Apparatus, methods, devices and machines for operations associated with histological tissue sample preparation

Abstract

A histologic tissue sample support device (600) includes a tissue cassette (616), a cassette feature (626), and a frame (612). The tissue cassette (616) has at least one side wall (616a) and is coupled to the cassette feature (626). The cassette feature (626) has at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The tissue cassette (616) is movably coupled to the frame (612) that has a bottom edge (612f). The tissue cassette (616) and the cassette feature (626) are capable of moving from a first position to a second position with respect to the frame (612) and, in the second position, at least a portion of the cassette feature (626) and at least a portion of the side wall (616a) extend beyond the bottom edge (612f) of the frame (612) for sectioning in the microtome.

Description

APPARATUS, METHODS, DEVICES AND MACHINES FOR OPERATIONS ASSOCIATED WITH HISTOLOGICAL TISSUE SAMPLE PREPARATIONCross Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 707,995 filed October 16, 2024 (pending) and U.S. Provisional Patent Application Serial No. 63 / 845,712, filed July 17, 2025 (pending), the disclosures of which are incorporated by reference herein in their entirety.Technical Field

[0002] The present invention relates to apparatus, devices, machines, methods and the like for preparing tissue samples for pathological analysis and, more particularly, wherein tissue sample support devices can receive one or more tissue samples for purposes of embedding and subsequent microtome operations and, ultimately, for making microscope slides suitable for pathological analysis of the tissue samples.Background

[0003] To accurately diagnose various tissue diseases and conditions, medical personnel must remove one or more samples of tissue from the body of a patient. This process of harvesting tissue from the body is known as a biopsy. Once the tissue sample or samples are removed and sent to a pathology laboratory, the tissue will go through a series of procedures performed by a histotechnician and, ultimately, a pathologist, to diagnose one or more conditions associated with the tissue. The present disclosure generally relates to those procedures that are normally performed by the histotechnician to prepare the tissue sample or samples into slides that may be analyzed under a microscope by the pathologist.

[0004] Although the singular term “sample” is used throughout this specification, it should be understood that this term likewise encompasses two or more “samples” as well. Once a tissue sample is removed from the body of a patient, in any form that may be subsequently processed and diagnosed, it is typically placed into a specimen container containing a tissue fixative solution and then the container is transported to apathology laboratory. The tissue will undergo a process known as “grossing-in” in the pathology lab during which a histotechnician will retrieve the tissue sample from the container, and may cut the tissue into appropriate sizes for tissue processing. The tissue sample is placed in the appropriate sized small plastic tissue cassette and a tracking number is assigned to each cassette. The assignment of tracking numbers is usually done by printing the tracking number on the cassette, or onto a label which is then applied to the cassette. These tracking numbers are then logged into a tracking system used in the laboratory. For the smallest tissue samples, which may only be scrapings, the cassette includes fine mesh openings on the sides and bottoms. In other situations involving very small tissue samples, the samples are placed into a bag that resembles a tea bag preventing the smallest tissue samples from escaping. Larger tissue samples are positioned into cassettes having somewhat larger slotted openings which are nevertheless smaller than the tissue sample inside the cassette. No matter the size(s) of the openings, these perforated containment structures allow passage of the necessary processing fluids.

[0005] For purposes of processing the tissue samples, the cassettes are then positioned into a stainless steel perforated basket and run through a tissue processing machine, often overnight. This machine uses a combination of vacuum, heat, and liquid reagents or chemicals to remove the interstitial fluids within the tissue. Once the fluids have been removed from the tissue samples, the processing machine immerses the tissues samples in a bath of a hardenable material such as molten paraffin (i.e., a form of wax) so that the interstices in the tissue are replaced with paraffin. The histotechnician then removes the basket from the machine and removes the individual tissue cassettes.

