Systems, methods, and devices for sample processing

Abstract

Systems, methods, and devices for the transfer of collected biological samples are provided. Sample transfer methods include collecting the sample on a collection surface disposed within a transfer chamber having an aperture in a wall thereof. Sample transfer methods further include advancing the sample towards the aperture by reducing a volume of the transfer chamber and ejecting a first a portion of the sample through the aperture. Sample transfer methods further include transferring a second portion of the sample to a sample transfer surface.

Description

SYSTEMS, METHODS, AND DEVICES FOR SAMPLE PROCESSINGTECHNICAL FIELD

[0001] The present invention is directed to systems, methods, and devices configured to facilitate sample processing, including automated sample processing for rapid on-site sample evaluation.BACKGROUND

[0002] Rapid On-Site Evaluation (ROSE) is an important aspect of biopsy procedures that can decrease the number of needle passes, increase patient safety, and increase diagnostic yield. A purpose of ROSE is to determine whether a biopsy sample has adequate cellular and tissue content to produce a definitive diagnosis when analyzed in a pathology lab. Other uses for ROSE include informing tissue collection and triage, as well as providing a preliminary diagnosis to the interventionalist.

[0003] Traditionally in ROSE, a biopsy sample is smeared or touch imprinted onto a glass slide by a cytotechnologist or cytopathologist to create a thin layer of cellular material. The slide is then manually stained to increase contrast between different biological elements of the slide using a rapid stain such as Diff Quik, Toludine Blue, or others. Finally, the slide is examined by cytology personnel under a light microscope and analyzed for adequacy, triage, and / or preliminary diagnosis.

[0004] ROSE has proven its utility in a wide range of biopsy sites including thyroid, liver, pancreas, lung, breast, sentinel lymph nodes, bone marrow, and more. ROSE is recommended by many leading clinical societies such as the Pulmonary Pathology Society, Papanicolaou Society of Cytopathology, and American Thyroid Association. Furthermore, ROSE may become increasingly important in procedures such as bronchoscopic lung biopsy in order to facilitate delivery of therapeutics (cryotherapy, microwave ablation, drug delivery, etc.) immediately following ROSE-facilitated confirmation of positive biopsy results.

[0005] However, ROSE is only used in roughly half of non-dermatological 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, since long procedure times put additional strain on the cytology department’s resources. Furthermore, ROSE adequacy and diagnosis is subject to interoperator variability in both slide preparation and interpretation- no two cytologists will produce an equivalent slide or make the same adequacy call- which is often a source of frustration and time delays for the interventional staff.For complex procedures such as bronchoscopic lung biopsy, 20-40% or more of biopsies are unsuccessful in providing an ultimate diagnosis in the pathology lab — requiring repeat biopsy procedures — even with the use of traditional ROSE methods.

[0006] Given the shortcomings of traditional ROSE, it is not surprising that other approaches have been tried to improve the process of adequacy assessment and on-site diagnosis. There are several devices that provide ROSE slide digitization and transmission, or telerobotic microscopes that enable cytopathologists to view ROSE slides remotely. However, such devices still rely on cytology personnel in the operating room to prepare slides, which does not overcome the associated logistical and interoperator variability problems with some ROSE implementations.

[0007] Some potential solutions, such as raman scattering microscopy of excised tissue and needle-based confocal laser microscopy are being pursued. While attractive in principle, these approaches do not match the resolution and fidelity of tissue imaged on glass slides. Furthermore, these approaches create unfamiliar images which requires new training for interventionalists and pathologists.

[0008] Accordingly, there is a need for improved sample processing methods and technology to facilitate automated ROSE.SUMMARY

[0009] In an embodiment, the techniques described herein relate to a method of transferring a sample, the method including: collecting the sample on a collection surface disposed within a transfer chamber, the transfer chamber having an aperture in a wall thereof; advancing the sample towards the aperture by reducing a volume of the transfer chamber; ejecting a first a portion of the sample through the aperture; and transferring a second portion of the sample to a sample transfer surface.

[0010] In another embodiment, the techniques described herein relate to a method of transferring a sample, the method including: collecting the sample on a sample collection surface; advancing the sample collection surface towards a sample transfer surface; contacting the sample transfer surface with the sample; and transferring the sample to the sample transfer surface.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The accompanying figures, which are incorporated herein, form part of the specification and illustrate embodiments of systems, methods, and devices for sample preparation. Together with the description, the figures further explain the principles of and enable a person skilled in the relevantart(s) 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.

[0012] FIG. 1 illustrates a system for performing rapid on site evaluation system (ROSE) for sample analysis.

[0013] FIG. 2A illustrates a sample transfer method consistent with embodiments hereof.

[0014] FIG. 2B illustrates additional steps that may be performed in the sample transfer method after completion of sample transferring operation.

[0015] FIGS. 3A-3B illustrate an example of a transfer chamber suitable for performing the sample transfer metho.

[0016] FIG. 3C illustrates an example alternative configured of a transfer chamber.

[0017] FIG. 3D, FIG. 3E, FIG. 3F, and FIG. 3G illustrate operation of a sample transfer method.

[0018] FIG. 3J illustrates a ridged structure on a sample advancement surface.

[0019] FIG. 3K illustrates a sample transfer device having a cutting blade disposed at an aperture thereof.

[0020] FIG. 4A through FIG. 4H illustrate a method of sample transfer consistent with embodiments hereof.

[0021] FIG. 5A illustrates a sample transfer device in a sectional view.

[0022] FIG. 5B illustrates the sample transfer device in a perspective view.

[0023] FIG. 5C illustrates the sample transfer device in a perspective.

[0024] FIG. 5D illustrates the sample transfer device in a perspective view.

[0025] FIG. 5E illustrates a sample transfer device consistent with embodiments hereof.

[0026] FIG. 5F illustrates a sample transfer device consistent with embodiments hereof.

[0027] FIG. 5G illustrates a sample storage disk consistent with embodiments hereof.

[0028] FIGS. 6A-6C illustrate steps in a method of sample transfer.

[0029] FIGS. 7-10 illustrate devices and methods that facilitate sample transfer.

[0030] FIG. 7A illustrates a sample collection device configured to facilitate, improve, optimize, or otherwise improve sample transfer.

[0031] FIG. 7B illustrates a scraping edge having a taper.

[0032] FIG. 7C illustrates a scraping edge having an obtuse angle with respect to the sample collection surface.

[0033] FIG. 7D illustrates a scraping edge having an acute angle with respect to the sample collection surface.

[0034] FIG. 7E illustrates a sample collection device configured to facilitate, improve, optimize, or otherwise improve sample transfer.

[0035] FIG. 7F-7H illustrate a sample collection device configured to facilitate, improve, optimize, or otherwise improve sample transfer.

[0036] FIG. 8 illustrates a mesh aided sample transfer device consistent with embodiments hereof.

[0037] FIG. 9 illustrates a vortex sample transfer device consistent with embodiments hereof.

[0038] FIG. 10 illustrates a pinching sample transfer device consistent with embodiments hereof.

[0039] FIGS. 10A-10G illustrate a sample transfer pinch device consistent with embodiments hereof.

[0040] FIGS. 11 A and 1 IB illustrate a slide chuck consistent with embodiments hereof.

[0041] FIG. 12 is a flow chart illustrating a computer aided vision sample transfer method. DETAILED DESCRIPTION

[0042] The following detailed description is merely illustrative in nature and is not intended to limit the invention or the application and uses of the invention. Although the description of the invention is in the context of systems, methods, and devices for facilitating automated ROSE techniques, the disclosure should not be considered so limiting. For example, although systems, methods, and devices may be discussed herein with respect to ROSE of biopsy samples, any biological samples may be suitable for analysis by embodiments hereof. Modifications may be made to the embodiments described herein without departing from the spirit and scope of the present invention. Therefore, the following detailed description is not meant to be limiting. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, summan'. or the following detailed description.

[0043] The present disclosure addresses issues outlined above. The disclosure relates to sample processing methods to facilitate automated sampling processing to assist in rapidly producing consistent high-resolution cytologic images using raw biopsy samples harvested by an interventional staff, and is therefore suitable for ROSE. In particular the methods, devices,and techniques described herein are suited for transferring a collected sample to a sample transfer surface on a substrate. The substrate is suitable for further processing, e.g., drying, staining and / or imaging, and may include, for example, a specimen slide. The methods, devices, and techniques described herein are selected and optimized to facilitate transfer of a sample in an appropriate size, amount, and disposition to facilitate further processing. An optimal or ideal sample transfer may deposit a single layer (monolayer) of cells with "moderate" density that preserves the "cytoarchitecture" of the sample, e.g. spatial relationships inherent to clumps of cells that may be important in determining the types of cells present.

[0044] The present disclosure describes devices, systems, and methods for facilitating sample transfer and sample processing. The presented combinations of features are discussed by way of example only, and the sample transfer methods, transfer devices, and sample transfer systems described herein may each be used or employed with alternate methods, systems, and devices, as the case may be. Further, individual aspects of each 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 example or illustrative purposes. Although the extensive variety of all such combinations prevents an individual description of each combination herein, it is understood that all such combinations fall within the scope of this disclosure.

[0045] For example, any of the methods or portions of the methods described herein may be carried out with suitable portions of the devices and systems described herein without requiring the entirety of the devices and systems described herein and / or may be employed with alternate devices and systems. Some methods or portions of methods may also be carried out manually with suitable portions of the devices described herein and or with systems described herein using different devices. Devices described herein may be earned out with suitable portions of the methods and systems described herein without requiring the entirety of the methods and systems described herein and / or may be employed with alternate methods and systems. Systems described herein may be carried out with suitable portions of the methods and devices described herein without requiring the entirety of the methods and devices described herein and / or may be employed with alternate methods and devices.

[0046] In embodiments, the integrated sample transfer, preparation, staining and imaging system may be configured, through the use of actuators and other robotic devices, to carry out the methods and techniques described herein. The various devices and structures herein may be manipulated by an integrated sample transfer, preparation, staining and imaging systemhaving suitable actuators and robotic devices. Further, various elements of the devices described herein may be integrated into cartridges, frames, and / or any other suitable structure to facilitate automated processing.

