Sample processing systems, methods, and devices

Abstract

The present disclosure provides systems, methods, and devices for sample processing. Sample processing may include rapid on-site assessment of samples, and additional types of sample processing. The sample processing methods and techniques provided herein facilitate consistent and rapid sample processing to obtain sample slides and sample images. The sample processing systems and devices provided herein facilitate the sample processing methods.

Description

[Technical field]

[0001] Related inventions This application claims priority to U.S. Provisional Application No. 63 / 210,972, filed June 15, 2021, and U.S. Provisional Application No. 63 / 323,187, filed March 24, 2022, each of which is incorporated herein by reference.

[0002] The present invention relates to systems, methods, and devices configured to facilitate sample processing, including automated sample processing and rapid on-site sample grading. [Background technology]

[0003] Rapid on-site evaluation (ROSE) is an important aspect of the biopsy procedure that can reduce the number of needle passes, improve patient safety, and increase diagnostic yield. The goal of ROSE is to determine whether a biopsy sample contains sufficient cellular and tissue content to produce a definitive diagnosis when analyzed in a pathology laboratory. Other uses of ROSE include informing tissue collection and triage, and providing a preliminary diagnosis to the interventional physician.

[0004] Traditionally, in ROSE, biopsy samples are smeared or touch imprinted onto glass slides by a cytotechnologist or cytopathologist to create a thin layer of cellular material. The slides are then manually stained using rapid stains such as Diff Quik or Toludine Blue to enhance the contrast between the different biological elements of the slide. Finally, the slides are examined under a light microscope by a cytologist and analyzed for relevance, triage, and / or preliminary diagnosis.

[0005] ROSE has proven its usefulness in a wide range of biopsy sites, including thyroid, liver, pancreas, lung, breast, sentinel lymph node, bone marrow, and others. ROSE is recommended by many major clinical societies, including the Society of Pulmonary Pathology, the Papanicolaou Cytopathology Society, and the American Thyroid Association. Additionally, ROSE may become increasingly important in procedures such as bronchoscopic lung biopsy to facilitate delivery of therapeutic agents (cryotherapy, microwave ablation, drug delivery, etc.) immediately following confirmation of a ROSE-facilitated positive biopsy result.

[0006] However, ROSE is only used in approximately half of non-skin biopsy procedures due to cytology staff shortages, logistical challenges, and pathologist bandwidth. These challenges are amplified in procedures such as bronchoscopic lung biopsy, endobronchial ultrasound (EBUS) lymph node staging, and percutaneous CT-guided biopsy, where long procedure times place additional strain on cytology department resources. Furthermore, ROSE validity and diagnosis are subject to inter-operator variability in both slide preparation and interpretation (two cytologists will not produce equivalent slides or make the same validity judgments), often causing frustration and time delays for interventional staff. For complex procedures such as bronchoscopic lung biopsy, even using traditional ROSE techniques, more than 20-40% of biopsies fail in providing a final diagnosis in the pathology laboratory, necessitating a repeat biopsy procedure.

[0007] Given the shortcomings of traditional ROSE, it is not surprising that other approaches have been attempted to improve the process of validation and on-site diagnosis. There are several devices that provide digitization and transmission of ROSE slides, or remote-operated microscopes that allow cytopathologists to view ROSE slides remotely. However, such devices still rely on cytologists in the operating room to prepare the slides, and do not overcome the logistical and inter-operator variability issues associated with some ROSE implementations.

[0008] Several potential solutions are being pursued, such as Raman scattering microscopy of excised tissue and needle-based confocal laser microscopy. Although attractive in principle, these approaches fall short of the resolution and fidelity of tissue imaged on a glass slide. Moreover, these approaches produce unfamiliar images that require new training for interventionalists and pathologists.

[0009] Thus, there is a need for improved sample processing methods and techniques that reduce sample processing time, increase the uniformity of sample processing, and reduce the operator time required for sample processing. Summary of the Invention

[0010] In one embodiment, a method of sample separation is provided that may include depositing a sample into a sample receptacle, the sample receptacle including a membrane, aligning the sample receptacle with a sample slide, applying a probe to a lower surface of the sample receptacle to cause movement of the membrane, and pressing the sample against the sample slide via the movement to deposit at least a portion of the sample on the sample slide.

[0011] In one embodiment, a method of sample smearing is provided, which may include engaging a gripping device with a first side of a smear plate via an actuation probe, controlling the actuation probe to cause contact between a second side of the smear plate and a sample disposed on a surface of a sample slide, controlling a force applied to the smear plate during contact with the sample, and causing relative movement between the smear plate and the sample slide to distribute the sample on the surface of the sample slide.

[0012] In one embodiment, a method of sample staining is provided, which may include placing a sample slide and a coverslip in a flood start position, the flood start position being defined such that a slide surface of the sample slide with the sample disposed thereon and a slip surface of the coverslip have a vertical gap and the sample slide and coverslip have a horizontal overlap, the vertical gap and the horizontal overlap defining a volume, applying fluid to at least one of the sample slide or coverslip such that when the sample slide and coverslip are placed in the flood start position, fluid is present in the vertical gap, placing the sample slide and coverslip through relative movement that increases the horizontal overlap in a flood end position, the flood end position being defined such that the horizontal overlap has a maximum horizontal distance whereby the fluid fills the volume, and applying additional fluid to at least one of the sample slide or coverslip to fill the volume as the horizontal overlap increases.

[0013] In one embodiment, a sample cartridge is provided that may include a first cartridge component including a slide support configured to support a sample slide and a second cartridge component including a coverslip support configured to support a coverslip at a coverslip window, the second cartridge component configured for movement relative to the first cartridge component, the first cartridge component and the second cartridge component configured to cooperate to maintain a vertical gap between the sample slide and the coverslip, and the second cartridge component further configured to move from a flood start position relative to the first cartridge component to a flood end position relative to the first cartridge component.

[0014] In one embodiment, a method for sample preparation is provided. The method may include: placing a sample slide disposed in a first cartridge component of a sample cartridge and a cover slip disposed in a second cartridge component of the sample cartridge in a flood start position, the flood start position being defined such that the slide surface of the sample slide on which the sample is disposed and the slip surface of the cover slip have a vertical gap, the sample slide and the cover slip have a horizontal overlap, and the vertical gap and the horizontal overlap define a volume; receiving a fluid in the vertical gap between the sample slide and the cover slip; and moving the second cartridge component relative to the first cartridge component from the flood start position to a flood end position.

[0015] In one embodiment, a sample processing system is provided that may include at least one processing circuit, an insertion bay configured to receive a sample cartridge having a first cartridge component and a second cartridge component, and a cartridge drive system controllable by the at least one processing circuit and configured to generate relative movement between the first cartridge component and the second cartridge component.

[0016] In one embodiment, a sample cartridge is provided that may include one or more sample receptacles, one or more sample slides, one or more stains, and one or more coverslips.

[0017] In one embodiment, a sample processing system is provided that includes a sample handling system including a sample transport mechanism, a sample smearing mechanism, and a sample movement mechanism, a fluid distribution system, and a control system.

[0018] In one embodiment, a sample cartridge is provided comprising a first cartridge component including a slide support configured to support a sample slide, and a second cartridge component including a receptacle window configured for movement relative to the first cartridge component, the second cartridge component configured to adopt a sampling position relative to the first cartridge component to support a sample receptacle, and the second cartridge component configured to adopt a transfer position relative to the first cartridge component when positioned in the slide support that aligns the receptacle window with the slide support in a position that allows transfer of a sample in the sample receptacle to the sample slide.

[0019] In one embodiment, a method for sample preparation is provided, comprising depositing a sample in a sample receptacle of a sample cartridge, with a first cartridge component and a second cartridge component disposed in a sampling position relative to one another, moving the second cartridge component relative to the first cartridge component from the sampling position to a transfer position that aligns a sample slide supported on a slide support of the first cartridge component with a receptacle window of the second cartridge component, and transferring the sample from the sample receptacle to the sample slide.

[0020] In one embodiment, a sample cartridge is provided that includes a first cartridge component including a slide support configured to support a sample slide and a second cartridge component including a smear plate support configured to support a smear plate, the second cartridge component configured to adopt a smear position relative to the first cartridge component that aligns the smear plate with the sample slide for smearing a sample.

[0021] In one embodiment, a method for sample preparation is provided, comprising: placing a second cartridge component of a sample cartridge in a smearing position relative to a first cartridge component of the sample cartridge, aligning a smear plate support of the second cartridge component with a sample slide supported by the first cartridge component; and smearing a sample onto the sample slide using a smear plate disposed within the smear plate support. [Brief description of the drawings]

[0022] The accompanying figures incorporated herein form part of the specification and illustrate embodiments of systems, methods, and devices for rapid on-site cytological assessment. Together with the specification, the figures further explain the principles of the methods, systems, and devices described herein and enable one of ordinary skill in the art to make and use the methods, systems, and devices described herein. The drawings are provided to illustrate various features of the embodiments described herein and are not necessarily drawn to scale. In the drawings, like reference numbers indicate identical or functionally similar elements.

[0023] [Figure 1] 1 illustrates an integrated sample processing system consistent with embodiments herein. [Figure 2A-2C] 1 illustrates a sample cartridge consistent with embodiments herein. [Fig. 2D-2F] 1 illustrates a cartridge frame consistent with embodiments herein. [Fig. 2G-2I] 1 illustrates a cartridge drawer consistent with embodiments herein. [Fig. 2J-2L] 1 illustrates a sample processing component consistent with embodiments herein. [Fig. 2M-2N] 1 illustrates a fluid storage component consistent with embodiments herein. [Figures 3A-3H] 1 illustrates features of a sample cartridge consistent with embodiments herein. [Figure 4A-4E] 1 illustrates a sample receptacle consistent with embodiments herein. [Diagram 5] 1 illustrates a sampling location for a sample cartridge consistent with embodiments herein. [Figure 6] 1 illustrates a receptacle release position of a sample cartridge consistent with embodiments herein. [Figure 7] 1 illustrates a sample cartridge transfer position consistent with embodiments herein. [Figure 8] 1 illustrates a sample cartridge smear location consistent with the present embodiment. [Figure 9A-9B] 13 illustrates the ejection position of a sample cartridge consistent with the present embodiment. [Figure 10A-10D] 1 illustrates a series of staining positions for a sample cartridge consistent with embodiments herein. [Figure 11] 1 illustrates a computer system consistent with embodiments herein. [Figure 12A-12B] 1 illustrates features of an integrated sample processing system consistent with embodiments herein. [Figure 13] 1 illustrates a sample movement mechanism consistent with embodiments herein. [Figure 14A-14D] 1 illustrates aspects of a sample movement mechanism of a sample handling system consistent with embodiments herein. [Figure 15] 1 illustrates aspects of a sample smearing mechanism of a sample handling system consistent with embodiments herein. [Figure 16A-16B] 1 illustrates aspects of a fluid distribution system consistent with embodiments herein. [Figures 17A-17C] 1 illustrates a slide ejection operation consistent with embodiments herein. [Figure 18] 1 illustrates a receptacle receiving system consistent with embodiments herein. [Figure 19] 1 illustrates a sample processing method consistent with embodiments herein. [Figure 20A-20B] 1 illustrates a sample transfer operation consistent with embodiments herein. [Figure 21A-21B] 1A and 1B illustrate sample transfer operations consistent with embodiments herein. [Figure 22] 1 illustrates features of a sample cartridge consistent with embodiments herein. [Figure 23A-23B] 1A-1D show features of a sample slide consistent with embodiments herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. Although the present invention is described in the context of systems, methods, and devices for facilitating automated ROSE procedures, the present disclosure should not be considered as so limiting. For example, although the systems, methods, and devices may be discussed herein with respect to ROSE of biopsy samples, any biological sample may be suitable for analysis by the embodiments herein. Changes may be made to the embodiments described herein without departing from the spirit and scope of the invention. Therefore, the following detailed description is not intended to be limiting. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, summary, or the following detailed description.

[0025] The present disclosure addresses the problems outlined above. The present disclosure presents a robotic, automated sample processing device that uses live biopsy samples taken by interventional staff to rapidly generate consistent, high-resolution cytological images, and is therefore suitable for ROSE. Images can be displayed directly to the interventionalist on the machine and can be available to be sent for remote consultation by a cytopathologist. AI algorithms can assist the cytopathologist by identifying key regions of interest and cell types. As enabled by highly repeatable sample preparation and imaging, fully automated validation and diagnosis (using AI) can be made available directly to the interventionalist without the need for remote consultation. Using the approach described herein, interventionalists and remote cytopathologists can view high-resolution smear images prepared and stained in a familiar manner, without the need for an on-site cytology technician. Thus, the embodiments of the present disclosure provided herein can help reduce the time it takes an operator to perform ROSE, increase throughput, reduce time to results, and improve consistency of results.

[0026] The embodiments disclosed herein may facilitate rapid assessment of samples by sample separation techniques that use minimal or reduced sample volumes compared to other methods. The remainder of the collected sample, which may be many or the majority of the collected sample, may then be stored for further analysis, if desired. The sample transfer and separation techniques discussed herein may be further configured to preserve the structure of the sample to aid in further analysis.

[0027] In embodiments, the systems, methods, and devices described herein can be used to evaluate, measure, or assess the effectiveness of a treatment on a sample tissue. For example, after a treatment (e.g., a drug, ablation, etc.) is administered, tissue can be taken to determine the effectiveness of the treatment. For example, tissue taken from an area in the periphery of a tumor after ablation may be evaluated to confirm or determine that the area was sufficiently ablated at the cellular level. Similarly, tissue taken from an area in the periphery of a tumor after a drug is injected into a tumor may be evaluated to confirm or determine that the drug has sufficiently penetrated the tissue at the cellular level.

[0028] The present disclosure describes devices, systems, and methods for facilitating sample processing. The sample processing methods described herein include collection, deposition, transfer, smearing, staining, and evaluation of samples (e.g., tissue samples or other biological samples). The sample processing devices described herein include sample cartridges having various features that facilitate, enable, or enhance the sample processing methods described herein. The sample processing systems described herein include integrated sample processing systems configured to perform one or more of the sample processing steps described above, optionally using aspects of the sample cartridges described herein. Sample processing embodiments are described herein that employ integrated sample processing systems that perform the sample processing methods through the use of sample cartridges. This combination of features is discussed for illustrative purposes only, and the sample processing methods, sample cartridges, and integrated sample processing systems described herein may each be used or employed with alternative methods, systems, and devices, as the case may be. Additionally, each individual aspect of the methods, systems, and devices described herein may be employed individually or in any suitable combination with any other individual aspects of the methods, systems, and devices described herein. Some of these individual combinations may be discussed herein for purposes of illustration or description, it being understood that the wide variety of all such combinations precludes individual description of each combination herein, but all such combinations are within the scope of the present disclosure.

[0029] For example, any of the methods or portions of the methods described herein can be implemented using suitable portions of the devices and systems described herein and / or can be employed using alternative devices and systems, without requiring the entirety of the devices and systems described herein. Some methods or portions of the methods can also be implemented manually using suitable portions of the devices described herein and / or can be implemented using the systems described herein using different devices. The devices described herein can be implemented using suitable portions of the methods and systems described herein and / or can be employed using alternative methods and systems, without requiring the entirety of the methods and systems described herein. The systems described herein can be implemented using suitable portions of the methods and devices described herein and / or can be employed using alternative methods and devices, without requiring the entirety of the methods and devices described herein.

[0030] In an embodiment, the integrated sample processing system 100 may be configured to operate with common glass slides. This configuration may impose particular demands on the integrated sample processing system 100 for precision manipulators, grippers, and other positioning actuators. In an embodiment, as described herein, the sample processing system 100 may be configured to accept one or more specialized cartridges, such as the sample cartridge 200 described below. Such a sample cartridge 200 may include some or all of the sample processing components required for a particular sample processing sequence. The sample processing components may include, but are not limited to, a sample slide or slides, a cover slip, a smearing element (e.g., a smear plate), a sample collection receptacle, and one or more stain storage units. The sample cartridge may hold each element in a sufficient relative position as required for the sample processing step. By incorporating suitable precision within the sample cartridge, the precision requirements on the processing system may be correspondingly reduced. Furthermore, the sample cartridge may also be configured to accommodate all of the contaminated elements for safe disposal and prevention of contaminating the processing system.

[0031] The present disclosure may include references to relative terms such as "top," "bottom," "upper," and "lower." These terms are used for clarity and ease of reference. For example, the "top" of a structure or device may refer to the portion of that structure or device that faces upward during use as described herein. The relative directional terms used herein are not limiting and do not restrict the orientation, position, angle, or functionality of the structures and devices discussed herein. Furthermore, the methods, systems, and devices discussed herein are not limited to use in the orientations as described herein. For example, although the sample cartridge is described with the sample slide "on" the cover slip, the disclosure is not limited to this arrangement. One or more aspects of the system may be inverted relative to the orientations disclosed herein without departing from the scope of the present disclosure.

[0032] FIG. 1 illustrates a rapid on-site assessment system consistent with embodiments herein. The rapid on-site assessment system 1000 may include various components. The components may be housed on a mobile cart 101 or as a benchtop system. The components may include a cart chassis with wheels, an integrated sample processing system 100 for preparing and imaging biopsy samples, a display 102 for viewing the prepared and imaged samples, and a user interface 103 including one or more user input devices, a reservoir for a disposable cartridge (in which a biopsy sample may be loaded), and one or more consumable repositories. A waste bin may also be included. The integrated sample processing system 100 may include one or more input slots into which a disposable cartridge containing a sample may be loaded, one or more output slots for removing prepared slides for future analysis, and an area for removing used cartridges ready for disposal. In addition, there may be controls on the cart, such as one or more user input devices of a user interface 103 that facilitate entering system parameters and performing operations such as manipulating the on-screen microscope image by panning, zooming, and jumping to various areas of interest.

