Also, as described below, system 10 can be used for additional sample processing steps, such as introducing reagents to the sample container. Therefore, references to aliquot container holder 18 and aliquot container 20 themselves should be understood to be exemplary and not limiting. For example, the terms "auxiliary container holder" and "auxiliary container" can be used interchangeably with aliquot container holder and aliquot container.

[0039] More specifically, sample container holder 16 and aliquot container holder 18 are each mounted on (or integrally formed with) an underlying rotatable platform (not shown) that is rotatably coupled to or near the floor of chassis 14. Each rotation platform, and thus container holders 16 and 18, selectively rotates in a clockwise or counterclockwise direction about the central z-axis of each holder 16 and 18. In particular, and with further reference to FIG. 16 , a sample dispersion drive assembly is provided that mixes the contents of sample containers 12 held in sample container holders 16 at relatively high speeds to disperse cells and / or other particulate matter suspended within the liquid sample prior to further sample processing. The sample dispersion rotary drive assembly includes a sample dispersion motor (not shown) mounted adjacent the floor of chassis 14, the sample dispersion motor having a rotary output shaft that extends through the chassis floor and rotates drive wheel 81. Drive wheel 81, in turn, rotates larger diameter drive wheel 93 via drive belt 88. The high / low speed clutch 82 is operably connected to the drive wheel 93 and selectively engages the drive wheel 93 with the respective rotational platform associated with the sample container holder 16 via a rotary drive shaft (not shown) that extends rearwardly through the floor of the chassis, thereby also rotating the sample container holder 16 to disperse particles contained in the sample container 12 at relatively high speeds prior to further processing of the sample.

[0040] Continuing to refer to FIG. 15, system 10 further includes a capping drive assembly that simultaneously rotates both sample and aliquot container holders 16 and 18 at a relatively slow speed to remove and replace caps 43, 45, respectively, on sample and aliquot containers 12 and 20 held in the respective sample and aliquot container holders 16 and 18, as described in more detail below. The capping drive assembly includes a capper motor 39 (seen in FIG. 3) mounted on or near the floor of chassis 14 in lower compartment 28 of cabinet 11. The capper motor is reversible, providing rotational motion in clockwise and counterclockwise directions. Capper motor 39 has a rotary output shaft that passes through the floor of chassis 14 and rotates drive gear 84, which in turn rotates a larger drive gear 91 via drive belt 85. A high / low speed clutch 82 is operatively connected to drive gear 91 and selectively engages drive gear 91 with the rotating platforms associated with sample container holder 16 and aliquot container holder 18 via a rotating shaft (not shown) that passes from drive gear 91 back through the chassis floor. Notably, one or more drive gears / wheels and belts (not shown) are further disposed on the bottom of the chassis below the respective rotating platforms of sample container holder 16 and aliquot container holder 18 to simultaneously distribute the rotational motion of wheel 91 to the respective rotating platforms. In this manner, operation of the capping motor simultaneously rotates sample container holder 16 and aliquot container holder 18 at a relatively slow speed, depending on the direction of rotation of the motor output shaft, to remove and reinstall caps 43 and 45.

[0041] Referring to FIG. 4, the system 10 includes an automated tool head 30 rotatably mounted on a load-bearing shaft assembly 34, the tool head 30 configured to pivot or reciprocate about an axis of rotation, as indicated by dashed line 33 in FIG. 7. Preferably, the rotational range of the tool head 30 passes through an arc of at least 270 degrees about the axis of rotation 33, although no specific minimum amount of rotational movement s is required beyond that necessary to perform the function of a particular system embodiment. In the illustrated embodiment, the tool head rotates at least 270 degrees about the axis of rotation 33. The load-bearing shaft assembly 34 preferably includes a spin bearing (not shown) to minimize friction between the tool head 30 and its mounting shaft (not shown). A tool head rotation actuation motor 36 is mounted on the load-bearing shaft assembly 34, and an output shaft (not shown) of the motor 36 is operably coupled to a shaft within the tool head 30 or to rotate the tool head 30 via a drive belt 74. The rotary actuation motor 36 is reversible and selectively provides rotary movement of the tool head 30 in both a clockwise and a counterclockwise direction.

[0042] 4, motor 36 is housed within a block-type support housing (also referred to as item 36 in the figures), which is threadedly mounted to a vertical lead screw 55 (best seen in FIG. 15) located at the rear of chassis 14. Lead screw 55 is actuated by tool head linear actuation motor 32, which is mounted to the rear wall (near the top) of chassis 14. Tool head linear actuation motor 32 is reversible, selectively providing rotational motion of lead screw 55 in both clockwise and counterclockwise directions. In particular, rotation of lead screw 55 in one of a clockwise and counterclockwise rotational direction causes motor block 36, and therefore each load-bearing shaft assembly 34 of tool head 30, to move linearly upward relative to the chassis along a vertical (or "z") axis of movement, as shown by dashed line 51 in FIG. 14 , and rotation of lead screw 55 in the other of a clockwise and counterclockwise rotational direction causes motor block 36, and therefore each load-bearing shaft assembly 34 of tool head 30, to move linearly downward relative to chassis 14 along vertical axis 51. As described further below, this mechanical configuration configures automated tool head 30 to selectively and controllably rotate about rotational axis 33 in each of a clockwise and counterclockwise rotational direction, and to selectively and independently move up and down along vertical axis 51, including simultaneous rotational and translational motion. Operation of rotary actuation motor 36 controls the rotational position of tool head 30 about rotation axis 33 , and operation of linear actuation motor 32 controls the vertical position of tool head 30 along vertical axis 51 inside cabinet 11 .

