Tissue processing tools and methods of using such tools

Abstract

Devices and systems for processing tissue samples are described. In some instances, the disclosed devices may comprise: (i) a first cassette comprising an array of blades oriented in a first direction and configured to cut a tissue sample placed on a tissue plate into a plurality of smaller tissue samples, at least one blade oriented in a second direction and configured to cut said plurality of smaller tissue samples into smaller tissue fragments, and an array of pins oriented in the first direction and configured for addressable ejection of tissue fragments from openings in the array of blades into a container; and (ii) a second cassette comprising: a plurality of containers, the containers of the plurality being configured to be selectively positioned to receive tissue fragments from a selected region of the tissue plate. The disclosed systems can be configured to actuate the cassettes and collect images of the tissue.

Description

Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40TISSUE PROCESSING TOOLS AND METHODS OF USING SUCH TOOLSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 691,256, filed September 5, 2024, and U.S. Provisional Patent Application No. 63 / 742,289, filed January 6, 2025, each which is hereby incorporated by reference in its entirety.FIELD

[0002] The present disclosure relates to a device and a method used to excise cellular tissue in smaller sections and to store the fragments into multiple containers for storage and transportation.BACKGROUND

[0003] Currently, when a tumor is removed from a patient, the tumor may need to be cut into smaller fragments for analysis by a pathologist. For example, in Tumor Infiltrating Lymphocytes (TILs) treatments, the tumor is excised into smaller pieces to be processed per the treatment protocol. Usually these are cut manually in roughly 2x2x2mm cubic fragments during a tedious process by skilled operators.

[0004] Thus, what is desired in the art are devices and systems that can automate the process of cutting the tumor or cell tissue in smaller fragments, making it more consistent, while collecting images (e.g., via microscopy) and data for tissue selection and pathologist analysis.BRIEF SUMMARY

[0005] Devices and systems that can automate the process of cutting tissue samples (e.g., tumor or cell tissue samples) into smaller fragments are described. The disclosed devices and systems provide more consistent tissue sample processing, while enabling the collection of images (e.g., via fluorescence and / or hyperspectral imaging microscopy) and data for tissue selection and pathologist analysis.

[0006] Disclosed herein are devices for processing tissue samples comprising: a first cassette, the first cassette comprising: an array of blades oriented in a first direction and configured to cut a tissue sample placed on a tissue plate into a plurality of smaller tissue1MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 samples; at least one blade oriented in a second direction that is orthogonal to the first direction, and configured to move transversely to the first direction to cut said plurality of smaller tissue samples into a plurality of smaller tissue fragments; and an array of pins oriented in the first direction and disposed on or within the first cassette, each pin in the array corresponding to an opening formed by the array of blades oriented in the first direction, the array of pins being configured for addressable ejection of tissue fragments from openings in the array of blades oriented in the first direction into a container; and a second cassette, the second cassette comprising: a plurality of containers, the containers of the plurality being configured to be selectively positioned to receive tissue fragments from a selected region of the tissue plate.

[0007] In some embodiments, the first cassette and second cassette are configured to be removably coupled together. In some embodiments, the first cassette further comprises mating features for alignment and secure connection of the first cassette to the second cassette.

[0008] In some embodiments, the array of blades oriented in the first direction are arranged in a square or rectangular structure to form substantially square or rectangular opening for receiving tissue fragments. In some embodiments, the array of blades oriented in the first direction are arranged in a honeycomb-like structure to form substantially hexagonal openings for receiving tissue fragments.

[0009] In some embodiments, the at least one blade oriented in the second direction comprises a plurality of parallel blades oriented in the second direction. In some embodiments, the at least one blade oriented in the second direction is spring-loaded and cuts the plurality of smaller tissue samples into smaller tissue fragments when a locking mechanism is released.

[0010] In some embodiments, the tissue plate is mounted in the second cassette. In some embodiments, the cutting of the tissue sample by the array of blades oriented in the first direction occurs when the first cassette is pressed onto the second cassette.

[0011] In some embodiments, the tissue plate is mounted on an end of a plunger. In some embodiments, cutting of the tissue sample by the array of blades oriented in the first direction occurs when the plunger is used to press the tissue sample against the array of blades oriented in the first direction.2MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0012] In some embodiments, at least a portion of each container of the plurality of containers is optically transparent to allow monitoring of the tissue fragments. In some embodiments, a first planar wall and / or an opposing second planar wall of each container of the plurality of containers is optically transparent.

[0013] In some embodiments, the containers of the plurality of containers are preloaded with fluids or media for preservation or processing of the tissue fragments.

[0014] In some embodiments, the device is configured to be sterilized. In some embodiments, the device is configured for single-use. In some embodiments, the device is configured for reuse by separating multi-use and disposable components.

[0015] Also disclosed herein are systems for processing tissue samples comprising: a device comprising: a first cassette, the first cassette comprising: an array of blades oriented in the first direction and configured to cut a tissue sample placed on a tissue plate into a plurality of smaller tissue samples; at least one blade oriented in a second direction that is orthogonal to the first direction, and configured to move transversely to the first direction to cut said plurality of smaller tissue samples into a plurality of smaller tissue fragments; and an array of pins oriented in the first direction and disposed on or within the first cassette, each pin in the array corresponding to an opening formed by the array of blades oriented in the first direction, the array of pins being configured for addressable ejection of tissue fragments from openings in the array of blades oriented in the first direction into a container; and a second cassette, the second cassette comprising: a plurality of containers, the containers of the plurality being configured to be selectively positioned to receive tissue fragments from a selected region of the tissue plate; a first actuator configured to selectively actuate pins in the array of pins to eject tissue fragments from selected regions of the tissue plate; a second actuator configured to selectively position containers of the plurality of containers to collect tissue fragments from selected regions of the tissue plate; and a user interface configured to allow a user to select the regions of the tissue plate for which tissue fragments will be ejected and / or to select containers in which ejected tissue fragments will be collected.

[0016] In some embodiments, the system further comprises a third actuator configured to press the first cassette onto the second cassette to thereby cut a tissue sample placed on the tissue plate. In some embodiments, the third actuator comprises a clamping mechanism that mates with a component of the first cassette or the second cassette.3MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0017] In some embodiments, the system further comprises a third actuator configured to press a plunger comprising the tissue plate against the array of blades oriented in the first direction to thereby cut a tissue sample placed on the tissue plate.

[0018] In some embodiments, the system further comprises a fourth actuator configured to move the tissue plate in the first direction.

[0019] In some embodiments, the first actuator and / or the second actuator comprises a robotic arm. In some embodiments, the first actuator and / or the second actuator is operable remotely.

[0020] In some embodiments, the system further comprises at least one sensor configured to detect a position of the at least one blade oriented in the second direction. In some embodiments, the system further comprises at least one sensor configured to detect a position of a container of the plurality of containers.

[0021] In some embodiments, the system further comprises an imaging system configured to capture images of the tissue sample before, during, or after being cut into smaller tissue fragments. In some embodiments, the imaging system comprises at least one light source, at least one image sensor, and magnifying optics. In some embodiments, the imaging system is a fluorescence imaging system or a hyperspectral imaging system.

[0022] In some embodiments, the user interface is configured to allow a user to set up the system, command execution of tissue sample processing tasks, review images and data collected during tissue sample processing, and / or document results and record control functions.

[0023] In some embodiments, all or a portion of the system is mounted on or within a cart for mobility. In some embodiments, the system is configured for use in an operating room, a remote location, or a manufacturing facility.

[0024] Disclosed herein are methods for processing tissue samples, the methods comprising: placing a tissue sample on a tissue plate, wherein the tissue plate is a component of a second cassette of a device configured for processing tissue samples; aligning a first cassette of the tissue processing device above the tissue plate of the second cassette, wherein the first cassette comprises an array of blades oriented in a first direction; compressing the4MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 first cassette and second cassette together to cut the tissue sample into a plurality of smaller tissue samples; actuating at least one blade oriented in a second direction that is orthogonal to the first direction and disposed within the first cassette to further cut the plurality of smaller tissue samples into a plurality of smaller tissue fragments; selectively activating pins of an array of pins disposed on or within the first cassette to eject selected tissue fragments from openings in the array of blades oriented in the first direction; and collecting the ejected tissue fragments into a selected container of a plurality of containers housed within the second cassette.

[0025] Also disclosed herein are methods for processing tissue samples, the methods comprising: placing a tissue sample on a tissue plate, wherein the tissue plate is a component of a plunger; pressing the tissue sample against an array of blades oriented in a first direction and disposed within a first cassette of a tissue processing device; aligning and connecting the first cassette of the tissue processing device to a second cassette of the tissue processing device; actuating at least one blade oriented in a second direction that is orthogonal to the first direction and disposed within the first cassette to further cut the plurality of smaller tissue samples into a plurality of smaller fragments; selectively activating pins of an array of pins disposed on or within the first cassette to eject selected tissue fragments from openings in the array of blades oriented in the first direction; and collecting the ejected tissue fragments into a selected container of a plurality of containers housed within the second cassette.

[0026] In some embodiments, the method further comprises imaging the tissue sample and / or tissue fragments before, during, and / or after cutting the tissue sample into a plurality of smaller fragments.