[0033] 2A-2C show a sample cartridge consistent with embodiments herein. The sample cartridge 200 is designed to maximize ease of use for the interventional physician team, minimize system maintenance, and facilitate isolation and disposal of biological material. The sample cartridge 200 may include an opening or receptacle for sample insertion, one or more sample slides for microscopic imaging, a movable smearing element such as a smear plate, and one or more stain storage units. The sample cartridge 200 described herein may facilitate the sample processing methods described herein by providing a structure to house and align sample processing components. The sample cartridge 200 may be disposable and may also facilitate isolation and disposal of biological material by providing a defined housing for the sample processing components.

[0034] The sample cartridge 200 includes a first cartridge component and a second cartridge component configured for relative movement in a dimension, such as a linear dimension, relative to one another. As used herein, relative movement refers to a change in position of the two components relative to one another. During relative movement, one or both of the components may experience absolute movement relative to an external reference frame. During relative movement, one of the components may remain stationary relative to an external reference frame. Relative movement in further dimensions may be limited or unavailable. In an embodiment, the first cartridge component includes a cartridge frame 201 and the second cartridge component includes a cartridge drawer 202 configured for relative movement relative to one another, as discussed herein. The sample cartridge 200 may be configured to support and facilitate manipulation of one or more sample processing components during sample processing. The sample processing components may include at least a sample receptacle 301, one or more sample slides 401, a smear plate 501, and a coverslip 601.

[0035] 2D-2F show a cartridge frame consistent with embodiments herein. The cartridge frame 201 may be of a generally rectangular shape having a pair of cartridge walls 231 extending substantially parallel to one another over the length of the cartridge frame 201. The cartridge frame 201 further includes a bridge portion 241 extending between the cartridge walls 231 and having an outer surface 242. The cartridge frame 201 may have a leading end 291 and a trailing end 292. The terms "leading" and "rear" are used for convenience of reference only and do not limit the orientation or function of the cartridge frame 201. The cartridge frame 201 is configured to support one or more sample slides 401 in a slide support portion 211 disposed within the bridge portion 241. The cartridge frame 201 is further configured to provide at least partial support to a sample receptacle 301 by supporting the sample receptacle in cooperation with the cartridge drawer 202, as discussed in more detail below. In an embodiment, one or more sample slides 401 may optionally be included in the sample cartridge 200. Further features of the cartridge frame 201 are discussed in more detail below.

[0036] The sample slide(s) 401 may be a conventional glass slide and / or may be made of any other material suitable for sample imaging. The sample slide(s) 401 may be generally flat (e.g., having a length and width significantly greater than a height) and may be shaped according to any suitable shape. In embodiments, the sample slide 401 may be sized and shaped according to a conventional slide, or may be sized and shaped according to any other suitable size. In embodiments, the sample slide 401 may be replaced with other types of sample substrates. For example, a sample substrate including a plurality of microwells may be employed in place of the sample slide 401, as discussed further below.

[0037] The slide support 211 includes a slide window 221, a support tab 217, a support arm 218, and a support clip 219. The slide window 221 is an opening or aperture in the bridge portion 241. In an embodiment, the slide window 221 is approximately the same width as the sample slide 401. In an embodiment, the slide window 221 may be longer than the length of the sample slide 401. The slide window 221 may have a first end located proximate the leading end 291 and a second end located proximate the trailing end 292.

[0038] The support tabs 217 extend inwardly from the bridge portion 241 into the sliding window 221 to provide a surface on which the sample slide(s) 401 rest. As such, the support tabs 217 are configured to underlie the sample slide(s) 401 to support the sample slide(s) 401. The support tabs 217 are disposed on the long sides of the sliding window 221. The support tabs 217 may include two support tabs 217 (or any suitable number) positioned opposite each other. In an embodiment, the support tabs 217 may include two support tabs 217 opposed to each other and extending all or a portion of the length of the sliding window 221.

[0039] The support arm 218 extends inwardly into the sliding window 221 from a bridge portion 241 at a first end of the sliding window 221. The support arm 218 is configured with a support notch 222 (best seen in FIG. 5). The support notch 222 of the support arm 218 contacts the top surface of the sample slide 401 when the sample slide 401 is disposed in the slide support 211. When two sample slides 401 are disposed in the slide support 211, the support notch 222 contacts the top surface of the bottom sample slide 401. When one sample slide 401 is disposed in the slide support 211, the support notch 222 contacts the top surface of the one sample slide 401.

[0040] The support clip 219 extends inwardly from the bridge portion 241 into the sliding window 221 at a second end of the sliding window 221 opposite the first end. The support clip 219 is a rotatable structure configured to rotate about a location proximate the rear end 292 of the sliding window 221. The support clip 219 may be constructed of metal, plastic, or the like. The support clip 219 is biased (e.g., spring loaded) toward the sample slide 401 disposed within the slide support portion 211. Thus, the support clip 219 provides a downward force against the sample slide 401. In one embodiment, the support tab 217 does not extend beyond where the support clip 219 contacts the sample slide 401. This configuration causes the force provided by the support clip 219 to generate a torque about the support tab 217 (acting as a fulcrum) on which the sample slide 401 rests. This torque is opposed by the support arm 218, located at the opposite end of the sliding window 221 from the support clip 219. Thus, the sample slide 401 may be held in place by a downward force applied to the stack of two sample slides 401 by the support clip 219 at one end and a downward force applied to the bottom sample slide 401 of the stack by the support arm 218 at the opposite end. As discussed below, when the bottom sample slide 401 is removed, the support clip 219 and support arm 218 may apply a force to the top surface of both the same sample slides 401.

[0041] This configuration, in which the sample slide(s) 401 are supported by the sample cartridge 200 at only a few points, may prevent twisting, bending, or torque forces experienced by the sample cartridge 200 from being transmitted to the sample slide(s) 401. Thus, the sample slide(s) 401, which may comprise brittle materials such as glass, may be protected from damage due to rough handling of the sample cartridge 200.

[0042] 2G-2I illustrate a cartridge drawer consistent with embodiments herein. The cartridge drawer 202 may be of a generally rectangular shape including a generally rectangular cartridge base 232. The cartridge drawer 202 is configured to support a smear plate 501 at a smear plate support 214, a coverslip 601 at a coverslip support 216, and provide at least partial support for a sample receptacle 301 as discussed further below. Each of the smear plate support 214 and the coverslip support 216 may be disposed within the cartridge base 232. In embodiments, one or more of the smear plate 501, the coverslip 601, and the sample receptacle 301 may be optionally included in the sample cartridge 200. Further features of the cartridge drawer 202 are discussed in more detail below.

[0043] The smear plate 501 (FIG. 2K) may have a substantially flat first surface 511 and, optionally, a substantially flat second surface 512. The smear plate 501 is generally planar and has a width and length greater than its height. For example, the smear plate 501 may be generally square or rectangular with a length and width greater than five times its height. The smear plate 501 may have a substantially flat first surface 511 configured for smearing a sample between the first surface 511 and the sample slide 401. The second surface 512 opposite the first surface 511 may also be substantially flat to facilitate gripping by a suction cup, as discussed further below. In further embodiments, the second surface 512 may also include additional or different features to facilitate gripping by any type of automated or manual gripping device. In an example, the smear plate 501 may be a glass slide. In further embodiments, the first surface 511 of the smear plate 501 may have a substantially flat portion configured for smearing a sample and may further include one or more features to facilitate the smearing action. For example, the first surface 511 may include one or more tabs configured to offset the smear plate 501 from another surface to which it is brought in close proximity.

[0044] The smear plate 501 may be disposed within the smear plate support 214. The smear plate support 214 may include a number of guides 273 surrounding the smear plate 501 when the smear plate 501 is disposed within the smear plate support 214. The smear plate support 214 may further include a support frame 274 surrounding the smear plate window 215. The support frame 274 is a surface configured to support the smear plate 501 within the cartridge drawer 202. The guide 273 of the smear plate support 214 may be, for example, a post, a tab, a partial wall, or any other structure extending approximately perpendicularly from the support frame 274. The guide 273 may be configured to not completely surround the smear plate 501, or may be configured as a wall to completely surround the smear plate 501. The guide 273 of the smear plate support 214 serves to restrain and guide the movement of the smear plate 501. The smear plate window 215 is configured to allow an actuation probe, arm, or other tool to interact with the smear plate 501 from outside the sample cartridge 200.

[0045] The cartridge drawer 202 further includes a coverslip support 216. The coverslip support 216 includes a support tab 275 that extends into the coverslip window 276 and a support ledge 277 that is disposed around the coverslip window 276 opposite the support tab 275. The coverslip window 276 is an opening or window in the cartridge base 232. The coverslip window 276 is sized larger than the coverslip 601 such that when the coverslip is positioned in the cartridge drawer 202, the support tab 275 contacts the coverslip 601 at one end and the support ledge 277 contacts the coverslip 601 at the other end while leaving a long side of the coverslip 601 unsupported. The coverslip 601 may be a piece of transparent, flat material such as, for example, glass or plastic. In embodiments, the coverslip 601 may include rounded ends, as illustrated in FIG. 2H, which may facilitate fluid drainage, as discussed further below. In embodiments, the coverslip 601 may be secured to the cartridge drawer 202 via an adhesive. This configuration, in which the coverslip 601 is supported by the sample cartridge 200 at only a few points, may prevent twisting, bending, or torque forces experienced by the sample cartridge 200 from being transferred to the coverslip 601. Thus, the coverslip 601, which may comprise a brittle material such as glass, may be protected from breakage due to rough handling of the sample cartridge 200.

[0046] In embodiments, the coverslip 601 may be releasably secured within the cartridge drawer 202. Some sample staining protocols (e.g. DiffQuik) may be beneficial for the coverslip 601 to remain within the sample cartridge and separate from the prepared sample slide 401 for purposes of subsequent processing and imaging. Such protocols may be facilitated by the securing of the coverslip 601 to the cartridge drawer 202. Some sample staining protocols (e.g. Toludine Blue) may rely on the coverslip 601 remaining attached to the sample slide 401 for purposes of subsequent processing and imaging. Such protocols may be facilitated by the releasability of the coverslip 601 from the cartridge drawer 202.

[0047] The cartridge frame 201 and cartridge drawer 202 are configured to facilitate sample collection, preparation, and staining (collectively referred to as sample processing) via manual, partially manual, and / or automated means. The cartridge frame 201 and cartridge drawer 202 are configured to cooperate with one another to facilitate sample processing.

[0048] As discussed above, the sample cartridge includes a first cartridge component and a second cartridge component that are functionally capable of interlocking and moving relative to each other in a first dimension, such as a linear dimension, while being defined as having limited movement relative to each other in other dimensions. For example, in xyz space, the first cartridge component and the second cartridge component are configured to move relatively in the x dimension, while having more limited relative movement in the y and z dimensions. In another example, the first dimension may be a rotational dimension. As described below, limited relative movement in the y or z dimensions may be tolerated for functional and / or manufacturing reasons. In the embodiments described herein, the first cartridge component may be a cartridge frame 201 and the second cartridge component may be a cartridge drawer 202. The cartridge frame 201 and the cartridge drawer 202 are not limited by the specific embodiments described above, nor are they limited by the structural implications of the use of the terms "frame" and "drawer." For example, the embodiments described herein include a description of a cartridge frame 201 configured to receive a cartridge drawer 202. In further embodiments, the cartridge drawer 202 may be configured to receive the cartridge frame 201. In another example, in one embodiment, one of the cartridge walls 231 of the sample cartridge 200 may be disposed on the cartridge drawer 202 and the other cartridge wall 231 of the sample cartridge 200 may be disposed on the cartridge frame 201. In one embodiment, the cartridge drawer 202 may include a pair of cartridge walls 231 and the cartridge frame 201 may not include a cartridge wall 231. Additionally, various supports for sample processing components may be disposed on the cartridge drawer 202 or the cartridge frame 201 in any suitable combination.For example, the sample slide 401 may be supported by the cartridge drawer 202 and the coverslip 601 may be supported by the cartridge frame 201 .

[0049] The cartridge frame 201 and cartridge extractor 202 are configured for relative movement with respect to one another to adopt or establish various positions to facilitate or enable various aspects of sample processing. In embodiments, the cartridge frame 201 and cartridge extractor 202 can adopt one or more of a sampling position, a transfer position, a receptacle release position, a smear position, a start flood position, an end flood position, a rinse position, and a slide eject position with respect to one another. These positions are described in further detail below.

[0050] 2J-2N show sample processing components, which may include at least a sample receptacle 301, one or more sample slides 401, a smear plate 501, a stain storage unit 701, and a coverslip 601. As discussed above, the sample cartridge 200 is configured to house each of the sample processing components, which may be packaged together with the sample cartridge 200 or may be packaged separately from the sample cartridge 200.

[0051] A staining solution storage unit 701 (FIGS. 2M, 2N) may be disposed on the sample cartridge 200, for example in the cartridge frame 201. The staining solution storage unit 701 may include one or more staining solution storage modules 702, each configured to individually accommodate a volume of fluid (e.g., staining solution, water, alcohol, etc.). Each staining solution storage module 702 may include a fluid outlet 703 and a fluid seal 704. The fluid outlet 703 is configured at a first end of the staining solution storage module 702 to allow release of fluid stored in the staining solution storage module 702, and the fluid seal 704 is configured to prevent release of fluid at the opposite end. In one embodiment, the fluid seal 704 may be movable or deformable, and pressure or force applied to the fluid seal 704 may deform or move the fluid seal 704, thereby providing pressure to the fluid in the staining solution storage module 702. Pressure on the fluid in the staining fluid storage module 702 causes the fluid to be expelled at a fluid outlet 703, which may be a nozzle, orifice, or any other type of opening. The fluid outlet 703 may be positioned, configured, and arranged to be applied to the coverslip 601 or specimen slide 401 as the fluid is expelled, as described in more detail below. In an embodiment, the fluid outlet 703 may be of a size small enough to prevent the release of fluid when no pressure is applied. In an embodiment, the fluid outlet 703 may include a seal, such as a membrane, that may break or be released when pressure is applied to the fluid. In further embodiments, the staining fluid storage unit 701 may include a pouch, bag, or any other suitable fluid container.

[0052] In embodiments, the sample cartridge 200 and various sample processing components may be provided or packaged in any convenient or suitable combination. For example, separate or combined packaging may be selected or determined to facilitate sterilization of parts that require sterilization while allowing other parts to be provided non-sterile. For example, it may be beneficial to sterilize the sample receptacle 301 but not necessarily the sample cartridge 200. Sterilization may be required for some applications (e.g. percutaneous biopsy) but not for other applications (because in bronchoscopic biopsy the airway is not sterile and the entire procedure is considered not strictly sterile). For sterile biopsy, the sample receptacle 301 requires minimal sterilization since the biopsy needle may touch the sample receptacle 301 and then return to the patient.

[0053] 3A-3D illustrate features of the sample cartridge 200 that may facilitate relative movement between the cartridge frame 201 and the cartridge drawer 202. The cartridge frame 201 includes a pair of frame rails 310 (310A / 310B) on the interior side of the cartridge wall 231 that are configured to engage a corresponding pair of pull rails 311 (311A / 311B) disposed longitudinally around the periphery of the cartridge base 232 of the cartridge drawer 202. The engagement between the frame rails 310 and the pull rails 311 provides a bearing surface that allows the cartridge frame 201 and the cartridge drawer 202 to move relative to one another.

[0054] In embodiments, a reinforcing structure may be included within the sample cartridge 200 along one or both of the long sides of the sample cartridge 200, as shown, for example, in Figures 3E-3H. The reinforcing structure 390 may contain one or more reinforcing elements 391 contained within a reinforcing housing 392. The reinforcing housing 392 is a housing that extends along the length of the sample cartridge 200 and is formed at the junction of the cartridge frame 201 and the cartridge drawer 202. The reinforcing housing 392 surrounds and contains the reinforcing element 391. Because the reinforcing housing 392 is formed from the junction of the cartridge frame 201 and the cartridge drawer 202, it changes size as the cartridge frame 201 and the cartridge drawer 202 are offset from one another. The minimum length of the stiffening housing 392 is approximately the minimum overlap length of the cartridge frame 201 and cartridge drawer 202 (taking into account the end walls) and the maximum length is approximately the length of the sample cartridge 200 when the cartridge frame 201 and cartridge drawer 202 are aligned or flush with one another. The minimum length is shown in Figures 3E and 3H, and the maximum length is shown in Figures 3F and 3G.

[0055] In one embodiment, the one or more reinforcing elements 391 include rigid rods, such as rods of steel or other metal, as illustrated in Figure 3E. When the cartridge frame 201 and cartridge drawer 202 are offset from one another, the steel rods may substantially fill (e.g., 80% or more, 90% or more, 95% or more, etc.) the length of the reinforcing housing 392, thus providing rigidity to the sample cartridge 200. When the cartridge frame 201 and cartridge drawer 202 are aligned with one another, the steel rods occupy a portion of the reinforcing housing 392, thus providing rigidity to the sample cartridge 200.