[0043] A number of sample processing devices (or "tools") are arranged circumferentially around the tool head 30 and are configured such that the respective functions accomplished by each device are accomplished by one or both of rotation of the tool head about its rotation axis 33 and movement of the tool head 30 along its vertical movement axis 51, without requiring movement of the tool head 30 in the x direction (i.e., sideways relative to the cabinet 11) or the y direction (i.e., back and forth relative to the cabinet 11). In the illustrated embodiment, these devices include an indicia reader 31 configured to read indicia, such as a barcode, on a sample container 12; a first capping device 42 having a pneumatically controlled gripper configured to releasably grip the cap 43 of a sample container 12 being processed; 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 a reagent); a pipettor 37 (best seen in FIG. 15) extending outward from the tool head 30 and having a pipette tip engaging member 38 configured to releasably engage a pipette tip; a specimen collection and transfer device (hereinafter "specimen transfer device") 40 having a working end extending outward from the tool head 30 and configured to collect a specimen sample from a specimen container; and a slide loading bed or "platform" 46 (described in more detail below) configured to receive a slide 50 that is delivered by the tool head 30 to a slide holder 57 of a slide positioner assembly 56.

[0044] Devices 31, 42, 44, 37 / 38, 40, and 46 are each positioned on tool head 30 at various circumferential and / or angular positions and orientations about rotation axis 33, and each of these devices rotates with tool head 30 as tool head 30 rotates about rotation axis 33 under the control of rotation actuation motor 34 and moves vertically up and down within cabinet 11 along vertical axis 51 under the control of translation actuation motor 32. Thus, the rotational and / or vertical translational movement of tool head 30 positions each device in a relative rotational and vertical position within cabinet 11 to perform its respective function, as further described herein. It will be appreciated that the particular devices or tools provided on tool head 30 in the illustrated embodiment are not required or limiting. For example, in alternative embodiments, more or fewer devices / tools can be mounted on tool head 30. For example, only a single capping device (e.g., 42 or 44) and / or reader 31 can be provided at a location remote from tool head 30, including not within cabinet 11. As a further example, slide loading platform 46 may be omitted in some embodiments, in which case the system operator loads slides directly into a slide holder, such as slide holder 57. These and / or other variations and permutations of interim devices / tools on tool head 30 are also intended to be within the scope of the present disclosure.

[0045] As seen in FIGS. 3 and 4 , pump 47 with pump head 49 supplies pressurized air stored in high-pressure tank 71, which supplies pressurized air to operate various pneumatic devices within 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 specimen transfer device 40 (described in more detail below). For clarity, the transmission paths for pressurized air, such as the solid and / or flexible tubing lines interconnecting pump 47 to tank 71 and connecting tank 71 to the various pneumatic devices, are not shown to more clearly display the system components located within cabinet 11 without obstruction by tubing. However, the flexible conduits 23 connecting the various pneumatic plumbing and electrical conductions to tool head 30 and the devices located thereon, such as cappers 42 and 44, pipettor 37, and specimen transfer device, are shown (only) in FIG. 2 . Bundling the various tubes and wires through a single conduit 23 reduces the chance that a tube or wire will snag or become dislodged from a connector due to manipulation of the tool arm 30. In particular, the length of the tubes and electrical connections through the conduit 23 is long enough to allow the conduit 23 to move with the tool head 30 as the tool head 30 moves linearly along its vertical axis 51 and rotates about its axis of rotation 33.

[0046] 2 and 3, reader 31 is configured to read identifying indicia, such as (but not limited to) a patient identifier and / or medical record identifier, date, or medical facility from which the sample was obtained, on any of specimen container 12, aliquot container 20, slide 50, and / or filter 54. Reader 31 may be an optical camera that captures an image of a barcode, QR code, machine-readable alphanumeric text, and / or label that is read and / or identified using optical character recognition (OCR) software, or an electronic reader configured to read an NFC chip, RFID, or other electronic tag, or other reader configured to read a readable indicia. Examples of such alternative indicia storage technologies for slides are described in U.S. Pat. No. 7,083,106 and U.S. Patent Publication No. 20070148041, the disclosures of which are incorporated herein by reference in their entireties. In the illustrated embodiment, reader 31 is configured to read indicia, among other things, in the form of a barcode. The indicia on the sample container 12 are read by reader 31 and transmitted via system controller 60 (described in further detail below) to slide printer 13 and aliquot container printer 19, respectively, which print matching or otherwise corresponding indicia on slides 50 and / or aliquot containers 20 used in the sample processing procedure.