[0027] In some embodiments, the selective activation of pins to eject selected tissue fragments from opening in the array of blades oriented in the first direction is based on the imaging of the tissue sample and / or tissue fragments before, during, and / or after cutting the tissue sample into the plurality of smaller fragments. In some embodiments, the selective activation of pins to eject selected tissue fragments from opening in the array of blades oriented in the first direction is based on one or more other user- specified criteria.

[0028] In some embodiments, the method further comprises retrieving one or more containers of the plurality of containers for storage and / or transportation of tissue fragments.5MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0029] In some embodiments, the method further comprises transferring the contents of one or more containers of the plurality of containers into one or more bioreactors.

[0030] In some embodiments, the method is performed remotely without requiring a skilled surgeon or pathologist to be present.DESCRIPTION OF THE FIGURES

[0031] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0032] FIGS. 1 and 2 show exemplary devices that have two main parts: a first (e.g., top) cassette and a second (e.g., bottom) cassette.

[0033] FIG. 3 shows a bottom view of the first (e.g., top) cassette without the bottom lid.

[0034] FIG. 4 show a detailed view of first direction (e.g., vertical) blades, which are composed of multiple layers of thin blades, shaped to create small pockets, like in a honeycomb structure.

[0035] FIGS. 5a and 5b show the same view as in FIG. 3, but after the second direction (e.g., horizontal) blades have been released.

[0036] FIG. 6 shows the first direction (e.g., vertical) pins placed in the first (e.g., top) cassette, which are then pressed down to remove the fragments and drop them into the second (e.g., bottom) cassette.

[0037] FIG. 7 shows the second (e.g., bottom) cassette without the top lid.

[0038] FIG. 8 shows a cross section of the second (e.g., bottom) cassette without the top lid.

[0039] FIG. 9 shows a cross section of the second (e.g., bottom) cassette sectioning through a container.

[0040] FIG. 10a shows an alternative embodiment of the second (e.g., bottom) cassette, also in cross section in FIG. 10b and in a bottom view without the bottom lid in FIG. 10c.6MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0041] FIG.11 shows an alternative embodiment of the first (e.g., top) cassette in which the blades stop is allowed to slide on the sliding rails with bushings or sliding bearings.

[0042] FIGS. 12a and 12b show an embodiment of the selection device that collects data and images, actuates the pins in the first (e.g., top) cassette and actuates the central body in the second (e.g., bottom) cassette.

[0043] FIG. 13 shows a detailed view of the selection device’s main components.

[0044] FIG. 14 shows a detailed view of the nest and intermediate tray.

[0045] FIG. 15 shows a detailed view of the arm.

[0046] FIGS. 16a and 16b show an alternative embodiment with a table top version of the arm 600 in which a rigid arm is moved along the top XY plane of the cassette, in X and Y directions, with two stages linear motion systems housed in the base.

[0047] FIG. 17 shows an embodiment of the optional draping system with drape for the arm and for the tray and cart top area.

[0048] FIG. 18 shows a flowchart of the method described herein, with the additional step of transferring the cells collected in the cassette to a manufacturing facility.

[0049] FIG. 19 shows an alternative embodiment of the first (e.g., top) cassette where an external handle 186 is attached to the second direction (e.g., horizontal) blade carrier.

[0050] FIG. 20 shows the same embodiment as in FIG. 19, in a cross section without the bottom lid, showing how the external handle can be used as a release mechanism for the second direction (e.g., horizontal) blades to cut the tissue under the preload of the springs.

[0051] FIG. 21 shows an embodiment of the cart, with the top plate sectioned to show the inside of the cart, in which the imaging and sensing system is housed.

[0052] FIG. 22 shows an embodiment of the cassette modified to allow an imaging system positioned in the cart to reach the specimen on the tissue plate.

[0053] FIG. 23a shows a simplified second (e.g., bottom) cassette embodiment in which the tissue plate is not present. FIG. 23b-e show embodiments of the plunger that can be used to push the tissue, either manually or robotically, in the first direction (e.g., vertical) blades.7MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0054] FIG. 24 shows an embodiment of the cart with a second nest where the first (e.g., top) cassette 100 can be loaded with the first direction (e.g., vertical) blades positioned to receive the tissue specimen.

[0055] FIG. 25a shows a simplified view of an alternative embodiment of the first (e.g., top) cassette with the first (e.g., top) cassette case sectioned.

[0056] FIG. 25b shows a combination of the cassettes shown in FIGS. 23a and 25a.

[0057] FIG. 26 shows a flowchart of an exemplary method described herein.

[0058] FIG. 27 shows the cross section of a simplified top and second (e.g., bottom) cassette assembly as an alternative embodiment where the wiper blade retraction is achieved by translation instead of rotation.

[0059] FIG. 28 shows another alternative embodiment of the cart, in which the robotic arm is replaced with a closed system, which contains the actuation, such as X, Y, Z linear stages similar to what described before, and the sensing / imaging system

[0060] FIG. 29 provides a schematic illustration of a computer system, in accordance with some embodiments of the present disclosure.

[0061] FIG. 30 provides a non-limiting example of a photograph of a prototype tissue processing device, in accordance with some embodiments of the present disclosure.

[0062] FIG. 31 provides a non-limiting example of a photograph of a robotic arm configured to actuate the pins in a prototype tissue processing device, in accordance with some embodiments of the present disclosure.

[0063] FIG. 32 provides a non-limiting example of a photograph of tissue fragments prepared using the prototype tissue processing device shown in FIG. 30.DETAILED DESCRIPTION

[0064] The following description sets forth exemplary devices, systems, methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. Throughout the present disclosure, the phrases “first direction” (e.g.. “vertical”) and “second direction” (e.g., “horizontal”) are used to indicate a8MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 first direction and a second direction that are orthogonal to each other without intending to imply a preferred orientation. Similarly, the phrases “first cassette” (or “top cassette”) and “second cassette” (or “bottom cassette”) are used to indicate two components of the disclosed tissue processing device without intending to imply a preferred orientation.

[0065] The devices and systems described herein automate the process of cutting the tumor or cell tissue in smaller parts, making it more consistent, while collecting images, like microscopy, and data for tissue selection and pathologist analysis, something unprecedented and hardly possible with current technologies. It allows the doctor to also separate the excised fragments in different containers based on images, location or other criteria. It can be operated remotely without requiring a skilled surgeon or pathologist to be present at the same time the tissue is excised, in the operating room for example, increasing patient access in remote areas and simplifying surgeons scheduling, or in manufacturing facilities.

[0066] FIGS. 1 and 2 show an embodiment of the device composed of two main parts, the first (e.g., top) cassette 100 and the second (e.g., bottom) cassette 200. Both can be single use or designed to be easily reprocessed, for example by separating multi-use parts from disposable plastics parts. They can be sterilized using common methods, like electron-beam, gamma radiation, EtO, autoclave or other methods, and stored inside sterile pouches until ready to be used and placed in the sterile field in the operating room.

[0067] During the surgery, the removed cellular tissue is placed on the tissue plate 210 and compressed between the top and second (e.g., bottom) cassette. An optional plunger can be used to press the tissue in place. The top and second (e.g., bottom) cassette have mating features, respectively 120 and 220, that securely connect the two together and support the forces needed to cut the tissue. These also serve as centering guiding features, using ramps, chamfers, pins and slots, or similar alignment features to locate the first direction (e.g., vertical) blades 130 on top of the tissue plate 210. By pressing the first (e.g., top) cassette on the second (e.g., bottom) cassette the tissue is then cut into multiple pieces. The alignment between the first direction (e.g., vertical) blades 130 and the tissue plate 120 can be such that the former is preloaded against the latter when the two cassettes are engaged. This can be achieved by compression of the first direction (e.g., vertical) blades against the tissue plate, or with an additional preload element, like a spring or elastically deformed element.9MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0068] The first (e.g., top) cassette can be equipped with a lever, over-center latch or clamping mechanism in order to apply the force needed for the first direction (e.g., vertical) blades to cut the tissue. This can be actuated, robotic or manual, and include self-centering and self-aligning features as described for other features. In this embodiment, the clamping mechanism 110 engages with mating features 250 in order to secure and preload the first (e.g., top) cassette against the second (e.g., bottom) cassette. The tissue plate 210 can be flat, concave or with edges to contain the tissue while it is being cut, with the first (e.g., top) cassette’s first direction (e.g., vertical) blades 130 shaped to have negative matching features.

[0069] FIG. 4 shows a detailed view of the first direction (e.g., vertical) blades 130, which are composed of multiple layers of thin blades, shaped to create small pockets, like in an honeycomb structure. In this embodiment, this is created by bending the blade 135 into an S-shaped or waving pattern. By spot-welding or otherwise connecting or stacking many identical blades, phased, mirrored or placed opposite to each other, the blades create the close-to-round pockets. When the first (e.g., top) cassette is pressed onto the second (e.g., bottom) cassette, the cell tissue is excised into small columns that fill these pockets. The first direction (e.g., vertical) blades are secured in place by the structure 175 connected to the first (e.g., top) cassette case 102.