[0006] U.S. Patent Nos. 5,817,032 (the ‘032 patent); 7,156,814; 7,179,424; 7,722,810; 7,776,274; and 8,383,067 disclose various improvements to this area of technology, including new manners of holding tissue samples during the grossing in, embedding, and microtome or slicing procedures. Without limiting the invention herein, the disclosures of the ‘032 patent, 7,156,814; 7,179,424; 7,722,810; 7,776,274; and 8,383,067 are hereby fully incorporated by reference herein. For example, the ‘032 patent relates to a tissue trapping and supporting device, which may be a cassette, andwhich may be successfully sectioned using a microtome. When a sectionable cassette such as this is used, the tissue sample is immobilized within the cassette and subjected to the process for replacing tissue fluids with paraffin. Then, both the tissue sample and the cassette are sliced at the same time for later mounting on microscope slides. Because the tissue sample is never removed from the cassette from the time it is processed in the tissue processing machine to the time that it is cut or sliced with the microtome, a significant amount of handling time is saved. Moreover, the chance for human error or tissue loss is significantly reduced due to the elimination of separate tissue handling steps. The '032 patent and the other above-incorporated patent properties also generally disclose further improvements that help automate the overall process and, in conjunction with the novel tissue supports (e.g., cassettes), can even further reduce the handling steps during the entire procedure and make the procedure more reliable.

[0007] Subsequent improvements have been made to the sectionable cassettes and frame assemblies, including those disclosed in U.S. Patent Nos. 11,226,272;11 ,774,330; 11 ,498,077; and 11 ,872,565. Also without limiting the invention herein, the disclosures of these patents are hereby incorporated by reference herein. These improvements generally involve connecting the lids of the cassettes to the frames, as well as other improvements. Continuing improvements in this general area of technology are desirable, such as to allow customization of cassette and / or tissue sample holding, containment, orientation and other features in furtherance of pathologically diagnosing disease and / or other conditions apparent in the tissue sample.Summary

[0008] In various embodiments, a histologic tissue sample support device for carrying a tissue sample is provided for use during processing and through sectioning of the tissue sample for purposes of analysis by a medical professional. The device may be a cassette configured to hold the tissue sample. The tissue cassette includes at least one side wall. The tissue cassette is formed of material that may be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. A cassette feature may be coupled to the tissuecassette. The cassette feature includes at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. These one or more elements may take many different forms, depending on the desired function(s), and a few examples are given herein for illustration. The cassette feature is formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. A frame includes a bottom edge, the tissue cassette being movably coupled to the frame. The tissue cassette and the cassette feature are capable of moving from a first position to a second position with respect to the frame and, in the second position, at least a portion of the cassette feature and at least a portion of the side wall extend beyond the bottom edge of the frame for sectioning by the microtome. Various types of features are discussed herein illustrated as examples of customized elements that may be formed by additive and / or subtractive manufacturing techniques. This allows the feature or features to be tailored and customized to the use case demands of an end user, such as a histology laboratory, best suited for a particular type of tissue sample, procedural requirements, or other factors, while also providing a rapid, cost effective and robust procedure for those involved.

[0009] In additional or alternative aspects, a lid may be coupled to at least one of the frame or the tissue cassette, the lid being capable of moving from the first position to the second position with respect to the frame. A lid feature may be coupled to the lid, the lid feature may include at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The lid feature may be formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. A biasing feature may be coupled to the lid, the biasing feature may be configured to bias a tissue sample against the bottom wall of the tissue cassette. The biasing feature may be formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process, and stain tissue. A customized feature may be coupled to the biasing feature. The customized feature may include at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The may be formed of material that can be successfully sectioned in themicrotome and is resistant to degradation from solvents and chemicals used to fix, process, and stain tissue. A tissue sample support device may of any desired configuration, for example, a simple platform-type support to a more involved baskettype form. It also may have any desired shape, such as circular, oval, or other shapes that have multiple sides.

[0010] In another illustrative embodiment, a histologic tissue sample support device is provided for carrying a tissue sample, the device embodied in a tissue cassette configured to hold the tissue sample. The tissue cassette includes at least one side wall. The tissue cassette may be formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. A frame includes a bottom edge, the tissue cassette being movably coupled to the frame. A lid is coupled to at least one of the frame or tissue cassette and a lid feature is coupled to the lid. The lid feature includes at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The lid feature is formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. The lid, the lid feature and the tissue cassette are capable of moving from a first position to a second position with respect to the frame and, in the second position, at least a portion of the lid feature and at least a portion of the side wall extend beyond the bottom edge of the frame for sectioning in the microtome.

[0011] In another illustrative embodiment, a histologic tissue sample support device is provided for carrying a tissue sample, the device embodied in a tissue cassette configured to hold the tissue sample. The tissue cassette includes at least one side wall. The tissue cassette may be formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. A frame includes a bottom edge, the tissue cassette being movably coupled to the frame. A lid is coupled to at least one of the frame or tissue cassette and a biasing feature is coupled to the lid. The biasing feature includes an element to bias a tissue sample and a customized feature is coupled to the biasing feature. The customized feature includes at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The customized featureis formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. The lid, the customized feature, the biasing feature, and the tissue cassette are capable of moving from a first position to a second position with respect to the frame and, in the second position, at least a portion of the biasing feature and at least a portion of the side wall extend beyond the bottom edge of the frame for sectioning in the microtome.