[0056] In one embodiment, the reinforcing structure 390 is configured for compressibility and extensibility. The one or more reinforcing elements 391 may include a plurality of reinforcing elements 391 including a material harder than the material of the sample cartridge, such as metal or hard plastic, as shown in FIG. 3F. The plurality of reinforcing elements 391 may include spheres, beads, or other elements. When the cartridge frame 201 and the cartridge drawer 202 are offset from one another, the reinforcing element 391 may be configured to shorten to substantially fill the reinforcing housing 392 (e.g., 80% or more, 90% or more, 95% or more, etc.) of the length of the reinforcing housing 392 over its shorter length, thus providing rigidity to the sample cartridge 200. When the cartridge frame 201 and the cartridge drawer 202 are aligned with one another such that the reinforcing housing 392 is lengthened, the plurality of reinforcing elements 391 may extend within the length of the reinforcing housing 392 to provide rigidity over the length of the reinforcing housing 392.

[0057] In an embodiment, the reinforcing elements 391 may be magnets, may house magnets, and / or may include magnets, as shown in Figures 3G and 3H. Each reinforcing element 391 may be aligned with an adjacent reinforcing element 391 such that the polarity of the included magnets matches, thus providing a force to push the reinforcing elements 391 away from each other. When the sample cartridge 200 is closed and the reinforcing housing 392 is lengthened, the magnets cause the reinforcing elements 391 to spread apart within the reinforcing housing 392. When the sample cartridge 200 is opened and the reinforcing housing 392 is shortened, the end walls of the reinforcing housing 392 cause the reinforcing elements 391 to move closer together. Thus, the reinforcing elements 391 may remain spaced apart within the reinforcing housing 392 and provide reinforcing support to the sample cartridge 200 regardless of the alignment of the cartridge drawer 202 with the cartridge frame 201. In embodiments, the compressibility and extensibility of the reinforcement structure 390 may be provided by biasing elements (springs, foam, etc.) and / or other elements such as elastic elements.

[0058] The sample cartridge 200 further includes a cartridge drive system 350. The cartridge drive system 350 (components of which are shown in Figures 2D-2I) is configured to drive relative movement between the cartridge frame 201 and the cartridge drawer 202. As discussed above, the frame rails 310 and the drawer rails 311 provide the bearing surfaces necessary for the relative movement. The cartridge drive system 350 provides a means for generating the relative movement. In one embodiment, the cartridge drive system 350 may include a frame gear drive rack 351 disposed on one of the cartridge walls 231 and a drawer gear drive rack disposed longitudinally along one end of the cartridge base 232. The frame gear drive rack 351 may include a rack having multiple gear teeth configured to engage and be driven by a pinion gear. The drawer gear drive rack 352 may also include a rack having multiple gear teeth configured to engage and be driven by a pinion gear. Relative movement between the cartridge frame 201 and the cartridge drawer 202 may be generated by separate pinion gears that engage and drive a frame gear drive rack 351 and a drawer gear drive rack 352. The cartridge drive system 350 may be engaged to generate relative movement between the cartridge frame 201 and the cartridge drawer 202 causing the cartridge frame 201 and the cartridge drawer 202 to adopt various positions relative to one another, as described herein.

[0059] In further embodiments, the cartridge drive system 350 may include alternative features configured to generate the linear motion necessary to cause the relative movement. For example, such features may include a pinch roller system, an external push rod system including a linear actuator configured to engage the cartridge drawer 202 and the cartridge frame 201 to cause back and forth movement, a differential gear system, and features for interacting with a pair of linear stages that engage the cartridge drawer 202 and the cartridge frame 201, respectively.

[0060] In embodiments, the relative movement of the sample cartridge 200 may be facilitated by the integrated sample processing system 100, as described in further detail with respect to Figure 13. In embodiments, the relative movement of the sample cartridge 200 may be facilitated by manual manipulation by an operator.

[0061] 4A-4D show a sample receptacle 301. The sample receptacle 301 may include a receptacle base 307 that supports a receptacle frame 302, a trough 303, a sample platform 304, and a sample lip 306. The receptacle base 307 provides a support structure for the receptacle frame 302. The receptacle base 307 may include multiple walls and a cavity in the center of the walls. The receptacle frame 302 is supported by the receptacle base and provides an outer support structure for the sample receptacle 301. The receptacle frame 302 may include a piece of material (e.g., a flexible material such as a polymer, rubber, plastic, etc.) having an outer perimeter and an inner perimeter. The receptacle frame 302 and the receptacle base 307 may be formed from a single material, may be integrally formed, may be separate adjacent pieces, or may include different materials. In embodiments, the receptacle base 307 may be formed from a material that is harder or stronger than the material of the receptacle frame 302. In embodiments, portions of the sample receptacle 301, such as the sample platform 304, may include or be formed from a material that resists puncture. For example, a needle may be used during sample deposition on the sample platform 304. The sample platform 304 may include a material that is sturdy enough to prevent or resist puncture, while being flexible enough to perform the functions disclosed herein.

[0062] The periphery of the receptacle frame 302 may be, for example, approximately square, trapezoidal (as shown in FIGS. 4A-4D), rectangular, circular, and / or any other suitable shape. A portion of the periphery of the receptacle frame 302 may extend beyond the receptacle base 307. For example, the receptacle frame 302 may include a frame support 309 and a drawer support 308 that extend beyond the periphery of the receptacle base 307. The receptacle frame 302 may have an interior opening surrounded by an inner periphery. A trough 303 is connected to a wall of the inner periphery of the receptacle frame 302. The trough 303 supports a sample platform 304 that is located within the interior opening of the receptacle frame 302. The trough 303 and the sample platform 304 together may be referred to as a membrane 317 or a flexible membrane. The sample platform 304 has a sample side 393 and a lower side 394 opposite the sample side 393. The trough 303 may be thinner in cross section than the receptacle frame 302 and the sample platform 304, thus allowing the sample platform 304 to move relative to the receptacle frame 302 through bending or flexing of the trough 303 or other portions of the membrane 317. The trough 303 may also serve to capture and contain excess amounts of sample provided to the sample platform 304. The sample platform 304 may be circular, square, or any other suitable shape, and may be concave in cross section to better contain the sample. The sample lip 306 is a protrusion of material that extends above the surface of the receptacle frame 302. In one embodiment, the sample lip 306 may be curved to fit the trough 303. The operation of the sample receptacle 301 is described in more detail below.

[0063] In embodiments, the sample receptacle 301 may include a membrane 317 without a trough, for example as shown in Figure 4E. In such embodiments, the membrane 317 may include the sample platform 304 and may extend to the receptacle frame 302 without the need for a trough.

[0064] In one embodiment, the sample receptacle 301 may further include a sample collection feature. The sample collection feature may be configured to facilitate release of the sample from a collection or biopsy tool, such as, for example, a biopsy brush. The sample collection feature may be configured as a notch, lip, ledge, port, hole, etc., and may be configured to facilitate release of the collected sample from the tool. For example, a biopsy brush may collect a sample in a series of bristles. Having the bristles extend across a sample collection feature, such as a notch, may aid in the release of the sample from the bristles.

[0065] In further embodiments, the sample receptacle 301 may be a substantially flat substrate and / or may be substantially rigid. In such embodiments, sample transfer may be accomplished by advancing the sample receptacle 301 to the sample slide 401 such that the sample contacts the sample slide 401 and the sample receptacle 301 is not deformed.

[0066] FIG. 5 illustrates a sampling position of the sample cartridge 200. The cartridge drawer 202 may be configured to adopt the sampling position relative to the cartridge frame 201 to expose the sample receptacle 301 for receipt of a sample. As shown in FIG. 5, in the sampling position, the cartridge frame 201 and the cartridge drawer 202 may be aligned such that their ends are flush with one another. In the sampling position, the cartridge frame 201 and the cartridge drawer 202 may cooperate to support the sample receptacle 301. The sample receptacle 301 may be supported by a frame receptacle support ledge 371 of the cartridge frame 201 on the frame support 309 and a drawer receptacle support ledge 372 of the cartridge drawer 202 on the drawer support 308. The frame receptacle support ledge 371 and the drawer receptacle support ledge 372 together form a receptacle support. In the sampling position, frame receptacle support ledge 371 and drawer receptacle support ledge 372 are spaced apart an appropriate distance so that they can engage and support sample receptacle 301 through contact with frame supports 309 and drawer supports 308. In further embodiments, sample receptacle 301 may be supported by receptacle supports formed solely in the cartridge frame 201 or solely in the cartridge drawer 202.

[0067] In an embodiment, the sample cartridge 200 may include one or more features for locking the cartridge frame 201 and cartridge drawer 202 in place, for example to prevent manual manipulation (intentional or unintentional). The integrated sample processing system 100 may include one or more actuators or actuation tools for disengaging the locking features. For example, the locking features may include snaps or pins that prevent relative movement between the cartridge frame 201 and the cartridge drawer 202. The integrated sample processing system 100 may disengage or release the snaps or pins to allow relative movement during sample processing, as described below. Following sample processing, the sample cartridge 200 may be released in the unlocked position, or relocked with snaps or pins (or new snaps or pins) to prevent further manipulation or reuse.

[0068] During sample processing methods consistent with embodiments herein, the sample cartridge 200 may be adapted to adopt a sampling position. In an example, the sample cartridge 200 may be packaged and provided to a user at the sampling position to facilitate ease of use. In an example, the sample cartridge 200 may be placed at the sampling position by the integrated sample processing system 100 or by a user prior to sample deposition. At the sampling position, a user or operator, such as a physician or other medical personnel, may obtain a sample (e.g., a tissue sample or other biological sample) and deposit the sample in a sample receptacle 301.

[0069] In further embodiments, deposition of the sample in the sample receptacle 301 may occur in any other suitable manner. For example, the sample receptacle 301 may be packaged and provided separately from the sample cartridge 200 and may receive the sample remotely from the sample cartridge 200. In an example, the integrated sample processing system 100 may present the sample receptacle 301 to a user or operator for sample deposition, separate or remote from activities involving the sample cartridge 200. After sample deposition, the user or operator may provide the sample receptacle 301 to the integrated sample processing system 100 or the sample cartridge 200. The methods, systems, and devices discussed herein are not limited by the location of the sample receptacle 301 during sample deposition or by the method of sample deposition.

[0070] 6 illustrates a receptacle release position of the sample cartridge 200. The cartridge drawer 202 may be configured to adopt the receptacle release position relative to the cartridge frame 201. As explained above, in the sampling position, the frame receptacle support ledge 371 of the cartridge frame 201 and the drawer receptacle support ledge 372 of the cartridge drawer 202 cooperate to support the sample receptacle 301 through contact with the receptacle frame 302. When adopting the receptacle release position, the cartridge frame 201 and the cartridge drawer 202 are moved relative to each other such that the distance D between the drawer receptacle support ledge 372 and the frame receptacle support ledge 371 is increased. In the receptacle release position, the distance D is greater than the length L of the sample receptacle 301. Thus, in the receptacle release position, the drawer receptacle support ledge 372 and the frame receptacle support ledge 371 cannot support the sample receptacle 301 and the sample receptacle 301 is free to drop, fall or otherwise move downward relative to the top surface of the sample cartridge 200. In one embodiment, the sample receptacle 301 may be released and pass through a receptacle window 212 disposed within the cartridge drawer 202. The receptacle window 212 may be configured to have dimensions larger than the dimensions of the sample receptacle 301. In further embodiments, the receptacle window 212 may be configured to have dimensions smaller than the dimensions of the receptacle frame 302, thereby receiving, housing and supporting the sample receptacle 301 in position on the cartridge drawer 202 and thus may move with the cartridge drawer 202 when the sample cartridge 200 is operated. As discussed above, sample deposition in the sample receptacle 301 can occur in a variety of ways, so releasing the receptacle may be an optional step. In an embodiment, the sample receptacle 301 may be supplied with sample and provided to the integrated sample processing system 100 separately from the sample cartridge 200.

[0071] In embodiments, the receptacle open position may be achieved through automated manipulation of the sample cartridge 200 by the integrated sample processing system 100, such as in response to a receptacle open position command, as described in further detail with respect to Figure 14A. In embodiments, the receptacle open position may be achieved through manual manipulation of the sample cartridge 200.

[0072] 7 illustrates a transfer position of the sample cartridge 200. The cartridge drawer 202 may be configured to adopt a transfer position relative to the cartridge frame 201. In the transfer position, the sample receptacle 301 is aligned with the sample slide 401. Additionally, the receptacle window 212 of the cartridge drawer 202 may be aligned with the slide support 211 of the cartridge frame 201. The alignment between the receptacle window 212 and the slide support 211 allows for the transfer of a sample or a portion of a sample from the sample receptacle 301 to a slide 401 disposed within the slide support 211. As discussed above, the receptacle window 212 may be sized to allow the passage of the sample receptacle 301. Thus, the sample receptacle 301 may pass through the receptacle window 212 to a position adjacent to the sample slide 401 disposed within the slide support 211. When the sample cartridge 200 is maintained in an upright position, such that the top surface 271 of the sample cartridge 200 faces upward, the sample receptacle 301 can access the bottom surface 402 of the sample slide 401 by passing through the receptacle window 212.

[0073] The sample in the sample receptacle 301 is then contacted with the sample slide 401, causing transfer of a portion of the sample to the sample slide 401. As discussed above, the methods and techniques described herein may facilitate sample transfer and sample separation that uses a reduced amount of tissue and allows a majority of the original sample to be preserved. Transfer may be facilitated in a number of different ways.

[0074] In an embodiment, pressure may be applied to the underside 394 of the sample platform 304 by a probe 421 operated manually or via automation. The application of pressure deflects or bends the membrane 317, allowing a sample located on the sample platform 304 to contact the sample slide 401. In an embodiment, the shape of the probe 421 may be selected or determined according to the characteristics or type of sample on the sample platform 304. For example, for samples that contain primarily liquid (e.g., fine needle aspirates), a pointed probe 421 may be selected to break the surface tension of the liquid and ensure efficient transfer. For samples that contain primarily solids, a blunt probe 421 may be selected to ensure that a large surface of the solid tissue contacts the slide without disturbing the structure of the tissue itself.

[0075] The probe 421 may be selected in advance, for example, during a sample processing procedure when the sample type is expected. The probe 421 may be selected during sample processing, for example, by a user who evaluates a deposited sample and selects a probe for a transfer operation. Additionally, the probe 421 may be selected via automated means, as discussed in more detail below.

[0076] In an embodiment, the transfer position may be achieved by automated manipulation of the sample cartridge 200 by the integrated sample processing system 100, as described in further detail with respect to Figure 14B. Additionally, the sample transfer operation may be performed by automated control of the probe 421 by the integrated sample processing system 100. In a further embodiment, the transfer position and sample transfer operation may be achieved by manual manipulation of the sample cartridge 200 and manual operation of the probe 421.

[0077] Although sample transfer is described above with respect to the sample cartridge 200, the disclosure is not so limited. The sample cartridge 200 described herein provides an exemplary device structure for aligning the sample receptacle 301 and the sample slide 401. The method of sample transfer and devices configured to facilitate the method may be performed with or without the sample cartridge 200 by aligning the sample receptacle 301 and the sample slide 401 and applying a probe 421 to the underside of the sample receptacle 301. For example, the method of sample transfer may be performed manually by an operator. In another example, the method of sample transfer may be performed by a sample processing system (e.g., the integrated sample processing system 100) configured to manipulate the sample slide 401 and the sample receptacle 301 without the sample cartridge 200. In a further example, a user or operator may directly transfer a sample from a sample collection device (needle, forceps, etc.) to the sample slide 401. A user or operator can place an appropriate amount of sample directly onto the specimen slide 401 (e.g., a small amount of FNA fluid or tissue contact preparation). The specimen slide 401 may then be further processed by the integrated sample processing system 100, for example in a smear operation.

[0078] FIG. 8 shows the smearing position of the sample cartridge 200. The cartridge drawer 202 may be configured to adopt the smearing position relative to the cartridge frame 201. In the smearing position, the smear plate 501 is aligned with the sample slide 401. Furthermore, the smear plate support 214 of the cartridge drawer 202 may be aligned with the slide support 211 of the cartridge frame 201. The alignment between the smear plate support and the slide support 211 allows smearing of the sample or a part of the sample between the smear plate 501 and the sample slide 401. The smear plate 501 is brought into contact with the sample deposited on the sample slide 401. The sample is pressed between the smear plate 501 and the sample slide 401 and then, optionally, smeared by relative movement between the smear plate 501 and the sample slide 401.

[0079] In an embodiment, the smearing operation may be performed by the integrated sample processing system 100, as discussed in further detail below with respect to Figure 15. In an embodiment, the smearing operation may be performed manually by an operator utilizing one or more tools configured to interact with the smear plate 501.

[0080] 9A-9B show the ejection position of the sample cartridge 200. The cartridge extractor 202 may be configured to adopt the ejection position relative to the cartridge frame 201. In the ejection position, one of the sample slides 401 may be extended beyond an end of the sample cartridge 200. The cartridge frame 201 and the cartridge extractor 202 are manipulated relative to each other to cause the sample slide 401 to extend out of one end of the sample cartridge 200. In the ejection position, the sample slide 401 may be gripped by an external gripper (e.g., manual or automated gripping) and pulled out of the sample cartridge 200 for use in further processing. In the ejection position, the sample slide 401 may also be maintained in an extended position, e.g., air-dried prior to further processing.