[0070] FIG. 3 shows a bottom view of the first (e.g., top) cassette 100 without the bottom lid 106. After the cell tissue is placed on the tissue plate, the first (e.g., top) cassette and second (e.g., bottom) cassettes are secured, and the first direction (e.g., vertical) blades cut the tissue into small columns, the second direction (e.g., horizontal) blades 140 cut these columns into small cubic-shaped fragments. The second direction (e.g., horizontal) blades 140 are multiple blades mounted in the first (e.g., top) cassette on a carrier 180. The carrier can move longitudinally by sliding on rails 150 with bushing 151, and preloaded with springs 152 or similar mechanisms. A locking mechanism 160 maintains the second direction (e.g., horizontal) blades in the loaded position. This can be an over-center lock, a bistable mechanism, lever or other locking mechanism that can be disengaged by the user or by an external device. In this embodiment, by pressing the button 161, the user can release the lock and let springs recoil, driving the second direction (e.g., horizontal) blades to cut through the tissue in the honeycomb in the second (e.g., horizontal) direction. This is made possible by the pockets 136 which are cut longitudinally in the first direction (e.g., vertical) blades allowing the second direction (e.g., horizontal) blades to pass through. These pockets 136 are10MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 windows cut through the center of the blades only in the section where the second direction (e.g., horizontal) blades travel. This leaves the sides of the first direction (e.g., vertical) blades solid, ensuring solidity and stability of the first direction (e.g., vertical) blades assembly. Similar pockets 176 in the structure 175 allow the second direction (e.g., horizontal) blades to slide while guiding and restraining them. Locating features between the structure 175 and the first direction (e.g., vertical) blades 130 ensure that the pockets 136 and 176 are aligned within tolerance to ensure clearance for the second direction (e.g., horizontal) blades to slide freely.

[0071] The second direction (e.g., horizontal) blades are shaped in a way to enhance the cutting capabilities, using a guillotine profile for example, and have an opening 142 that leaves the honeycomb clear in the first (e.g., vertical) direction after the cut.

[0072] FIGS. 5a and 5b show the same view as in FIG. 3 but after the second direction (e.g., horizontal) blades have been released. Once the springs have recoiled, and the second direction (e.g., horizontal) blades have completed the cut, the second direction (e.g., horizontal) blades rest against the blades stop 170, which also serves as a location feature to ensure that the second direction (e.g., horizontal) blades have completed the cut and cleared the space occupied by the tissue. An additional sensor can be used to verify that the second direction (e.g., horizontal) blades have completed the travel. The blades stop 170 or the second direction (e.g., horizontal) blades carrier 180 can have a pressure or contact switch or a probe for an external sensor, such as a non-contact presence sensor, a capacitive sensor, a photoelectric sensor to ensure the blades are seated. In this embodiment, the second direction (e.g., horizontal) blades carrier 180 is equipped with a small metal piece or magnet that can be detected by a sensor, like a Hall effect sensor, placed externally in the selection device, described later. This allows a non-contact sensor to detect the status of the blades, keeping the cassette completely passive with no electronics.

[0073] Once the second direction (e.g., horizontal) blades have cut through the tissue, the tissue fragments are captured in the honeycomb structure of the first direction (e.g., vertical) blades.

[0074] FIG. 6 shows the first direction (e.g., vertical) pins 190 placed in the first (e.g., top) cassette, which are then pressed down to remove the fragments and drop them into the second (e.g., bottom) cassette. This action is performed by the Selection device, described11MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 later. Because there is one pin for each honeycomb cavity, the device offers fine control over which pin to depress, allowing the user to select even small areas to be collected separately from others.

[0075] The pins are housed in the housing 104 which holds them in place until they get pressed into the honeycomb by an external force. It allows the pins only to slide down when an external force is applied. The drape 192 can be used as an extra measure to prevent contamination during use, and it is attached to anchor features 103 on the case 102. These can be grooves in which one or more gaskets or elastic bands part of the drapes can fit, double adhesive tape, bonding or other retention means.

[0076] Next, in order to collect the fragments which are pushed out by the pins, the second (e.g., bottom) cassette 200 is equipped with containers 231 which collects the fragments. FIG. 7 shows the second (e.g., bottom) cassette without the top lid 202, while FIG.8 shows a cross section of the same. Multiple containers are housed in the second (e.g., bottom) cassette and can be preloaded with media or other fluids. Each container can be moved, rotated or translated in place of the tissue plate 210 in order to collect fragments from individually selected pins, corresponding to specific areas in the tissue. In this embodiment, the containers 231 are selected by rotating the central body 230. The tissue plate 210 is also mounted on the central body 230 and it is allowed to move up and down while the central body rotates. This allows the tissue plate to be exposed and elevated when used to hold the tissue before cutting, while moving underneath the second (e.g., bottom) cassette top lid 202 when the central body rotates to expose a container. This can be achieved by a first direction (e.g., vertical) preload, a cam mechanism or other mechanisms that constrain the movement of the tissue plate relative to the central body except for the motion in the first (e.g., vertical) direction. In this embodiment that is achieved via the 4-bar linkage 215 that connects the tissue plate to the container body. A ramp 208 on the bottom lid controls the first direction (e.g., vertical) movement of the tissue plate as it rotates, and ramps or chamfers 211 on the tissue plate 210, and 203 on the top opening 205, facilitate the movement of the tissue plate as it moves out of the opening and under the top lid 202. A preload, such as a torsional or linear spring, can be used to ensure that the tissue plate stays on the bottom or top lid. The round bottom part 212 of the tissue plate also facilitates it sliding on the bottom lid.

[0077] In an alternative embodiment, the tissue plate is rigidly attached to the central body and placed under the top lid 202. In this case, the first direction (e.g., vertical) blades12MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40130 protrude out of the first (e.g., top) cassette to match and preload against the tissue plate. A similar round bottom part 212 can still be used to transfer the load, and ramps 208 can be used to preload the tissue plate against the top lid only when needed. This preload would also allow sensing the central body position and would signal to the Selection device that the tissue plate is in place by measuring the current during the rotation.

[0078] The central body is equipped with mating features 232 at the bottom which mates with an actuator of the selection device, or tray, described later. A bearing and rotating seal 238 supports and constraints the central body in the rotation along the rotation axis. Flanges, rings, grooves, and other common features for a rotary coupling are not shown.

[0079] The touchless sensor probe 209 can be read by an external sensor to verify the position of the central body. This can be a metal piece or magnet that can be read by an external Hall effect sensor.

[0080] FIG. 9 shows a cross section of the second (e.g., bottom) cassette sectioning through a container 231. The containers 231 are equipped with connectors 233 that reach to the bottom of the container with a cannula 234. These can be used to retrieve the liquid and the cells. A connector 239 and an air filter 235 allows filtered air to enter the containers, via conduits 236. By having this air at a higher pressure than the pressure in the cannula and connectors, the container can be emptied and the cells harvested. The top of the containers is sealed against the top lid 202 with a sliding seal 237. The cells can also be harvested from the opening 205 in the top lid with standard means such as liquid handlers or pipettes.

[0081] Openings 204 in the bottom lid 206 allow reaching the connectors 233 with an external consumable, such as a manifold cassette, or capital equipment, with mating connectors. The fluid connectors described here and below can be standard fluid connectors, such as luer-lock, push-pull, needle-free or other aseptic connect / disconnect connectors.Connectors 233 may be designed with a minimum section large enough to allow the fragment of cell tissue to be flushed through.

[0082] The bottom lid 206, and the containers 231, or alternatively the top lid 202, can be made of optically transparent plastic to allow a camera, vision system or other sensors to monitor the cells in the containers during the part of the process that may be executed while the cells are in the containers 231.13MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0083] FIG. 10a shows an alternative embodiment of the second (e.g., bottom) cassette 200, also in cross section in Fig.lO.b and in a bottom view without the bottom lid in FIG. 10c. In this embodiment the tissue plate 210 can be lowered by rotating the slider 240. This has cavities 241 which are slanted, and engage with cams or pins 213 of the tissue plate. By lowering the tissue plate, a cavity is created that forms a container, in which the cells can be housed when pressed out by the pins. Input and output connectors 251 and 252 allow fluid to be inserted and removed, empting the cavity each time. The sliding gasket 214 seals the tissue plate against the cavity 207 of the top lid. The slider 240 is equipped with gear-like mating surfaces 242, which mates with matching surfaces of an actuator, or motor, in the selection device or disposable tray.

[0084] FIG. 11 shows an alternative embodiment of the first (e.g., top) cassette 100 in which the blades stop 170 is allowed to slide on the sliding rails 150 with bushings or sliding bearings 171. In this embodiment, the springs 152 connected to the second direction (e.g., horizontal) blades carrier 180, are anchored to the blades stop 170. The blades stop is also rigidly connected to the first direction (e.g., vertical) blades honeycomb structure. Because the honeycomb structure is anchored to the first (e.g., top) cassette case 102 at anchor points 105, the preload force of springs 152 goes through the first direction (e.g., vertical) blades structure 130, compressing the honeycomb and slightly deforming it. After the tissue has been cut and placed inside the honeycomb structure, the release of the second direction (e.g., horizontal) blades removes the preload and the honeycomb structure returns to its original shape, ovalizing the honeycomb structures. This allows the honeycomb structure to slightly compress the cut tissue and to hold it in place securely until the first direction (e.g., vertical) pins are pressed down.

[0085] FIGS. 12a and 12b show an embodiment of the selection device 300 that collects data and images, actuates the pins in the first (e.g., top) cassette and actuates the central body in the second (e.g., bottom) cassette. In this embodiment, the selection device is mounted on a cart 400 which can be placed next to the surgical bed in an operating room setting. The selection device is composed of a nest 500, an arm 600, and a user interface 700.