[0012] In another aspect, a method for making a device for holding a histologic tissue sample while sectioning the tissue sample is provided, the method including loading a cassette preform into a manufacturing device, and manufacturing a cassette feature on the cassette preform. The cassette feature is configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, and is formed of material that can be successfully sectioned in a microtome. The cassette feature is further resistant to degradation from solvents and chemicals used to fix and process the tissue sample during a histologic procedure.

[0013] In additional or alternative aspects, the method may further include manufacturing a lid feature on the cassette preform. The lid feature may be configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The lid feature may be formed of material that can be successfully sectioned in a microtome. The lid feature may be resistant to degradation from solvents and chemicals used to fix and process the tissue sample during a histologic procedure.

[0014] In another aspect, a method for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device is provided. The method includes loading a cassette preform into a manufacturing device, and manufacturing a cassette from the cassette preform using the manufacturing device, including the formation of a cassette feature on the cassette preform. The cassette feature is formed of material that can be successfully sectioned in a microtome, and the cassette feature is resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure. The tissue sample is secured to the cassette, at least in part by using the cassette feature.

[0015] In additional or alternative aspects, the method may include closing a lid when the tissue cassette is positioned within a frame and in a first position relative to the frame. The method may include moving the lid and the tissue cassette into a second position within the frame where at least a portion of the tissue cassette and at least a portion of the cassette feature extend beyond a bottom edge of the frame for sectioning in the microtome. The method may include manufacturing a lid feature on the cassette preform using the manufacturing device. The lid feature may be formed of material that can be successfully sectioned in a microtome. The lid feature may be resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure. The method may further include securing the tissue sample to the cassette, at least in part by using the lid feature.

[0016] In another aspect, a method is provided for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device including a lid. The method includes loading a lid preform into a manufacturing device, manufacturing the lid from the lid preform using the manufacturing device, including the formation of a lid feature on the lid preform. The lid feature is formed of material that can be successfully sectioned in a microtome. The lid feature is further resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure. The tissue sample is secured to the lid at least in part by using the lid feature. The method further includes positioning the device within a frame and in a first position relative to the frame, closing the lid while the tissue sample is secured to the lid with the lid feature and moving the lid and the lid feature into a second position within the frame where at least a portion of the lid feature extends beyond a bottom edge of the frame for sectioning in the microtome.

[0017] In another aspect, a method is provided for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device including a cassette. The method includes loading a cassette preform into a manufacturing device, manufacturing the cassette from the cassette preform using the manufacturing device, including the formation of a lid feature on the cassette preform. The lid feature is formed of material that can be successfully sectioned in a microtome. The lid feature is further resistant to degradation from solvents and chemicals used tofix and process a tissue sample during a histologic procedure. The tissue sample is secured to the cassette, at least in part by using the lid feature.

[0018] In additional or alternative aspects, the method may include manufacturing a cassette feature on the cassette preform using the manufacturing device. The cassette feature may be formed of material that can be successfully sectioned in a microtome. The cassette feature may be resistant to degradation from solvents and chemicals used to fixed and process a tissue sample during a histologic procedure.The tissue sample may be secured to the cassette, at least in part by using the cassette feature.

[0019] In another illustrative embodiment, a cassette preform device includes a cassette preform body configured to form a portion of a tissue cassette for holding a biopsy tissue sample. A cassette preform element is coupled with the cassette preform body and is configured to allow for providing a manufactured cassette feature. The cassette feature is configured to secure, align, orient, bias, and / or provide indicia to identify the tissue sample.

[0020] In another illustrative embodiment, a cassette preform device includes a cassette preform body configured to form a portion of a lid for a holding a tissue sample. A cassette preform element is coupled with the cassette preform body and is configured to allow for providing a manufactured lid feature. The lid feature is configured to secure, align, orient, bias, and / or provide indicia to identify the tissue sample.

[0021] In another general aspect, an apparatus is provided for making a tissue sample support device. The apparatus includes a sensor configured to detect at least a portion of a preform and a manufacturing unit configured to provide a feature on the preform based at least in part on the detected portion of the preform. The feature is configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample.