[0047] The present disclosure may include references to relative terms such as “top,” “bottom,” “up,” and “down.” These terms are used for clarity and ease of reference. For example, a “top” of a structure or device may refer to the portion of that structure or device that faces up during usage as described herein. Relative directional terms as used herein are not limiting and do not limit the orientations, positions, angles, or functionality' of the structures and devices discussed herein. Furthermore, the methods, systems, and devices as discussed herein are not limited to use in the orientations as described herein. For example, although the some sample transfer methods are described with specific surfaces being located above or below other surfaces, methods described herein are not so limited, and such methods may be implemented in different orientations. One or more aspects of the system may be inverted with respect to the orientations disclosed herein without departing from the scope of this disclosure.

[0048] FIG. 1 illustrates a rapid onsite evaluation system consistent with embodiments hereof. The rapid onsite evaluation system 100 may include various components and may operate as an integrated sample transfer, preparation, staining and imaging system. The components may be housed on a moveable cart 101 or as a benchtop system. Components may include a cart chassis with wheels, integrated sample staining and processing modules that prepare, stain and image the biopsy samples, display 102 for viewing a prepared and imaged sample, and a user interface 103, including one or more user input devices, storage for disposable cartridges (into which the biopsy samples may be loaded) and one or more consumable repositories. A waste fluid bin may also be included. The rapid onsite evaluation system 100 may include one or more input slots into which disposable cartridges with sample may be loaded, one or more output slots for retrieving stained slides for future analysis, and an area to retrieve used cartridges that are ready for disposal. Additionally, there may be controls, such as one or more user input devices of a user interface 103, on the cart that facilitate inputting system parameters and performing operations such as manipulating the microscope image on the screen by panning, zooming, and jumping to various regions of interest.

[0049] FIG. 2A illustrates a sample transfer method consistent with embodiments hereof. The sample transfer method 1000 may be performed according to the systems, techniques, and devices disclosed herein. The sample transfer method 1000 may be suitable for transfer of liquid, semi-solid, and / or solid samples, including, for example fine needle aspirant (FNA) samples, which may include liquid and semi-solid samples, forceps samples, cryobiopsysamples, core needle samples, any type of biopsy samples, and surgically excited tissue samples. The systems, techniques, and devices discussed herein provide examples that illustrate the operation and performance of elements of the sample transfer method 1000 and are not exclusive. Accordingly, while the sample transfer method 1000 may be performed by employing a sample transfer device 300 (or any other sample transfer device discussed herein) in conjunction with the rapid onsite evaluation system 100 to carry out all of the steps described herein, this disclosure is not limited to such a combination. The steps and operations of the sample transfer method 1000 described herein may be carried out in any suitable order and in any suitable combination. In embodiments, some or all of the steps and operations of the sample transfer method 1000 may be carried out with the sample transfer device 300 (or other sample transfer device described herein) and manual processing techniques. In other examples, the rapid onsite evaluation system 100 may perform any selection of the steps and operations of the sample transfer method 1000 alone or in any combination, with or without the use of a sample transfer device. The steps and operations of the sample transfer method 1000 may each stand alone or may be performed in any suitable combination with other steps and operations of the sample transfer method 1000 and with any suitable combination of manual and automated processing techniques.

[0050] In an operation 1002, the sample transfer method 1000 includes collecting the sample in or on a collection surface. In embodiments, the collection surface may be part of a transfer chamber. In embodiments, the collection surface may be part of a transfer substrate. Examples of suitable collection surfaces are described below with respect to specific structural embodiments.

[0051] In embodiments, the transfer chamber may be a container having one or more walls with the sample collection surface disposed at one end thereof, as shown in FIG. 4A. The transfer chamber may be cylindrical, having a cylindrical wall, and / or may be any other suitable shape (square, oval, rectangular, etc ). The transfer chamber may be elongated. In a wall opposite the collection surface, the transfer chamber may include in aperture, window, or other opening. In embodiments, the transfer chamber may have rigid or substantially rigid walls, while in further embodiments the transfer chamber may have flexible walls. In embodiments, the transfer chamber may be transparent to facilitate viewing of the sample transfer, either by the eyes of the operator and / or by computer vision techniques. In embodiments, the transfer chamber may be a pipette, such as a positive displacement pipette.

[0052] In embodiments, the sample may be collected on the collection surface through transfer by a syringe or other suitable device or apparatus for collecting a sample in a clinicalenvironment. In such embodiments, the syringe may be removably secured to the transfer chamber or to an apparatus that supports or holds the collection surface. In such embodiments, the transfer chamber and / or the transfer surface may be removably secured to a support device or apparatus. Such removable securement may permit at least one of the syringe and collection surface to be secured to facilitate the sample transfer. In some embodiments, the sample may be transferred from a needle or other suitable device or apparatus for collecting a sample in a clinical environment to a temporary container (e.g., an Eppendorf tube, disposable or reusable lab ware, etc.) or surface prior to being transferred to the transfer chamber. For example, after collection in a clinical environment, the sample may be transferred to a temporary container or surface, and then collected or transferred into a pipette acting as the transfer chamber. This procedure is illustrated by way of example in FIG. 3L.

[0053] In an operation 1004, the sample transfer method 1000 includes advancing the sample towards a sample transfer surface. Advancing the sample towards the sample transfer surface may be performed in several different ways or combinations of several different ways according to embodiments hereof. The sample transfer surface may include, for example, a specimen slide or other suitable substrate for further sample processing.

[0054] In an embodiment, the sample may be advanced towards the transfer surface by advancing the collection surface towards the transfer surface. In embodiments that include a transfer chamber, the sample may be advanced towards the aperture of the transfer chamber. In embodiments, this may include advancing the collection surface towards the aperture of the transfer chamber, thereby reducing an interior volume or size of the transfer chamber. In embodiments that include a flexible walled transfer chamber, the interior volume or size of the transfer chamber may be reduced, causing the sample to be squeezed or pumped towards the aperture. In embodiments that do not include a transfer chamber, the collection surface may be advanced towards the transfer surface by manual or automated means to advance the sample towards the sample transfer surface.

[0055] In an operation 1006, the sample transfer method 1000 may include contacting the sample transfer surface with the sample. The sample may be brought into contact with the transfer surface. Bringing the sample into contact with the transfer surface may be the culmination of advancing the sample towards the transfer surface. After the sample contacts the transfer surface, advancing the sample may continue to ensure that a desired amount of sample is transferred from the collection surface to the transfer surface in the operation 1008, as discussed below.

[0056] A desired amount of sample may be caused to be transferred by maintaining a specific force between the collection surface and the transfer surface when contacting the sample to the transfer surface, by maintaining a specific distance between the collection surface and the transfer surface when contacting the sample, and / or by monitoring transfer conditions to identify and / or determine when the transfer conditions are suitable for the desired amount of sample to be transferred, as discussed below.

[0057] In embodiments, contacting the sample transfer surface with the sample may occur after an amount of sample has been ejected through the aperture of the transfer chamber, as discussed further below.

[0058] In an operation 1008, the sample transfer method 1000 may include transferring the sample from the collection surface to the transfer surface. The sample may be transferred from the collection surface to the transfer surface by increasing the relative distance between the collection surface and the transfer surface, e.g., by moving the two surfaces apart. Due to the dynamics of the sample, e.g., surface tension in a liquid (e.g., fine needle aspirant) sample or semi-solid sample or other types of adhesion in a solid or semi -solid sample, a portion of the sample remains on the sample transfer surface after the collection surface is moved away. Sample transfer may include transfer of all or a portion of the initially collected sample.

[0059] FIG. 2B illustrates additional steps that may be performed in the sample transfer method 1000 after completion of sample transferring operation 1008. In embodiments, the operations of FIG. 2B may be optionally performed in any suitable combination and at any suitable time with respect to the operations 1002, 1004, 1006, and 1008.

[0060] In an optional operation 1010, the sample transfer method 1000 may include preserving the collection surface and any sample remaining thereon. The collection surface (and the substrate or structure it is located on) may be transferred to a sample storage container and preserved with an appropriate preservation liquid, such as formalin, for later examination as necessary .

[0061] In an operation 1012, the sample transfer method 1000 may include performing a second sample transfer, for example, repeating the operations 1004, 1006, and 1008 with a second, different sample transfer surface.

[0062] FIGS. 3A-3B illustrate an example of a transfer chamber suitable for performing the sample transfer method 1000, as described above. FIG. 3 A illustrates a device configured for sample transfer while FIG. 3B shows a sectional view of the same device. In embodiments, the sample transfer device 300 may be configured for the transfer of a fine needle aspirant sample, a semi-solid tissue sample, and / or a solid tissue sample. The sample transfer device300 may include at least atransfer chamber 301 having one or more walls 304, an aperture 303, and a device frame 302. The transfer chamber 301 may include a cavity 306 configured to contain or hold a sample that is surrounded by the one or more walls 304. The transfer chamber301 may be elongated. As shown in FIG. 3A and FIG. 3B, the one or more walls 304 may include a single circular wall defining a cylindrical cavity 306 with an additional wall 304 at one end of the cavity 306, but further embodiments may include any suitable shape to the walls 304 and / or the cavity 306. The aperture 303 may be an opening in one of the plurality of walls 304 of the transfer chamber 301. The sample transfer chamber 301 may further include a sample collection surface configured as a sample advancement surface 307 disposed on a sample movement structure 309. The sample movement structure 309 may be, for example, a plunger configured to contact the interior of the walls 304 in the cavity 306. The sample movement structure 309 may be connected to, integral with, or otherwise engaged with an actuator 305. The actuator 305 be provided to advance the sample movement structure 309 and the advancement surface 307 within the transfer chamber 301 to advance a sample to the aperture 303. The actuator 305 may be any suitable type of actuator, include a lead screw, a hydraulic piston, a solenoid, etc.

[0063] The aperture 303 may be sized and configured to permit a needle, e.g., an FNA needle, to be inserted therethrough to permit collection of the sample on the advancement surface 307. The FNA needle may be inserted into the aperture 303 and the sample may be ejected directly into the transfer chamber 301. The aperture 303 may further be sized and configured to control a liquid or semi-solid sample as it is ejected through the aperture 303 as described below. When the sample is ejected through the aperture 303, the transfer chamber 301 may be oriented such that the sample is ejected in an upwards direction (e.g., within 0-45 degrees of completely vertical). During ejection, surface tension may be utilized to control formation of a sample droplet for transfer to a sample transfer surface 310, as discussed below. An aperture 303 that is sized too large may not permit the droplet to protrude or extend as far away from the aperture 303 as desired, and may not permit a small sample transfer volume to the sample transfer surface. At the same time, an aperture 303 that is too small may not allow enough room for a biopsy needle to be inserted easily through the aperture. Accordingly, appropriate sizes for the aperture 303 may be within a range of a size of the aperture is within a range of 0.5 to 6 mm, 2 to 5 mm, 2 to 6 mm, 2.5 to 5.5 mm, 3 to 5 mm, and 3.5 to 4.5 mm.