[0047] Referring (primarily) to Figures 2-5, a pipette tip dispenser gantry or "transporter" 22 is coupled to the chassis 14 in front of the aliquot container holder 18. The pipette tip dispenser transporter 22 includes a pipette tip dispenser holder 24 configured to fixedly mount a pipette tip dispenser 26 thereon. The pipette tip dispenser is configured to hold a plurality of pipette tips 48, e.g., eight pipette tips in the illustrated embodiment, which may be supplied as a pipette tip cartridge. The pipette tip dispenser 26 is removably attached to the holder 24 in any of several ways. In the illustrated embodiment, 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 enable the system controller 60 to verify, via sensor circuitry, that the dispenser 26 is properly attached and positioned relative to the holder 24. This is important to ensure that the pipette tip engaging members 38 mounted on the tool head 30 are properly aligned and thereby engage the pipette tips 48 held in their respective slots in the dispenser during the sample processing procedure.

[0048] 16, lateral movement of the pipette tip dispenser transporter 22 is effected by a motorized 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 rearward through the floor of the chassis and rotate respective shafts (not shown) that are mechanically coupled to the transporter 22, thereby moving the pipette tip holder 24 and the pipette tip dispenser 26 mounted thereon laterally as well between a storage position in which the pipette tip dispenser is located within the isolated chamber 28, as shown in FIG. 4, and a loading position in which the slots in 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 FIG. 7. In particular, the loading position varies depending on which slots in the dispenser 26 are occupied by pipette tips. In the storage position, each pipette tip holder 24 and its attached pipette tip dispenser 26 is positioned within a separation chamber 28 located within the sample processing cabinet 11, reducing the possibility of contamination of unused tips from sample processing operations taking place in the main interior area of ​​the cabinet 11.

[0049] 4 and 5, panel 52 (FIG. 4) is attached to the side of pipette tip dispenser 26, and is sized and shaped to close the opening through which holder 24 and dispenser 26 enter the isolation chamber. As shown in FIG. 3, pipette tip sensor 35 located in isolation chamber 28 tracks pipette tips 48 held in dispenser 26 and signals system controller 60 to move pipette tip dispenser transporter 22 to the correct position where tips 48 held in dispenser 26 align with pipette tip engaging members 38 on tool head 30, ensuring that dispenser 26 has appropriate pipette tips available. If dispenser 26 is empty or otherwise holds an insufficient number of pipette tips 48 to perform a particular sample processing procedure, system 10 pauses and does not perform further sample procedures until new pipette tips 48 are loaded into dispenser 26.

[0050] The used pipette tip waste bin 25 is mounted on a separate platform / holder 27 attached to the pipette tip transporter 22, and the pipette tip dispenser transporter is configured to selectively move the pipette tip waste bin 25 to a position where the tool head 30 disengages the pipette tips 48 that have engaged their pipette tip engaging members 38 from the waste container 25. Like 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 proper attachment via detection circuitry. In particular, the pipette tip waste bin holder 27 is mounted on the pipette tip transporter 22 relative to the pipette tip dispenser holder 24, such that when the pipette tip dispenser 26 is moved into the isolated chamber 28, the pipette tip waste bin 25 simultaneously moves to a position where the tool head 30 positions the pipette tip engaging members 38 to disengage the engaged / used pipette tips 48 into the waste bin 25.

[0051] 15, the pipettor 37 is positioned on the tool head with the pipette tip engaging member 38 at a slight angle relative to the pipette tip dispenser 26, which is likewise slightly angled to conform to engage a pipette tip 48 held in one of the slots by one or both of the rotational and translational movements of the tool head 30. The pipettor 37 may be, but is not limited to, a CAVRO® Air Displacement Pipettor (ADP) sold by Tecan Group Ltd. (www.tecan.com / components), which includes a spring-loaded engagement tip 53 (FIG. 15) that engages each pipette tip 48, such as by a compression fit of the release engagement tip 53, when inserted into the bore of the pipette tip. The pipette 37 is configured to selectively draw liquid from the sample container 12 into the pipette tip 48 when the pipette tip 48 engages (or is placed on) the pipette tip engaging member 38, and to dispense the liquid contained within the retracted pipette tip 48.

[0052] In this manner, during a sample processing procedure, the pipettor 37 engages a pipette tip 48 from the pipette tip dispenser 26. The pipettor 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 a known manner, the pipettor 37 is made of a conductive material (e.g., a conductive polymer) and uses impedance sensing circuitry in the pipettor 37 to ensure that the pipette tip 48 is submerged in liquid in order to draw a sample, e.g., an aliquot from a sample container, by applying a vacuum within the bore of the pipette tip 48 to draw a volume of sample into the pipette tip 48. The pipettor 37 then releases the vacuum to dispense the sample from the pipette tip 48, e.g., into the open aliquot container 20. The pipettor 37 is configured and operative so that only the pipette tip 48 comes into contact with the sample material, and the pipette tip engaging member 38 of the pipettor 37 is not contaminated by the sample material. The pipette tip engaging member 38 is configured to disengage 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 specimen transfer device 40 is carried by the tool head 30 and is configured to collect a specimen from a sample in the specimen container 12 and transfer the collected specimen to a slide 50. In the embodiment described above, the specimen transfer device 40 includes a cylindrical working end extending from the tool head 30 and configured to form a pressure-tight seal around a filter 54 that is seated thereon prior to initiating a sample processing procedure, as shown in FIG. 4 . The filter 54 includes a hollow cylinder having an open proximal end and a membrane with pores of a size selected to capture desired cells for the specimen and across the distal end to allow smaller cells, non-cellular particles, and liquid to pass through. Embodiments of the filter 54, as well as specimen sample collection and transfer devices and technology suitable for use in the illustrated system 10, are disclosed and further described in U.S. Pat. No. 8,119,399, U.S. Patent Publication No. 20050100483, and U.S. Patent Publication No. 20080145887, the disclosures of which are incorporated herein by reference in their entireties. When installed at the working end of the specimen transport device 40, the filter 54 extends from the tool head 30 a distance sufficient to insert the filter into the sample container 12 and collect the specimen sample on the membrane of the filter so that the sample liquid contacts only the filter and not any part of the specimen transport device 40. This ensures that the specimen transport device 40 is not contaminated with sample material as it collects the specimen sample from the sample container 12. Once the specimen transport device 40 has collected the specimen into the sample collector 54, it is operated to transfer the specimen from the filter 54 to the slide 50, as described in more detail below.