[0022] In additional or alternative aspects, an actuator may be configured to assist with providing the feature to the preform. The apparatus may include a receptacle configured to hold the preform and an actuator configured to move the preform. The sensor may be a scanner. More particularly the sensor may be a 3D scanner and may use various technologies such as LIDAR or others. Themanufacturing device may take any desired form, and both additive-type and / or subtractive-type manufacturing devices are usable in making features that are customized to the end user’s needs. Additive manufacturing and / or subtractive manufacturing devices may be used to form customized features anywhere on the tissue sample support device, such as a cassette having a lid and either a separate or integral frame used ultimately to secure the assembly and an embedded tissue sample, in a microtome for sectioning. For relatively higher volume production needs justifying the expense associating with tooling such as injection molding apparatus, additive and subtractive manufacturing techniques may not be used and any features made in this manner may be more universally applicable and then one or more customized features may be added via the lower volume manufacturing techniques provided by additive and subtractive manufacturing.

[0023] In another aspect, a method for preparing a biopsy tissue sample for histological examination using a histologic (i.e., biopsy) tissue sample support device is provided. The support device includes a surface, and the method includes positioning a tissue sample on the surface, scanning at least a portion of the surface with a sensor, creating a contour map based at least in part on the scanned surface and manufacturing a microtome sectionable surface feature such that the surface feature is coupled to the surface. The surface feature is manufactured based at least in part on the contour map, and the surface feature is configured to secure, orient, align, bias, and / or provide indicia to identify the biopsy tissue sample.

[0024] In additional or alternative aspects, the surface may be coupled with a frame, the frame including a bottom edge. The surface may be formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. The surface feature may be formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. The sensor may be a scanner. More particularly the sensor may be a 3D scanner and may use various technologies such as LIDAR or others.

[0025] In another aspect, a method for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device is provided.The support device includes a surface. The method includes positioning the tissue sample on the surface, scanning at least a portion of the surface with a sensor, creating a first contour map based at least in part on the scanned surface, and manufacturing a sectionable surface feature such that the surface feature is coupled to the surface. The surface feature is manufactured based at least in part on the contour map. The surface feature is configured to secure, orient, align, bias and / or provide indicia to identify the tissue sample. The method further includes scanning at least a portion of the surface feature and / or the surface with the sensor, creating a second contour map based at least in part on the scanned surface feature and / or the scanned surface, and manufacturing a sectionable securing feature coupled to the surface feature and / or the surface. The securing feature is manufactured based at least in part on the second contour map. The securing feature is configured to retain the tissue sample against the surface feature and / or the surface.

[0026] In additional or alternative aspects, the surface may be coupled with a frame, the frame including a bottom edge. The surface may be formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. The surface feature may be formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. The securing feature may be formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. The sensor may be a scanner. More particularly the sensor may be a 3D scanner and may use various technologies such as LIDAR or others.

[0027] Another illustrative embodiment or aspect, which is optional as are the other aspects and embodiments disclosed herein, provides a method for manufacturing a cassette preform. The method includes loading a material into a manufacturing device and manufacturing a cassette preform, the cassette preform manufactured to have a cassette preform feature. As set forth herein, the manufacturing device may take many different forms. Some examples are of the type that are designed to add material to create the feature or features and others are of the type that will take material away to create the feature or features.

[0028] In another aspect, a method for making a cassette is provided. The method includes loading material into a low volume manufacturing device and manufacturing a customized feature out of material by using the low volume manufacturing device. The customized feature is configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The customized feature is resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure, that is, a procedure designed to ultimately analyze a tissue sample for any reason. The method further includes inserting the customized feature into a high volume manufacturing device, loading material in the high volume manufacturing device, and manufacturing the cassette around or otherwise connected / coupled with the customized feature out of material by using the high volume manufacturing device.

[0029] In another aspect, a method for making a cassette is provided. The method includes loading material into a first high volume manufacturing device and manufacturing a customized feature out of material by using the first high volume manufacturing device. The customized feature is configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The customized feature is resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure. The method further includes inserting the customized feature into a second high volume manufacturing device, loading material into the second high volume manufacturing device, and manufacturing the cassette around or otherwise connected / coupled with the customized feature out material using the second high volume manufacturing device.