[0064] The advancement surface 307 may be a flexible, malleable, or otherwise deformable surface. When pressed against the aperture 303 during an ejection process, the advancement surface 307 may be configured to deform so as to fill the aperture 303 and thereby ensure thatthere is no dead space or dead volume in the transfer chamber 301. No dead space or no dead volume may mean that the volume of the transfer chamber is reduced to substantially zero. Substantially zero may mean that the transfer chamber volume is reduced to exactly zero and / or may mean that the transfer chamber volume is reduced to less than 1%, less than 0.5%, less than 0.25%, and / or less than 0.1% of a maximum transfer chamber volume. This may ensure that even the smallest amounts of collected sample may be available for transfer to the sample transfer surface 310.

[0065] The transfer chamber 301 may be sized and configured with a relatively small diameter to ensure that sample does not get stuck or situated along the intersection of the advancement surface 307 and the walls 304 of the transfer chamber 301. In an example, an inner diameter of the transfer chamber may be in a range of 2-7 mm, 3-6 mm, 4-5 mm, or approximately 4.65mm.

[0066] The transfer chamber 301 may be configured for removal from the device frame 302 to facilitate preservation in a storage container with a preservation fluid. In embodiments, in addition to removability from a device frame, a transfer chamber may be configured with a form factor that facilitates such storage, as illustrated in FIG. 3C.

[0067] FIG. 3C illustrates an example alternative configuration of a transfer chamber. The transfer chamber 351 may be configured to be removable from an actuator frame (not shown) to facilitate post transfer sample preservation in accordance with the operation 1010. The transfer chamber 351 includes one or more walls 354 defining a cavity 356, an aperture 353, a sample collection surface configured as a sample advancement surface 357, and a sample movement structure 359, similar to those found in the transfer chamber 301. The transfer chamber 351 may further include an actuator interface slot 358 and a frame 352. The frame 352 may be, for example, an annular structure from which walls 354 defining the cavity 356 extend. The actuator interface slot 358, is a cavity or opening in the frame 352 through which an actuator (not shown) may extend to interface with the sample movement structure 359 and thereby cause the advance of the sample advancement surface 357. The frame 352 and / or the walls 354 may be configured of a size and shape to be removably secured with an actuator device connected to the actuator that advances the sample advancement surface 357.

[0068] Upon completion of the sample transfer operation 1008, in a sample preservation operation 1010, the sample transfer chamber 351 may be removed from the actuator device and placed in a preservation container, for example, with a preservation fluid. In embodiments, the sample movement structure 359 and the sample advancement surface 357 may be preserved, separately or with the sample transfer chamber 351. Sample preservation operation 1010 maybe automatically performed by rapid onsite evaluation system 100 and / or may be partially performed by an operator. For example, the rapid onsite evaluation system 100 may separate the structures to be preserved and eject these to the operator, or the operator may collect these from the rapid onsite evaluation system 100 manually.

[0069] In embodiments, after completion of transfer, residual material within the transfer chamber may be directly ejected into a sample storage container for preservation in appropriate fluid. The aperture itself may be dipped or submerged in the preservative fluid to wash off residual material. The rapid onsite evaluation system 100 may be configured to carry out these steps. In embodiments, the sample transfer chamber 301 may be rotated prior to ejecting the remaining sample so that the remaining sample is ejected downwards and assisted by gravity. In embodiments, after ejecting the remaining sample, the actuator 305 may further advance the sample movement structure 359 to cause the sample advancement surface 307 to press against the top wall 304 of the sample transfer chamber 301. This pressure may cause the sample transfer chamber 301 to release from the sample device frame 302, permitting the sample transfer chamber 301 and sample movement structure 359 to be released into the sample storage container for preservation. Removability of the sample transfer chamber 301 may be facilitated by an actuated release, a snap, or any other suitable device.

[0070] The sample transfer device 300 may be operated according to the sample transfer method 1000, as illustrated in FIG. 3D, FIG. 3E, FIG. 3F, and FIG. 3G. The sample transfer device 300 may be operated in conjunction with a computer vision system configured to capture images of and identify the sample 399 as it is in the process of transfer from the advancement surface 307 (not shown) to the sample transfer surface 310. The sample may be collected or deposited on the advancement surface 307 in an operation 1002. The advancement surface 307 may be advanced, via operation of the actuator 305, towards the aperture 303. Upon the sample reaching the wall 304 in which the aperture 303 is located, the sample may start to protrude through the aperture 303, as shown in FIG. 3D. At any time during or after advancing the sample towards the aperture 303, a sample transfer surface 310 may be positioned opposite the aperture 303. At any time during or after advancing the sample towards the aperture, the sample transfer surface 310 may be moved into a position relative to the aperture 303 such that sample being ejected from the aperture 303 may contact the sample transfer surface 310. Thus, operation 1004 of advancing the sample towards the sample transfer surface 310 may occur at any time before, during, or after advancing the sample towards the aperture 303.

[0071] The sample advancement surface 307 may continue to be advanced towards the aperture 303 to continue pressing sample through the aperture 303 until a desired predetermined amount of sample is ejected from and protrudes through the aperture 303. As used herein, the term “ejected” may refer to the sample protruding from the aperture without being released from the aperture or may refer to the sample being released from the aperture. As shown in FIG. 3E, the sample 399 forms a protrusion protruding through the aperture 303. The protrusion may be hemispherical in shape, may be another portion of a sphere in shape, or may be another shape consistent with the sample viscosity. The protrusion may represent a first portion of the sample. The size of the protrusion may be determined according to the size of the aperture 303, with a larger aperture 303 permitting a larger protrusion. The computer vision system may image the 399 sample as it is ejected through the aperture 303 and determine when a desired amount of sample 399 protrudes through the aperture 303. In some embodiments, an amount of collected sample 399 may be too small to form a protrusion of the desired size. In such an example, the sample advancement surface 307 may be advanced as far as possible to eject as much sample 399 as possible.

[0072] After the desired amount of sample 399 is ejected, the sample transfer surface 310 and the aperture 303 may be brought together through movement of one or both. Thus, the sample is further advanced towards the sample transfer surface 310 as in operation 1004.

[0073] After ejection from the aperture 303, the first portion of the sample may remain disposed at the aperture. The sample may contact the sample transfer surface 310 in the operation 1006, as shown in FIG. 3F. Contact with the sample transfer surface 310 may be identified, detected, and / or monitored by the computer vision system, as discussed in greater detail below with respect to FIG. 12 and method 1200. In some embodiments, the aperture 303 and the sample transfer surface 310 may be brought within a predetermined distance of one another. In some embodiments, the computer vision system may monitor the level of contact between the sample 399 and the sample transfer surface 310 to identify wften enough contact has occurred for sample transfer. Contact between the sample 399 and the sample transfer surface 310 may be detected according to a change in shape of the ejected sample protrusion. A change in shape of the protrusion, e.g., as shown in FIG. 3F, may indicate contact between the sample and the sample transfer surface 310.

[0074] In further embodiments, ejection from the aperture 303 may occur before contact with the sample transfer surface 310 is made. In further embodiments, contact with the sample transfer surface 310 may occur as the sample is ejected from the aperture 303. In other words,the sample transfer surface 310 may be positioned appropriately for sample contact before, during, or after the sample being ejected from the aperture 303.

[0075] After contact with the sample transfer surface 310, the sample transfer surface 310 and the advancement surface 307 may be separated from one another to complete the sample transfer in the operation 1008, as shown in FIG. 3G. Separation of the sample transfer surface 310 and the sample advancement surface 307 may cause a second portion of the sample to remain on the sample transfer surface 310 for further processing. In embodiments, the second portion of the sample may be less than one fifth, less than one tenth, less than one twentieth, less than one fiftieth, less than on hundredth, or less than one thousandth of the original sample. In the operation 1008, the sample advancement surface 307 may be retracted to suck / pull a remainder of the sample 399 back into the transfer chamber, the aperture 303 and sample transfer surface 310 may be separated from each other via relative movement, or both of these actions may occur. In the operation 1008, retraction or withdrawing of the sample advancement surface 307 may cause an enlargement of the volume of the transfer chamber.

[0076] Further steps may be included to increase the robustness of the sample transfer process. For example, an air bubble may resemble a protrusion of sample to the computer vision system and may break against the glass surface when touched, but not deposit any measurable amount of sample. After operation 1008, sample transfer is completed, the sample transfer surface may be imaged to determine whether enough sample has been deposited. If the amount of transferred sample does not meet a threshold, the sample transfer process may be repeated.

[0077] In another example, the computer vision system may be used to monitor the aperture 303 to determine if any sample (e.g., tissue, FNA) is located on the outside of the aperture 303 (e.g., on the lip, walls, or edge of the aperture) before sample advancement. Such monitoring may be performed by comparing the aperture tip to the expected tip profile. If sample is detected outside of the aperture 303, the aperture 303 may be touched to the sample transfer surface 310 without advancing the sample tissue at / outside the tip, we can touch the tip to the glass slide without advancing the sample movement structure 359 to prevent transferring an excessive amount of sample.

[0078] In embodiments, the transfer chamber 301, the interior of the walls 304 of the transfer chamber 301, and / or the sample advancement surface 307 may include one or more features configured to mix, blend, grind, fracture, homogenize, and / or otherwise break up the sample 399 during sample transfer. Such blending / mixing could help homogenize the sample and / or break up discrete clots or tissue chunks in the sample and help liberate cells trapped in the clot / chunk. For example, the sample advancement surface 307 may include one or more ridgesfacilitating the blending of the sample 399, as illustrated in FIG. 3K. In another example, the sample movement structure 309 / 359 may be rotated to cause sample blending / mixing. In some examples, rotation of the sample movement structure 309 / 359 may be combined with ridges 383 on the sample advancement surface 307, e.g., as shown in FIG. 3 J. In yet another example, a mixing blade may be provided within the transfer chamber 301 to facilitate sample blending / mixing. In another example, ultrasonic or vibratory energy may be applied to the transfer chamber to facilitate blending / mixing / breakup of the sample. In any of these examples, the aperture opening of the transfer chamber may be covered with the sample transfer surface, a secondary lid, or another suitable surface during blending / mixing of the sample in order to prevent sample escape.