[0054] In particular, the specimen transfer device 40 and system 10, via one or both of the translational and rotational motions of the tool head 30, insert a filter membrane into the sample in the sample container and force the sample back and forth through the membrane, collecting the specimen sample on the membrane in a "suck" manner, depositing a thin layer of cells in the liquid sample on the outer surface of the membrane. The specimen transfer device 40 can be configured to circulate a vacuum (and pressure) within the working end of the specimen transfer device to move the sample back and forth through the membrane. Additionally or alternatively, the specimen transfer device 40 and system 10 can be configured to move the membrane up and down within the sample to shuttle the sample through the membrane and collect the specimen sample on the membrane. A method and apparatus using this same "sipping process" to determine whether a sufficient number of cells, but not too many, have been collected on the filter membrane is disclosed and described in the aforementioned U.S. Patent No. 8,119,399. Further details of the general specimen collection process, and the design and operation of specimen transfer device 40 (and filter 54) can be found in U.S. Patent No. 8,137,642, the disclosure of which, as well as several other patents mentioned above, is incorporated herein by reference in its entirety. Referring briefly to Figure 17, waste from the specimen collection process is removed through port 95 at the rear of cabinet 11.

[0055] The sample vessel capping device 42 includes movable pneumatic prongs or "grippers" configured to grip and hold the cap 43 of the sample vessel 12. As can be seen in FIG. 15 , the grippers are actuated by air pressure supplied to an actuation member 77 to provide a tweezers-like radially inward gripping motion or a radially outward release motion. Two or more grippers are preferably spaced approximately evenly around the circumference of the sample vessel cap 43 and can be positioned in an "capping" or "uncapping" position by one or more translational and rotational motions of the tool head 30. To remove the cap 43, the cappers 42 grip the cap 43 while the vessel holder 16 is rotated in either a clockwise or counterclockwise direction, and the tool head 30 is raised slightly and steadily, moving the cap 43 upward as it rotates on the threads of the vessel 12. When attaching a gripper-held cap 43 to a container 12, tool head 30 positions capper 42 over an open container and rotates holder 16 in the other of the clockwise and counterclockwise directions, causing tool head 30 to move slightly and steadily, while tool head 30 moves cap 43 downward onto container 12 as container holder 16 rotates the container relative to cap 43. Grippers used for sample container capping device 42 and for aliquot container capping device 44 described below include parallel style air grippers / two-finger, three-finger, and four-finger series grippers available from SMC Pneumatics.com.

[0056] The aliquot container capping device 44 operates in substantially the same manner as a sample container capper, and includes two or more prongs or grippers for releasably gripping the cap 45 of an aliquot container 20 while the aliquot container holder rotates clockwise or counterclockwise to remove or attach the cap 45 to the container 20. Again, the tool head 30 steadily moves up and down to accommodate movement of the cap relative to the container 20 during processing. Notably, as seen in FIG. 15 , the torque required to uncap and cap an aliquot container 20 is small, so the aliquot container grippers are powered using direct air pressure supplied via a 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 place and can be removed without removing the respective caps 43 and 45.

[0058] In an alternative embodiment, cappers 42 and 44 are each rotatable, and the capping process then includes steps in which capper 42 grips cap 43 and rotates while the sample holder remains stationary, and capper 44 grips grip cap 45 and rotates while the aliquot holder 18 remains stationary, as taught and apparent in, for example, the above-incorporated U.S. Pat. No. 9,335,336 and U.S. Patent Publication No. 2017 / 0052205.

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

[0060] As described above, slide positioner 56 includes slide holder 57 with pneumatic gripper 59 configured to grasp and remove slide 50 from loading platform 46 (this movement is seen in FIG. 5 ), and then position the slide to receive the specimen sample acquired by specimen transport device 40. The slide positioner is also movable in at least two degrees of freedom provided by slide positioner motor 63 and various hinge arms, and is supported by counterweight 64. After compressing the membrane of filter 54 against slide 50 to displace the specimen sample ( FIG. 12 ), the slide positioner is configured to move slide 50 and rotate slide 50 90 degrees adjacent an open container of fixative 58 secured in fixative container holder 61, whereupon slide positioner 56 grasps and moves slide 50. As a result, the slide positioner 56 includes a pneumatically controlled gripper 59 configured to grasp the slide 50 and remove it 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 specimen transport device 40 can transfer the specimen sample from the filter 54 to the slide 50, and then to a fixation position, as shown in Figure 11, where the analysis positioner 50 can deposit the specimen sample into a fixative container 58 containing a fixative that fixes the specimen sample to the slide 50. The system 10 includes a fixative container holder 61.