[0030] In another aspect, a method for making a cassette is provided. The method includes loading material into a high volume manufacturing device and manufacturing a cassette preform of material by using the high volume manufacturing device. The method further includes inserting the cassette preform into a low volume manufacturing device, loading the material into the low volume manufacturing device, and manufacturing a customized feature around or otherwise connected / coupled with the cassette preform out of material by using the low volume manufacturing device. The customized feature is configured to secure, align, orient, bias, and / or provide indiciato identify a tissue sample. The customized feature is resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure.

[0031] In another general aspect, an apparatus is provided for making a tissue sample support device. The apparatus including a low volume manufacturing device configured to manufacture at least a portion of a feature to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, and a high volume manufacturing device configured to manufacture the cassette. The cassette includes one or more customized features.

[0032] In another illustrative embodiment, a histologic tissue sample support device is provided and includes a surface, and a surface feature coupled to the surface. The surface feature includes at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The surface feature is formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.

[0033] In additional or alternative aspects, the surface may be coupled with a frame, the frame having a bottom edge. The surface and the surface feature could be capable of moving from a first position to a second position with respect to the frame, and in the second position, at least a portion of the surface feature and at least a portion of the surface extend below the bottom edge of the frame for sectioning in the microtome. The surface may be coupled with a lid. The lid may be coupled to at least one of a frame or a tissue cassette, the frame having a bottom edge.

[0034] In another illustrative embodiment, a histologic tissue sample support device is provided and includes a surface and a surface feature coupled to the surface. The surface feature includes at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample. The surface feature is formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue. A securing feature is coupled to the surface and / or the surface feature. The securing feature includes at least one component to retain a tissue sample against the surface. The securing feature is formed of material that can be successfully sectioned in a microtome and isresistant to degradation from solvents and chemicals used to fix, process and stain tissue.

[0035] In additional or alternative aspects, the surface is movably coupled with a frame, the frame having a bottom edge. The surface may be coupled with a lid frame. The lid frame may be coupled with a frame or a tissue cassette, the frame having a bottom edge. The surface is capable of moving from a first position to a second position with respect to the frame and, in the second position, at least a portion of the tissue cassette, and at least a portion of the surface extend below the bottom edge of the frame for sectioning in the microtome.

[0036] In another illustrative embodiment, a histologic tissue sample support device is provided. The device includes a surface and a securing feature coupled to the surface. The securing feature includes at least one component to retain a tissue sample against the surface. The component is formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.

[0037] In additional or alternative aspects, the surface may be coupled with a frame, the frame having a bottom edge. The surface couple be movably coupled with a lid frame. The lid frame may be coupled with a frame or a tissue cassette, the frame having a bottom edge.

[0038] In another illustrative embodiment, a histologic tissue sample support device includes a plurality of recesses and a detectable substance in the plurality of recesses. The detectable substance is usable for identification of a tissue sample held by the tissue sample support device, such as by forming a pattern associated with the filled recesses and detected and analyzed by human and / or machine capabilities.

[0039] In another aspect, a method for preparing one or more indicia on a tissue sample support device includes a tissue sample support device, a detectable substance, and a plurality of recesses. The method includes directing the detectable substance into at least one of the recesses and analyzing such as described herein.

[0040] Various additional features and advantages will become readily apparent to those of ordinary skill in the art upon review of the following detailed description of the illustrative embodiments, taken in conjunction with the accompanying drawings and theappendices, intended as illustrative exemplary discussion of specific implementation of the ideas and details but not to be taken as limiting of the general inventive aspects.Brief Description of the Drawings

[0041] FIG. 1 A is a perspective view of a plurality of devices to make indicia according to one illustrative embodiment.

[0042] FIG. 1 B is a top view of one of the plurality of devices in FIG. 1 A showing some of the recesses of the device filled with a detectable substance to produce a pattern detectable by human and / or machine.

[0043] FIG. 1 C is a cross sectional view of one of the devices in FIG. 1 A taken generally along line 10-10 of FIG. 1 B showing the 2D printer adding the detectable substance to the recesses.

[0044] FIG. 2A is a perspective view of a microscope slide made according to one illustrative embodiment.

[0045] FIG. 2B is a top view of the microscope slide in FIG. 2A showing sectioned indicia on the microscope slide.

[0046] FIG. 3A is a top view of a tissue cassette device according to one illustrative embodiment.

[0047] FIG. 3B is a top view of the device in FIG. 3A showing the tissue cassette in the open position with tissue secured to the lid.