[0079] FIG. 3K illustrates a sample transfer device having a cutting blade disposed at an aperture thereof. The sample transfer device 300, having the transfer chamber 301, of FIG. 3J is additionally equipped with a cutting blade 379, disposed at an aperture 303 thereof. As the sample 399 is ejected and advanced to the sample transfer surface 310 it may spread across the sample transfer surface 310. After appropriate spreading, the cutting blade 379 may be further advanced to contact the sample transfer surface 310 and cut the sample 399, leaving behind transferred portions 398.

[0080] FIG. 3L illustrates components that may be used in an example sample transfer method. A needle 395 or any other device or tool for collecting a biological sample may be used to collect a biological sample and deposit the biological sample into a temporary container 396. The temporary container 396 may be, for example, an Eppendorf tube, any suitable labware, a surface or substrate, etc. A sample transfer device 390 may be used to transfer the sample from the temporary container 396 to the sample transfer surface 310. In embodiments, the sample transfer device 390 may be any of the sample transfer devices discussed herein. As illustrated in FIG. 3L, the sample transfer device 390 may be a pipette or, more specifically, a positive displacement pipette, and may have a transfer chamber 391 and a sample advancement surface 397. When collecting sample from the temporary container in the sample transfer device 390, the tip of the sample transfer device 390 may contact the sample and collect sample on its exterior in addition to the sample that is drawn inside. When transferring the sample from the sample transfer device 391 to the sample transfer surface 310, the tip exterior of the sample transfer device 391 may be scraped, wiped, rubbed, or otherwise brought into contact with the sample transfer surface 310 to facilitate transfer of material from the exterior of the sample transfer device 391 to the sample transfer surface 310.

[0081] FIG. 4A through FIG. 4G illustrate a method of sample transfer consistent with embodiments hereof. The method 1000 as shown in FIGS. 4A-4H may include one or more sample transfers to one or more sample transfer surfaces. The method 1000 of sample transfer may include examples that do not require a transfer chamber 301 / 351 as shown in FIG. 3A. FIGS. 4A-4H illustrate the method 1000 as performed with a sample transfer surface 410 and a sample collection surface 407. In embodiments, the sample transfer surface 410 and the sample collection surface 407 may be manipulated by actuators of a device, such as the rapid onsite evaluation system 100.

[0082] As shown in FIG. 4A, a sample 499A may be collected on a collection surface 407 in a sample collection operation 1002. As shown in FIG. 4B, the sample 499A may be advanced towards a sample transfer surface 410, e.g., by relative movement between the sample collection surface 407 and the sample transfer surface 410 during the sample advancing operation 1004. In embodiments, the sample collection surface 407 may be advanced in an axial direction of the transfer chamber 301 / 351. In embodiments, the transfer chamber 301 / 351 may be elongated and the sample collection surface 407 may be advanced in an axial direction. Contact between the sample 499 and the sample transfer surface 410 may be made, as shown in FIG. 4B, during a sample contacting operation 1006. As illustrated in FIG. 4C, the sample collection surface 407 and the sample transfer surface 410 may then be separated to complete transfer of the sample 499A, consistent with the operation 1008. As shown in FIG. 4C, transfer of the sample includes transfer of a portion of the sample 499A as a first transferred sample 499B.

[0083] As shown in FIG. 4D, the sample transfer method 1000 may include a second sample contact step to reduce the size of the first transferred sample 499B. The sample transfer surface 410 is rotated (in embodiments, the sample transfer surface 410 may be rotated for the initial sample transfer depicted in FIGS. 4A-4C) to permit contact between the first transferred sample 499B and the collection surface 407 without also contacting the sample 499A. In embodiments, the sample transfer surface 410 may be rotated approximately 90 degrees or any other suitable amount so as to permit the first transferred sample 499B to contact the collection surface 407 while avoiding contact between the sample 499 A and the transfer surface 410. The sample transfer surface 410 may then be advanced towards the sample collection surface 407 via relative movement between the two surfaces to cause the first transferred sample 499B to contact the sample collection surface 407, as shown in FIG. 4D. The transfer surface 410 and the collection surface 407 may then be separated, as shown in FIG. 4E. The second contact causes a portion of the first transferred sample 499B to remain in contact with the collectionsurface 407 as a second transferred sample 499C. The transfer surface 410, having the first transferred sample 499B, now reduced in volume, may then be advanced .

[0084] The transfer surface 410 may then be advanced a third time to reduce the size of the first transferred sample 499B even further. As shown in FIGS. 4F and 4G, the first transferred sample 499B may be brought into contact with the collection surface 407 and then separated with third transferred sample 499D deposited on the collection surface 407. This third touch may serve to further reduce the volume of the first transferred sample 499B. Any number of additional sample transfer surfaces may be used to collect additional transferred samples through contact with the sample 499A, the second transferred sample 499C, or the third transferred sample 499C and the methods described above. After all samples have been transferred, the sample collection surface 407 with the sample 499A, the second transferred sample 499C, and the third transferred sample 499C deposited thereon, may then be removed for preservation.

[0085] FIGS. 5A-5D illustrate a sample transfer device consistent with embodiments hereof. The sample transfer device 500 is consistent with embodiments for transfer of liquid (e.g., FNA), semi-solid, and solid samples..

[0086] FIG. 5 A, FIG. 5B, FIG. 5C, and FIG. 5D illustrate a sample transfer device 500. FIG. 5A illustrates the sample transfer device 500 in a sectional view. FIG. 5B illustrates the sample transfer device 500 in a perspective view when the moveable wall 505 encloses the transfer chamber 501 and is secured. The moveable wall 505 may also be referred to as a lid. FIG. 5C illustrates the sample transfer device 500 in a perspective view when the moveable wall 505 encloses the transfer chamber 501 and is unsecured. FIG. 5D illustrates the sample transfer device 500 in a perspective view when the moveable wall 505 is in an open position. The sample transfer device 500 includes a transfer chamber 501 having a plurality of walls 504 that define a sample cavity 506. At least one of the plurality of walls 504 may include a moveable wall 505 configured to optionally open and close the transfer chamber 501. As shown in FIG. 5 A, the moveable wall 505 may open and close via action of a hinge 512. In other embodiments, the moveable wall 505 may open and close via a screw top, an interference fit, one or more latches, or any other suitable means. A latch 516 may be configured to latch the moveable wall 505 into a locked position. The moveable wall 505 (or any other wall 504 of the transfer chamber 501) may include an aperture 503 configured to permit passage of a sample. The sample transfer device 500 further includes a sample collection structure 508. The sample collection structure 508 may be configured from a flexible material to fit within a cross-section of the transfer chamber 501. The sample collection structure 508 may be, forexample, a plunger stopper or any suitable structure. The sample collection structure 508 may include a sample collection surface configured as a sample advancement surface 510. The sample transfer device 500 may further include an sample movement structure 509 configured to interface with an actuator to advance the sample advancement surface 510 within the transfer chamber 501.

[0087] In operation, the sample transfer device 500 may operate similarly to the sample transfer device 300. The moveable wall 505 may be opened to permit the collection of a sample and may be closed again prior to advancement of the sample to the aperture 303 or towards a sample transfer surface. Any of the features of the transfer chamber 501 may be combined with any of the features of the transfer chamber 301 as may be appropriate.

[0088] FIG. 5E illustrates a sample transfer device consistent with embodiments hereof. The sample transfer device 590 is consistent with embodiments for transfer of liquid (e.g., FNA), semi-solid, and solid samples. The sample transfer device 590 may include all of the features of the sample transfer device 500 in any suitable combination. The sample transfer device 590 may further include a sample substrate 591. The sample substrate 591 may be a substrate that is removable from the sample transfer device 590. In an embodiment, the sample transfer substrate 591 may be a disk or other circular substrate configured to fit within the sample cavity 506 of the transfer chamber 501. A first side of the sample substrate 591 may act as the sample advancement surface 510 while the second side of the sample substrate 591 may interface with the sample movement structure 509. The sample substrate 591 may be sized and configured such that its edges contact the interior of the plurality of walls 504. The sample transfer device 590 may operate similarly to the sample transfer device 500. After the sample is transferred (e.g., to a sample transfer surface), the sample substrate 591 may be removed from the sample transfer device 590 and transferred to a specimen container where it (and the remaining sample thereon) may be preserved. This modifies sample preservation by only requiring the storage of the relatively small sample substrate 591, rather than a larger portion of the sample transfer device 590.

[0089] In further embodiments, any portion of the sample transfer devices 500 and 590 that may come into contact with the sample may be configured for removal, including at least the moveable wall 505, the sample advancement structure 508, the sample movement structure 509, and the sample transfer chamber 501. . Accordingly, any structures of the sample transfer device 500 or 590 that do not come into contact with the sample may remain free of contamination for potential reuse.

[0090] FIG. 5E also illustrates a collection surface protrusion 592. The collection surface protrusion 592 may be incorporated in any of the sample transfer devices discussed herein, with or without the sample substrate 591 included. The collection surface protrusion 592 is a structure that protrudes or extends from or past the sample collection surface. The collection surface protrusion 592 is sized and configured to fill a volume of the aperture of the sample transfer device 590 (or any other sample transfer device that incorporates it), thus further eliminating dead space in the transfer chamber. The collection surface protrusion 592 facilitates the use of a sample transfer device with very small amounts of sample, as the collection surface protrusion 592 serves to ensure that very little or no sample may remain within the aperture of the sample transfer device.

[0091] FIG. 5E also illustrates a sample preservation wall 593. The sample preservation wall 593 may be incorporated in any of the sample transfer devices discussed herein, with or without the sample substrate 591 and the collection surface protrusion 592 included. The sample preservation wall 593 is a structure that is removable attached to the top of the transfer chamber 501. The sample preservation wall 593 may be flexible or rigid and may have a shape that conforms to the inner surface of the top wall of the transfer chamber 501. During operation, as the sample is ejected through the aperture 503, the sample is pressed against the sample preservation wall 593. After sample transfer, the sample preservation wall 593 may be removed from the sample transfer device 590 to a storage container for preservation. In this design, the sample preservation wall 593 is not required to support the full pressure of the sample during ejection, because it is supported by the top wall of the transfer chamber 501. Accordingly, the sample preservation wall 593 may be a relatively thin material, which may be more economical for transfer to a storage container for preservation.