[0081] The ejection position may be adopted by two partial movements. In a first ejection movement, the cartridge frame 201 and cartridge drawer 202 may be manipulated to expose the end of the bottom sample slide 401, thereby extending beyond the cartridge drawer 202, as shown in FIG. 9A. The slide release mechanism of the integrated sample processing system 100 may grip or attach to the exposed sample slide 401. After fixation to the sample slide 401, the cartridge frame 201 and cartridge drawer 202 may then be manipulated through a second ejection movement to adopt the ejection position. The cartridge frame 201 is moved back relative to the cartridge drawer 202 to increase the overlap. The slide release mechanism holds the position of the sample slide 401 as the cartridge frame 201 moves apart. The slide release mechanism may be configured to provide a vertical support or force that guides the sample slide 401 past a retention step, tab, or other feature in the cartridge frame 201. The end of the sample slide 401 secured by the support arm 218 is released as the cartridge frame 201 moves back towards the cartridge drawer 202, followed by the release of the portion of the sample slide 401 supported by the support tab 217. The unsupported sample slide 401 is aligned with the niche 234 in the cartridge drawer 202 and may freely drop into the niche 234, as shown in FIG. 9B. After the second ejection motion is completed, the bottom slide 401, having moved into position within the niche 234, is pushed over the end of the sample cartridge 200 where it may be further manipulated by the user and / or by a slide release mechanism of the integrated sample processing system 100.

[0082] As discussed above, a sample cartridge 200 consistent with embodiments herein may include two sample slides 401. In an exemplary sample processing operation, a first sample slide 401 may be used for subsequent processing. A sample is deposited on the first sample slide 401, then drained, treated with a fixative such as alcohol, and stored for further processing. Sample processing may then continue with the second sample slide 401 with a second transfer step, a second smear step, etc.

[0083] In an embodiment, the slide ejection operation may be performed by the integrated sample processing system 100, as discussed in further detail with respect to Figures 16A-16B. In an embodiment, the slide ejection operation may be performed manually by an operator.

[0084] 10A-10C show a series of staining positions for the sample cartridge 200. The staining positions include a flood start position, a flood end position, and a rinse position for the sample cartridge 200. The staining positions are selected and adapted to facilitate staining of the sample slide 401. The staining positions for a staining operation are configured and adapted for use with a single sample slide 401, and staining may be performed after the first sample slide 401 is ejected.

[0085] The cartridge drawer 202 and cartridge frame 201 may be configured to position the sample slide 401 and the coverslip 601 in a flood start position having a specific position relative to each other. In the flood start position, the sample slide 401 and the coverslip 601 are arranged such that the first slide surface 402 (e.g., bottom surface) of the sample slide 401 with the sample disposed thereon and the slip surface 602 of the coverslip 601 have a vertical gap g and a horizontal overlap o relative to each other. The vertical gap g may be defined by a vertical distance of about 0.03-0.3 mm. The horizontal overlap o may be defined by a horizontal distance of about 1-10 mm. The horizontal overlap o and the vertical gap g may be selected, for example, according to the fluid properties of the fluid expected to be used in the staining process.

[0086] In an embodiment, the cartridge frame 201 and cartridge drawer 202 are configured to provide the vertical gap g and horizontal overlap o defined above when maintaining a flood start position. Specifically, the frame rails 310 of the cartridge frame 201 and the drawer rails 311 of the cartridge drawer 202 may be configured such that the vertical gap g is maintained when the cartridge drawer 202 is in the cartridge frame 201, the sample slide 401 is in the slide support 211, and the coverslip is in the coverslip support 216. The horizontal overlap o may be determined by the relative linear movement between the cartridge frame 201 and the cartridge drawer 202.

[0087] In embodiments, the cartridge frame 201 and cartridge drawer 202 may be manufactured with loose tolerances, such as vertical "play", that aid in manufacturing techniques. In such embodiments, the vertical gap g may be achieved by providing a downward force on the outer surface 242 of the cartridge frame 201 while holding the cartridge drawer 202 stationary (and / or providing an upward force on the cartridge drawer 202 while holding the cartridge frame 201 stationary). The downward force presses the cartridge frame 201 and cartridge drawer 202 together, thus removing the excess "play" of the loose tolerances and achieving the vertical gap g. In embodiments, the downward force may be applied by the integrated sample processing system 100, as shown in further detail with respect to FIG. 13.

[0088] In an embodiment, the vertical gap g may be set during the manufacturing process through the use of an adhesive to secure the coverslip 601 and one or more spacers. For example, one or more spacers having a height equal to the desired vertical gap g may be placed between the coverslip 601 and the sample slide 401. An appropriate amount of adhesive may be applied at the locations described above to secure the coverslip 601 to the cartridge drawer 202. The cartridge frame 201 and cartridge drawer 202 may then be pressed together as described above to remove excess "play" from loose tolerances. The spacers maintain the vertical gap g between the coverslip 601 and the sample slide 401 during this process. The adhesive supporting the coverslip 601, when cured or hardened, is flattened, compressed, or expanded to maintain a height of the coverslip 601 that achieves the desired vertical gap g when the sample cartridge 200 is subjected to a downward force.

[0089] In the flood start position, flooding fluid (such as stain) may be applied to the coverslip 601 in the vertical gap g, as shown in FIG. 10A. For example, in one embodiment, fluid may be applied through the space 220 between the end of the specimen slide 401 and the bridge portion 241 of the cartridge frame 201 by a fluid dispenser, such as a pipette or syringe, associated with a fluid distribution system 1251, as discussed below. In another example, fluid may be applied in the gap from the stain storage unit 701 by discharging fluid from a fluid outlet 703 in the stain storage module 702. Fluid may be displaced from the stain storage unit 701 by action of the fluid distribution system 1251, as discussed below. Sufficient fluid may be applied such that the volume 1001 defined by the vertical gap g and the horizontal overlap o is filled with fluid. Additional fluid may then be deposited on the coverslip 601. The additional fluid may be deposited continuously as the sample slide 401 and the cover slip 601 advance to the flood end position, may be deposited prior to the movement, and / or may be deposited in discrete amounts at appropriate times during the movement. Prior to the start of the movement, the fluid completely occupies the volume 1001 between the sample slide 401 and the cover slip 601. The relative movement involves the sample slide 401 and the cover slip 601 being advanced such that the horizontal overlap o increases. During the movement, at least enough additional fluid is provided to completely fill the volume 1001 between the sample slide 401 and the cover slip 601 as the horizontal overlap o increases. Advancement from the flood start position to the flood end position in this manner serves to eliminate or reduce the occurrence of air bubbles or non-wetting spaces in the volume 1001 between the sample slide 401 and the cover slip 601. This approach may also reduce the waste of excess fluid. The process begins with the mating surfaces of the sample slide 401 and the cover slip 601 pre-wetted with fluid so that as the surfaces advance toward one another, surface tension pulls the fluid along, preventing the formation of air bubbles or voids.10B, the flood end position may be reached when the horizontal overlap reaches a maximum distance, i.e., when the horizontal distance of the horizontal overlap is equal to the shorter of the sample slide 401 and the coverslip 601. In an embodiment, the flood end position may be selected as the position where the horizontal overlap reaches a selected distance that is less than the maximum horizontal distance.

[0090] The relative movement of the sample slide 401 and coverslip 601 from the flood start position to the flood end position, as well as the application and addition of fluids, may be performed by the integrated sample processing system 100, as discussed below with respect to Figures 16A-16C. In further embodiments, the relative movement and addition of fluids may be performed manually and / or by another automated system.

[0091] In an embodiment, flooding fluid may be applied in a first initial amount in the vertical gap g when the sample slide 401 and coverslip 601 are in a flood start position. In an embodiment, flooding fluid may be applied in a first amount to the sample slide 401 or coverslip 601 prior to placing the sample slide 401 and coverslip 601 in a flood start position. In such an embodiment, fluid may then be received in the vertical gap g when the sample slide 401 and coverslip 601 reach the flood start position. The fluid received in the vertical gap g may be wicked up into a volume defined by the horizontal overlap o and the vertical gap g. In an embodiment, a first amount of fluid may be applied initially, followed by additional fluid in a second amount, third amount, fourth amount, etc., as needed, during or prior to the relative movement between the sample slide 401 and coverslip 601. In embodiments, the first amount of fluid and any amount (including all) of additional fluid may be applied simultaneously prior to or after the sample slide 401 and the cover slip 601 are placed in the flood start position. In embodiments, additional fluid may be applied as the horizontal overlap o between the sample slide 401 and the cover slip 601 increases. The additional fluid may be applied in a continuous stream and / or in discrete amounts. In embodiments, as the horizontal overlap o increases, the size of the volume increases. As the volume increases, sufficient additional fluid is applied to ensure that the volume remains sufficiently full to prevent the formation of air bubbles. The amount of additional fluid may be selected or determined according to the size of the volume. In each of the above embodiments, fluid may be provided to either the cover slip 601 or the sample slide 401 as appropriate, depending on the orientation of these components.

[0092] After completion of the fluid flooding operation, the sample slide 401 and the cover slip 601 may be rotated to adopt a flushing position, as shown in FIG. 10C. The flushing position may be adopted by automated or manual manipulation of the sample slide 401 and the cover slip 601 with or without the sample cartridge 200. In the flushing position, the sample slide 401 and the cover slip 601 are rotated with a matching movement to adopt a position having a flushing angle a with respect to a horizontal reference (i.e. the sample slide 401 and the cover slip 601 have similar or identical movements with limited relative movements). The flushing angle a may be selected according to the properties of the fluids involved and the vertical gap g. In the flushing position, a second, third or more fluids may be applied in the vertical gap g between the sample slide 401 and the cover slip 601. An additional fluid, which may be called a wash-off fluid, may flow through the volume 1001 between the specimen slide 401 and the coverslip 601, washing away the previous fluid. As used herein, "wash-off fluid" refers to a subsequently applied fluid that washes away the previous fluid. The wash-off fluid may include water, additional stain, alcohol, or any suitable fluid.

[0093] In this manner, a series of multiple fluids may be applied. A first fluid is applied before or during the transition of the specimen slide 401 and coverslip 601 from the flood start position to the flood end position. Once the volume 1001 between the specimen slide 401 and coverslip 601 is filled with fluid, additional fluid may be added to flush out the previous fluid without creating bubbles or gaps. Multiple fluids may be applied at appropriate times to complete the staining protocol. During the staining protocol, the specimen slide 401 and coverslip 601 may be rotated away from the flush position to better maintain the position of the added fluid, if necessary for the protocol. In an embodiment, the staining protocol may be completed by application of water, alcohol, or other fluid.

[0094] In an embodiment, the cartridge drawer 202 may include an excess fluid recess 297. The excess fluid recess 297 may be a cavity disposed with the cartridge base 232 at an end of the cartridge drawer 202 corresponding to the leading end 291. The excess fluid recess 297 may include an absorbent medium 298 positioned therein. The excess fluid recess 297 may include an opening proximate the end of the coverslip 601. During a staining operation, the excess fluid recess 297 and absorbent medium 298 may function as a reservoir to collect and hold excess applied fluid.

[0095] After completion of the staining protocol, the specimen slide 401 may be advanced to an ejection position (leaving the coverslip 601 in place within the cartridge) and ejected or allowed to air dry, as discussed above. In embodiments, air drying may include the forced application of heat or air flow to accelerate or facilitate drying. In embodiments, an imaging device 1281, as described below, may be used to image the specimen slide 401 during the drying procedure to determine if drying is complete. In embodiments, the specimen slide 401 may be imaged after a rinse step and before an ejection or air drying step, as discussed in more detail below.

[0096] The translation of the sample slide 401 and coverslip 601 from the end-flood position to the rinse position, as well as the application and addition of fluids, may be performed by the integrated sample processing system 100, as discussed below with respect to Figures 16A-16C. In further embodiments, the translation and fluid addition may be performed manually and / or by another automated system.

[0097] 11-18 illustrate features of an integrated sample processing system 100. An integrated sample processing system 100 as described herein may perform, enable, and / or facilitate the performance of various aspects of the sample processing methods as discussed herein. In embodiments, the integrated sample processing system 100 may be configured to receive and manipulate a sample cartridge 200 to perform sample processing operations as described herein. As discussed above, features of the integrated sample processing system 100 may be further configured to operate without a sample cartridge 200 and / or may perform more, less, or different sample processing operations than each of the sample processing operations discussed herein.

[0098] 11 illustrates a computer system consistent with embodiments herein. The control system 1100 is configured to provide commands to various actuators, devices, and other components of the integrated sample processing system 100. The control system 1100 may include dedicated hardware specific to the integrated sample processing system 100 and / or may include other types of computing systems configured to interface with various components of the integrated sample processing system 100. For example, the computing systems may include servers, personal computers, smartphones, and / or tablet computing devices. In addition, the functionality of the control system 1100 may be implemented via a cloud computing platform.

[0099] The control system 1100 may include one or more processors 1110 (also interchangeably referred to herein as processing units 1110, processors 1110, processor(s) 1110, processing circuits 1110, or processors 1110 for convenience), one or more storage or memory device(s) 1130, and / or other components. In other embodiments, the functions of the processors may be performed by hardware (e.g., through the use of application specific integrated circuits ("ASICs"), programmable gate arrays ("PGAs"), field programmable gate arrays ("FPGAs"), or any suitable combination of integrated circuits, etc.), or any combination of hardware and software. The storage device(s) 1130 include any type of non-transitory computer-readable storage medium (or media) and / or non-transitory computer-readable storage device. Such computer-readable storage media or devices may store computer-readable program instructions for causing the processor to implement one or more methodologies described herein. Examples of computer readable storage media or devices may include, but are not limited to, electronic storage devices, magnetic storage devices, optical storage devices, electromagnetic storage devices, semiconductor storage devices, or any suitable combination thereof, such as, but not limited to, computer diskettes, hard disks, random access memory (RAM), read only memory (ROM), erasable programmable read only memory (EPROM or flash memory), static random access memory (SRAM), portable compact disc read only memory (CD-ROM), digital versatile disc (DVD), memory sticks, etc., without being limited to these examples only.

[0100] The processor 1110 is programmed with one or more computer program instructions stored in the storage device 1130 and executable by the processor 1110. For example, the processor 1110 may be programmed with a movement manager 1111, an orientation manager 1112, a transport manager 1114, a smear manager 1116, a fluid manager 1118, a user interface manager 1120, an imaging manager 1122, and a process manager 1124. It will be understood that the functions of the various managers as discussed herein are representative and not limiting. In addition, the storage device 1130 may function as a data storage device providing data storage for the integrated sample processing system 100. For convenience, the various "managers" as used herein are described as performing an operation when the manager provides programming or software instructions to the processor 1110 (and thus to the control system 1100) to actually perform the operation. In an embodiment, some or all of the functions of the various managers described herein may be implemented by hardware (e.g., integrated circuits) or a combination of hardware and software.

[0101] In general, the movement manager 1111 is a software module that includes instructions to control actuators (e.g., sample movement mechanism 1241) that provide or cause relative movement between various components of the sample cartridge 200, or between such components when processed by the integrated sample processing system 100 without the sample cartridge 200. The orientation manager 1112 is a software module that includes instructions to control actuators (e.g., sample orientation system 1221) that provide or cause changes in the orientation of the sample cartridge 200, or between processing components when processed by the integrated sample processing system 100 without the sample cartridge 200. The transport manager 1114 is a software module that includes instructions to control actuators (e.g., sample transport mechanism 1211) that perform sample transfer operations, such as probes and / or arms that manipulate the sample receptacle 301. The smear manager 1116 is a software module that includes instructions to control actuators (e.g., sample smear mechanism 1231) that manipulate the smear plate 501 for smearing operations. The fluid manager 1118 is a software module that includes instructions to control actuators (e.g., fluid distribution system 1251) that provide fluids (e.g., staining fluid such as Diff-Quik®, additional fluids such as water, alcohol, etc.) during staining operations. The user interface manager 1120 is a software module that includes instructions to control the system user interface 103, e.g., to receive user input and provide user output, e.g., on the display 102. The imaging manager 1122 is a software module that includes instructions to control actuators and imaging devices (e.g., imaging device 1281) to perform various imaging operations discussed herein. Finally, the process manager 1124 is a software module that includes instructions to organize the processing and command structure of the other managers and to perform any data analysis steps that may be required, as discussed herein. The various managers described herein may issue commands to various actuators of the integrated sample processing system 100, as discussed below.

[0102] 12A and 12B show features of an integrated sample processing system 100 consistent with embodiments herein. FIG. 12 shows a sample handling system 1201, a fluid distribution system 1251, a sample slide receiving system 1271 (a portion of the slide receiving system 1271 is illustrated in FIG. 12 and other portions are illustrated in FIGS. 17A-17C), a sample orientation system 1221, and a sample receptacle receiving system 1291. The sample handling system 1201 further includes a sample transfer mechanism 1211, a sample smearing mechanism 1231, a sample orientation system 1221, and a sample movement mechanism 1241. In an embodiment, the sample handling system 1201 may include an insertion bay 1216. The individual subsystems and mechanisms of the integrated sample processing system 100 may be configured to perform sample processing operations consistent with those discussed herein, and may be configured to perform such operations in conjunction with a sample cartridge 200. In embodiments, various aspects of the integrated sample processing system 100 may be configured to perform sample processing operations consistent with those discussed herein without the use of a sample cartridge 200.

[0103] 13 illustrates a sample movement mechanism 1241 configured to facilitate or effect relative movement of the sample processing components. In an embodiment, the sample movement mechanism 1241 may be configured to facilitate or effect relative movement of the sample processing components via manipulation of a housing configured to receive and support one or more of the sample processing components, such as the sample cartridge 200.