[0048] FIG. 4 is a schematic diagram view of the steps to create a 3D printed object.

[0049] FIG. 5 is a perspective view of a two cassette type stand-alone manufacturing device according to one illustrative embodiment.

[0050] FIG. 6 is a perspective view of the device of FIG. 5 showing the tissue cassettes inside the device.

[0051] FIG. 7 is a cross-sectional view of the device of FIG. 5 taken of FIG. 6 showing the tissue cassette inside the device.

[0052] FIG. 8 is a schematic or diagrammatic top view of the manufacturing of a tissue cassette according to one illustrative embodiment.

[0053] FIG. 9 is a schematic or diagrammatic top view of the manufacturing of a tissue cassette according to another illustrative embodiment.

[0054] FIG. 10A is a perspective view of a tissue cassette device according to another illustrative embodiment.

[0055] FIG. 10B is a top view of the device in FIG. 10A showing the tissue cassette in an open position with tissue retained or held in an oriented position on the lid.

[0056] FIG. 10C is a cross sectional view of the device in FIG. 10A taken generally along line 10C-10C of FIG. 10B.

[0057] FIG. 10D is a cross sectional view similar to that in FIG. 10C, but with the lid in a closed position.

[0058] FIG. 10E is a cross sectional view similar to that in FIG. 10D, but with the cassette and the lid in a staged position ready for sectioning in a microtome.

[0059] FIG. 11 A is a perspective view of a tissue cassette device according to another illustrative embodiment.

[0060] FIG. 11 B is a cross sectional view of the device in FIG. 11 A taken generally along line 11 B-11 B and showing the tissue cassette in an open position with tissue inserted on the lid.

[0061] FIG. 11C is a cross sectional view similar to that in FIG. 11 B, but with the lid of the cassette in a closed position and biasing a tissue sample against a bottom wall or sectioning plane associated with the cassette.

[0062] FIG. 12A is a perspective view of a tissue cassette device according to another illustrative embodiment.

[0063] FIG. 12B is a cross sectional view of the device in FIG. 12A taken generally along line 12B-12B and showing the cassette body inserted into the frame.

[0064] FIG. 13A is a perspective view of a tissue cassette device according to another illustrative embodiment.

[0065] FIG. 13B is a cross sectional view of the device in FIG. 13A taken generally along line 13B-13B.

[0066] FIG. 13C is an enlarged cross sectional view of a tissue sample orientation feature shown in FIG. 13B.

[0067] FIG. 13D is a top view of the orientation feature shown in FIG. 13B.

[0068] FIG. 14A is a perspective view of a tissue cassette device according to another illustrative embodiment.

[0069] FIG. 14B is a cross sectional view of FIG. 14A taken generally along lines 14B-14B.

[0070] FIG. 15 is a cross sectional view of a tissue cassette device according to another illustrative embodiment.

[0071] FIG. 16 is a cross sectional view of a tissue cassette device according to another illustrative embodiment.

[0072] FIG. 17 is a cross sectional view of a tissue cassette device according to another illustrative embodiment.

[0073] FIG. 18A is a perspective view of a tissue cassette device according to another illustrative embodiment.

[0074] FIG. 18B is a cross sectional view of the device in FIG. 18A taken generally along line 18B-18B.

[0075] FIG. 18C is a cross sectional view similar to that of FIG. 18B, but without the matrix feature.

[0076] FIG. 19A is a perspective view of a tissue cassette device according to another illustrative embodiment.

[0077] FIG. 19B is a cross sectional view of the device in FIG. 19A taken generally along line 19B-19B.

[0078] FIG. 20 is a perspective view of a subtractive manufacturing device adding a customized feature to the tissue cassette device of FIGS. 19A and 19B.Detailed Description