[0092] FIG. 5F illustrates a sample transfer device consistent with embodiments hereof, he sample transfer device 580 is consistent with embodiments for transfer of liquid (e.g., FNA), semi-solid, and solid samples. The sample transfer device 580 may include all of the features of the sample transfer device 500 in any suitable combination. The sample transfer device 580 may further include a sample substrate 581 and a rotary plunger 582. The rotary plunger 582 is an actuator configured to translate linearly and rotationally. The rotary plunger 582, may translate linearly towards and away from the moveable wall 505, thus allowing the sample cavity 506 to change in size. The rotary plunger may further include a rotary face 583 configured to translate rotationally. The rotary face 583 includes one or more raised spiral features 584 that protrude from a base 585. The raised spiral features 584 are ridges that extend outwards from the center of the base 585 in a spiral fashion. The sample substrate 581 mayhave a face that acts as the sample advancement surface 510. During operation, the sample substrate 581 may be advanced (e.g., by the rotary plunger 582) through the sample cavity 506 such it presses against an interior of the movable wall 505. The sample substrate 581 is flexible and may conform the raised spiral features 584 of the rotary face 583. When the rotary plunger 582 rotates the rotary face 583 while the sample substrate 581 is pressed against the interior of the moveable wall 505, the rotational action of the raised spiral features 584 provide a peristaltic effect that pumps or moves any sample located on the sample substrate 581 towards a center of the sample substrate 581, thus permitting ejection through the aperture 503 for collection.

[0093] FIG. 5G illustrates a sample storage disk consistent with embodiments hereof. The sample storage disk 530 provides a convenient means of transferring remaining sample (e.g., sample not transferred to the sample transfer surface 540) to a sample storage container for preservation. The sample storage disk 530 may be provided with the sample transfer device 500 or any other sample transfer device discussed herein. The sample storage disk 530 is a planar structure having a relatively small height in comparison to its width and length. In embodiments, the sample storage disk 530 may be sized and configured to cover all or a portion of the top surface of the sample transfer device 500. The sample storage disk 530 may have a height (thickness) of 1 mm or less. The sample storage disk 530 may be round, rectangular, or any other suitable shape. The sample storage disk 530 is configured with ahole 531 or aperture therein that may be aligned with the aperture 503 of the sample transfer device 500. When the sample 570 is advanced and ejected via the aperture 503 it passes further through the hole 531 in the sample transfer disk 530. The sample transfer surface 540 may then be brough into contact with the sample 570, as discussed herein, to transfer the sample 570. Remaining amounts of sample 570 within the sample transfer device 500 may be ejected through the aperture 503 and the hole 531 to be disposed on the surface of the sample storage disk 530. The sample storage disk 530 may then be removed to a sample storage container for preservation by a suitable preservative liquid.

[0094] FIGS. 6A-6C illustrate steps in a method of sample transfer. The illustrated method may be referred to as a “touch preparation method.” The method includes collecting a sample 603 on a collection surface 602 of a transfer plate 604 (e.g., according to operation 1002 of method 1000), advancing the collection surface 602 towards a sample transfer surface 601 of a sample substrate 605 (e.g., according to operation 1004 of method 1000), contacting the sample transfer surface 601 with the sample 603 (e.g., according to operation 1006 of method1000), and transferring the sample 603 to the sample transfer surface 601 (e.g., according to operation 1008 of method 1000).

[0095] The transfer plate 604 may include a collection surface 602 upon which a sample 606 is disposed. The transfer plate 604 may be a specimen slide or any other suitable substrate, such as any relatively flat or low profile structure, having a collection surface on one side thereof. The sample transfer surface 601 may be a surface of a sample substrate 605. The sample substrate 605 may include, for example, a specimen slide or any other suitable substrate having a surface suitable for sample disposition. Movement of the sample substrate 605 and the transfer plate 604 according to methods described herein may be accomplished according to various means. For example, the sample substrate 605 and the transfer plate 604 may be mounted with a sample cartridge that is configured to facilitate relative movement therebetween. In further examples, the sample substrate 605 and the transfer plate 604 may be manipulated by actuators of a sample processing system (e.g., sample processing system 100), such as suction cups, grippers, pinchers, or other suitable grasping devices. In embodiments, the sample substrate 605 and the transfer plate 604 may each be contained or disposed within a frame.

[0096] During a sample transfer operation, such as method 1000, a sample 603, including, for example, a solid sample, a semi-solid sample, or a liquid sample, may be deposited on a collection surface 602 of the transfer plate 604.

[0097] During a sample transfer operation, such as method 1000, the sample substrate 605 and the transfer plate 604 may be advanced towards one another (thus advancing the sample transfer surface 601 and the collection surface 602 towards one another), according to operation 1004. Advancing the sample substrate 605 and the transfer plate 604 may include advancing either or both of the sample substrate 605 and the transfer plate 604. Movement of the sample substrate 605 and the transfer plate 604 may be facilitated by actuators, e.g., of a sample processing system as discussed above.

[0098] The collection surface 601 and the sample transfer surface 602 may be brought into proximity with one another close enough such that the sample 603 contacts the sample transfer surface 601, e.g. according to operation 1006. Upon drawing the collection surface 601 and the sample transfer surface 602 apart, as shown in FIG. 6C, at least a portion of the of the sample 603 is transferred to and remains on the sample transfer surface 602 as transferred sample 606.

[0099] During sample transfer, contact between the sample transfer surface 601 and the sample 603 may be monitored to ensure appropriate contact is made for sample transfer. Contact maybe monitored according to a measurement of force generated by the contact, according to a measurement of displacement between the sample transfer surface 601 an the sample collection surface 601, through the use of computer vision, and / or other means. Such measurements may be made by force sensors and / or displacement sensors of any suitable type.

[0100] A computer vision aided sample transfer method may operate as follows. Computer vision aided sample transfer methods may be used with liquid, semi-solid, and solid tissue samples and may be combined with any of the sample transfer techniques discussed herein, as appropriate. The computer vision aided methods discussed with respect to FIGS. 3D-3G may be incorporated within and / or combined with the methods discussed with respect to FIG. 12. FIG. 12 is a flow chart illustrating the steps of a computer vision aided sample transfer method 1200. The computer vision aided sample transfer method 1200 may be carried by the rapid onsite evaluation system 100, e.g., by robotic actuators, computer system components, and optical devices situated therein. The computer vision aided sample transfer method 1200 may be carried by any suitable collection of hardware, including actuators, computer system components, and optical devices that may be configured to carry out the following steps. Discussion below may refer to the “system,” which may encompass any of the necessary computer, hardware, software, robotic, and / or optical devices / apparatuses to carry out the method 1200.

[0101] After a sample has been collected on a sample collection surface, e.g., via a step similar to step 1002 of sample transfer method 1000, the sample collection surface is advanced towards a sample transfer surface in a pair of steps corresponding to step 1004 of the sample transfer method 1000.

[0102] In an operation 1202, the computer vision aided sample transfer method 1200 may include a fast sample advance. A “fast” sample advance may be used to bring the sample collection surface and the sample transfer surface within a threshold distance of one another quickly to ensure that the sample transfer process can be completed quickly. One or more actuators may be used to advance either or both of the sample collection surface and the sample transfer surface towards the other. Computer vision techniques may use a side view camera or other optical device to monitor the distance between a surface of the sample and the surface of the sample transfer surface. When the distance between the sample transfer surface and the sample is less than the threshold distance, the fast sample advance may end.

[0103] In some embodiments, the threshold distance may be predetermined as a distance that will ensure the sample does not contact the sample transfer surface. In such a case, the sample collection surface and the sample transfer surface may be advanced towardsone another until their distance is lower than the threshold distance, as measured by any conventional means of monitoring robotic motion.

[0104] In an operation 1204, the computer vision aided sample transfer method 1200 may include a slow sample advance at a first slow advancement speed. The first slow advancement speed may be approximately 50% or less, 25% or less, 15% or less, 10% or less, or 5% or less of the fast advancement speed. The “slow” sample advance may be used to slowly bring the sample collection surface and the sample transfer surface towards one another such that contact between the sample and the sample transfer surface may be monitored.

[0105] In the following operations 1206 and 1208, the sample may be contacted to the sample transfer surface, in an example of step 1006 of sample transfer method 1000.

[0106] In an operation 1206, the computer vision aided sample transfer method 1200 may include detecting contact between the sample and the sample transfer surface. Contact may be detected by an optical device, such as a camera, configured with a side, top, or bottom view of the sample transfer surface. The sample transfer surface may be appropriately transparent to facilitate viewing by the optical device. Contact may be detected according to a change in shape of the sample, which may be detected by comparing a current frame or image to a previously captured frame or image. After contact is detected, slow advancement may continue and contact may be monitored via computer vision techniques. In some embodiments, advancement of the sample collection surface and the sample transfer surface towards one another may be further slowed down after contact detection to a second slow advancement speed, which may 50% or less, 25% or less, etc., of the first slow advancement speed.

[0107] In an operation 1208, the computer vision aided sample transfer method 1200 may include monitoring contact between the sample and the sample transfer surface. Monitoring contact may include identifying whether a large change in the sample shape occurs over a short time period (e.g., over a small number of camera frames). Such a rapid change may be indicative of the sample being a liquid or semi-solid sample and of surface tension being broken in the liquid or semi-solid sample. A rapid change may be defined by a change in sample shape that has a significantly greater rate of change than a previous rate of change (which may be close to zero, e.g., no change). A rapid change may be measured based on a comparison of a current image or frame to a previous image or frame and a corresponding determination of correlation (or other measurement of change) between a size of the sample in each frame. In embodiments, the previous image or frame may be an image or frame immediately preceding the current image or frame. In embodiments, the current image or frame may be compared to an image or frame captured a set interval previously. If a changeexceeds a predetermined threshold of change over a set period of time, it may be considered a “rapid change.” The predetermined threshold may be determined experimentally through tests of multiple liquid, semi-solid, and solid samples. The predetermined threshold for “rapid” change may depend on sample size, advancement rate, camera frame rate (if measuring across frames rather than in a specific period of time), and other factors. The predetermined threshold may be selected so as to indicate a distinction between liquid based samples having surface tension (e.g., liquid samples and some semi-solid samples) and other samples that do not display surface tension characteristics.