[0104] The sample moving mechanism 1241 may be configured to manipulate the sample cartridge 200 provided to and accommodated within the insertion bay 1216. The insertion bay 1216 is a frame structure configured to receive the sample cartridge 200. In an embodiment, the insertion bay 1216 may be configured to provide a downward force to the outer surface 242 of the sample cartridge 200, as previously discussed. The downward force may be provided, for example, by one or more angled surfaces that provide a downward force as the sample cartridge 200 advances laterally. In further embodiments, the insertion bay 1216 may provide the downward force via an automated or motorized actuator and / or by a lever-based system. In an embodiment, the insertion bay 1216 may include one or more compliant components, such as springs, compliant materials, etc., to control the amount of force provided to the sample cartridge 200.

[0105] The sample mover mechanism 1241 includes a linear drive system 1242 configured to interact with the cartridge drive system 350 described above. In an embodiment, the linear drive system 1242 may be a gear drive system including a frame drive gear 1243 and a drawer drive gear 1244. The frame drive gear 1243 may be configured to engage with a frame gear drive rack 351 disposed on the cartridge frame 201, and the drawer drive gear 1244 may be configured to engage with a drawer gear drive rack 352 disposed on the cartridge drawer 202. The sample mover mechanism 1241 is configured to receive commands from the movement manager 1111 to drive relative movement between the cartridge frame 201 and the cartridge drawer 202 to align various sample processing components during sample processing operations. The relative movement drive by the sample mover mechanism 1241 may be selected to provide specific positions for the cartridge frame 201 and the cartridge drawer 202 to adopt, as discussed herein.

[0106] In further embodiments, the sample movement mechanism 1241 and linear drive system 1242 may include any type of linear actuation device configured to engage and be controlled to generate relative movement with the sample cartridge 200, including hydraulic, chain drive systems, lead screws, magnetic drive systems, pinch roller systems, external push rod systems, differential gear systems, linear stage systems, etc. In further embodiments, the sample movement mechanism 1241 may be configured to cause relative movement between individual interactions and engagements with individual sample processing components.

[0107] Figures 14A-B show embodiments of a sample transfer mechanism 1211 of the sample handling system 1201. Figure 14A shows the sample transfer mechanism 1211, also referred to herein as a probe driven system, performing a sample receptacle capture operation in conjunction with a sample mover mechanism 1241 that causes the sample cartridge 200 to adopt a receptacle release position. Figure 14B shows the sample transfer mechanism 1211 performing a sample transfer operation in conjunction with the sample mover mechanism 1241 that causes the sample cartridge to adopt a sample transfer position.

[0108] 14A, in response to a release position command from the processor 1110, the sample movement mechanism 1241 may operate to cause the cartridge drawer 202 to adopt a receptacle release position relative to the cartridge frame 201. In the receptacle release position, as discussed above, the sample cartridge 200 is manipulated such that the sample receptacle 301 is no longer supported by the frame receptacle support ledge 371 and the drawer receptacle support ledge 372. In conjunction with the release position command, the sample transfer mechanism 1211 may receive a command from the processor to adopt a receptacle capture position.

[0109] 14A, the sample transfer mechanism 1211 may include a rotational actuator 1212, a translational actuator 1213, a receptacle capture mechanism 1214, one or more probes 421, one or more probe actuators 422, and a transfer frame 1217. The transfer frame 1217 is a mechanical structure that is coupled to and supports the various actuators of the sample transfer mechanism 1211. The rotational actuator 1212 may include, for example, a motor (e.g., a stepper motor, an RC servo, a DC motor, a brushless motor, etc.) configured to provide rotational motion to the transfer frame 1217. The translational actuator 1213 is configured to provide translational movement of the receptacle capture mechanism 1214. The translational actuator 1213 may include, for example, one or more actuator drive linkages for providing lateral movement to the receptacle capture mechanism 1214. The receptacle capture mechanism 1214 is configured to grip, hold, or otherwise capture the sample receptacle 301. In an embodiment, the receptacle capture mechanism 1214 may include a vacuum chuck configured to capture the sample receptacle 301 via suction. The sample transfer mechanism 1211 further includes one or more probes 421 driven by one or more probe actuators 422. In an embodiment, as shown for example in FIG. 14A, each probe(s) 421 may have a designated probe actuator 422 configured to advance and retract the probe 421 through a central opening of the receptacle capture mechanism 1214 into contact with the sample receptacle 301. In a further embodiment, a single probe actuator 422 may be configured to operate or actuate more than one different probe 421. In an embodiment, one or more probes 421 may be manually configurable on the probe actuator 422. In a further embodiment, one or more probes 421 may be automatically selected by the sample transfer mechanism 1211 and installed by the probe manufacturer.

[0110] The rotational actuator 1212 and the translational actuator 1213 cooperate to provide rotational and translational motion to cause the receptacle capture mechanism 1214 to adopt a receptacle capture position, a sample transfer position, and an idle position. The idle position is any position in which the sample transfer mechanism 1211 is held so as not to obstruct or interfere with other aspects of the sample handling system 1201, as shown, for example, in FIG.

[0111] 14A, the receptacle capture position is adopted by the sample transfer mechanism 1211 to move the receptacle capture mechanism 1214 into a position to grip or capture the sample receptacle 301 when released from the sample cartridge 200 to the receptacle release position. In one embodiment, the rotational actuator 1212 and the translational actuator 1213 cooperate to move the receptacle capture mechanism 1214 into contact with the sample receptacle 301, the receptacle capture mechanism 1214 is activated to grip / capture the sample receptacle 301 (e.g., a vacuum chuck provides suction), and the sample transfer mechanism 1241 is actuated to cause the sample cartridge 200 to adopt the receptacle release position. The sample receptacle 301 may then be moved down through the receptacle window 212 and away from the sample cartridge 200.

[0112] 14B may be adopted by the sample transfer mechanism 1211 in conjunction with the sample transfer mechanism 1241 causing the sample cartridge 200 to adopt the transfer position, for example in response to a transfer position command. The sample transfer mechanism 1241 may operate to align the sample slide 401 with the sample transfer position of the sample transfer mechanism 1211 such that the sample slide 401 contacts a sample contained in the sample receptacle 301. In an embodiment, the sample transfer mechanism 1241 may manipulate the sample cartridge 200 such that the sample slide 401 is aligned with the receptacle window 212 of the cartridge drawer 202. The sample transfer mechanism 1241 may raise the sample receptacle 301 into proximity with the sample slide 401 through the receptacle window 212 to adopt the sample transfer position.

[0113] Once in the sample transfer position, the sample transfer mechanism 1211 may, for example in response to a probe transfer command, cause sample transfer via the probe actuator 422 to extend the probe 421 into contact with the lower surface 394 of the sample receptacle 301. The force against the lower surface 394 of the sample receptacle 301 raises the sample platform 304 and brings the sample into contact with the sample slide 401, as described above.

[0114] The probe 421 may be applied to the underside of the sample receptacle 301 according to one or more probing characteristics. The probing characteristics may include a plurality of probe motion characteristics and / or probe shape characteristics. The probe 421 may be actuated with a plurality of probe motion characteristics including one or more of a probe force, a probe velocity, and a probe trajectory. The probe force is the amount of force the probe exerts on the underside of the sample receptacle. The probe velocity is the speed at which the probe moves to transfer the sample. The probe trajectory may include a time-varying profile of the probe velocity and the probe force. Each of the probe force and the probe velocity may take on various values ​​according to the probe trajectory motion profile during actuation. The probe motion characteristics may be selected according to the sample type and thus may correspond to the sample type.

[0115] In addition, probe shape characteristics may be selected according to the sample type. For example, for solid or cohesive tissues, a blunt probe 421 may be selected to contact a wide portion of the membrane 317 of the sample receptacle 301 with the sample slide 401, as shown in FIG. 14C. For low viscosity samples, such as fluids, a thin or sharp probe 421 may be selected to cause a narrower, more localized deformation of the membrane 317 to break the surface tension of the fluid to allow deposition onto the sample slide 401, as shown in FIG. 14D.

[0116] In embodiments, both the probe shape characteristics and the probe movement characteristics may be selected according to the type of probe. For example, a high speed combined with a "sharp" probe may be used for samples (fluids) with low viscosity to break the surface tension of the fluid for controlled deposition onto the slide. A low speed combined with a "blunt" probe may be used for solid / cohesive tissue samples for controlled "touch imprint" of the tissue. As discussed above, the shape of the probe 421 may also be selected according to the characteristics of the sample, such as viscosity. For example, a sharp, thin, or pointed probe tip may be suitable for the transfer of samples with lower viscosity, and a blunt, flat, or rounded probe tip may be suitable for the transfer of samples with higher viscosity.

[0117] The probe movement characteristics and probe shape characteristics of the probe 421 may be selected in advance (preselected), for example, during a sample processing procedure when a particular type of sample is expected. The probe movement characteristics and shape of the probe 421 may be selected during sample processing, for example, by a user evaluating the deposited sample and selecting a probe for a transfer operation. Furthermore, the probe movement characteristics and shape of the probe 421 may be selected via automated means. For example, the imaging device 1281 may capture an image for the sample control system 1100 to make a decision to select an appropriate probe. In one embodiment, the sample receptacle 301 may be tilted by the sample transfer mechanism 1211 and the imaging device 1281 (or other sensor) may be used to sense the movement. If a threshold amount of movement is detected, it may be determined that the sample contains a lot of liquid and a sharp profile probe with a higher probe speed may be selected and utilized. If there is less than a threshold amount of movement, it may be determined that the sample is mostly solid and a flat profile probe with a slower movement speed for "touch imprint" may be used.

[0118] The sample transfer mechanism 1211 described herein is configured to position the sample receptacle 301 proximate to the sample slide 401 and apply a probe 421 to the sample receptacle 301 to transfer the sample. The particular collection of actuators and components, such as the rotational actuator 1212, translational actuator 1213, receptacle capture mechanism 1214, probe actuator(s) 422, and transfer frame 1217, are provided for illustrative purposes only. Other combinations of rotational actuators and linear actuators may be used to facilitate or produce the described functions.

[0119] In embodiments, the sample transfer mechanism 1211 may manipulate the sample receptacle 301 (and the sample contained therein) in various ways to improve sample transfer. For example, prior to sample transfer initiated by the probe 421, the sample receptacle 301 may be positioned at an angle or tilted to cause fluid associated with the sample to flow away from the solid material of the sample and into the trough 303. Separating the fluid in this manner before initiating sample transfer allows tissue particles in the sample to better adhere to the sample slide 401.

[0120] In an embodiment, the sample transfer mechanism 1211 may apply vibration or ultrasonic energy to the sample in the sample receptacle 301. For example, the sample transfer mechanism 1211 may include one or more actuators, such as an ultrasonic probe or vibration actuator, to apply such energy to the sample receptacle 301. The vibration or ultrasonic energy may break up any blood clots that may be present in the sample. At times, cells of interest may be contained within the blood clot and it may be desirable to deposit these onto the sample slide 401, however, standard contact transfer of the blood clot may result in only blood being transferred.

[0121] In an embodiment, the sample transfer mechanism 1211 may apply pressurized or forced air to the sample in the sample receptacle 301 to manipulate the sample. For example, it may be desirable to touch imprint different sides of a sample acquired by forceps. The forced or pressurized air may be used to reposition the sample, thus facilitating multiple touch imprints on different sides of the sample.

[0122] In further embodiments, the sample transfer mechanism 1211 may operate in an alternative manner to transfer the sample from the sample receptacle to the sample slide. In some embodiments, alternative sample receptacles and / or alternative mechanisms may be utilized. For example, in one embodiment, as shown in FIG. 20A and FIG. 20B, the sample receptacle 2001 may include a cup-shaped container 2002 with a hole 2003 at the bottom, optionally at the end of the nozzle 2004. The hole 2003 may be sized such that the sample does not leak through the hole when added to the sample receptacle 2001. During sample transfer, the sample transfer mechanism 1211 may position the sample receptacle 2001 over the sample slide 401 and apply pressure to the sample, for example via a plunger 2005 or other mechanism, to push the sample through the hole 2003 and onto the sample slide 401.

[0123] In another example, the sample transfer mechanism 1211 may operate as follows, as shown in FIG. 21A and FIG. 21B. The sample receptacle 2101 may include a substantially flat substrate configured to receive a sample. The sample receptacle may be contained within a sample cartridge consistent with the present disclosure and / or may be handled separately by the integrated sample processing system 100. The sample tube 2102 is brought into contact with the sample receptacle 2101 at the sample location. The sample tube 2102 is a hollow cylinder. Thus, when the sample tube 2102 is brought into contact with the sample receptacle 2101, a portion of the sample is contained within the sample tube 2102, as shown in FIG. 21B. Optionally, the end of the sample tube 2102 may be sharp and configured to cut the sample. Fluid is applied by the fluid distribution system 1251 (or other fluid system associated with the integrated sample processing system 100) to rinse or wash away excess sample on the sample receptacle 2101 outside of the sample tube 2102. In an embodiment, the fluid may be formalin or other preservation fluid, and excess sample may be rinsed into the sample storage container. The sample tube 2102 may then be lifted away from the sample receptacle 2101 by the sample transfer mechanism 1211. The sample remains in the sample tube 2102. In an embodiment, the opposite end of the sample tube 2102 may be sealed to help maintain the sample in the sample tube 2102. The sample movement mechanism 1241 may then be actuated to expose a portion of the sample slide 401 and align the sample slide 401 with the sample tube 2102 held by the sample transfer mechanism 1211. The sample tube 2102 is then brought into proximity or contact with the sample slide 401 and the sample released onto the sample slide 401. In an embodiment, the release of the sample may be performed by release of a seal at the opposite end of the sample tube 2102, by vibration or other agitation, and / or by applying air pressure to the opposite end of the sample tube 2102.In embodiments, the sample slide 401 may be placed in the sample cartridge 200, or in an integrated sample processing system 100 without a sample cartridge 200, with the deposition surface of the sample slide 401 facing upwards to facilitate this technique.

[0124] In an embodiment, the imaging device 1281 may be utilized before, during, or after a sample transfer operation to assist with sample transfer. The imaging device 1281 may include one or more cameras, CCD, CMOS devices, and / or other devices capable of capturing images. The imaging device 1281 may further include optics, lenses, and / or other means for focusing, magnifying, and generally facilitating image capture. For example, the imaging device 1281 may include multiple magnification microscope lenses. In an embodiment, the imaging device 1281 may include multiple imaging devices. For example, the first imaging device 1281 may be configured to capture images of the sample slide 401 during processing to help guide the processing steps, as discussed below. The second imaging device 1281 may be configured to capture higher resolution images of the sample disposed on the sample slide 401, for example, after completion of slide staining for use in cytological evaluation. The imaging device 1281 may be positioned and configured to capture images of the sample slide 401 when the sample slide 401 is positioned in the sample transfer position. In an embodiment, the imaging device 1281 may be coupled to one or more actuators that facilitate movement of the imaging device 1281, for example to properly position the imaging device 1281 for image capture. The imaging device 1281 may operate in response to one or more imaging commands.

[0125] The imaging device 1281 may capture an image of the sample slide 401 prior to sample transfer. Such an image may be processed or otherwise analyzed by the control system 1100 (e.g., the process manager 1124) to determine that the sample slide 401 is properly positioned. The imaging device 1281 may capture an image of the sample in the sample receptacle 301 prior to sample transfer. Such an image may be processed or otherwise analyzed by the control system 1100 to determine characteristics of the sample that may be used for probe selection. Such an image may be processed to determine characteristics of the sample that may be stored in association with any other acquired sample data for later use. For example, the control system 1100 may operate to count or otherwise determine various characteristics of the sample, such as the number of tissue masses in the sample. Such characteristics may assist in assessing sample image information.

[0126] The imaging device 1281 may capture an image of the sample slide 401 after sample transfer. Such images may be processed or otherwise analyzed by the control system 1100 (e.g., process manager 1124) to determine whether the sample transfer was successful, such as whether an appropriate amount of sample was transferred to the sample slide 401. If too little sample was transferred, the control system 1100 may cause the sample transfer mechanism 1211 to repeat the sample transfer operation. If too much sample was transferred, the control system 1100 may cause the sample transfer mechanism 1211 to perform a sample scrape operation.

[0127] The sample scraping action may be performed by the sample transfer mechanism 1211 bringing the sample lip 306 of the sample receptacle 301 into close proximity with the transferred sample. The translation actuator 1213 may then cause the sample lip 306 of the sample receptacle 301 to scrape or drag across the transferred sample, with or without touching the sample slide 401, to reduce the amount of sample on the sample slide 401. In embodiments, the sample scraping action may replace the sample smearing action described herein to distribute the transferred sample across the slide. In embodiments, the sample smearing action, described in more detail below, may utilize features of the sample receptacle 301, such as the sample lip 306, to perform the sample smearing.

[0128] In further embodiments, the sample transfer mechanism 1211 may perform one or more additional sample processing steps. For example, the sample receptacle 301 may include additional features configured to interact with or process the sample. In one example, a tool, such as a blade, needle, or other cutting instrument, may extend from the sample receptacle 301. In such an embodiment, the sample transfer mechanism 1211 may be configured to manipulate the sample receptacle and a tool disposed thereon to further process the sample, for example, by disrupting blood clots or tissue debris.