[0061] Referring to FIG. 17 , the system 10 also includes one or more processors, collectively referred to as a controller 60, located on the rear panel of the cabinet. The controller 60 is operatively coupled to, communicates with, and controls the automated operation of various components of the system 10, including the tool head 30, the tool head actuator 32, the pipettor 37, the specimen transfer device 40, the first capping device 42, the second capping device 44, the slide positioner 56, and the reader 31. The controller 60 includes a computer processor, input / output interfaces, and other supporting electronics that communicate with and control the operation of the system components. The controller 60 includes a user input device that allows a system operator to input commands, data, and the like into the controller 60. The user input device may be a touchscreen / display 62, as described below. The controller 60 also includes system software that programs the controller to communicate with and control the system 10 to execute procedures for preparing sample specimens and / or aliquot samples from biological or other samples contained in the sample containers 12, as described herein. In the illustrated embodiment, a touchscreen / display 62 is mounted on the chassis, preferably incorporated into the cabinet housing, and is positioned to allow a system operator to input instructions (e.g., when prompted by the system 10) and to view the status of items being performed during sample processing procedures. The touchscreen / display 62 is configured to display graphics generated by the controller 60, including information regarding the operation of the system 10, such as operating status, data, etc. The touchscreen / display 62 may be any suitable display, such as a liquid crystal display (LCD), an LED display, an AMOLED, etc.

[0062] An exemplary sample processing procedure will now be described with reference to Figures 1-14 to illustrate and explain the various elements and components of system 10. In particular, the exemplary sample processing steps include first obtaining an aliquot of a sample and then processing the sample to produce a biological specimen slide. This process is described for purposes of illustration and not limitation, and it should be understood that other types of sample processing can be performed using the disclosed and described system and variations thereof while remaining within the scope of this disclosure. By way of example, and without limitation, each method of using an automated system to process a sample contained in a sample container as set forth in the appended claims should be considered an additional exemplary sample processing procedure that can be performed using the illustrated system 10.

[0063] To begin processing a given patient sample container 12, the system operator inputs instructions, for example, by touching a "start button" or similar symbol on the user interface 62. The system controller 60 causes the tool head 30 to assume a "start" position (if the tool head 30 is not within the cabinet 11), in which case the tool head 30 is positioned within the cabinet 11 and rotates to position the reader 31 in a convenient location for the system operator to view the sample vial 12, as shown in FIG.

[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 indicia on the sample container 12 are within the field of view of the reader 31. The reader 31 reads the indicia 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 an indicia matching or corresponding to the indicia 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 an indicia on the aliquot container 20, which also matches or corresponds to the indicia on the sample container 12.

[0065] The pipette tip dispenser transporter 22 moves to a loading position (FIG. 2) to expose the pipette tip dispenser 26 when additional tips 48 need to be added. Loading of the sample containers 12, aliquot containers 20, slides 50, and pipette tip dispensers 26 into the system 10 can be automated, such as by using a robot, or can be performed manually by a system operator. The latter is assumed for simplicity. In particular, the system operator loads the (capped) sample containers 12 into the sample container holder 16 and the (capped) aliquot containers 20 into the aliquot container holder 18, in each case verifying that the respective sample and aliquot container labels match after reading the reader 31. The system operator loads the slide 50 face-down onto the slide loading platform 46, i.e., the slide has indicia and a "sample spot" area printed on its side, face-down to receive the specimen sample on the platform 46. The system operator loads a new filter 54 into the working end of the specimen transport device 40, ensures that the pipette tip dispenser 26 has the appropriate number of (at least one) unused pipette tips 48, and that the pipette tip waste bin is empty. Once all consumables are loaded, the system operator closes the door 15 of the cabinet 11 and, assuming all system verifications are complete, indicates via the user interface that the sample processing procedure can begin.

[0066] In particular, the system 10 will not begin a sample processing procedure unless the sensor 35 indicates that at least one sufficient number of pipette tips 48 are present in the dispenser 26, and unless the pipette tip dispenser 26 and waste bin 25 are properly positioned and magnetically coupled to their respective mounting platforms 24 and 27 on the pipette tip dispenser transporter 22. The specimen transporter 40 also performs a "dry" test to verify the integrity of the filter 54, specifically ensuring that the distal membrane is not punctured (indicating that the filter 54 has already been used), blocked, or torn. Specifically, once the presence of the appropriate pipette tips 48 is confirmed, the system moves the pipette tip dispenser transporter and places the pipette tip dispenser in the isolation chamber 28. From that point until the sample processing procedure is complete, no system operator intervention is typically required.