[0108] A rapid change may be brought about by a break in surface tension of the liquid of a liquid or liquid containing semi-solid sample. When a sample contacts the sample transfer surface surface tension in the sample may be broken. When surface tension is broken, the liquid or liquid containing semi-solid sample may spread out very rapidly at a rate significantly faster than the slow advance of the sample collection surface can account for and at a rate significantly faster than a similarly sized sample non exhibiting surface tension. Thus, a rapid change in sample shape after contact may be indicative of a liquid or liquid containing sample, and more specifically, of surface tension breaking in a liquid or liquid containing sample. As noted above, the distinction between “rapid” change and normal change may be determined experimentally based on testing of liquid and liquid based samples having surface tension and other samples not displaying surface tension characteristics. Appropriate thresholds for “rapid” change may depend on the specific set up of a sample transfer method. After detecting such a rapid change, the system may determine that sample transfer is complete (e.g., as in step 1008 of sample transfer method 1000), and advance to operation 1210, whereby the sample collection surface and the sample transfer surface are separated.

[0109] Monitoring contact may further include monitoring whether a force threshold or a distance threshold between the sample collection surface and the sample transfer surface has been reached. After contact detection, while the system continues to use computer vision techniques to monitor the shape of the sample to detect a potential rapid change, the system also monitors a force required to advance the sample collection surface and the sample transfer surface towards one another and a distance between the sample collection surface and the sample transfer surface. Distance may be monitored, e.g., by computer vision techniques and / or by other sensors or actuators in the system (e.g., sensors that detect distance, location, etc., and / or actuators that report a distance travelled). Force may be monitored, e.g., by force sensors. If a force threshold is reached or if a distance threshold is reached, it may indicate that a semi-solid or solid sample has been pressed between the sample collection surface and thesample transfer surface. After achieving a force or distance threshold, it may be determined, by the system, that sample transfer has occurred and the system may move to operation 1210. A distance threshold may be predetermined, e.g., approximately 0.5, 1, 1.5, 2, 2.5, 3 mm, or within a range between 0.5 and 3.0 mm.

[0110] In an operation 1210, the computer vision aided sample transfer method 1200 may include separation of the sample collection surface and the sample transfer surface. Separating the sample collection surface and the sample transfer surface may occur at a slow speed similar to the first or the second slow advancement speed or at any suitable speed. During the step of separating the sample collection surface and the sample transfer surface, contact between the sample and the sample collection surface and the sample transfer surface may further be monitored, e.g., by optical devices of the system. Separation of the sample collection surface and the sample transfer surface may continue until it is detected that the sample does not contact both the sample collection surface and the sample transfer surface, indicating that sample transfer is complete.

[0111] In embodiments, further scraping, smearing, leveling etc., steps may be taken if it is detected, e.g., by the computer vision system, that the transferred amount of sample (e.g., the amount of sample remaining on the sample transfer surface) is in excess of a required amount.

[0112] FIGS. 7-10 illustrate devices and methods that facilitate sample transfer. In sample transfer embodiments, the irregularity of some samples may provide difficulties in the sample transfer process. Sample transfer methods and devices described herein are configured to result in a sample transfer surface having a sample disposed thereon in an amount and disposition suitable for further sample processing (e.g., staining, imaging, etc.). Such sample processing may be hindered if too much or too little sample adheres to the sample transfer surface. Accordingly, devices and methods are provided herein to correct, optimize, or otherwise improve the disposition of a transferred sample on the sample transfer surface.

[0113] FIG. 7A illustrates a sample collection device configured to facilitate, improve, optimize, or otherwise improve sample transfer. The sample collection device 700, which may be particularly suitable for use with solid and / or semi-solid samples, includes a collection base 702 including at least a sample collection surface 701, an excess sample trough 708, a scraping edge 705, and one or more spacers 706. The collection base 702 is a structure that is square, rectangular, or any other suitable shape and is configured to support the other features described herewith. The collection base 702 may be configured for machine or robotic handling. Thecollection base 702 supports the sample collection surface 701, which may function similarly to the collection surface 602 as discussed above.

[0114] After sample transfer, an amount of sample that is in excess of a desired amount may remain on the sample transfer surface. The scraping edge 705 extends substantially perpendicularly from the collection base 702 to a height above the sample collection surface 701 and may be used to scrape the transferred sample. During scraping, stuck tissue is scraped off of the sample transfer surface On either side of the scraping edge 705, one or more spacers 706 extend above the scraping edge 705. The one or more spacers 706 may be rounded or curved. When the sample transfer surface (not shown) is brought into contact with the one or more spacers 706, a gap between the scraping edge 705 and the one or more spacers 706 is created due to the extension 707 (illustrated in the inset illustration) of the one or more spacers 706 above the scraping edge 705. The height of the extension 707 (and therefore the height of the gap) may be between 250-25 microns, between 250-200 microns, between 200-150 microns, 100-80 microns, between 80-50 microns, between 60-40 microns, between 50-25 microns, etc., when the sample transfer surface is positioned substantially perpendicular to the sample collection surface 701. Due to the curved or rounded shape of the spacers 706, the sample collection device 700 may be rotated to expand the gap between the scraping edge 705 and the sample transfer surface.

[0115] During operation, after sample transfer, the sample transfer surface may be brought into contact with the one or more spacers 706. The sample transfer surface and the scraping edge 705 may be moved relative to one another to cause the scraping edge 705 to pass over the transferred sample and scrape from, smear across, or otherwise level the sample on the sample transfer surface to a maximum height or thickness corresponding to the gap. Excess sample that is removed may collect in the excess sample trough 708. After use, the sample collection device 700 may be transferred to a sample storage container for tissue preservation.

[0116] In embodiments, one or more aspects of the sample collection device 700 may be flexible, permitting the one or more spacers 706 to remain in contact with the sample transfer surface despite potential small differences in the positioning of the sample transfer surface and sample collection device 700.

[0117] The sample collection device 700 is described above with respect to specific angles and orientations as shown in FIG. 7A. The sample collection device 700, however, is not limited by the description and illustration. For example, the scraping edge 705 may be positioned at any angle and have any extension length relative to the collection base 702, solong as it remains configured to be spaced apart from the sample transfer surface by the one or more spacers 706 so as to perform the sample leveling described above.

[0118] Some examples of alternate configurations are illustrated in FIGS. 7B-7D. FIGS. 7B-7D are cut-away illustrations of sample collection device 700 that omit the one or more spacers 706 to provide a better view of the scraping edge 705. For example, 7B illustrates a scraping edge 705 having a tapered edge. FIG. 7C illustrates a scraping edge 705 having an obtuse angle with respect to the sample collection surface 701. FIG. 7D illustrates a scraping edge 705 having an acute angle with respect to the sample collection surface 701. Due to the inclusion of the excess sample trough 708, the acute angle of the scraping edge 705 may be achieved by the arcing or curling shape of the scraping edge 705 illustrated in FIG. 7D.

[0119] FIG. 7E illustrates a sample collection device configured to facilitate, optimize, or otherwise improve sample transfer. The sample collection device 710, which may be suitable for liquid or FNA samples, includes a collection base 712 including at least a sample collection surface 711, an excess sample trough 718, a top surface 713, and a scraping edge 715. The collection base 712 is a structure that is square, rectangular, or any other suitable shape and is configured to support the other features described herewith. The collection base 712 may be configured for machine or robotic handling. The collection base 712 supports the sample collection surface 711, which may function similarly to the collection surface 602 as discussed above, and extends at least as high as the top surface 713 of the collection base 702 to facilitate sample transfer. In embodiments, the sample trough 718 may be formed of a flexible material, permitting the collection surface 711 to be moved upwards relative to the sample trough 718 (e.g., due to pressure or force provided on a back of the collection surface 711). In further embodiments, any aspect of the sample collection device 710 may be flexible or rigid as may be suitable. After sample transfer, an amount of sample that is in excess of a desired amount may remain on the sample transfer surface. The scraping edge 715 extends substantially perpendicularly from the collection base 712 to a height above the sample collection surface 711. In operation, after sample transfer, the scraping edge 715 may be used to scrape across the sample transfer surface to remove any tissue that has stuck to the sample transfer surface. In cases where the sample is FNA or other liquid, clots or other small bits of solid or semi-solid tissue may be included within the sample. In such cases, the scraping edge 715 may function to dislodge these from the sample transfer surface. After use, the sample collection device 700 may be transferred to a sample storage container for tissue preservation.

[0120] FIGS. 7F, 7G and 7H illustrates a sample collection device configured to facilitate, optimize, or otherwise improve sample transfer. The sample collection device 720may include a sample collection surface 701, a sample transfer substrate 725 having a sample transfer surface 726, a first scraper 721, and a second scraper 722. The sample transfer substrate 725 may include, for example, a specimen slide or other suitable structure. In embodiments, one of the first and second scrapers 721 / 722 may be fixed while the other is moveable. The sample collection device 720 may be operated as follows. A sample may be deposited on the sample collection surface 701. The sample transfer substrate 725 may be brought near the device 720 by an actuator (or manually by an operator). The sample transfer surface 726 of the sample transfer substrate 725 is touched to the sample on the sample collection surface 701. Part of the sample may then transfer to the sample transfer surface 726, and the sample transfer substrate 725 may then be raised to the level of the scrapers 721 / 722. Each scraper 721 / 722 has a scraping edge 723 and two spacers 724 arranged on either side of the scraping edge 723. The spacers 724 are raised above the scraping edge 723 by a height between 250-25 microns, between 250-200 microns, between 200-150 microns, 100-80 microns, between 80-50 microns, between 60-40 microns, between 50-25 microns, etc. The sample transfer surface 726 of the sample transfer substrate 725 is brought into contact with the spacers 724. The first scraper 721 is drawn across the sample transfer surface 726 (e.g., by an appropriate actuator). The scraping edge 723 acts to scrape the any stuck tissue from the sample transfer surface 726 while the gap between the spacers 724 and the scraping edge 723 permit a layer of sample to remain adhered to the sample transfer surface. The dislodged tissue may fall back to the sample collection surface 701, or remain adhered to the scrapers. When they meet, the scrapers together serve as a set of “pinchers” to pull adhered tissue off the sample collection surface in a direction orthogonal to the collection surface, to prevent the adhered tissue from sticking to the sample transfer surface 726 and therefore being pushed along the sample transfer surface 726 to an end of the surface and then rolling around the end of the surface to end up on an opposite side of the transfer surface. In embodiments, both scrapers 721 / 722 may be moveable. In other embodiments, the sample transfer surface 726, and / or scrapers 721 or 722 may contain absorptive material, such as cotton or gauze, that serves to absorb excessive fluid in the tissue sample. After sample transfer, the sample collection surface 701 and the scraper 721 / 722 may be transferred to a sample storage container for preservation.