[0086] FIG. 13 shows a detailed view of the selection device main components. The nest 500 has mating features 505 that locate and secure the second (e.g., bottom) cassette in place. A single-use, sterile intermediate tray 810 can be used to separate the sterile field, where the sterile cassettes are placed, from the multi-use capital equipment. The intermediate tray 81014MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 is part of the draping system described below. The intermediate tray 810 has the same features and functions of the nest 500 lo locate and secure the second (e.g., bottom) cassette, as well as transmit motion for the actuator 510 using similar mating features.

[0087] FIG. 14 shows a detailed view of the nest 500 and intermediate tray 810. The actuator 510 is the motor or rotary actuator used to rotate the central body or slider in the second (e.g., bottom) cassette and it is digitally controlled by the control Software. It is provided with mating features 515 which engages with corresponding features on the tray 815 or alternatively to the second (e.g., bottom) cassette’s mating features 232. A sealed bearing 511 and the design of the mating features 515 and 505 facilitate cleaning and disinfection of the nest. In this embodiment the nest features are positive protruding features, and the tray or second (e.g., bottom) cassette have matching negative features. The arrangement can also be inverted to facilitate cleaning and disinfection. The nest is equipped with a temperature control system, such as Peltier-plate based on heated / cooled fluid convection based for example, housed in the cart, to maintain the cassettes at the desired temperature. The nest is equipped with touch-less sensors that can verify the state of the cassettes. It includes readers, such as Hall effect sensors, or optical sensors 520, to read the current position of the central body in the second (e.g., bottom) cassette. It also includes presence sensors, such as capacitive sensors or contact switches, RFID readers for traceability and identification in the sensory system 530. The intermediate tray 810 is equipped with centering and mating feature 812 which mate with corresponding features 225 in the second (e.g., bottom) cassette and function as locating features. Similarly to the other mating features used in the system, these can be self-centering features such as ramps, chamfers, snaps or bending elements, round or diamond pins in round or slot holes or other locating elements that facilitate insertion by an automated system and a human operator.

[0088] FIG. 15 shows a detailed view of the arm. The arm 600 is composed of a passive, manually operated or robotic arm 610 and an End effector 620. The End effector houses the actuator 630 that pushes down the pins based on the input selection. This can be a linear motor, such as an electric motor with a lead or ball screw, rack and pinion, a rotary motor with an eccentric cam, links, 4-bar mechanisms or other motion systems. The End effector also houses an optical system 640, which can be composed of multiple sensors, from a simple camera, to a plenoptic or multi- spectral camera, to a microscope. Multiple optics and multiple cameras could be housed in the End effector, which would scale in size accordingly. A 3D15MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 camera or scanner can also be included for 3D reconstruction of the tissue. These images are collected for Quality control reasons, pathology reasons and for training an Al model in recognizing different areas of the tissue. In the case of TILs therapy, the TIL performance from different areas can be used to create a training set with the imaging database. Other sensors included in the End effector can be a camera for position recognition and QR tag scanning, an RFID reader or other sensors used for identification, traceability and Quality control. A dedicated illumination system 650 provides the needed light exposure for each sensor. The round End effector can be mounted on a motor and bearing system 621 to allow it to rotate along its axis, relative to the robot wrist. Some or all of the arm joints 612, 614, 616 can also be actuated, with rotary motors or in combination with a linear motion system in the wrist 618. This allows the arm to position the pin actuator 630 in space precisely above the desired pin. Different joint arrangements and kinematics in both the arm and the nest can be used to achieve the same result, see for example FIGS. 16a and 16b.

[0089] The End effector can also be used to preload the containers 231 in the second (e.g., bottom) cassette with media or other fluids to preserve the cells, using for example a fluid line connected to a reservoir in the cart 400. The fluid line can be external or internal to the arm 600 and attached to the end effector, allowing the arm to position it on top of the opening 205 of the second (e.g., bottom) cassette.

[0090] In this embodiment, the cart 400 is equipped with storage space. These can be used for sterile cassettes, housed in sterile pouches, for media or other fluids. The storage space can be temperature controlled for either cold and / or warm environments, in the latter case for maintaining the cassettes at a temperature that does not shock the cells. One or multiple pumps could be included to facilitate controlling fluid dispensing.

[0091] The user interface 700, such a monitor, touchscreen and / or input device, allows the user to set-up the system, commands the execution of tasks, review images, take notes and other common control functions.

[0092] An arm serving button, lever or touch sensor, like a capacitive or resistive sensor, located in the End Effector or wrist, can be used to activate serving mode, or to release the brakes, on the arm joints so that the user can manually position the arm, for cleaning, draping, positioning or other activities.16MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0093] The actuation systems mentioned here are considered including the state of the art components, such as motors, gear reducers, bearings, encoders and control systems. Other systems, such as power, control, computation, communication, thermal management, etc. are included as needed following the state of the art.

[0094] In an alternative embodiment, the imaging system is located inside the cart 400 instead of the End Effector 620. This allows the use of larger and more complex imaging systems, such as microscopes, hyperspectral or multispectral cameras, FTIR spectroscopy systems, low-field MRI or similar scanners, large optics or a combination thereof of these and other sensing systems. These would be pointed from the cart toward the second (e.g., bottom) cassette, and may be moved by a motion system in order to position the imaging system at the correct distance from the specimen. An observation window in the nest 500 and the second (e.g., bottom) cassette lid 206 allow the imaging system to see the tissue and accommodate the needs of the vision system, as further described below.

[0095] FIG. 21 shows an embodiment of the cart, with the top plate of the nest 500 sectioned to show the inside of the cart, in which the imaging and sensing system 420 is housed. The sensing system can be actuated by a motion control system that moves the sensing system 420 at the desired distance from the specimen, and then removes it when the pins are actuated and the current layer of the tissue is distributed to the different containers, as described before. The motion system can be for example a linear motion, such as a ballscrew actuated by an electric brushless DC motor, or other types of linear motion, constrained by a railing system. The cart can also be equipped with a fine adjustment motion system that can move the top plate with the cassettes, and thus the specimen, relative to the imaging system 420 in all directions for getting to the location and fine adjustments. Motion, adjustment, imaging, retraction can be repeated for each layer of the tissue or according to the user commands.

[0096] FIG. 22 shows an embodiment of the cassette modified to allow an imaging system positioned in the cart to reach the specimen on the tissue plate 210. In this embodiment, the tissue plate 210 and its round bottom part 212 are shaped to be hollow and optically transparent. The Bottom lid 206 has an opening or optically transparent area 216 positioned under the tissue plate, or the area corresponding to the specimen. This allows the imaging and sensing system positioned in the cart to reach the specimen to perform the17MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 needed measurements and collect data. The spring loaded 4-bar linkage 215 constraints the motion of the tissue plate as the central body 230 is actuated.

[0097] FIG. 23a shows a simplified second (e.g., bottom) cassette embodiment in which the tissue plate is not present. This allows the imaging system to reach the specimen through a larger opening or optically transparent area 216. The absence of the tissue plate requires a different loading of the tissue specimen in the first (e.g., top) cassette’s blades 130. One method is to place the tissue directly on the blades 130, with the first (e.g., top) cassette placed upside down for example, and to push the tissue, thus cutting it in the first (e.g., vertical) direction, with a plunger 50, as shown in FIG. 23b.

[0098] FIGS. 23c-e show embodiments of the plunger 50 that can be used to push the tissue, either manually or robotically, in the first direction (e.g., vertical) blades 130. The curvature on the plunger head 55 can be chosen as to allow a gentle and gradual pressure on the tissue as the plunger is moved down and rotated, side to side (FIG. 23d) or along its axis (FIG. 23e). If actuated by a robotic or automation system, the plunger can have the surface in contact with the specimen as a disposable part that snaps or connect to the plunger, which is designed to be either draped or sterilized. Presence sensors such as induction, capacitive, Hall-effect, optical sensors or others can be used to detect the relative motion between the first (e.g., top) cassette and the plunger in a safe way. The passive probe would be included in the disposable first (e.g., top) cassette while the active part of the sensors would be included in the capital equipment side of the plunger, mounted on the robotic or automated system.

[0099] FIG. 24 shows an embodiment of the cart with a second nest 550 where the first (e.g., top) cassette 100 can be loaded with the first direction (e.g., vertical) blades 130 positioned to receive the tissue specimen. The plunger 50 presses, manually or robotically, the specimen on the first direction (e.g., vertical) blades, performing the first direction (e.g., vertical) cut. The second (e.g., bottom) cassette 200 is then loaded in the nest 500 and the top cassette with the specimen is secured on top of it. A sterilizable or disposable tray 850 is designed to be secured in the nest 550, it can be part of the draping system, or used to lock the cart drape, similarly to tray 810. Self-centering, guiding, locking and / or snap features 855, similar to those described before, are used also in the second nest, and mate with corresponding features 101 of the first (e.g., top) cassette 100. The imaging and sensing system 640 in the end effector can be used in this case to take images and pathology data of18MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 the specimen in the first (e.g., top) cassette, in combination or alternatively to the imaging and sensory system 420 in the cart.