[0079] The present disclosure generally relates to apparatus, methods, devices, and machines for preparing tissue samples and, subsequently, microscope slides including thin slices of one or more of those tissue samples, that may be analyzed under a microscope by a pathologist. The term “tissue sample” is inclusive of the terms “biopsy”, “skin”, and other variations of these terms or similar terms related to histology used throughout this disclosure as will be understood by one of ordinary skill in the art. The tissue sample may be of any biologic tissue in any form and taken from human oranimal, for example, to analyze for any reason. A tissue sample support device and / or related methods, systems and apparatus is described herein and these may involve “histologic” tissue sample supports or “biopsy” tissue sample supports. In this regard, the terms “histologic” and “biopsy” are used synonymously and do not imply a specific method or process for obtaining the tissue sample. The tissue sample support device is described as having a pre-made portion, e.g., a “preform” or synonymously a "base unit” or similar terms, and a portion that is manufactured for purposes of providing customized features, e.g., a “cassette feature”, a “lid feature”, or a “support feature.” Preform includes “cassette preforms”, “lid preforms”, “preform bodies”, and any other preform used throughout this disclosure. The pre-made portion may be made in larger production volumes, such as through mass production molding processes, while the customized feature may be made in a relatively lower volume process such as via additive, subtractive or other customized manufacturing processes. The terms manufacture, manufacturing, manufactured, and other versions of these terms include or are inclusive of “additive manufacturing”, “reductive manufacturing”, “subtractive manufacturing” and other types of manufacturing that could be used in this disclosure for customizing features of the cassette. The histologic tissue sample support device system may provide manufactured features including, but not limited to, making tissue alignment and orientation features, indicia and other features consistent with this disclosure. The system also includes the manufactured features being made of materials capable of being successfully sectioned in a microtome after incorporation into a hardened block of material, such as one utilizing paraffin.

[0080] The term “feature” and “features” include portions that are manufactured to secure, align, orient, bias, and / or prepare indicia to identify a tissue sample. These preforms may be used as the “base” or “base unit” where the manufactured features are added to the preform. The preform may be constructed as a base or base unit for any portion of the cassette, such as a lid of the cassette, a body of the cassette, or any portion or portions thereof. In some embodiments, the cassette may include a recess or basket portion that receives a tissue sample but in other embodiments, the cassette may instead be a support device that comprises a platform on which a tissue sample issecured. Therefore, “cassette” as used in this disclosure is not meant to be limited to any particular structure for holding and / or otherwise securing a tissue sample.

[0081] By using custom manufacturing in conjunction with existing sectionable cassette preforms the end-user may create on-demand cassette features, like skin orientation or core biopsy, as an option at the point of use. Cassette features, lid features, customized features, and other features are described throughout this disclosure as being posts, torsionally biased plates, spring fingers, troughs, and may include other user desired features to align, orient, secure, and provide indicia to identify a tissue sample. Any of the features discussed above may be an element of structure. Embodiments throughout this disclosure allow for several features to be added to fit the need of the user. As shown in FIG. 1A to FIG. 2B, sectionable identifying indicia is an additional feature. Terms such as “identify”, “identifying” or similar terms when used in the context of indicating information about a tissue sample, and any like terminology, encompasses tracking the tissue sample from the gross-in procedure to the diagnosis procedure as well as other portions of the overall process. Identifying indicia allows the histotechnician to trace the tissue sample back to the patient. The indicia may be used for other reasons as well. One main advantage of the sectionable indicia pertains especially to cases where the tissue sample of interest is completely consumed in the production of the initial histologic slides, and no tissue sample remains in the paraffin block for recuts or special studies. This mostly occurs in biopsy procedures that typically produce a small tissue sample, such as endoscopic gastrointestinal (Gl) biopsies, bronchoscopic biopsies, stereotactic brain biopsies, and various small core biopsies.

[0082] The indicia may be made from materials that do not require a preservative. The indicia may also be made from a detectable substance such as polyethylene or a “gel” as well as any other material that could be used to identify a tissue sample. As shown in FIGS. 1A, 1B, and 1 C, a structure 10 could be made to contain a plurality of very small wells or recesses 12. A 2D printer or other fluid dispensing device 14 dispenses a fluid substance 20 into the recesses 12, making a dot indicator. The fluid substance 20 cures or dries in the recess 12. The term “recesses” is used throughout this disclosure and includes “wells”, as well as any other structurethat allows for a similar use. Ultimately, the dried or cured substance 20 in a particular well 12 is referred to as a “dot” and multiple such recesses 12 containing cured substance 20 are referred to herein as “dots”. These recesses 12 could be filled in patterns to replicate the accession number and / or to also add an individual slide number for each slide produced in microtomy. The dots may be arranged in any pattern used by machine scanners, whether as a line or dot matrix pattern for example, or any other pattern. The dots could be arranged to be read by a machine or a human. A simple change to the type of detectable substance 20 in a 2D printer 14 may provide high volume deposition of a detectable substance 20, like gel, into recesses 12. Alternatively, the structure 10 could be made from either a woven or non-woven sectionable filament or fabric such as a cellulose material. Then the structure 10 could be embossed to create recesses 12 which are capable of accepting a detectable substance 20. The structure 12 could then create a matrix of indicia, which may also be formed of a material that may be successfully sectioned in a microtome.