[0129] FIG. 15 shows an embodiment of a sample smearing mechanism 1231 of the sample handling system 1201. The sample smearing mechanism 1231 includes a gripping mechanism 1232, a force sensor 1233, a smearing mechanism frame 1234, and a rotation actuator 1235. The force sensor 1233, the smearing mechanism frame 1234, and the rotation actuator 1235 may be referred to as an actuation probe. The smearing mechanism frame 1234 is fixed to the rotation actuator 1235 and provides a structure in which the gripping mechanism 1232 and the force sensor 1233 are located. The rotation actuator 1235, which may be a motor such as a stepper motor, is configured to provide a rotational motion to the smearing mechanism frame 1234 to bring the gripping mechanism 1232 into contact with the smear plate 501. The gripping mechanism 1232 may include a compliant structure having a contact surface, such as a suction cup. The smear plate 501 may be disposed within the smear plate support 214 of the sample cartridge 200. In some embodiments, the sample smearing mechanism 1231 may retrieve or obtain a smear plate from an alternative location to perform the smearing operation.

[0130] In a sample smearing operation, the sample moving mechanism 1241 may receive a smearing position command that causes the smear plate 501 and the sample slide 401 to adopt a smearing position. In an embodiment, the smearing position may be adopted via manipulating the sample cartridge 200 via the sample moving mechanism 1241. In the smearing position, the smear plate 501 and the sample slide 401 may be vertically aligned. Within the sample cartridge 200, the smear plate window 215 may be vertically aligned with the sample slide window 11.

[0131] The sample smearing mechanism 1231 may receive a smear command configured to rotate the rotation actuator 1235 and bring the gripping mechanism 1232 into contact with the second surface 512 of the smear plate 501. Further rotation of the rotation actuator 1235 brings the smear plate 501 closer to the slide 401 and into contact with the sample disposed thereon. The smear plate 501 may be brought to a predetermined distance from the sample slide 401 to push or smear the sample against the sample slide 401. Thereafter, the sample moving mechanism 1241 may then move the sample slide 401 relative to the smear plate 501 to continue the smearing process.

[0132] The smearing process may be enhanced by the operation of the compliant structure of the gripping mechanism 1232 and the force sensor 1233. The compliant nature of the gripping mechanism may aid in contacting the smear plate 501 with the sample. For example, the sample may not be uniformly distributed, may be solid or semi-solid, and / or may not be centered relative to the smear plate 501, so the compliant nature of the gripping mechanism 1232 may allow the gripping mechanism to flex or deform to better enable the smear plate 501 to contact and distribute the sample. The force sensor 1233 may be utilized to control the amount of force applied during the smearing operation. The amount of force applied may be selected or determined according to one or more characteristics of the sample being smeared, for example, based on image information acquired by the imaging device 1281. For example, if it is determined based on the image information that blood clots or large tissue pieces are present, a greater amount of force may be applied to flatten the tissue for better visualization by the imaging device 1281. Conversely, if only a thin layer of tissue is present on the sample slide 401, a light smear using a small amount of force may be used to ensure that the cells in the sample are not crushed. In embodiments, the smearing operation may be omitted entirely based on a determination made by the control system 1100 via analysis of the image information. For example, if contact preparation of a solid tissue piece is performed, the cells may already appear in a monolayer on the glass slide and smearing may cause the cells to rupture or crush. In embodiments, the force may be dynamically adjusted during the smearing operation according to the output from the force sensor 1233. Dynamic adjustment may include adjusting the force to maintain a constant force or to follow a predetermined force profile.

[0133] In an embodiment, the smearing operation may operate without the smear plate 501 discussed above. For example, the smearing mechanism 1231 may include a roller that is gripped by the gripping mechanism 1232 or disposed on the smearing mechanism frame 1234 in place of the gripping mechanism 1232. The smearing mechanism 1231 may be configured to provide a charge, such as a positive or negative charge, to the roller that causes the roller to repel the sample. The roller may then be utilized to smear, for example by rolling over or moving back and forth over the sample deposited on the sample slide 401. The charge on the roller helps to prevent the sample from adhering to the roller. After use, the roller may be discarded and / or cleaned / disinfected. In another example, the smearing operation may utilize features of the sample receptacle 301, such as the sample lip 306 or other features, to perform sample smearing without the use of the smear plate 501.

[0134] In further embodiments, the sample smearing mechanism 1231 may perform one or more additional sample processing steps. For example, the sample cartridge 200 may include additional features configured to interact with or process the sample. In one example, as shown in FIG. 22, one or more tools 2201, such as a blade, needle, or other cutting instrument, may be housed in a tool holder 2202 of the sample cartridge 200 with a window below it to allow access by the sample smearing mechanism 1231. A gripping mechanism 1232 or other actuator associated with the sample handling system 1201 may be configured to grip or control a tool to perform additional sample processing before or after the smearing operation. In such an embodiment, the sample smearing mechanism 1231 may be configured to manipulate the sample receptacle and a tool disposed thereon to further process the sample, for example, by breaking up blood clots or tissue debris.

[0135] In an embodiment, the imaging device 1281 may be utilized after a sample smearing operation. The imaging device 1281 may be used to capture images of the smeared sample to analyze one or more smear characteristics, such as thickness of the smeared sample. Such images may be processed or otherwise analyzed by the control system 1100 (e.g., process manager 1124) to determine whether the smeared sample is acceptable for further sample processing steps (e.g., staining, imaging).

[0136] In an embodiment, sample separation and / or smearing or dispersion on the sample slide 401 may be performed outside of or remote from the integrated sample processing system 100. The sample slide 401 may then be inserted into the sample processing system 100 (with or without the sample cartridge 200). The imaging device 1281 may be used to capture images of the prepared sample or sample slide 401. Such images may be processed or otherwise analyzed by the control system 1100 (e.g., process manager 1124) to determine whether the prepared sample slide 401 is acceptable for further sample processing steps (e.g., staining, imaging).

[0137] The image of the specimen slide 401 may be analyzed for various potential defects, for example, the quantity of the specimen may be assessed, or the composition of the specimen may be assessed.

[0138] In an embodiment, if the prepared sample is not acceptable, the sample processing system may eject the sample slide 401 (or sample cartridge 200) and prompt the user to take appropriate steps, such as, for example, adding additional sample to the sample slide 401, providing a new sample slide 401 and / or a new sample cartridge 200, removing excess blood, clots, or other material from the sample slide 401, or any other suitable action. In an embodiment, the integrated processing system 100 itself may take action if the sample is not acceptable. For example, if there is too little sample, the integrated processing system 100 may operate to repeat the sample transfer and sample smearing operations to add more sample. In the case of a sample containing excess blood, clots, or other material, the integrated processing system 100 may operate to perform a scraping technique using the sample lip 306, as described above.

[0139] 16A-16C show an embodiment of a fluid distribution system 1251. The fluid distribution system 1251 may include one or more fluid dispensers 1252, also referred to as fluid deposition devices, coupled to one or more dispensing actuators. The one or more fluid dispensers 1252 may include syringes, pipettes, or other suitable devices for dispensing fluids. The dispensing actuators may include one or more actuators for movement (horizontal and / or vertical) of the fluid dispenser 1252 and one or more actuators for controlling dispensing of fluid by the fluid dispenser 1252. The fluid distribution system 1251 may be configured as a "suck and spit" system configured to obtain the required fluid from a refillable or replaceable container. The fluid distribution system 1251 may also be configured with tubing to directly supply the required fluid to the fluid dispenser 1252. In embodiments, the fluid dispenser 1252 may additionally or alternatively include one or more actuators or actuation tools configured to interact with the staining fluid storage unit 701 of the sample cartridge to cause fluid deposition, as discussed further below. For example, the fluid dispenser 1252 may be configured to apply a force or pressure to the fluid seal 704 of the staining fluid storage module 702 to cause the ejection of fluid from the fluid outlet 703.

[0140] In an embodiment, the fluid distribution system 1251 may operate in conjunction with the sample handling system 1201 to perform staining operations. The control system 1100 may provide a flood start command to the sample moving mechanism 1241 to cause the sample slide 401 and the coverslip 601 to adopt a flood start position ( FIG. 16A ), for example, in response to a flood start position command. The control system 1100 may further provide a fluid dispense command to the fluid distribution system 1251 to cause the fluid distribution system 1251 to deliver fluid to the vertical gap g between the sample slide 401 and the coverslip 601, as discussed above. A flood end command provided by the control system 1100 to the sample moving mechanism 1241 may be configured to move the sample slide 401 and the coverslip 601 relative to one another from the flood start position to the flood end position ( FIG. 16B ), for example, in response to a flood end position command. As discussed above, during the flooding motion, additional fluid may be supplied to the coverslip 601 by the fluid delivery system 1251. After completion of the flooding motion, the staining operation may continue at the flood end position along with a fluid washing operation.

[0141] A sample rotation command may be provided by the control system 1100 to the sample orientation system 1221. In response to the sample rotation command, the sample orientation system 1221 may cause a rotation of the sample slide 401 and the coverslip 601. In an embodiment, the sample orientation system 1221 may include a motor or other actuator configured to change the orientation of the sample handling system 1201. In a further embodiment, the sample orientation system 1221 may include a motor or other actuator configured to change the orientation of the sample cartridge 200 without rotating the remainder of the sample handling system 1201. After the rotation, additional fluid may be supplied to the gap between the sample slide 401 and the coverslip 601, for example to wash away previous fluids in response to a flush command, as discussed above.

[0142] As discussed above, the fluid distribution system 1251 may include one or more actuators or actuation tools configured to interact with the stain storage unit 701 of the sample cartridge 200.

[0143] In embodiments, various agitation techniques may be used during a slide staining operation to increase the efficiency or completeness of staining or to reduce the time required for staining. For example, the sample moving mechanism 1241 may be used to induce relative movement between the sample slide 401 and the cover slip 601 and to generate shear forces in the fluid therebetween. In another example, the sample moving mechanism 1241, or other actuators associated with the integrated processing system 100, may be used to vibrate the sample cartridge 200 and therefore also the sample slide 401 and the cover slip 601. In another example, an ultrasonic actuator may be used to agitate the sample slide 401 and the cover slip 601. In yet another example, any of the actuators associated with the integrated sample processing system 100, for example as part of the sample transport mechanism 1211, the sample smearing mechanism 1231, the fluid distribution system 1251, or any additional actuators added to the integrated sample processing system 100 for this purpose, may be utilized to contact and press against the coverslip 601 or the sample slide 401, causing a slight bending or flexing of these features and agitating the staining fluid.

[0144] In further embodiments, the fluid distribution system 1251 may operate to selectively stain portions of the sample slide 401 with different staining solutions at different locations. In one embodiment, the fluid distribution system 1251 may cause selective staining by depositing staining solutions onto the coverslip 601 in strips extending along the length of the coverslip 601. As the coverslip 601 and sample slide 401 advance from the flood start position to the flood end position, different strips of staining solutions may stain different portions of the sample slide 401. During the transition from the flood start position to the flood end position, due to the low level of movement and agitation, mixing between the strips of different staining solutions may be limited. Mixing between the different strips may be further limited or eliminated by either the sample slide 401 or the coverslip 601 including a series of longitudinal ridges 2301 (which may be of the same height as the vertical gap g) extending along its length, as shown in Figures 23A and 23B. When the sample slide 401 and the coverslip 601 are placed in close proximity to one another, the lengthwise ridges 2301 create channels through which staining fluids can be distributed. The fluid distribution system 1251 may dispense fluids separately into each channel such that when the coverslip 601 and the sample slide 401 are moved to a position of greater overlap, fluids fill each longitudinal channel and provide longitudinal strips of alternating stains. In one embodiment, a series of widthwise ridges may be included on either the sample slide 401 or the coverslip 601. Such ridges create widthwise channels through which different fluids from the fluid distribution system 1251 are distributed, providing widthwise strips of alternating stains. In one embodiment, the fluid dispensing cartridge may operate to dispense volumes of fluids across different portions of the sample slide 401 or the coverslip 601 before bringing them in close proximity to create different regions of stains.

[0145] In an embodiment, the imaging device 1281 may be utilized after a slide staining operation to capture images of the sample disposed on the sample slide 401 for further analysis, as discussed below. For example, after completion of staining, water may be the only fluid between the cover slip 601 and the sample slide 401. Thus, images may be captured with the fluid and cover slip 601 in place without excessive distortion from the stained fluid. Imaging through a cover slip may facilitate a better refractive index match compared to imaging a bare air-dried slide without a cover slip.

[0146] In an embodiment, the imaging device 1281 may be utilized after or during a specimen staining operation. The imaging device 1281 may be used to capture images of the stained specimen. Such images may be processed or otherwise analyzed by the control system 1100 (e.g., the process manager 1124) to determine whether the stained specimen is acceptable for further sample processing steps (e.g., staining, imaging). For example, the control system 1100 may make a determination that the specimen is not uniformly stained or is not completely stained. The control system 1100 may then operate to add additional stain or to perform one or more of the staining operation steps again. In an embodiment, the imaging device 1281 may be utilized for such evaluation after or during any portion of the specimen staining operation, from initial stain deposition, to stain dispense, flushing steps, etc.

[0147] 17A-17C show slide ejection operations performed by the sample moving mechanism 1241 and the slide receiving system 1271. The sample transfer mechanism 1211 is not shown in FIG. 17A-17C to provide a clear view of the slide receiving system 1271. The sample moving mechanism 1241 operates to manipulate the sample cartridge, for example, as described with respect to FIG. 9A and FIG. 9B, to perform a first ejection movement and a second ejection movement to adopt a slide ejection position, for example, in response to a slide ejection command. In the first ejection movement, the sample moving mechanism 1241 causes a relative movement between the cartridge frame 201 and the cartridge drawer 202 to expose the sample slide 401 for gripping by the slide release mechanism 1272 of the slide receiving system 1271. The slide receiving system 1271 is a system including actuators and other elements configured to receive the sample slide 401 from the sample cartridge 200 and place the sample slide 401 in a receptacle. The slide release mechanism 1272 may include a gripping device, such as a suction cup, robotic fingers, or other gripper, disposed on an actuation arm and configured for vertical and horizontal movement. In a second ejection motion, the sample transfer mechanism 1241 causes relative movement between the cartridge frame 201 and the cartridge drawer 202 to pull the cartridge frame 201 back onto the cartridge drawer 202 while the sample slide 401 is held in place laterally (optionally further guided vertically) by the slide release mechanism 1272 to advance the sample slide 401 out of the sample cartridge 200 (e.g., out of the rear end 292). After the slide ejection motion, the sample slide 401 may be fully removed from the sample cartridge 200 or may be allowed to air dry prior to capture by the slide receiving system 1271. In an embodiment, the slide release mechanism 1272 may be further configured to guide the sample slide 401 into a receptacle of the slide receiving system 1271. The slide receiving system 1271 may include a container that facilitates organization of the specimen slides 401 created during a single biopsy procedure.The containers may include a receptacle for stained slides 401, an alcohol and / or fixative container for unstained sample slides 401, and a receptacle for formalin and / or preservative container for receiving the sample receptacle 301.

[0148] In embodiments, air drying may include the forced application of heat or air currents to accelerate or facilitate drying. In embodiments, an imaging device 1281, as described below, may be used to image the sample slide 401 during the drying procedure to determine if drying is complete.

[0149] In an embodiment, the sample slide 401 may be advanced to a slide eject position without the cover slip 601 for air drying, imaging, or any other further processing. In a further embodiment, the sample slide 401 may be configured for release and advancement to an eject position with a cover slip attached. For example, after staining, an actuator of the integrated sample processing system 100, such as the sample transport mechanism 1211 or the sample smearing mechanism 1231, may be configured to engage the cover slip 601 in the cartridge drawer 202, release the cover slip 601 from the cartridge drawer 202, and adhere the cover slip 601 to the sample slide 401. In an example, the sample slide 401 and the cover slip 601 may be adhered due to the presence of a staining fluid. In a further example, one or more substances (e.g., adhesives) may be included on the sample slide 401 or the cover slip 601 to facilitate such adhesion. Such techniques may be utilized for use with stains that are typically observed with a coverslip, such as Toludine Blue.

[0150] In an embodiment, the imaging device 1281 may operate during an imaging operation after completion of a slide ejection operation. For example, the imaging device 1281 may be configured to capture an image of a sample disposed on the sample slide 401 when the sample slide 401 is in a slide ejection position (e.g., extending from the sample cartridge 200). In an embodiment, the slide receiving system 1271 may capture the sample slide 401 and transport the sample slide 401 to an alternative location for imaging by the imaging device 1281.

[0151] 18 illustrates aspects of the receptacle receiving system 1291. In an embodiment, at any time after the sample transfer operation for the second sample slide 401, the sample receptacle 301 may be transferred to the receptacle receiving system 1291 for storage and preservation. The receptacle receiving system 1291 may include at least a container of storage fluid (or, for example, a frame or holder configured to hold such a container). In an embodiment, the sample transfer mechanism 1211 may operate as part of the receptacle receiving system 1291. A receptacle release command provided to the receptacle receiving system 1291 (e.g., to the sample transfer mechanism 1211) may cause the sample transfer mechanism 1211 to lower the sample receptacle 301 into proximity with the container of the receptacle receiving system 1291. The sample receptacle 301 may be released by the sample transfer mechanism 1211 for storage in a storage fluid contained in a container of the receptacle receiving system 1291. The stored sample may be withdrawn from the system and delivered to a pathology laboratory for further processing. The storage fluid may include any suitable fluid, such as formalin or related medium, saline, RPMI or related medium, etc., appropriate for storing the expected sample type. In an embodiment, the container of the receptacle receiving system 1291 may include more than one container and / or storage fluid to store multiple different types of samples. In an embodiment, the container of the receptacle receiving system 1291 and the container of the slide receiving system 1271 may be the same container. In an embodiment, the integrated sample processing system 100 may mark or label the container with an identification indicia to associate the contained sample slide 401 and sample receptacle 301 with images and data acquired during sample processing operations.