[0067] 4-6, at the start of a sample processing procedure, the pipette tip dispenser transporter 22 moves the pipette tip dispenser to a storage position within the isolation chamber 28 (FIG. 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 as the reader 31 reads the indicia on the side 50 to confirm that the indicia match the indicia on the sample container 12 and the aliquot container 20, respectively. Assuming a match is confirmed, the system 10 continues to execute the automated process to prepare specimen and aliquot samples in each component of the system 10 operated and controlled by the controller 60.

[0068] As shown in Figure 6, tool head 30 is rotated and moved vertically downward by tool head actuator 34 to position sample container capping device 42 over cap 43 of sample container 42 and aliquot container capping device 44. Respective capping devices 42 and 44 remove and grasp caps 43 and 45 in cooperation with the rotation of respective container holders 156 and 18.

[0069] As shown in Figure 7, the pipette tip dispenser transporter 22 moves to the loading position to position and attach a pipette tip 48 included in the pipette tip dispenser 26 to the pipette tip engaging member 38 of the pipettor 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 into the pipette tip 48.

[0070] 8, the pipette tip dispenser transporter 22 returns to the storage position. The tool head 30 rotates and moves vertically to place the pipette tip 48 on the pipettor 37 into the sample in the sample container 12. The pipettor 37 applies a vacuum within the pipette tip 48 to draw a volume of sample (an aliquot sample) into the pipette tip 48.

[0071] 9, tool head 30 rotates and moves vertically to position pipette tip 48 within aliquot container 20. Pipettor 37 releases vacuum to dispense an aliquot sample from pipette tip 48 into aliquot container 20. After dispensing the aliquot sample into aliquot container 20, tool head 30 rotates and moves to place aliquot container capping device 44 in place and replace cap 45 onto aliquot container 20 (the same position as shown in FIG. 6).

[0072] 10, the tool head 30 is rotated and moved vertically to position the pipette tip 48 on or within the waste container 25. The pipette tip engaging member 38 then disengages (ejects) the used pipette tip 48 into the waste bin.

[0073] 11, the tool head 30 is rotated and moved to place the filter 54 mounted on the specimen transfer device 40 in place, and the specimen sample is collected from the specimen container 20 onto the filter membrane by following the process described above, i.e., by moving the filter up and down, such as by cycling vacuum and / or moving the tool head 30 via the tool head actuator 34, to move the sample back and forth through the membrane. This process allows for the collection of a thin layer or monolayer of cells onto the membrane.

[0074] As shown in FIG. 12 , the tool head 30 rotates and moves to place the filter membrane in place and transfer the specimen sample to the slide 50 held by the gripper 59 of the slide holder 57. The specimen transport device 40 and / or slide positioner 56 are then operated to contact the membrane with the specimen sample thereon onto the slide 50. The tool head 30 is moved by the tool head actuator 34 to operate the specimen transport device 40. To transfer the specimen sample (e.g., a thin layer of cells) to the slide 50 without disturbing its spatial distribution, it is generally desirable for the filter membrane 54 to first contact the slide 50 at a single location, form a predetermined small preliminary contact angle between the membrane and the deposition surface of the slide 50, and then gently and gradually make full contact with the slide 50. This is achieved by operating the specimen transport device 40 and slide positioner 56 in coordination.

[0075] As shown in FIG. 13 , the tool head 30 can also move downward to provide space for the slide positioner 56 to place the slide 50 with the specimen sample thereon into a fixative container 58 containing a fixative that will secure the specimen sample to the slide 50. After the specimen sample is transferred to the slide 50, the tool head 30 moves and / or rotates to press the filter membrane onto the pins 41 ( FIG. 4 ), destroying the filter membrane and preventing it from being reused. As also shown in FIG. 13 , the slide positioner 56 is actuated to place the slide 50 with the specimen sample into the fixative container 58. Once the sample processing procedure is complete, the system operator can remove the specimen slide 50 from the fixative solution in the container 58, or remove the fixative container containing the specimen slide 50 and replace (or place a new one in) the fixative container 58 in the holder 61 before starting a new sample processing procedure.

[0076] The tool head 30 is rotated and moved downwards to put the sample vessel capping device 42 into place and reattach the cap 43 to the sample vessel 12 (in the same position as shown in Figure 4).

[0077] This completes the automated process of preparing specimen samples and aliquot samples. The slide 56 with the specimen sample fixed by the fixative is then removed from the fixative container 58 and is available 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 dumped into a waste bin, discarding the used pipette tip 48. The waste container 25 is then placed back onto the waste container platform 27.

[0078] The process described herein can be repeated as needed for additional sample vessels containing respective samples.

[0079] While particular embodiments have been shown and described, it should be understood that the above description is not intended to limit the scope of these embodiments. While variations of many aspects of the embodiments disclosed herein have been disclosed and described, it should be understood that the foregoing disclosure is provided for purposes of illustration and example only, and that various changes and modifications may be made to the disclosed embodiments without departing from the scope of the following claims. For example, not all of the components shown and described in the embodiments are required, and alternative embodiments may include any suitable combination of the described components, and the general shapes and relative sizes of the components may be changed.