[0100] FIG. 25a shows a simplified view of an alternative embodiment of the first (e.g., top) cassette with the first (e.g., top) cassette case 102 sectioned. In this embodiment, an additional wiper blade 112 is added at the bottom of the first direction (e.g., vertical) blades 130. The wiper blade 112 is retractable, and allows the specimen to be fully encapsulated in the first (e.g., top) cassette by covering the opening once the specimen has been inserted with the plunger 50. Additionally, the wiper can be used to ensure that all the fragments pushed by the selected pins have been dropped or removed for each selection and for each layer. In addition, the wiper itself can act as second direction (e.g., horizontal) blade, to cut the tissue that the selected pins have pushed forward, replacing the second direction (e.g., horizontal) blades 140. The wiper retraction and motion can be actuated by a motor housed inside the cart, with a motion transmission through the second (e.g., bottom) cassette and interfaces similar to what described for the central body 230 and actuator 510, i.e. mating features 232 and 515. In this embodiment, the wiper rotates around a pivot point 113, such as bushing or bearing, but other motions can be used, such as translational motion or a combination of translational and rotational motion. The wiper can be supported along its travel with sliding supports that encapsulate it during the motion. A groove or recess 116 holds the wiper in its closed state and serves as a hard-stop for the motion as well as a way to wipe out any residue from the wiper blade. The wiper motion can also be aided by a preload and energy storage, such as a spring or elastic element, and a locking mechanism that releases the stored energy, in order to obtain a fast motion, for example to aid cutting. In this embodiment, the first direction (e.g., vertical) blades 130 are composed of straight interlocking blades instead of a honeycomb assembly. This is achieved by having first direction (e.g., vertical) cuts in the blade, for the top half in the y-direction blades, and the bottom half in the x-direction blades. In this way, the linear blades can be nested together perpendicular to each other, forming the square matrix pattern. An extra sheet can be used to wrap around the assembly and secure it in place. The sheet can be closed on itself using standard methods such as welding, bonding, interlocking features, or an external plastic or metal straps.

[0101] FIG. 25b shows a combination of the cassettes shown in FIGS. 23a and 25a, where the wiper actuation is made through the shaft 260 with an actuator in the cart, similar to actuator 510, using mating features as described before.19MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40

[0102] FIG.26 shows a flowchart of the method described so far, with the main steps involved.

[0103] FIG. 27 shows the cross section of a simplified top and second (e.g., bottom) cassette assembly as an alternative embodiment where the wiper blade retraction is achieved by translation instead of rotation. In this embodiment, the wiper blade 112 is supported by a carrier 114 that slides on guide rails 115, mounted on the first (e.g., top) cassette case 102, not shown here to expose the inner components of the cassette. A recess area or groove 116 accepts the wiper blade at the end of the travel to close the first direction (e.g., vertical) blade surface, as described before. Alternatively or in addition to using a rigid blade, a thin wire can also be used, tensioned between the two side supports 115. This wire can also be moved along its axis for increased sawing action. The actuation of the wiper blade assembly can be accomplished manually or robotically. Similar to what shown in FIG. 25b, a shaft from the second (e.g., bottom) cassette can be connected to a motor inside the cart, and rotate a pinion inside the first (e.g., top) cassette which in turns actuate a rack gear attached to the carrier 114. Other types of linear actuation methods can be used, such as lead screw for example, commonly known in the state of the art.

[0104] FIGS. 16a and 16b show an alternative embodiment with a table top version of the arm 600 in which a rigid arm 606 is moved along the top XY plane of the cassette, in X and Y directions, with two stages linear motion systems 608 and 609 housed in the base 410. These can be standard linear systems, such as belt driven systems, lead or ball screw motors. The Z motion is the direction of the pin actuator 630 and can be limited to the linear actuator 630 or included in the base for the arm 609. An End effector 620 similar to what described before is at the distal end of the arm. In a similar fashion, the robot arm could be stationary, and the nest 500 with the cassettes could be moving in space relative to it. This would be beneficial especially if the End effector includes large or heavy sensory systems, such as microscopes or other heavy vision systems.

[0105] With reference again to FIG. 1, the locating features 201 in the second (e.g., bottom) cassette is shown, which are used by an automated system to move the cassettes, individually or assembled together, in a manufacturing facility. These features are locating the cassette on the manufacturing robot gripper, or lab automation system, not shown here, and facilitating grasping by having self-centering features mentioned before, such as ramps, chamfers, pins, pockets and similar features. The locating features 201 present positive20MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 engagement features which mate with the robotic gripper, not shown here, to ensure that they can stay in place under gravity, i.e. in case of power loss of the gripper.

[0106] Both the top and second (e.g., bottom) cassette are equipped with these features, as well as labels and QR tags for traceability and to facilitate locating them with a visual system.

[0107] FIG. 17 shows an embodiment of the optional draping system 800 with drape 860 for the arm and 820 for the tray and cart top area. Other drapes for other parts of the system are not shown. Drape 860 is formed by the drape 865 which is attached, with bonding, tape or other means, to the End effector interface plate 864. This connects to the End effector via standard means such as plastic snaps, elastic elements, fasteners, tape, magnets or others. The drape 865 covers the arm while allowing joint motion. Drape 820 is formed by drape 825 and the tray 810 and covers the top of the cart 400. These two components can be bond together or assembled during use, with the tray 810 trapping the drape 820 in the nest 500. Drapes are joined, and attached to the system, using standard methods such as tape, magnets, plastic snaps, or other anchoring systems. Features like pockets and other usability features of the drapes are not shown here.

[0108] FIG. 18 shows a flowchart of the method described so far, with the additional step of transferring the cells collected in the cassette to a manufacturing facility, such as an automated lab, where the cells can be manually or automatically processed in the containers, or extracted from the containers in the second (e.g., bottom) cassette and moved to multiple bioreactors, or in different compartments in the same bioreactor, for expansion and subsequent processing such as testing, activation, editing or other cell-related processes.

[0109] FIG. 19 shows an alternative embodiment of the first (e.g., top) cassette 100 where an external handle 186 is attached to the second direction (e.g., horizontal) blade carrier 180. In this way, the actuation of the second direction (e.g., horizontal) blades can be repeated or controlled by the operator or an external actuation system. A seal and bushing 108 allows the handle to slide in and out of the cassette.

[0110] FIG. 20 shows the same embodiment in a cross section without the bottom lid, showing how the external handle can be used as a release mechanism for the second direction (e.g., horizontal) blades to cut the tissue under the preload of the springs 152. In this embodiment, the external handle is connected to a bayonet lock 189, which has a mating cut-21MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 out 109 in the cassette case. The bayonet lock 189 is attached to the second direction (e.g., horizontal) blades carrier 180, so that only the rotation along the handle axis is allowed.

[0111] By rotating the bayonet lock via the external handle, the lock 189 and thus the handle and the second direction (e.g., horizontal) blades can be aligned with the cut-out 109 and slide through in order to cut the tissue. Once the spring recoil is completed, the top part 187 of the handle remains external, allowing the operator to reload the second direction (e.g., horizontal) blades, and repeat the operation or remove them for servicing purposes. Similar locks can be used instead of the bayonet lock, such as an oval, eccentric or other profiles. Ramps and hard stops can be used to facilitate the operation of the external handle.

[0112] FIG. 28 shows another alternative embodiment of the cart 400, in which the robotic arm is replaced with a closed system 680 which contains the actuation, such as X, Y, Z linear stages similar to what described before, and the sensing / imaging system. A door 490 can be used to fully close the system, for example when used in a manufacturing facility. This allows the system to be more easily cleaned, and to house a large imaging and sensing system as required by the application, as described before. A user interface 700 completes the system.

[0113] Polymeric materials: The disclosed tissue processing devices may be fabricated from any of a variety of materials (or combinations thereof) known to those of skill in the art including, but not limited to, glass (e.g., borosilicate glass, soda lime glass, etc.), fused silica (quartz), polymer (e.g., polystyrene (PS), tissue culture-treated polystyrene (TCPS), macroporous polystyrene (MPPS), polymethylmethacrylate (PMMA), polycarbonate (PC), polypropylene (PP), polyethylene (PE), high density polyethylene (HDPE), cyclic olefin polymers (COP), cyclic olefin copolymers (COC), polyethylene terephthalate (PET), polydimethylsiloxane (PDMS), etc.), polyetherimide (PEI) and perfluoroelastomer (FFKM) as more chemically inert alternatives, or any combination thereof. FFKM is also known as Kalrez.

[0114] Fabrication techniques: The disclosed tissue processing devices may be fabricated using any of a variety of techniques (or combinations thereof) known to those of skill in the art, where the choice of fabrication technique is often dependent on the choice of material used, and vice versa. Examples of suitable fabrication techniques include, but are not limited to, injection molding, casting, extrusion, drawing, precision computer numerical22MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 control (CNC) machining and boring, laser photoablation, micro-molding, embossing, 3D- printing, thermal bonding, ultrasonic welding, adhesive bonding, anodic bonding, and the like.