[0152] As discussed above, the imaging device(s) 1281 described herein may be configured to capture images of the sample disposed on the sample slide 401 for sample assessment at various times during sample processing. For example, after completion of staining, after sample slide ejection, and / or after receipt of the sample slide 401 by the slide receiving system 1271. The captured images of the sample on the sample slide 401 may be used for sample assessment. The sample may be assessed for adequacy to determine whether the sample obtained is sufficient for the purpose for which it was collected. The sample may also be assessed to generate a preliminary diagnosis.

[0153] In one embodiment, the specimen slide is scanned or imaged by imaging device 1281 using a raster scan with an automated XY or XYZ stage. The captured images may include images that are stitched together and stored, transmitted, or otherwise used as a single digital file for viewing by a remote pathologist, viewing on display 102, and / or automated analysis.

[0154] In an embodiment, the captured images may be displayed via the display 102, which may be a high resolution display. Displaying such images on the display 102 in the integrated sample processing system 100 may enable a local user (e.g., an interventionalist) to make a judgment or decision (validation, preliminary diagnosis, etc.) based on the captured images immediately after collection of the sample.

[0155] In further embodiments, a remotely located pathologist may review and evaluate the captured images and provide the results to a user / operator of the integrated sample processing system 100. In further embodiments, the remotely located pathologist may control the X and Y translation of the slide along with the Z focus during imaging in making a remote assessment of adequacy and / or a preliminary diagnosis.

[0156] In embodiments, machine learning systems, expert systems, or other artificial intelligence systems or models may be used to make an automatic validity assessment during sample assessment, identify tissue / cell type, or provide a diagnosis. This information may be displayed to the interventionalist on the display 102 along with the confidence level of the AI ​​decision. The artificial intelligence analysis may run on the control system 1100 and / or via a remote computing system.

[0157] In further embodiments, each sample slide 401, sample receptacle 301, and any containers housing them may be automatically labeled with a sample identification by the integrated sample processing system 100 using laser etching or printer elements, for example with a patient or sample identification and clinical context for the biopsy sample. The sample identification may take the form of a QR code, a bar code, a serial number, or any other suitable identifying indicia that may be interpreted using a scanner or imaging device in the laboratory for further review of the slide. In addition, the integrated sample processing system 100 may associate the sample identification in an internal database or record store with any information, including image information acquired, generated, or created by the integrated sample processing system 100 during processing of the sample associated with the labeled sample slide 401, and any further information derived therefrom.

[0158] In further embodiments, the control system 1100 of the integrated sample processing system 100 may interface with other computer systems, for example, by wired or wireless connections. In one example, the control system 1100 may interface with a surgical navigation system, or other clinical system. The control system 1100 may exchange information related to sample processing with external / other computer systems. For example, in interfacing with a surgical navigation system, the control system 1100 may receive information related to the collected sample from the surgical navigation system. Such information may include the location of collection, the method of collection, and the type of sample. Such information collected by the surgical navigation system may be stored in an internal database or record storage in association with stored image information related to the sample. In an embodiment, the control system 1100 may transmit data to an external computer system. For example, in interfacing with a surgical navigation system, the control system 1100 may transmit any information collected or generated related to sample processing. In one example, the control system 1100 may transmit the identification of the sample to the surgical navigation system so that a user can review the information in the surgical navigation system and associate the collected sample with the images and information acquired by the integrated sample processing system 100. In another example, the control system 1100 may transmit the pathology results of the information analysis associated with the sample (e.g., tumor, necrosis, normal tissue, malignancy, biomarkers, etc.) for association with the collection location or action within the surgical navigation system.

[0159] In another embodiment, while the sample slide 401 is being imaged using the imaging device 1281, a new sample cartridge 200 may be loaded into the machine for parallel scanning of the current sample and sample processing of the next sample.

[0160] In embodiments, as discussed above, a sample substrate containing a plurality of microwells may be utilized in place of the sample slide 401. Sample transfer and smearing operations may operate similarly, where a sample (e.g., tissue) is deposited and smeared across the plurality of microwells such that the sample is deposited in one or more of the plurality of microwells. After such deposition, each well in the plurality of microwells may be individually stained and / or imaged.

[0161] FIG. 19 illustrates a sample processing method consistent with embodiments herein. The sample processing method 1900 may be performed according to the systems, techniques, and devices disclosed herein. The systems, techniques, and devices discussed herein provide examples illustrating the operation and performance of the elements of the sample processing method 1900, but are not exclusive. Thus, although the sample processing method 1900 may be performed by utilizing a sample cartridge 200 in combination with an integrated sample processing system 100 to perform all steps described herein, the disclosure is not limited to such combinations. The steps and operations of the sample processing method 1900 described herein may be performed in any suitable order and in any suitable combination. In embodiments, some or all of the steps and operations of the sample processing method 1900 may be performed using the sample cartridge 200 and manual processing techniques. In other examples, the integrated sample processing system 100 may perform any selection of the steps and operations of the sample processing method 1900, alone or in any combination, with or without the use of a sample cartridge. The steps and operations of the sample processing method 1900 may be performed alone or in any suitable combination with other steps and operations of the sample processing method 1900, and in any suitable combination of manual and automated processing techniques.

[0162] In operation 1902, the sample processing method includes sample deposition. Sample deposition may include depositing a sample in a sample receptacle that includes a membrane. The sample receptacle may be a sample receptacle 301, as described herein. The sample receptacle may be disposed in a sample cartridge during or after sample deposition, as described herein. The sample receptacle may be received by an integrated sample processing system, alone or disposed in a sample cartridge, as described herein. The sample receptacle may be housed or disposed in an integrated sample processing system (with or without a sample cartridge) when the sample is deposited.

[0163] In operation 1904, the sample processing method includes sample transfer. Sample transfer, also referred to herein as sample separation, includes aligning a sample receptacle with a sample slide, applying a probe to an underside of the sample receptacle to press the sample against the sample slide, and depositing at least a portion of the sample on the sample slide. In embodiments, this may include deforming the sample receptacle (or a portion thereof, such as a membrane) despite the application of the probe. In embodiments, the sample receptacle may be flat and / or rigid, and the probe may advance the sample receptacle to the sample slide without deformation. In embodiments, aligning the sample receptacle with the sample slide may be performed in accordance with operation of a sample cartridge, as described herein. In embodiments, aligning the sample receptacle with the sample slide may include bringing the sample receptacle and the sample slide into close proximity to one another. In embodiments, aligning the sample receptacle with the sample slide may be performed by an integrated sample processing system with or without a sample cartridge as described herein. The sample cartridges described herein represent exemplary methods of facilitating sample transfer, but are not required. The sample transfer operation may be performed by any manually or automatically operated structure or device capable of maintaining relative positioning and inducing relative movement between the sample slide and the sample receptacle. For example, the sample slide may be manipulated by the slide transfer mechanism without a sample cartridge and aligned with a sample receptacle gripped by the sample transfer mechanism. In embodiments, a probe may be applied to the underside of the sample receptacle by a probe actuator or manually, as described herein. Additional methods and techniques for sample transfer are described above.

[0164] In operation 1906, the sample processing method includes sample smearing. Sample smearing includes steps and techniques adapted to spread, smear, or otherwise distribute a deposited sample across a sample slide in preparation for staining and imaging. Sample smearing may include engaging a smear plate with a gripping device disposed on an actuation probe, controlling the actuation probe to cause contact between the smear plate and a sample disposed on the sample slide, controlling the force applied by the smear plate, and causing relative movement between the smear plate and the sample slide to distribute the sample. Sample smearing may be performed by the integrated sample processing system discussed herein with or without the use of a sample cartridge. The sample cartridge described herein represents an exemplary method of facilitating sample smearing, but is not required. The sample smearing operation may be performed by any manually or automatically operated structure or device capable of maintaining relative positioning between the sample slide and the smear plate and causing relative movement. For example, the sample slide may be manipulated by a slide movement mechanism without a sample cartridge and engaged by a smear plate gripped by the smear mechanism. Further methods and techniques for sample smearing are described above.

[0165] In operation 1908, the sample processing method includes sample staining. Sample staining includes steps and techniques described herein adapted for applying a fluid (e.g., a staining fluid) to a sample including a sample slide. Sample staining may include placing the sample slide and cover slip in a flood start position having a vertical gap and a horizontal overlap, applying a fluid in the vertical gap, and placing the sample slide and cover slip in a flood end position through relative movement. The relative movement between the sample slide and cover slip increases the horizontal overlap between the sample slide and cover slip and fills the volume between the sample slide and cover slip with fluid. The flood start position may be defined such that the slide surface of the sample slide and the slip surface of the cover slip have a vertical gap of a predefined vertical distance and the sample slide and cover slip have a horizontal overlap of a predefined horizontal distance. The flood end position may be defined such that the horizontal overlap has a maximum horizontal distance. Additional fluid may be applied during the relative movement to ensure there is enough fluid to fill the volume between the sample slide and the cover slip. In an embodiment, the sample staining operation may further include rotating the sample slide and cover slip to a wash angle and applying additional fluid to the vertical gap. The sample staining operations described herein may be performed by an integrated sample processing system with or without a sample cartridge. The sample cartridge described herein represents an exemplary method of facilitating sample staining, but is not required. The sample staining operation may be performed by any manually or automatically operated structure or device capable of maintaining the relative positioning between the sample slide and the cover slip and causing the relative movement. Additional methods and techniques for staining samples are described above.

[0166] In operation 1910, the sample processing method includes imaging the sample. Imaging the sample may include capturing an image of the sample via an imaging device including one or more cameras and one or more lenses (e.g., microscope lenses, etc.). The imaging device may be included within the integrated sample processing system and / or may be located remotely. The image of the sample may be captured at various resolutions and magnifications. The image of the sample may be captured according to a single image capture or as multiple image captures (e.g., in a scanning process). The images of the sample may be collected together as a single image file or as multiple image files for storage, transmission, analysis, etc. The image of the sample may be analyzed by an operator or user at the integrated sample processing system 100 (e.g., via a display) or at a remote location. The image of the sample may be analyzed fully or partially through an artificial intelligence system locally at the integrated sample processing system and / or via remote computing (e.g., cloud services, remote servers, etc.). The image of the sample may be analyzed for various purposes, including, but not limited to, determining the adequacy of the sample, an initial diagnosis, a preliminary diagnosis, or a partial diagnosis, or other.

[0167] In operation 1912, the sample processing method includes ejecting the sample slide, which is captured by the slide receiving system and stored in a container with a storage fluid for further processing or use.

[0168] Thus, the sample processing methods described herein may provide improved accuracy and consistency, reduced analysis time, and increased sample processing throughput. Such advantages may be particularly valuable when provided in an on-site environment to provide rapid sample assessment and improve results. The sample processing methods described herein are not limited to on-site processing, but may be utilized to improve sample processing in any environment, including surgical tumor or tissue resections, remote or off-site pathology laboratories, clinical facilities, academic research institutions, and the like.

[0169] The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting of the present invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly indicates otherwise. Furthermore, it will be understood that the terms "includes" and / or "including" as used herein specify the presence of stated features, elements, steps, operations, elements, and / or components, but do not exclude the presence and addition of one or more other features, elements, steps, operations, elements, components, and / or groups thereof.

[0170] The above-described embodiments are illustrative examples, and the present invention should not be construed as being limited to these specific embodiments. It should be understood that the various embodiments disclosed herein may be combined in different combinations than those specifically shown in the specification and accompanying drawings. It should also be understood that, depending on the example, certain operations or events of any of the processes or methods described herein may be performed in a different order, added, combined, or omitted entirely (e.g., not all operations or events described may be essential to perform the method or process). In addition, although certain features of the embodiments herein are described as being performed by a single module or unit for clarity, it should be understood that the features and functions described herein may be performed by any combination of units or modules. Thus, various changes and modifications may be made by one skilled in the art without departing from the spirit or scope of the present invention, as defined in the appended claims.

[0171] Further embodiments include the following.

[0172] Embodiment 1 is a method of sample separation comprising depositing a sample into a sample receptacle, the sample receptacle including a membrane, aligning the sample receptacle with a sample slide, applying a probe to an underside of the sample receptacle to cause movement of the membrane, and pressing the sample against the sample slide via the movement to deposit at least a portion of the sample on the sample slide.

[0173]

[0023] Embodiment 2 is the method of embodiment 1, further comprising selecting a probe according to a sample type, wherein the shape of the selected probe corresponds to the sample type.

[0174] Example 3 is the method of example 1 or 2, further comprising selecting a probing characteristic according to a sample type.

[0175] Example 4 is the method of example 3, wherein the probing characteristics include probe motion characteristics including at least one of a probe force, a probe velocity, and a probe trajectory.

[0176] Example 5 is the method of example 3 or 4, wherein the probing characteristics include probe shape characteristics.

[0177] Example 6 is the method of any of Examples 1-5, further comprising evaluating the sample to determine at least one of an amount of the sample deposited and a property of the sample.

[0178] Example 7 is the method of example 6, wherein evaluating the sample is performed based on the captured image.

[0179] Embodiment 8 is the method of embodiment 6 or 7, wherein evaluating the sample is performed during deposition of the sample.

[0180] Example 9 is the method of any of Examples 1-8, further comprising engaging a lip of the membrane with the sample to remove excess sample from the sample slide.

[0181] Embodiment 10 is a method of sample smearing comprising: engaging a gripping device with a first side of a smear plate via an actuation probe; controlling the actuation probe to cause contact between a second side of the smear plate and a sample disposed on a surface of a sample slide; controlling a force applied to the smear plate during contact with the sample; and causing relative movement between the smear plate and the sample slide to distribute the sample on the surface of the sample slide.

[0182] Example 11 is the method of example 10, wherein controlling the force is performed according to a force measurement made by a force sensor associated with the actuation probe.

[0183] Embodiment 12 is the method of embodiment 10 or 11, wherein the gripping device comprises a compliant suction cup.

[0184] Example 13 is the method of any of Examples 10-12, wherein controlling the force includes dynamically adjusting the force during the relative movement.

[0185] Example 14 is the method of any of Examples 10-13, further comprising determining the amount of force to be applied according to acquired image information of the sample disposed on the surface.

[0186] Embodiment 15 is the method of any of embodiments 10-14, further comprising controlling the distance between the smear plate and the surface of the sample slide.

[0187] Embodiment 16 is a method of any of embodiments 10 to 15, further comprising: evaluating the sample dispersed on the slide according to the image of the sample to determine a smear characteristic; and in response to the smear characteristic, causing additional relative movement between the smear plate and the sample slide to further distribute the sample on the surface of the sample slide.

[0188] Embodiment 17 is a method of sample staining comprising: placing a sample slide and a coverslip in a flood start position, the flood start position being defined such that a slide surface of the sample slide with the sample disposed thereon and a slip surface of the coverslip have a vertical gap, the sample slide and the coverslip have a horizontal overlap, the vertical gap and the horizontal overlap defining a volume; applying fluid to at least one of the sample slide or the coverslip such that when the sample slide and the coverslip are placed in the flood start position, fluid is present in the vertical gap; placing the sample slide and the coverslip through relative movement that increases the horizontal overlap to a flood end position, the flood end position being defined such that the horizontal overlap has a maximum horizontal distance whereby the fluid fills the volume; and applying additional fluid to at least one of the sample slide or the coverslip to fill the volume as the horizontal overlap increases.

[0189] Example 18 is the method of Example 18, further comprising: positioning the sample slide and cover slip in a wash-off position through a conforming motion, the wash-off position being defined by an angle within the wash-off between the sample slide and cover slip and a horizontal reference; and applying additional fluid to the vertical gap to wash away the fluid.

[0190] Embodiment 19 is the method of any of embodiments 14-18, wherein the vertical gap is defined by a vertical distance of about 0.05-0.25 mm and the horizontal overlap at the flood start location is defined by a horizontal distance of 1-10 mm.

[0191] Embodiment 20 is a sample cartridge comprising a cartridge frame including a slide support configured to support a sample slide, and a cartridge drawer including a coverslip support configured to support a coverslip in a coverslip window, the cartridge drawer configured for movement relative to the cartridge frame, wherein the cartridge frame and the cartridge drawer are configured to cooperate to maintain a vertical gap between the sample slide and the coverslip, and the cartridge drawer is further configured to move from a flood start position relative to the cartridge frame to a flood end position relative to the cartridge frame.

[0192] Embodiment 21 is the sample cartridge of embodiment 20, wherein the cartridge puller further comprises a smear plate support configured to support the smear plate, and the cartridge puller is further configured to adopt a smear position relative to the cartridge frame that aligns the smear plate with the sample slide for smearing the sample.

[0193] Embodiment 22 is a sample cartridge of embodiment 20 or 21, further comprising a receptacle support, the cartridge puller further comprising a receptacle window, the cartridge puller configured to adopt a sampling position relative to the cartridge frame, the receptacle support supporting a sample receptacle, and the cartridge puller configured, when positioned in the slide support, to adopt a transfer position relative to the cartridge frame that aligns the receptacle window with the slide support in a position that enables transfer of the sample in the sample receptacle to the sample slide.

[0194] Embodiment 23 is the sample cartridge of embodiment 22, wherein movement by the cartridge extractor from the flood start position to the flood end position is configured to spread staining solution between the coverslip and the sample slide.

[0195] Embodiment 24 is the sample cartridge of any of Embodiments 20-23, further comprising a fluid receiver configured to receive an absorbent medium.