[0121] FIG. 8 illustrates a mesh transfer device. The mesh transfer device 800 includes a mesh 801 attached to a frame 802. In embodiments, the frame 802 may be connected to the mesh transfer device 800 by ahinge. The mesh transfer device 800 may be used in conjunction with a sample collection surface 803. The tissue sample is placed on the sample collection surface 803 within the mesh transfer device 800. The frame 802 is placed over the sample,e.g., by action of a hinge, either by an operator or automatically by the rapid onsite evaluation system 100, such that the tissue sample is arranged below the mesh 801. The rapid onsite evaluation system 100 or operator proceeds with sample transfer (e.g., by a touch preparation method) as described herein. The sample collection surface 803 with the mesh transfer device 800 laid thereon is presented upwards towards a sample transfer surface to make contact through the mesh 801, e.g., the mesh 801 is interposed between the sample collection surface 803 and the sample. Once a particular force level between the sample transfer surface and the collection surface 803 is reached, the sample transfer surface may be removed. The sample transfer surface then as an imprint of the tissue sample deposited thereon through the mesh 801. The threads of the mesh 801 may be quite thin, e.g., less than 100 microns, to ensure sample transfer for small tissue samples. The mesh 801 may also be “sparse” (e.g., having a small thread size relative to pore sizes) to ensure enough material is transferred. The mesh and the collection surface with the residual tissue thereon may then be placed into a sample storage container with preservative for downstream pathology processing.

[0122] FIG. 9 illustrates a vortex transfer device. The vortex transfer device 900 includes at least a vortex frame 902, an air intake port 901, a torus chamber 903, and one or more air output ports 904. The vortex transfer device 900 is configured to receive high pressure air (or other gas) via the air intake port 901. The received air is directed, via internal channels in the vortex frame 902 into the torus chamber 903 which is a toroidal chamber. The high pressure air circulates in the toroidal chamber 903 and is output via the air output ports 904 to form an air vortex in the vortex window 905. The vortex window 905 is a an aperture or window disposed centrally to the torus chamber 903. When used during a sample transfer operation, the sample transfer surface, with the transferred sample deposited thereon, may be disposed such that the transferred sample is located within the vortex window 905. Operation of the vortex transfer device 900 generates an air vortex within the vortex window 905. The moving air may dislodge tissue of the transferred sample that is stuck to the sample transfer surface. With the sample transfer surface arranged above the collection surface, the dislodged tissue may fall from the sample transfer surface to the collection surface, leaving behind a layer of sample without the excess tissue.

[0123] FIGS. 10A-10F illustrates a sample transfer pinch device consistent with embodiments hereof. The sample transfer pinch device 1061 includes at least one support frame 1062 at and least one tip 1070. The at least one support frame 1062 includes the at least one tip 1070 disposed at one or more ends thereof. In an embodiment, e.g., as illustrated in FIGS. 10A-10F, the support frame 1062 is a flexible sheet having a tip 1070 at each end thereof.The support frame 10162 may be a planar structure, and may be rectangular in shape. The tips 1060 may be the opposing short edges of a rectangular planar structure. The support frame 1062 is flexible and may be caused to flex or curl such that the tips 1070 approach each other and, in some configurations, meet. Bending or flexing the support frame 1062 may be performed by one or more actuators, e.g., of rapid onsite evaluation system 100.

[0124] In a sample transfer operation, a transferred sample 1056 may be transferred from a sample collection surface to a sample transfer surface 1052 as discussed herein. In some embodiments, a sample collection surface 1051 may be disposed on the support frame 1062 of the sample transfer pinch device 1011. In a case where the transferred sample 1056 sticks to the sample transfer surface, as shown in FIG. 10 A, the sample transfer pinch device 1011 may be employed to remove excess sample. As shown in FIGS. 10B-10D, the sample transfer pinch device 1011 may be curled or bent such that the tips 1020 approach each other from opposite sides of the stuck, transferred sample 1056. The tips 1020 may scrape or contact the sample transfer surface 1052 as they come together between the transferred sample 1056 and the sample transfer surface 1052. The tips 1020 dislodge the excess transferred sample 1057, as shown in FIG. 10E, leaving behind a layer of transferred sample 1056 suitable for further processing, as shown in FIG. 10F. The excess transferred sample 1057 may then be transferred to a sample storage container 1058 for preservation in a suitable preservative liquid (e.g., formalin) for storage and preservation, as shown in FIG. 10G.

[0125] FIGS. 11A and 1 IB illustrate a substrate chuck consistent with embodiments hereof. Methods for sample transfer described herein employ substrates, e.g., specimen slides, upon which sample transfer and sample collection surfaces may be located. Such substrates may be manipulated by the rapid onsite evaluation system 100, as described herein. In some embodiments, the rapid onsite evaluation system 100 may employ the substrate chuck 1100, as illustrated in FIGS. 11 A and 1 IB.

[0126] The substrate chuck 1100 includes a mounting frame 1104, a manifold 1103, and one or more suction arms 1102. The mounting frame 1104 is a structure that permits the substrate chuck 1100 to be mounted to the rapid onsite evaluation system 100. The manifold 1103 is disposed on the mounting frame 1104 and includes a suction conduit 1114 that supplies negative air pressure to each of the suction arms 1102. The substrate chuck 1100 may include one or more suction arms 1102, and, in certain embodiments, includes three more suction arms 1102.

[0127] Each suction arm 1102 includes a flexible boot 1107 and a rigid rod 1106. The suction conduit 1114, which is in fluid communication with the interior of the flexible boots1107 may be connected to a pump or other device to provide negative air pressure. Thus, each flexible boot 1107 may have a negative air pressure in the interior and act as a suction cup when placed against a substrate 1101. The rigid rod 1106 is disposed within an interior of the flexible boot 110 and positively locates the substrate 1101. When suction, or negative air pressure, is applied to the substrate 1101 via the flexible boot 1107, the flexible boot 1107 contracts until the substratel lOl contacts the rigid rod 1106. Each of the rigid rods 1106 is sized and configured to extend a predetermined distance from the mounting frame 1104 (or any other suitable reference structure). By providing three rigid rods 1106, each extending the predetermined distance away from the mounting frame 1104, a plane of the substrate 1101 may be established within a narrow tolerance for both location and orientation. The distance tolerance (e.g., distance from a reference structure) may be less than 100 microns, less than 50 microns, and / or less than 25 microns. Such narrow tolerances may be facilitated by the rigid rods 1106, which can be machined and / or otherwise manufactured according to a specific and narrow tolerance. In contrast, if suction cups or the flexible boots 1107 were used alone, their flexibility would make it difficult to maintain the same narrow tolerancing.

[0128] In embodiments, various enhancements or adjustments may be applied to any or all of the previously discussed methods, as discussed below.

[0129] In further embodiments consistent with the present disclosure, refrigeration may be used to assist in sample transfer with any of the methods and devices discussed above. For example, a sample collection surface, a sample transfer surface, and / or a sample may be refrigerated and / or chilled. In one example, a sample collection surface may be chilled below a freezing temperature (e.g., below 0 C). In another example, the sample collection surface may be chilled to between -1 C and -10 C. When a sample is deposited thereon, a layer of the sample in contact with the sample collection surface may freeze, causing the sample to stick to the collection surface. When the sample contacts the sample transfer surface (e.g., at a top portion of the sample that is not frozen) a layer of cells from the sample may be transferred while the excess sample remains in contact with the collection surface. Because only a small layer of sample in contact with the collection surface is frozen, the majority of the sample is not compromised by the freezing action. In another example, a sample removal surface may be chilled below a freezing temperature. In embodiments, the sample removal surface may be located on the same structure as the sample collection surface. For example, a single substrate may have an uncooled portion to act as the sample collection surface and a cooled portion to act as the sample removal surface. In embodiments, the sample removal surface may be located on a separate structure from the sample collection surface. After initial transfer from the samplecollection surface to the sample transfer surface, the sample removal surface may be introduced if the sample remains stuck to the sample transfer surface. The chilled sample removal surface may be brought close to the sample transfer surface and touched to the sample on the sample transfer surface. The chilled surface of the sample removal surface may cause the sample to adhere, permitting the sample to be pulled away from the sample transfer surface, leaving behind a layer of cells. The sample removal surface may then quickly be warmed above freezing to prevent damage to the sample and placed into a storage container with a preservative fluid. Warming the sample removal surface may be performed by the preservative fluid itself. In another embodiment, the sample removal surface may be ahigh thermal conductivity surface (e.g., aluminum, copper, etc.) and may be attached directly to a cooling device, such as a Peltier cooler. After sample removal, the Peltier cooler may be operated in reverse to warm the sample removal surface.

[0130] In embodiments, any of the sample transfer methods and devices described herein for solid and semi-solid sample transfer may eliminate use of a collection surface. As described herein, a collection surface may be used to receive a sample and then transfer the sample to a sample transfer surface. In further embodiments, the sample may be deposited directly onto a sample transfer surface. Thereafter, any of the methods and devices described herein for scraping, spreading, etc., the sample from the sample transfer surface may be employed to leave an appropriate amount of sample remaining on the sample transfer surface. For example, excess sample may be scraped off by scraping edges and or pinchers as described herein. In some examples, such scraping / pinching devices may be deployed from above the sample transfer surface to grab or lift excess tissue or fluid from the slide to pull the excess sample away and leave a thin layer of sample (e.g., a thin layer of cells) behind on the sample transfer surface.

[0131] In embodiments, any of the sample transfer methods and devices described herein may use either a fixed force or a fixed displacement during sample transfer. As discussed above, many of the methods and techniques described herein employ a “touch preparation” method that involves touching the sample located on the collection surface to a sample transfer surface to cause transfer. Such touch preparation methods may employ fixed force touching, e.g., by repeatedly using a same amount of force during the sample transfer. This may serve to increase repeatability and consistency among sample transfer operations. Touch preparation methods may also employ fixed displacement touching, e.g., by repeatedly using a same amount of displacement between the sample collection surface and the sample transfer surface during the sample transfer. This may serve to increase repeatability andconsistency among sample transfer operations. In still further embodiments, as described further above, force and displacement between the sample collection surface and the sample transfer surface may be dynamically controlled according to closed loop feedback from optical devices (e.g., cameras) configured to monitor the transfer.

[0132] In further embodiments, sample scraping, leveling, dislodgement, smearing, wiping, etc., may employ a string, line, wire, or other similar tool. Any of the scraping or scraping edges, tips, or blades may be replaced by a string, line, wire, or other similar tool to facilitate uniformity of sample transfer.