[0115] Optical sensing and / or imaging modules: The disclosed tissue processing systems may comprise optical sensing and / or imaging instrumentation (e.g., bright- field imaging, fluorescence imaging, hyperspectral imaging, etc.). In some instances, the optical sensing and / or imaging instrumentation may comprise one or more light sources, one or more objective lenses, one or more image sensors or cameras, one or more processors or controllers, one or more additional optical components (e.g., lenses, mirrors, prisms, beamsplitters, optical filters, colored glass filters, narrowband interference filters, broadband interference filters, dichroic reflectors, diffraction gratings, apertures, shutters, optical fibers, optical waveguides, acousto-optic modulators, auto-focus sub-systems, and the like), or any combination thereof. In some instances, the optical sensing and / or imaging instrumentation may comprise a focus mechanism, e.g., an autofocus mechanism. In some instances, the optical sensing and / or imaging instrumentation may be configured to perform multichannel imaging, e.g., multichannel fluorescence imaging comprising the use of excitation light at one or more excitation wavelengths, and imaging the emitted fluorescence at two or more different emission wavelengths. In some instances, the optical sensing may comprise a laser emitter and fiber optics sensors, fiber optics grating or other laser-based measuring systems.

[0116] Any of a variety of image sensors may be used for imaging purposes, including but not limited to, photodiode arrays, charge-coupled device (CCD) sensors or cameras, short-wavelength infrared (SWIR) cameras, Indium Gallium Arsenide (InGaAs) sensors, complementary metal-oxide-semiconductor (CMOS) image sensors or cameras, or negativechannel metal-oxide semiconductor (NMOS) image sensors or cameras. Imaging sensors may be one-dimensional (linear) or two-dimensional array sensors. Imaging sensors may be monochrome image sensors (z.e., configured to capture greyscale images) or color image sensors (z.e., configured to capture RGB or color images). In some instances, the imaging sensors or cameras incorporated into the disclosed systems may be designed for acquiring images in the 400 - 1700 nm spectral range (e.g., from the short wave limit of visible light to infrared light), or any sub-range thereof.

[0117] The image sensor may be used to capture a single image or a series of images (e.g., a single image, a series of single images, or video data) of the sample or object plane.23MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40The series of images may comprise images (or video frames) that correspond to images captured before, during, and / or after an event, for example before, during, and / or after [[addition of a reagent to a sample]]. The series of images may comprise at least 1 image, at least 2 images, at least 3 images, at least 4 images, at least 5 images, at least 10 images, at least 20 images, at least 30 images, at least 40 images, at least 50 images, at least 100 images, at least 200 images, at least 300 images, at least 400 images, at least 500 images, at least 1000 images, at least 2000 images, at least 3000 images, at least 4000 images, at least 5000 images, at least 10,000 images, or more.

[0118] The image sensor may capture the series of image frames at a predefined capture or image acquisition rate. For example, the image acquisition rate may range from about 0.01 frames per second to about 1000 frames per second.

[0119] Image sensors may vary in terms of pixel size and pixel count. The image resolution may depend on the pixel size and pixel count. Image sensors may have a pixel count of about or more than 0.5 mega pixels, 1 mega pixels, 4 mega pixels, 10 mega pixels, 20 mega pixels, 50 mega pixels, 80 mega pixels, 100 mega pixels, 200 mega pixels, 500 mega pixels, or 1000 mega pixels. The pixel size corresponding to the image sensor may be about or less than 5 microns, 3.5 microns, 2 microns, 1 micron, 0.5 microns, or 0.1 micron.

[0120] System control module: The disclosed tissue processing systems may comprise one or more system control modules (or system controllers) configured to synchronize and control data communication between other functional units of the system, e.g., one or more optical sensing and / or imaging modules, one or more fluidics modules, one or more temperature control modules, one or more motion control modules, or any combination thereof. In some instances, a system control module may comprise one or more processors, one or more power supplies, one or more wired and / or wireless data communication interfaces, one or more memory storage devices, one or more user interface devices, or any combination thereof. In some instances, the system control function may be provided by an external computer or computer system. In some instances, the one or more system control modules may interface with one or more external computers or computer systems.

[0121] System control software: In some instances, the disclosed tissue processing systems may comprise a computer (or processor) and computer-readable media that includes code for providing a user interface as well as manual, semi-automated, or fully-automated24MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 control of all system functions and subsystems, e.g. control of the pin array for ejection of tissue fragments into collection containers, control of collection container selection, and / or control of a fluid flow controller and / or fluid dispensing system (or sub-system), a temperature control system (or sub-system), an imaging system (or sub-system), etc. In some instances, the system computer or processor may be an integrated component of the instrument system (e.g. a microprocessor or mother board embedded within the instrument). In some instances, the system computer or processor may be a stand-alone module, for example, a personal computer or laptop computer. Examples of fluid flow control functions that may be provided by the instrument control software include, but are not limited to, volumetric fluid flow rates, fluid flow velocities, the timing and duration for sample and reagent additions, rinse steps, and the like. Examples of temperature control functions that may be provided by the instrument control software include, but are not limited to, specifying temperature set point(s) and control of the timing, duration, and ramp rates for temperature changes. Examples of imaging system control functions that may be provided by the instrument control software include, but are not limited to, autofocus capability, control of illumination or excitation light exposure times and intensities, control of image acquisition rate, exposure time, data storage options, and the like.

[0122] Image processing software: In some instances of the disclosed tissue processing devices and / or systems, any of a variety of image processing methods known to those of skill in the art may be used for image processing / pre-processing of images acquired of tissue or cell samples within the tissue processing device. Examples include, but are not limited to, Canny edge detection methods, Canny-Deriche edge detection methods, first-order gradient edge detection methods (e.g., the Sobel operator), second order differential edge detection methods, phase congruency (phase coherence) edge detection methods, other image segmentation algorithms (e.g., intensity thresholding, intensity clustering methods, intensity histogram-based methods, etc.), feature and pattern recognition algorithms (e.g., the generalized Hough transform for detecting arbitrary shapes, the circular Hough transform, etc.), and mathematical analysis algorithms (e.g., Fourier transform, fast Fourier transform, wavelet analysis, auto-correlation, etc.), or any combination thereof.

[0123] Computing devices and systems: FIG. 29 illustrates an example of a computing device or system in accordance with one or more examples of the disclosure. Device or system 2900 can be a host computer connected to a network. Device or system 2900 can be a25MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 client computer or a server. As shown in FIG. 29, device or system 2900 can be any suitable type of microprocessor-based device, such as a personal computer, workstation, server, or handheld computing device (portable electronic device), such as a phone or tablet. The device can include, for example, one or more of processor 2910, input device 2920, output device 2930, storage 2940, and communication device 2960. Input device 2920 and output device 2930 can generally correspond to those described above, and they can either be connectable or integrated with the computer.

[0124] Input device 2920 can be any suitable device that provides input, such as a touch screen, keyboard or keypad, mouse, or voice-recognition device. Output device 2930 can be any suitable device that provides output, such as a touch screen, haptics device, or speaker.

[0125] Storage 2940 can be any suitable device that provides storage, such as an electrical, magnetic, or optical memory including a RAM, cache, hard drive, or removable storage disk. Communication device 2960 can include any suitable device capable of transmitting and receiving signals over a network, such as a network interface chip or device. The components of the computer can be connected in any suitable manner, such as via a physical bus 2970 or wirelessly.

[0126] Software 2950, which can be stored in memory / storage 2940 and executed by processor 2910, can include, for example, the programming that embodies the functionality of the present disclosure (e.g., as embodied in the devices and systems described above).

[0127] Software 2950 can also be stored and / or transported within any non-transitory computer-readable storage medium for use by or in connection with an instruction execution system, apparatus, or device, such as those described above, that can fetch instructions associated with the software from the instruction execution system, apparatus, or device and execute the instructions. In the context of this disclosure, a computer-readable storage medium can be any medium, such as storage 2940, that can contain or store programming for use by or in connection with an instruction execution system, apparatus, or device.

[0128] Software 2950 can also be propagated within any transport medium for use by or in connection with an instruction execution system, apparatus, or device, such as those described above, that can fetch instructions associated with the software from the instruction execution system, apparatus, or device and execute the instructions. In the context of this disclosure, a transport medium can be any medium that can communicate, propagate, or26MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 transport programming for use by or in connection with an instruction execution system, apparatus, or device. The transport readable medium can include, but is not limited to, an electronic, magnetic, optical, electromagnetic, or infrared wired or wireless propagation medium.

[0129] Device or system 2900 may be connected to a network, which can be any suitable type of interconnected communication system. The network can implement any suitable communications protocol and can be secured by any suitable security protocol. The network can comprise network links of any suitable arrangement that can implement the transmission and reception of network signals, such as wireless network connections, T1 or T3 lines, cable networks, DSL, or telephone lines.