Claims

1. 1. An automated system for processing a sample contained in a liquid sample container, comprising: a sample vessel holder configured to hold a sample vessel; an auxiliary container holder configured to hold an auxiliary container; an automated tool head configured to rotate about a first axis and translate along a second axis different from the first axis; a first capping device disposed on the automated tool head and configured to controllably grip and release caps of sample vessels held in the sample vessel holder, the automated tool head configured to automatically position the first capping device adjacent to the caps of the sample vessels through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis, the first capping device operatively cooperating with the sample vessel holder to remove or install the caps of the sample vessels; a second capping device disposed on the automated tool head and configured to controllably grip and release a cap of an auxiliary container held in the auxiliary container holder, the automated tool head configured to automatically position the second capping device adjacent to the cap of the auxiliary container through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis, the second capping device operatively cooperating with the auxiliary container holder to remove or install the cap of the auxiliary container; a pipette tip dispenser; a pipettor carried by the automated tool head, the pipettor having a pipette tip engaging member configured to releasably engage a pipette tip, the automated tool head configured to automatically position the pipette tip engaging member proximate the pipette tip dispenser to enable the pipette tip engaging member to engage a pipette tip held by the pipette tip dispenser through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis; and An automated system comprising:

2. 2. The automated system of claim 1, wherein the sample vessel holder is configured to automatically rotate in one of a clockwise direction and a counterclockwise direction while the first capping device is engaged with the cap of the sample vessel to remove the cap of the sample vessel from the sample vessel, and the sample vessel holder is configured to automatically rotate in the other of the clockwise direction and the counterclockwise direction while the second capping device is engaged with the cap of the sample vessel to attach the cap of the sample vessel onto the sample vessel.

3. 3. The automated system of claim 2, wherein the auxiliary container holder is configured to automatically rotate in one of a clockwise direction and a counterclockwise direction while the second capping device is engaged with the cap of the auxiliary container to remove the cap of the auxiliary container from the auxiliary container, and the auxiliary container holder is configured to automatically rotate in the other of the clockwise direction and the counterclockwise direction while the second capping device is engaged with the cap of the auxiliary container to attach the cap of the auxiliary container onto the auxiliary container.

4. 4. The automated system of claim 3, wherein the first capping device and the second capping device are offset from each other on the automated tool head, such that when the first capping device is in a position to grasp and remove the cap of the sample container, the second capping device is in a position to grasp and remove the cap of the auxiliary container without further rotational movement of the automated tool head.

5. The automated system of claim 4 , wherein the auxiliary container is one of a reagent container and an aliquot container.

6. 2. The automated system of claim 1, wherein the auxiliary container holder is configured to automatically rotate in one of a clockwise direction and a counterclockwise direction while the second capping device is engaged with the cap of the auxiliary container to remove the cap of the auxiliary container from the auxiliary container, and the auxiliary container holder is configured to automatically rotate in the other of the clockwise direction and the counterclockwise direction while the second capping device is engaged with the cap of the auxiliary container to attach the cap of the auxiliary container onto the auxiliary container.

7. 7. The automated system of claim 6, wherein the first capping device and the second capping device are offset from each other on the automated tool head, such that when the first capping device is in a position to grasp and remove the cap of the sample container, the second capping device is in a position to grasp and remove the cap of the auxiliary container without further rotational movement of the automated tool head.

8. The automated system of claim 7 , wherein the auxiliary container is one of a reagent container and an aliquot container.

9. 2. The automated system of claim 1, wherein the first capping device and the second capping device are offset from each other on the automated tool head, such that when the first capping device is in a position to grasp and remove the cap of the sample container, the second capping device is in a position to grasp and remove the cap of the auxiliary container without further rotational movement of the automated tool head.

10. The automated system of claim 9 , wherein the auxiliary container is one of a reagent container and an aliquot container.

11. 3. The automated system of claim 2, wherein the first capping device and the second capping device are offset from each other on the automated tool head, such that when the first capping device is in a position to grasp and remove the cap of the sample container, the second capping device is in a position to grasp and remove the cap of the auxiliary container without further rotational movement of the automated tool head.

12. The automated system of claim 11 , wherein the auxiliary container is one of a reagent container and an aliquot container.

13. The automated system of claim 1 , wherein the auxiliary container is one of a reagent container and an aliquot container.

14. The automated system of claim 2 , wherein the auxiliary container is one of a reagent container and an aliquot container.

15. The automated system of claim 3 , wherein the auxiliary container is one of a reagent container and an aliquot container.

16. An automated system for processing a sample contained in a liquid sample container, comprising: a sample vessel holder configured to hold a sample vessel; an auxiliary container holder configured to hold an auxiliary container; an automated tool head configured to rotate about a first axis and translate along a second axis different from the first axis; a first capping device disposed on the automated tool head and configured to controllably grip and release caps of sample vessels held in the sample vessel holder, the automated tool head configured to automatically position the first capping device adjacent to the caps of the sample vessels through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis, the first capping device operatively cooperating with the sample vessel holder to remove or install the caps of the sample vessels; a second capping device disposed on the automated tool head and configured to controllably grip and release a cap of an auxiliary container held in the auxiliary container holder, the automated tool head configured to automatically position the second capping device adjacent to the cap of the auxiliary container through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis, the second capping device operatively cooperating with the auxiliary container holder to remove or install the cap of the auxiliary container; an analytical element positioner having an analytical element holder configured to releasably grasp an analytical element; a specimen transfer device carried by the automated tool head at a circumferential position on the automated tool head that is angularly spaced about the first axis from the first capping device and the second capping device, whereby the specimen transfer device rotates with the automated tool head when the automated tool head is rotated about the first axis, and the automated tool head is configured to automatically position a working end of the specimen transfer device through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis to acquire a specimen from a sample container held in the sample container holder and transfer the specimen acquired from the sample container to an analytical element held by the analytical element holder, respectively; An automated system comprising:

17. 2. The automated system of claim 1, further comprising a pipette tip dispenser transporter, wherein the pipette tip dispenser is mounted on the pipette tip dispenser transporter, and the pipette tip dispenser transporter is configured to translate the pipette tip dispenser relative to the automated tool head such that the automated tool head can selectively translate the pipette tip dispenser to a position where the automated tool head positions the pipette tip engaging member to engage pipette tips from the pipette tip dispenser.

18. 18. The automated system of claim 17, further comprising a pipette tip disposal bin mounted on the pipette tip dispenser transporter, the pipette tip dispenser transporter configured to selectively translate the pipette tip disposal bin to a position where the automated tool head positions the pipette tip engagement member to disengage pipette tips into the pipette tip disposal bin.

19. 2. The automated system of claim 1, wherein the automated tool head is configured to automatically position the pipette tip engaging member to a position where a pipette tip engaged on the pipette tip engaging member is inserted into a sample container held in the sample container holder and to a position where the engaged pipette tip is inserted into an auxiliary container held in the auxiliary container holder, through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis, respectively.

20. 1. An automated system for processing a sample contained in a liquid sample container, comprising: a sample vessel holder configured to hold a sample vessel; an auxiliary container holder configured to hold an auxiliary container; an automated tool head configured to rotate about a first axis and translate along a second axis different from the first axis; a first capping device disposed on the automated tool head and configured to controllably grip and release caps of sample vessels held in the sample vessel holder, the automated tool head configured to automatically position the first capping device adjacent to the caps of the sample vessels through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis, the first capping device operatively cooperating with the sample vessel holder to remove or install the caps of the sample vessels; a second capping device disposed on the automated tool head and configured to controllably grip and release a cap of an auxiliary container held in the auxiliary container holder, the automated tool head configured to automatically position the second capping device adjacent to the cap of the auxiliary container through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis, the second capping device operatively cooperating with the auxiliary container holder to remove or install the cap of the auxiliary container; a pipettor carried by the automated tool head, the pipetter having a pipette tip engaging member configured to releasably engage a pipette tip, the automated tool head configured to automatically position the pipette tip engaging member through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis to a position where a pipette tip engaged on the pipette tip engaging member is inserted into a sample container held in the sample container holder and a position where the engaged pipette tip is inserted into an auxiliary container held in the auxiliary container holder, respectively; wherein the automated system is configured to automatically cause the pipette tip engaging member to draw an aliquot of sample from the sample container and dispense the aliquot of the drawn sample into the auxiliary container.

21. further comprising a pipette tip dispenser; 21. The automated system of claim 20, wherein the automated tool head is configured to automatically position the pipette tip engaging member proximate the pipette tip dispenser to enable the pipette tip engaging member to engage with pipette tips held by the pipette tip dispenser through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis.

22. an analytical element positioner having an analytical element holder configured to releasably grasp an analytical element; a specimen transfer device carried by the automated tool head at a circumferential position on the automated tool head that is angularly spaced about the first axis from the first capping device and the second capping device, whereby the specimen transfer device rotates with the automated tool head when the automated tool head is rotated about the first axis, and the automated tool head is configured to automatically position a working end of the specimen transfer device through one or both of rotation of the automated tool head about the first axis and translation of the automated tool head along the second axis to acquire a specimen from a sample container held in the sample container holder and transfer the specimen acquired from the sample container to an analytical element held by the analytical element holder, respectively; 21. The automated system of claim 20, further comprising:

23. 21. The automated system of claim 20, wherein the sample vessel holder is configured to automatically rotate in one of a clockwise direction and a counterclockwise direction while the first capping device is engaged with the cap of the sample vessel to remove the cap of the sample vessel from the sample vessel, and the sample vessel holder is configured to automatically rotate in the other of the clockwise direction and the counterclockwise direction while the second capping device is engaged with the cap of the sample vessel to attach the cap of the sample vessel onto the sample vessel.

24. 24. The automated system of claim 23, wherein the auxiliary container holder is configured to automatically rotate in one of a clockwise direction and a counterclockwise direction while the second capping device is engaged with the cap of the auxiliary container to remove the cap of the auxiliary container from the auxiliary container, and the auxiliary container holder is configured to automatically rotate in the other of the clockwise direction and the counterclockwise direction while the second capping device is engaged with the cap of the auxiliary container to install the cap of the auxiliary container onto the auxiliary container.

25. 25. The automated system of claim 24, wherein the first capping device and the second capping device are offset from each other on the automated tool head, such that when the first capping device is in a position to grasp and remove the cap of the sample container, the second capping device is in a position to grasp and remove the cap of the auxiliary container without further rotational movement of the automated tool head.

26. 26. The automated system of claim 25, wherein the auxiliary container is one of a reagent container and an aliquot container.

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