[0196] Embodiment 25 is the sample cartridge of any of Embodiments 20 to 24, wherein the cartridge frame further comprises a pair of rails, and the cartridge drawer is configured for relative movement with respect to the cartridge frame on the pair of rails.

[0197] Embodiment 26 is a sample cartridge of embodiment 25, wherein the cartridge frame further comprises a frame gear drive rack configured to receive the frame drive gear, and the cartridge drawer further comprises a drawer gear drive rack configured to receive the drawer drive gear, and the frame gear drive rack and the drawer gear drive rack are configured to cause relative movement between the cartridge frame and the cartridge drawer.

[0198] Embodiment 27 is a sample cartridge of any of embodiments 20 to 26, wherein the sample slide is a second sample slide and the slide support portion is configured to support a first sample slide disposed below the second sample slide.

[0199] Embodiment 28 is the sample cartridge of any of embodiments 20 to 27, wherein the cartridge extractor is further configured to adopt a receptacle release position relative to the cartridge frame to release the sample receptacle from the sample cartridge.

[0200] Embodiment 29 is the sample cartridge of any of embodiments 20-28, wherein the cartridge extractor is further configured to move the sample slide to a slide ejection position.

[0201] Embodiment 30 is a method for sample preparation comprising: positioning a sample slide disposed in a cartridge frame of a sample cartridge and a cover slip disposed in a cartridge drawer of the sample cartridge in a flood start position, the flood start position being defined such that the slide surface of the sample slide with the sample disposed thereon and the slip surface of the cover slip have a vertical gap, the sample slide and the cover slip have a horizontal overlap, and the vertical gap and the horizontal overlap define a volume; receiving fluid in the vertical gap between the sample slide and the cover slip; and moving the cartridge drawer relative to the cartridge frame from the flood start position to a flood end position.

[0202] Embodiment 31 is the method of embodiment 30, further comprising depositing a sample in a sample receptacle; moving the cartridge drawer relative to the cartridge frame from a sampling position to a transfer position in which a sample slide supported in the slide support of the cartridge frame is aligned with a receptacle window of the cartridge drawer; and transferring the sample from the sample receptacle to the sample slide by passing the sample receptacle through the receptacle window to allow the sample to contact the sample slide.

[0203] Embodiment 32 is the method of embodiment 30 or 31, further comprising moving the cartridge drawer relative to the cartridge frame to a smearing position in which the smear plate support of the cartridge frame is aligned with the sample slide, and smearing the sample onto the sample slide using a smear plate disposed within the smear plate support.

[0204] Example 33 is the method of any of Examples 30-32, further comprising spreading fluid between the sample slide and the coverslip during movement by the cartridge extractor from the flood start position to the flood end position.

[0205] Example 34 is the method of any of Examples 30-33, further comprising receiving a flushing fluid in the vertical gap and flushing the fluid with the flushing fluid.

[0206] Embodiment 35 is the method of any of embodiments 30-34, further comprising absorbing excess or wash-off fluid with an absorbent medium disposed within the fluid receiver of the sample cartridge.

[0207] Embodiment 36 is a method of any of embodiments 30 to 35, wherein moving the cartridge drawer relative to the cartridge frame includes engaging a frame gear drive rack disposed on the cartridge frame with a frame drive gear, engaging a drawer gear drive rack disposed on the cartridge drawer with a drawer drive gear, and controlling movement of the cartridge drawer on a pair of rails of the cartridge frame using at least one of the frame drive gear and the drawer drive gear.

[0208] Embodiment 37 is the method of any of embodiments 30 to 36, wherein the sample slide is a second sample slide, and the method further includes transferring the sample from the sample receptacle to a first sample slide disposed below the second sample slide, smearing the sample on the first sample slide, and ejecting the first sample slide.

[0209] Embodiment 38 is any of the methods of embodiments 30 to 37, wherein moving the cartridge puller relative to the cartridge frame from the sampling position to the transfer position includes moving the cartridge puller to a receptacle release position and receiving the sample receptacle by the sample transfer mechanism.

[0210] Example 39 is the method of any of Examples 30-38, further comprising moving the specimen slide to an ejection position.

[0211] Embodiment 40 is the method of any of embodiments 30-39, further comprising acquiring an image of the sample slide.

[0212] Embodiment 41 is the method of embodiment 40, wherein acquiring an image of the sample slide is performed while the sample slide and the cover slip are overlapping.

[0213] Embodiment 42 is the method of embodiment 40 or 41, further comprising ejecting the specimen slide prior to acquiring the image.

[0214] Embodiment 43 is a sample processing system comprising at least one processing circuit, an insertion bay configured to receive a sample cartridge having a cartridge frame and a cartridge drawer, and a linear drive system controllable by the at least one processing circuit and configured to generate relative movement between the cartridge frame and the cartridge drawer.

[0215] Embodiment 44 is the sample processing system of embodiment 43, further including a probe disposed on the probe drive system, wherein at least one processing circuit is configured to provide a transport position command to the linear drive system to cause the cartridge drawer to adopt a transport position relative to the cartridge frame that aligns a receptacle window of the cartridge drawer with a sample slide supported by the cartridge frame, provide a probe transport command to the probe drive system to bring the sample receptacle into proximity with the sample slide, and transfer the sample from the sample receptacle to the sample slide by the probe.

[0216] Embodiment 45 is a sample processing system of embodiment 43 or 44, further comprising an imaging device, and at least one processing circuit is configured to provide an imaging command to the imaging device to cause the imaging device to capture image information of the sample on the sample slide.

[0217] Embodiment 46 is a sample processing system of any of embodiments 43 to 45, further comprising an actuating probe including a gripping mechanism, wherein at least one processing circuit is configured to provide a smear position command to the linear drive system to align a smear plate disposed in the cartridge drawer with the sample slide, cause the cartridge drawer to adopt a smear position relative to the cartridge frame, and provide a smear command to the actuating probe to contact the gripping mechanism disposed on the actuating probe with the smear plate and press the sample on the sample slide against the smear plate.

[0218] Embodiment 47 is a sample processing system of any of embodiments 43 to 46, further comprising a fluid dispenser, wherein at least one processing circuit is configured to provide a flood start position command to the linear drive system to cause the cartridge drawer to adopt a flood start position in which a coverslip disposed in the cartridge drawer is maintained with a vertical gap between the sample slide and the coverslip, provide a fluid dispense command to cause the fluid dispenser to provide fluid to the coverslip in the vertical gap, and provide a flood end position command to the linear drive system to cause the cartridge drawer to adopt an end flood position.

[0219] Embodiment 48 is the sample processing system of embodiment 47, further comprising a sample orientation system, and the at least one processing circuit is further configured to provide a rotation command to the sample orientation system to rotate the insertion bay from a substantially horizontal position to an angled position.

[0220] Embodiment 49 is the sample processing system of embodiment 48, wherein at least one processing circuit is further configured to provide a flush command to cause the fluid dispenser to provide flush fluid to the vertical gap to flush the fluid.

[0221] Embodiment 50 is a sample processing system of any of embodiments 43 to 49, wherein at least one processing circuit is configured to provide a receptacle release position command to the linear drive system to cause the cartridge puller to adopt a receptacle release position relative to the cartridge frame to release a sample receptacle from the sample cartridge.

[0222] Embodiment 51 is a sample processing system of any of embodiments 43 to 50, wherein at least one processing circuit is configured to provide a slide ejection command to the linear drive system to cause the cartridge drawer to adopt a slide ejection position.

[0223] Embodiment 52 is a sample processing system of any of embodiments 44 to 51, wherein at least one processing circuit is configured to provide a receptacle release command to the probe driving system to cause the probe driving system to release the sample receptacle to the receptacle receiving system.

[0224] Embodiment 53 is the sample processing system of any of embodiments 43-52, wherein the linear drive system is configured to engage with a cartridge drive system of the sample cartridge.

[0225] Embodiment 54 is a sample cartridge including one or more sample receptacles, one or more sample slides, one or more staining fluids, and one or more coverslips.

[0226] Embodiment 55 is the sample cartridge of embodiment 54, further comprising a first cartridge component and a second cartridge component, the first cartridge component and the second cartridge component being configured for relative movement with respect to each other in a linear dimension.

[0227] Embodiment 56 is the sample cartridge of embodiment 54 or 55, wherein at least one of the one or more sample receptacles and the one or more sample slides is removable.

[0228] Embodiment 57 is a sample cartridge of any of embodiments 54 to 56, wherein the sample cartridge is configured to facilitate processing of a sample contained therein and is configured such that no portion of the sample comes into contact with a sample processing system operating on the sample cartridge.

[0229] Embodiment 58 is a sample processing system comprising a sample handling system including a sample transport mechanism, a sample smearing mechanism, and a sample moving mechanism, a fluid distribution system, and a control system.

[0230] Embodiment 59 is the sample processing system of embodiment 58, further comprising at least one imaging device.

[0231] Embodiment 60 is a sample processing system of embodiment 58 or 59, wherein the sample handling system is configured to receive a sample cartridge containing a sample, and the control system is configured to cause the sample handling system to operate the sample cartridge to perform a sample processing step without the sample contacting the sample transport mechanism, the sample smearing mechanism, the sample orientation mechanism, or the sample movement mechanism.

[0232] Embodiment 61 is a sample cartridge comprising a first cartridge component including a slide support configured to support a sample slide, and a second cartridge component including a receptacle window, the second cartridge component configured for relative movement with respect to the first cartridge component, wherein the second cartridge component is configured to adopt a sampling position relative to the first cartridge component to support a sample receptacle, and the second cartridge component is configured to adopt a transfer position relative to the first cartridge component that, when positioned in the slide support, aligns the receptacle window with the slide support in a position that enables transfer of a sample in the sample receptacle to the sample slide.

[0233] Embodiment 62 is a method for sample preparation comprising depositing a sample in a sample receptacle of a sample cartridge in which a first cartridge component and a second cartridge component are positioned in a sampling position relative to each other, moving the second cartridge component relative to the first cartridge component from the sampling position to a transfer position in which a sample slide supported on the slide support of the first cartridge component is aligned with a receptacle window of the second cartridge component, and transferring the sample from the sample receptacle to the sample slide.

[0234] Embodiment 63 is a sample cartridge comprising a first cartridge component including a slide support configured to support a sample slide, and a second cartridge component including a smear plate support configured to support a smear plate, the second cartridge component configured to adopt a smear position relative to the first cartridge component that aligns the smear plate with the sample slide for smearing the sample.

[0235] Embodiment 64 is a method for sample preparation comprising: placing a second cartridge component of a sample cartridge in a smearing position relative to a first cartridge component of the sample cartridge, aligning a smear plate support of the second cartridge component with a sample slide supported by the first cartridge component; and smearing a sample onto the sample slide using a smear plate disposed within the smear plate support.

Claims

1. A method for sample staining, comprising: Placing a sample slide and a cover slip at a flood start position, wherein the flood start position is such that the slide surface of the sample slide on which the sample is disposed and the slip surface of the cover slip have a vertical gap, the sample slide and the cover slip have a horizontal overlap, and the vertical gap and the horizontal overlap are defined so as to define a volume; Applying the fluid to at least one of the sample slide or the cover slip such that when the sample slide and the cover slip are placed at the flood start position, the fluid is present in the vertical gap; Placing the sample slide and the cover slip at a flood end position through a relative movement that increases the horizontal overlap, wherein the flood end position is defined such that the horizontal overlap has a maximum horizontal distance, whereby the fluid fills the volume; Applying additional fluid to at least one of the sample slide or the cover slip to fill the volume as the horizontal overlap increases.

2. Placing the sample slide and the cover slip at a rinse position through a conforming movement, wherein the rinse position is defined by a rinse angle and a horizontal reference between the sample slide and the cover slip; The method according to claim 1, further comprising applying a second fluid to the vertical gap to rinse the fluid.

3. A sample cartridge, comprising: A first cartridge component including a slide support configured to support a sample slide; A second cartridge component including a cover slip support configured to support a cover slip at a cover slip window. The second cartridge component is configured for movement relative to the first cartridge component, and the first cartridge component and the second cartridge component are configured to cooperate to maintain a vertical gap between the sample slide and the cover slip. The second cartridge component is further configured to move from a flood start position relative to the first cartridge component to a flood end position relative to the first cartridge component. A sample cartridge.

4. A method for sample preparation, placing a sample slide disposed in a first cartridge component of a sample cartridge and a cover slip disposed in a second cartridge component of the sample cartridge at a flood start position, wherein the flood start position is such that the slide surface of the sample slide on which the sample is disposed and the slip surface of the cover slip have a vertical gap, the sample slide and the cover slip have a horizontal overlap, and the vertical gap and the horizontal overlap are defined to define a volume; receiving a fluid in the vertical gap between the sample slide and the cover slip; moving the second cartridge component relative to the first cartridge component from a flood start position to a flood end position. A method comprising:

5. A sample processing system, at least one processing circuit, an insertion bay configured to receive a sample cartridge having a first cartridge component and a second cartridge component, A sample processing system comprising a linear drive system that is controllable by the at least one processing circuit and is configured to generate relative movement between the first cartridge component and the second cartridge component. **Claim 6** further comprising a probe disposed on the probe drive system, wherein the at least one processing circuit provides a transfer position command to the linear drive system to align the receptacle window of the second cartridge component with a sample slide supported by the first cartridge component, and causes the second cartridge component to adopt the transfer position with respect to the first cartridge component, provides a probe transfer command to the probe drive system, brings the sample receptacle close to the sample slide, The sample processing system according to claim 5, wherein the sample is configured to be transferred from the sample receptacle to the sample slide by the probe. **Claim 7** A sample cartridge, comprising one or more sample receptacles, one or more sample slides, one or more staining fluids, one or more cover slips. **Claim 8** a first cartridge component, a second cartridge component, further comprising The sample cartridge according to claim 7, wherein the first cartridge component and the second cartridge component are configured for relative movement with respect to each other in a linear dimension. **Claim 9** A sample processing system, a sample handling system, a sample transfer mechanism, A sample application mechanism, A sample handling system including a sample transfer mechanism, and A fluid dispensing system, A sample processing system comprising a control system.

10. The sample handling system is configured to receive a sample cartridge for accommodating a sample, The control system is configured to cause the sample handling system to operate the sample cartridge so that the sample performs a sample processing step without contacting the sample transfer mechanism, the sample application mechanism, the sample orientation mechanism, or the sample transfer mechanism. The sample processing system according to claim 9.

11. A sample cartridge, A first cartridge component including a slide support configured to support a sample slide, A second cartridge component including a receptacle window, and The second cartridge component is configured for movement relative to the first cartridge component, The second cartridge component is configured to adopt a sampling position relative to the first cartridge component to support a sample receptacle, The second cartridge component is configured to adopt a transfer position relative to the first cartridge component to align the receptacle window with the slide support at a position that enables transfer of a sample in the sample receptacle to the sample slide when positioned in the slide support. Sample cartridge.

12. A method for sample preparation, Depositing a sample in a sample receptacle of a sample cartridge in which a first cartridge component and a second cartridge component are arranged in a sampling position relative to each other, Moving the second cartridge component relative to the first cartridge component from the sampling position to a transfer position where a sample slide supported at a slide support portion of the first cartridge component is aligned with a receptacle window of the second cartridge component; Transferring the sample from the sample receptacle to the sample slide, the method comprising:

13. A sample cartridge, comprising: A first cartridge component including a slide support portion configured to support a sample slide; A second cartridge component including a smear plate support portion configured to support a smear plate; provided with: The second cartridge component is configured to adopt a smearing position with respect to the first cartridge component for aligning the smear plate with the sample slide for smearing the sample.

14. A method for sample preparation, comprising: Placing a second cartridge component of a sample cartridge in a smearing position relative to a first cartridge component of the sample cartridge, the smearing plate support portion of the second cartridge component being aligned with a sample slide supported by the first cartridge component; Smearing the sample onto the sample slide using a smear plate disposed within the smear plate support portion.

15. A method for sample separation, comprising: Depositing a sample on a sample receptacle including a membrane; Aligning the sample receptacle with a sample slide; Applying a probe to a lower surface of the sample receptacle to cause movement of the membrane. Pressing the sample against the sample slide through the movement to deposit at least a part of the sample on the sample slide, a method. **Claim 16** Further comprising selecting the probe according to the sample type, The shape of the probe corresponds to the sample type, the method according to claim 15. **Claim 17** The method according to claim 16, further comprising selecting probing characteristics according to the sample type. **Claim 18** The probing characteristics include probe movement characteristics including at least one of probe force, probe speed, and probe trajectory, the method according to claim 17. **Claim 19** A method of sample smearing, Engaging a gripping device with a first surface of a smearing plate through an actuating probe, Controlling the actuating probe to cause contact between a second surface of the smearing plate and a sample disposed on the surface of a sample slide, Controlling the force applied to the smearing plate during contact with the sample, Causing relative movement between the smearing plate and the sample slide to disperse the sample on the surface of the sample slide, a method. **Claim 20** The method according to claim 19, further comprising determining the amount of force to be applied according to the acquired image information of the sample disposed on the surface. **Claim 21** The method according to claim 19, further comprising controlling the distance between the smearing plate and the surface of the sample slide. **Claim 22** Evaluating the sample dispersed on the sample slide according to an image of the sample to determine smearing characteristics, The method according to claim 19, further comprising causing additional relative movement between the spreading plate and the sample slide to further disperse the sample on the surface of the sample slide in response to the spreading characteristics.

Images