[0130] Device or system 2900 can implement any operating system suitable for operating on the network. Software 2950 can be written in any suitable programming language, such as C, C++, Java, or Python. In various instances, application software embodying the functionality of the present disclosure can be deployed in different configurations, such as in a client / server arrangement or through a web browser as a web-based application or web service, for example.ENUMERATED EMBODIMENTS

[0131] The following enumerated embodiments are representative of some aspects of the invention.1. A device for processing tissue samples comprising: a first cassette, the first cassette comprising: an array of blades oriented in a first direction and configured to cut a tissue sample placed on a tissue plate into a plurality of smaller tissue samples; at least one blade oriented in a second direction that is orthogonal to the first direction, and configured to move transversely to the first direction to cut said plurality of smaller tissue samples into a plurality of smaller tissue fragments; and an array of pins oriented in the first direction and disposed on or within the first cassette, each pin in the array corresponding to an opening formed by the array of blades oriented in the first direction, the array of pins being configured for27MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 addressable ejection of tissue fragments from openings in the array of blades oriented in the first direction into a container; and a second cassette, the second cassette comprising: a plurality of containers, the containers of the plurality being configured to be selectively positioned to receive tissue fragments from a selected region of the tissue plate.2. The device of embodiment 1, wherein the first cassette and second cassette are configured to be removably coupled together.3. The device of embodiment 1 or embodiment 2, wherein the first cassette further comprises mating features for alignment and secure connection of the first cassette to the second cassette.4. The device of any one of embodiments 1 to 3, wherein the array of blades oriented in the first direction are arranged in a square or rectangular structure to form substantially square or rectangular opening for receiving tissue fragments.5. The device of any one of embodiments 1 to 3, wherein the array of blades oriented in the first direction are arranged in a honeycomb-like structure to form substantially hexagonal openings for receiving tissue fragments.6. The device of any one of embodiments 1 to 5, wherein the at least one blade oriented in the second direction comprises a plurality of parallel blades oriented in the second direction.7. The device of any one of embodiments 1 to 6, wherein the at least one blade oriented in the second direction is spring-loaded and cuts the plurality of smaller tissue samples into smaller tissue fragments when a locking mechanism is released.8. The device of any one of embodiments 1 to 7, wherein the tissue plate is mounted in the second cassette.9. The device of embodiment 8, wherein the cutting of the tissue sample by the array of blades oriented in the first direction occurs when the first cassette is pressed onto the second cassette.28MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.4010. The device of any one of embodiments 1 to 7, wherein the tissue plate is mounted on an end of a plunger.11. The device of embodiment 10, wherein cutting of the tissue sample by the array of blades oriented in the first direction occurs when the plunger is used to press the tissue sample against the array of blades oriented in the first direction.12. The device of any one of embodiments 1 to 11, wherein at least a portion of each container of the plurality of containers is optically transparent to allow monitoring of the tissue fragments.13. The device of embodiment 12, wherein a first planar wall and / or an opposing second planar wall of each container of the plurality of containers is optically transparent.14. The device of any one of embodiments 1 to 13, wherein the containers of the plurality of containers are preloaded with fluids or media for preservation or processing of the tissue fragments.15. The device of any one of embodiments 1 to 14, wherein the device is configured to be sterilized.16. The device of any one of embodiments 1 to 15, wherein the device is configured for single-use.17. The device of any one of embodiments 1 to 16, wherein the device is configured for reuse by separating multi-use and disposable components.18. A system for processing tissue samples comprising: a device comprising: a first cassette, the first cassette comprising: an array of blades oriented in the first direction and configured to cut a tissue sample placed on a tissue plate into a plurality of smaller tissue samples; at least one blade oriented in a second direction that is orthogonal to the first direction, and configured to move transversely to the first direction to cut said plurality of smaller tissue samples into a plurality of smaller tissue fragments; and29MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 an array of pins oriented in the first direction and disposed on or within the first cassette, each pin in the array corresponding to an opening formed by the array of blades oriented in the first direction, the array of pins being configured for addressable ejection of tissue fragments from openings in the array of blades oriented in the first direction into a container; and a second cassette, the second cassette comprising: a plurality of containers, the containers of the plurality being configured to be selectively positioned to receive tissue fragments from a selected region of the tissue plate; a first actuator configured to selectively actuate pins in the array of pins to eject tissue fragments from selected regions of the tissue plate; a second actuator configured to selectively position containers of the plurality of containers to collect tissue fragments from selected regions of the tissue plate; and a user interface configured to allow a user to select the regions of the tissue plate for which tissue fragments will be ejected and / or to select containers in which ejected tissue fragments will be collected.19. The system of embodiment 18, further comprising a third actuator configured to press the first cassette onto the second cassette to thereby cut a tissue sample placed on the tissue plate.20. The system of embodiment 19, wherein the third actuator comprises a clamping mechanism that mates with a component of the first cassette or the second cassette.21. The system of embodiment 18, further comprising a third actuator configured to press a plunger comprising the tissue plate against the array of blades oriented in the first direction to thereby cut a tissue sample placed on the tissue plate.22. The system of any one of embodiments 18 to 21, further comprising a fourth actuator configured to move the tissue plate in the first direction.23. The system of any one of embodiments 18 to 22, wherein the first actuator and / or the second actuator comprises a robotic arm.24. The system of any one of embodiments 18 to 23, wherein the first actuator and / or the second actuator is operable remotely.30MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.4025. The system of any one of embodiments 18 to 24, further comprising at least one sensor configured to detect a position of the at least one blade oriented in the second direction.26. The system of any one of embodiments 18 to 25, further comprising at least one sensor configured to detect a position of a container of the plurality of containers.27. The system of any one of embodiments 18 to 26, further comprising an imaging system configured to capture images of the tissue sample before, during, or after being cut into smaller tissue fragments.28. The system of embodiment 27, wherein the imaging system comprises at least one light source, at least one image sensor, and magnifying optics.29. The system of embodiment 27 or embodiment 28, wherein the imaging system is a fluorescence imaging system or a hyperspectral imaging system.30. The system of any one of embodiments 18 to 29, wherein the user interface is configured to allow a user to set up the system, command execution of tissue sample processing tasks, review images and data collected during tissue sample processing, and / or document results and record control functions.31. The system of any one of embodiments 18 to 30, wherein all or a portion of the system is mounted on or within a cart for mobility.32. The system of any one of embodiments 18 to 31, wherein the system is configured for use in an operating room, a remote location, or a manufacturing facility.33. A method for processing tissue samples, the method comprising: placing a tissue sample on a tissue plate, wherein the tissue plate is a component of a second cassette of a device configured for processing tissue samples; aligning a first cassette of the tissue processing device above the tissue plate of the second cassette, wherein the first cassette comprises an array of blades oriented in a first direction; compressing the first cassette and second cassette together to cut the tissue sample into a plurality of smaller tissue samples;31MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 actuating at least one blade oriented in a second direction that is orthogonal to the first direction and disposed within the first cassette to further cut the plurality of smaller tissue samples into a plurality of smaller tissue fragments; selectively activating pins of an array of pins disposed on or within the first cassette to eject selected tissue fragments from openings in the array of blades oriented in the first direction; and collecting the ejected tissue fragments into a selected container of a plurality of containers housed within the second cassette.34. A method for processing tissue samples, the method comprising: placing a tissue sample on a tissue plate, wherein the tissue plate is a component of a plunger; pressing the tissue sample against an array of blades oriented in a first direction and disposed within a first cassette of a tissue processing device; aligning and connecting the first cassette of the tissue processing device to a second cassette of the tissue processing device; actuating at least one blade oriented in a second direction that is orthogonal to the first direction and disposed within the first cassette to further cut the plurality of smaller tissue samples into a plurality of smaller fragments; selectively activating pins of an array of pins disposed on or within the first cassette to eject selected tissue fragments from openings in the array of blades oriented in the first direction; and collecting the ejected tissue fragments into a selected container of a plurality of containers housed within the second cassette.35. The method of embodiment 33 or embodiment 34, further comprising imaging the tissue sample and / or tissue fragments before, during, and / or after cutting the tissue sample into a plurality of smaller fragments.36. The method of embodiment 35, wherein the selective activation of pins to eject selected tissue fragments from opening in the array of blades oriented in the first direction is based on32MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 the imaging of the tissue sample and / or tissue fragments before, during, and / or after cutting the tissue sample into the plurality of smaller fragments.37. The method of any one of embodiments 33 to 36, wherein the selective activation of pins to eject selected tissue fragments from opening in the array of blades oriented in the first direction is based on one or more other user-specified criteria.38. The method of any one of embodiments 33 to 37, further comprising retrieving one or more containers of the plurality of containers for storage and / or transportation of tissue fragments.39. The method of any one of embodiments 33 to 38 further comprising transferring the contents of one or more containers of the plurality of containers into one or more bioreactors.40. The method of any one of embodiments 33 to 39, wherein the method is performed remotely without requiring a skilled surgeon or pathologist to be present.EXAMPLES

[0132] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.Example 1: Prototype tissue processing device and system

[0133] This example illustrates the use of a prototype of the tissue processing devices described herein to process a tissue sample (e.g., chicken liver) and generate smaller tissue fragments collected from selected regions of the original sample.

[0134] FIG. 30 provides a photograph of the prototype tissue processing device. The array of ejection pins is visible on the top side of the top cassette, which has been attached to the bottom cassette of the device. Prior to engaging the top cassette with the bottom cassette, a tissue sample was placed on the tissue plate contained within the bottom cassette. The act of engaging the top cassette with the bottom cassette resulted in cutting the tissue sample to generate smaller tissue fragments.

[0135] FIG. 31 provides a photograph of a robotic arm configured to actuate the ejection pins in the prototype tissue processing device and eject small tissue fragments from selected33MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 regions of the original sample. As described elsewhere herein, the array of ejection pins are aligned with openings in the array of vertical blades (z.e., the array of blades oriented in a first direction) housed within the top cassette. The robotic arm actuated individual pins in order to eject small tissue fragments from selected openings in the array of vertical blades for collection in a collection container.