[0133] In further embodiments, sample scraping techniques described herein with respect to solid and / or semi-solid sample transfer may also be used in conjunction with liquid (e.g., FNA) sample transfer. In particular, scraping devices that include a scraping edge such as scraping edge 705 with spacers 706 (e.g., as shown in FIG. 7A) provide a fixed distance between the scraping edge 705 and the sample transfer surface. Such a fixed distance may be selected so as to scrape or level a transferred sample to a height consistent with a cellular monolayer.

[0134] In further embodiments that may be used in combination with any of the devices and methods discussed herein, a sample transfer surface may have saline or another innocuous liquid deposited thereon prior to sample transfer (e.g., by spraying, pouring, dropping, etc.) A saline deposit prior to sample transfer may reduce a likelihood of tissue sticking to the sample transfer surface.

[0135] In further embodiments, air transfer methods may be employed to facilitate sample transfer, particularly with liquid (e.g., FNA) samples. Air transfer methods refer to methods that do not require touch preparation. In an example, ultrasonic or vibratory means may be employed to break the surface tension of a liquid sample in a sample transfer device. For example, the sample transfer device 300 (or other suitable sample transfer device described herein) may be used to advance a liquid sample through the aperture 303 as described herein to form a liquid protrusion. The liquid protrusion may be hemispherical in shape, may be another portion of a sphere in shape, or may be another shape consistent with the sample viscosity. Rather than touching a sample transfer surface, the sample transfer device may be vibrated or excited via ultrasound to cause droplets from the liquid protrusion to be ejected onto a sample transfer device. Adjusting the frequency and amplitude of the vibration / ultrasound may permit controlled transfer of the sample. Other methods of air transfer may include high acceleration / deceleration methods. For example, a flexible tube with a droplet at the end or a membrane may be tapped, flicked, flung, etc., to cause either a highacceleration or a high deceleration to dislodge a fluid droplet to be transferred through air onto a sample transfer surface.

[0136] In a further embodiment, a core wash method may be employed to facilitate sample transfer. In such a method, a semi-solid or solid sample may be washed with a fluid, for example saline, RPMI (Roswell Park Memorial Institute fluid), or other fluids. Washing may include mixing the semi-solid or solid sample with the fluid, e.g., by agitating, shaking, or stirring. The washing step may serve to transfer cells from the sample to the fluid. The fluid may then be transferred to a sample transfer surface, e.g., by any means discussed herein, for further processing.

[0137] In a still further embodiment, a sample swab transfer method may be employed to facilitate sample transfer. In such a method, a sample swab (e.g., a standard specimen swab or similar tool) may be pressed to a solid or semi -solid sample to collect at least a portion of the sample on the swab. The swab may then be inserted into a fluid contained in a cartridge. The swab may be agitated or otherwise mixed in the fluid to cause transfer of the sample to the fluid. The fluid may then be transferred to a sample transfer surface, e.g., by any means discussed herein, for further processing. In another embodiment, the swab may be touched directly to a sample transfer surface with use of an intermediate fluid, thereby transferring cells to the transfer surface for further processing. The touch may be performed automatically using methods described herein.

[0138] In a still further embodiment, force and displacement measurements made by the system during sample transfer may be recorded for further use. For example, as discussed above with respect to the transfer of solid or semi-solid tissue, force and displacement between the sample collection surface and the sample transfer surface may be measured during sample transfer. Companng force and displacement after contact between the sample and the sample transfer surface may be used to estimate the elasticity of the sample. Such estimates may be used after sample processing during sample assessment, for example, as a measurement or predictor of the type of tissue that is present. For example, measurements of force and displacement, as an estimate of elasticity or combined in other ways, may be used, along with imaging results of samples, as an input to a machine learning algorithm to predict or estimate a condition of cells in the sample, such as, for example, cancerous cells.

[0139] The sample transfer devices and methods described herein may contribute to automated sample processing methods that provide for increased accuracy and consistency of sample processing procedures, resulting in decreased analysis time, and increased throughput of sample processing. Such advantages may be particularly valuable when provided in an on-site environment for providing rapid sample evaluation and thus improving outcomes. The sample processing methods described herein are not limited to on-site processing, and may be employed 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 others.

[0140] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "includes" and / or "including," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0141] The embodiments described above are illustrative examples and it should not be construed that the present invention is limited to these particular embodiments. It should be understood that various embodiments disclosed herein may be combined in different combinations than the combinations specifically presented in the description and accompanying drawings. It should also be understood that, depending on the example, certain acts or events of any of the processes or methods described herein may be performed in a different sequence, may be added, merged, or left out altogether (e.g., all described acts or events may not be necessary to carry out the methods or processes). In addition, while certain features of embodiments hereof are described as being performed by a single module, device, or unit for purposes of 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 affected by one skilled in the art without departing from the spirit or scope of the invention as defined in the appended claims.

Claims

WE CLAIM:

1. A method of transferring a sample, the method comprising: collecting the sample on a collection surface disposed within a transfer chamber, the transfer chamber having an aperture in a wall thereof; advancing the sample towards the aperture by reducing a volume of the transfer chamber; ejecting a first a portion of the sample through the aperture; and transferring a second portion of the sample to a sample transfer surface.

2. The method of claim 1, wherein: the sample is a liquid sample or a semi solid sample, ejecting the first portion includes forming a protrusion of sample at the aperture, and transferring the second portion includes touching the protrusion to the sample transfer surface.

3. The method of claim 2, further comprising imaging the protrusion to determine that the first portion meets a volume threshold for transfer.

4. The method of claim 2, wherein reducing a volume of the transfer chamber is performed by advancing the collection surface towards the aperture.

5. The method of claim 2, further comprising ejecting a third portion of the sample into a storage container.

6. The method of claim 5, further comprising ejecting the transfer chamber into the storage container.

7. The method of claim 2, further comprising enlarging a volume of the transfer chamber to pull the first portion away from the sample transfer surface.

8. The method of claim 7, wherein enlarging the volume of the transfer chamber includes withdrawing the collection surface away from the aperture.

9. The method of claim 1, wherein the second portion of the sample is less than one fifth, less than one tenth, less than one twentieth, less than one fiftieth, less than one hundredth, or less than one thousandth of the sample.

10. The method of claim 1, wherein the transfer chamber is elongated and the wall is disposed at an end thereof11. The method of claim 10, wherein the sample collection surface is advanced in an axial direction of the elongated transfer chamber.

12. The method of claim 1, wherein the at least a portion of the sample is measured via one or more imaging technique.

13. The method of claim 1, further comprising preserving a remaining portion of the sample after transfer.

14. The method of claim 1, wherein the transfer chamber is substantially rigid and the volume of the transfer chamber is reduced by advancing the sample collection surface through the transfer chamber.

15. The method of claim 1, further comprising mixing, homogenizing, grinding or fracturing the sample within the transfer chamber by at least one of a blade, ultrasound, ridged surface, grinding surface, and vibration.

16. The method of claim 15, further comprising covering the aperture prior to the mixing, homogenizing, grinding or fracturing of the sample.

17. The method of claim 1, further comprising cutting the sample via a blade disposed adjacent to the aperture.

18. The method of claim 1, wherein collecting the sample includes transferring the sample via a needle inserted through the aperture.

19. The method of claim 18, wherein transferring the sample via the needle includes removably securing the needle to the transfer chamber.

20. The method of claim 18, wherein transferring the sample via the needle includes removably securing the transfer chamber.

21. The method of claim 1, wherein collecting the sample includes: collecting the sample; transferring the sample to a temporary container; and transferring the sample to the transfer chamber.

22. The method of claim 21, wherein the transfer chamber includes a pipette.

23. The method of claim 1, wherein the transfer chamber is transparent.

24. The method of claim 1, wherein the transfer chamber includes a hinged lid.

25. The method of claim 1, further comprising disposing a sample storage disk between the sample transfer surface and the aperture prior to the transferring and ejecting a remaining portion of the sample to the sample storage disk after the transferring.

26. The method of claim 1, wherein a size of the aperture is within a range of 0.5 to 6 mm, 2 to 5 mm, 3 to 5 mm, or 3.5 to 4.5 mm.

27. The method of claim 1, further comprising reducing the volume of the transfer chamber to substantially zero.

28. A method of transferring a sample, the method comprising: collecting the sample on a sample collection surface; advancing the sample collection surface towards a sample transfer surface; contacting the sample transfer surface with the sample; and transferring the sample to the sample transfer surface.

29. The method of claim 28, wherein the sample is a fine needle aspirant sample.

30. The method of claim 28, wherein the sample is a semi-solid or solid sample.

31. The method of claim 28, further comprising imaging the sample during the contacting.

32. The method of claim 31, further comprising controlling a distance between the sample collection surface and the sample transfer surface based on the imaging.

33. The method of claim 28, wherein a temperature of the sample collection surface is reduced below freezing prior to the contacting.

34. The method of claim 28, further comprising interposing a mesh between the sample and the sample transfer surface prior to the contacting.

35. The method of claim 28, further comprising removing excess sample from the sample transfer surface by at least one of a wipe, a string, a pinching device, a scraper, a scraping edge, and / or a blade.

36. The method of claim 28, further comprising removing excess sample from the sample transfer surface by: contacting the excess sample with a reduced temperature surface having a below freezing temperature to cause the excess sample to stick to the reduced temperature surface, and separating the reduced temperature surface from the sample transfer surface.

37. The method of claim 36, wherein the temperature of the reduced temperature surface is between -1 C and -IO C.

38. The method of claim 28, further comprising removing excess sample from the sample transfer surface by two scrapers, wherein each scraper includes a scraping edge and a pair of spacers, the pair of spacers being configured to maintain a fixed distance between the sample transfer surface and the scraping edge.

39. The method of claim 28, further comprising further comprising removing excess sample from the sample transfer surface by two scrapers, wherein the two scrapers are advanced relative to one another until touching, then the two scrapers are moved away from the sample transfer surface.

40. The method of claim 28, wherein contacting the sample transfer surface is performed by halting advancement of the sample collection surface to the sample transfer surface when a threshold displacement is reached.

41. The method of claim 28, wherein contacting the sample transfer surface is performed by halting advancement of the sample collection surface to the sample transfer surface when a threshold force is reached.

42. The method of claim 28, further comprising storing the collection surface in a storage container with a preservative fluid.

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