[0136] FIG. 32 provides a photograph of small tissue fragments prepared using the prototype tissue processing device shown in FIG. 30. The original size of the tissue samples used in this study were approximately 1 - 2 cm across. Processing of the tissue sample by the prototype device resulted in cutting and ejection of small tissue fragments of relatively uniform size (approximately 3 - 4 mm across).

[0137] It should be understood from the foregoing that, while particular implementations of the disclosed methods, devices, and systems have been illustrated and described, various modifications can be made thereto and are contemplated herein. It is also not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the preferable embodiments herein are not meant to be construed in a limiting sense. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. Various modifications in form and detail of the embodiments of the invention will be apparent to a person skilled in the art. It is therefore contemplated that the invention shall also cover any such modifications, variations and equivalents.34MOFO-360426286

Claims

Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40CLAIMSWhat is claimed is:

1. A device for processing tissue samples comprising: a first cassette, the first cassette comprising: an array of blades oriented in a first direction and configured to cut a tissue sample placed on a tissue plate into a plurality of smaller tissue samples; at least one blade oriented in a second direction that is orthogonal to the first direction, and configured to move transversely to the first direction to cut said plurality of smaller tissue samples into a plurality of smaller tissue fragments; and an array of pins oriented in the first direction and disposed on or within the first cassette, each pin in the array corresponding to an opening formed by the array of blades oriented in the first direction, the array of pins being configured for addressable ejection of tissue fragments from openings in the array of blades oriented in the first direction into a container; and a second cassette, the second cassette comprising: a plurality of containers, the containers of the plurality being configured to be selectively positioned to receive tissue fragments from a selected region of the tissue plate.

2. The device of claim 1, wherein the first cassette and second cassette are configured to be removably coupled together.

3. The device of claim 1 or claim 2, wherein the first cassette further comprises mating features for alignment and secure connection of the first cassette to the second cassette.

4. The device of any one of claims 1 to 3, wherein the array of blades oriented in the first direction are arranged in a square or rectangular structure to form substantially square or rectangular opening for receiving tissue fragments.

5. The device of any one of claims 1 to 3, wherein the array of blades oriented in the first direction are arranged in a honeycomb-like structure to form substantially hexagonal openings for receiving tissue fragments.35MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.

406. The device of any one of claims 1 to 5, wherein the at least one blade oriented in the second direction comprises a plurality of parallel blades oriented in the second direction.

7. The device of any one of claims 1 to 6, wherein the at least one blade oriented in the second direction is spring-loaded and cuts the plurality of smaller tissue samples into smaller tissue fragments when a locking mechanism is released.

8. The device of any one of claims 1 to 7, wherein the tissue plate is mounted in the second cassette.

9. The device of claim 8, wherein the cutting of the tissue sample by the array of blades oriented in the first direction occurs when the first cassette is pressed onto the second cassette.

10. The device of any one of claims 1 to 7, wherein the tissue plate is mounted on an end of a plunger.

11. The device of claim 10, wherein cutting of the tissue sample by the array of blades oriented in the first direction occurs when the plunger is used to press the tissue sample against the array of blades oriented in the first direction.

12. The device of any one of claims 1 to 11, wherein at least a portion of each container of the plurality of containers is optically transparent to allow monitoring of the tissue fragments.

13. The device of claim 12, wherein a first planar wall and / or an opposing second planar wall of each container of the plurality of containers is optically transparent.

14. The device of any one of claims 1 to 13, wherein the containers of the plurality of containers are preloaded with fluids or media for preservation or processing of the tissue fragments.

15. The device of any one of claims 1 to 14, wherein the device is configured to be sterilized.

16. The device of any one of claims 1 to 15, wherein the device is configured for single-use.

17. The device of any one of claims 1 to 16, wherein the device is configured for reuse by separating multi-use and disposable components.

18. A system for processing tissue samples comprising:36MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 a device comprising: a first cassette, the first cassette comprising: an array of blades oriented in the first direction and configured to cut a tissue sample placed on a tissue plate into a plurality of smaller tissue samples; at least one blade oriented in a second direction that is orthogonal to the first direction, and configured to move transversely to the first direction to cut said plurality of smaller tissue samples into a plurality of smaller tissue fragments; and an array of pins oriented in the first direction and disposed on or within the first cassette, each pin in the array corresponding to an opening formed by the array of blades oriented in the first direction, the array of pins being configured for addressable ejection of tissue fragments from openings in the array of blades oriented in the first direction into a container; and a second cassette, the second cassette comprising: a plurality of containers, the containers of the plurality being configured to be selectively positioned to receive tissue fragments from a selected region of the tissue plate; a first actuator configured to selectively actuate pins in the array of pins to eject tissue fragments from selected regions of the tissue plate; a second actuator configured to selectively position containers of the plurality of containers to collect tissue fragments from selected regions of the tissue plate; and a user interface configured to allow a user to select the regions of the tissue plate for which tissue fragments will be ejected and / or to select containers in which ejected tissue fragments will be collected.

19. The system of claim 18, further comprising a third actuator configured to press the first cassette onto the second cassette to thereby cut a tissue sample placed on the tissue plate.

20. The system of claim 19, wherein the third actuator comprises a clamping mechanism that mates with a component of the first cassette or the second cassette.37MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.4021. The system of claim 18, further comprising a third actuator configured to press a plunger comprising the tissue plate against the array of blades oriented in the first direction to thereby cut a tissue sample placed on the tissue plate.

22. The system of any one of claims 18 to 21, further comprising a fourth actuator configured to move the tissue plate in the first direction.

23. The system of any one of claims 18 to 22, wherein the first actuator and / or the second actuator comprises a robotic arm.

24. The system of any one of claims 18 to 23, wherein the first actuator and / or the second actuator is operable remotely.

25. The system of any one of claims 18 to 24, further comprising at least one sensor configured to detect a position of the at least one blade oriented in the second direction.

26. The system of any one of claims 18 to 25, further comprising at least one sensor configured to detect a position of a container of the plurality of containers.

27. The system of any one of claims 18 to 26, further comprising an imaging system configured to capture images of the tissue sample before, during, or after being cut into smaller tissue fragments.

28. The system of claim 27, wherein the imaging system comprises at least one light source, at least one image sensor, and magnifying optics.

29. The system of claim 27 or claim 28, wherein the imaging system is a fluorescence imaging system or a hyperspectral imaging system.

30. The system of any one of claims 18 to 29, wherein the user interface is configured to allow a user to set up the system, command execution of tissue sample processing tasks, review images and data collected during tissue sample processing, and / or document results and record control functions.

31. The system of any one of claims 18 to 30, wherein all or a portion of the system is mounted on or within a cart for mobility.38MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.4032. The system of any one of claims 18 to 31, wherein the system is configured for use in an operating room, a remote location, or a manufacturing facility.

33. A method for processing tissue samples, the method comprising: placing a tissue sample on a tissue plate, wherein the tissue plate is a component of a second cassette of a device configured for processing tissue samples; aligning a first cassette of the tissue processing device above the tissue plate of the second cassette, wherein the first cassette comprises an array of blades oriented in a first direction; compressing the first cassette and second cassette together to cut the tissue sample into a plurality of smaller tissue samples; actuating at least one blade oriented in a second direction that is orthogonal to the first direction and disposed within the first cassette to further cut the plurality of smaller tissue samples into a plurality of smaller tissue fragments; selectively activating pins of an array of pins disposed on or within the first cassette to eject selected tissue fragments from openings in the array of blades oriented in the first direction; and collecting the ejected tissue fragments into a selected container of a plurality of containers housed within the second cassette.

34. A method for processing tissue samples, the method comprising: placing a tissue sample on a tissue plate, wherein the tissue plate is a component of a plunger; pressing the tissue sample against an array of blades oriented in a first direction and disposed within a first cassette of a tissue processing device; aligning and connecting the first cassette of the tissue processing device to a second cassette of the tissue processing device; actuating at least one blade oriented in a second direction that is orthogonal to the first direction and disposed within the first cassette to further cut the plurality of smaller tissue samples into a plurality of smaller fragments;39MOFO-360426286Privileged and Confidential - Morrison & Foerster LLP 32820-20003.40 selectively activating pins of an array of pins disposed on or within the first cassette to eject selected tissue fragments from openings in the array of blades oriented in the first direction; and collecting the ejected tissue fragments into a selected container of a plurality of containers housed within the second cassette.

35. The method of claim 33 or claim 34, further comprising imaging the tissue sample and / or tissue fragments before, during, and / or after cutting the tissue sample into a plurality of smaller fragments.

36. The method of claim 35, wherein the selective activation of pins to eject selected tissue fragments from opening in the array of blades oriented in the first direction is based on the imaging of the tissue sample and / or tissue fragments before, during, and / or after cutting the tissue sample into the plurality of smaller fragments.

37. The method of any one of claims 33 to 36, wherein the selective activation of pins to eject selected tissue fragments from opening in the array of blades oriented in the first direction is based on one or more other user- specified criteria.

38. The method of any one of claims 33 to 37, further comprising retrieving one or more containers of the plurality of containers for storage and / or transportation of tissue fragments.

39. The method of any one of claims 33 to 38 further comprising transferring the contents of one or more containers of the plurality of containers into one or more bioreactors.

40. The method of any one of claims 33 to 39, wherein the method is performed remotely without requiring a skilled surgeon or pathologist to be present.40MOFO-360426286

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