[0083] More specifically, FIG. 1A shows structures 10 with recesses 12. Recesses 12 are capable of being filled with detectable substance 20. Once the recesses 12 are filled with the detectable substance 20, the dots may be capable of being read by a machine or a human, or both. The recesses 12 include wells that are not filled with the detectable substance 20. While this illustrative embodiment shows a certain pattern, any pattern may be created by filling the recesses 12 with the detectable substance 20. As shown in more detail in FIG. 1 B, the dots create a pattern that may be used by machine scanners or by a human. FIG. 1C shows the 2D printer 14 filling the recesses 12 of the structure 10 with the detectable substance 20. The 2D printer 14 includes a nozzle 16, a supply tube 22, and a substance chamber 24. The supply tube 22 directs the detectable substance to the substance chamber 24. Any other dispensing structure may be used instead. Once the detectable substance 20 is in the substance chamber 24, the nozzle 16 is operated to release a droplet 26 of the detectable substance 20 into the recesses 12. Once a recess 12 is filled as desired with one or more droplets 26 of the detectable substance, the 2D printer 14 moves the nozzle 16 to fill another recess 12. After the intended pattern is created by the 2Dprinter 14, the structure 10 may be used to identify a tissue sample or for any other purpose.

[0084] An alternative approach may be to extrude a gel with an easy to read (by humans or otherwise) identifying indicia throughout the length of a gel extrusion, such as a Roman numeral. For example, a zero for the parent sample and then progressively a one, two, or three identifier for subsequent blocks in cross section. The product could be extruded from gel that may be clear for the border and opaque for the indicia in the center. That may produce an elongated sample which could be cut into sections perhaps 1 mm to 3mm thick. Each time that indicator gel is sectioned the number (e.g., 2) may show up on each slide sectioned with that gel. Successive numbers starting with the parent tissue indicator (e.g., 0) may be extruded and sliced and placed on a product placard in ascending order for use in the pathology laboratory. Each time a block is prepared for sectioning, the histotechnician may place one of the sections appropriate for each block in the cassette. Since each block is already numbered with the accession number on the cassette frame, an identifying indicia may indicate each unique block and each section derived from that block. While each section is not individually numbered it produces a ’’series” number from which tracing may be related to a specific block. Therefore, it could be an easy and reliable way for a pathologist to see how many sections were produced from that tissue with that identifying indicia. If more than one section was created from the tissue, it may warrant a step up in the tissue number indicating that those sections came from a second or third, etc., section from the tissue.

[0085] FIGS. 2A and 2B illustrate a microscope slide 30 with a tissue sample 32. The tissue sample 32 is embedded in paraffin wax 34 and attached to the microscope slide 30. Within the paraffin wax 34 is sectionable indicia 36 which may be used to identify the tissue sample 32. The indicia 36 may be any identifying number or other identifier information. The microscope slide 30 includes an accession number bar code 38 to further identify the tissue sample 32. The pathologist may scan the accession number bar code 38 to verify the tissue sample 32. The indicia 36 may be also included in the indicia bar code 40. The indicia bar code 40 is another way that the pathologist may identify the tissue sample 32. The accession bar code number 38 and the indiciabar code number 40 are attached to the microscope slide 30 as a sticker 42 and 44, respectfully. Alternatively, the accession bar code number 38 and the indicia bar code number may be inscribed into the microscope slide 30, for example. Alternatively, the bar codes 38, 40 may be a QR code, for example, or any other method of attaching indicia to a microscope slide. Any combination of bar codes and sectionable indicia may be used to identify and / or track the tissue sample 32 and is in no way limited by this disclosure.

[0086] One main advantage of the sectionable indicia 36 is a case where the tissue is completely consumed in the production of the paraffin blocks. In other cases there is unused tissue which is then returned to an archive sample container in case there was some concern that required the leftover sample to be retrieved and processed for further analysis.

[0087] Some surgical cases produce tissue samples where the entire tissue sample(s) is consumed in the production of the paraffin blocks. A good example of this is a prostate biopsy procedure. The biopsies are usually taken with a coring device that can expel each sample or samples from the prostate lobe that it was taken from into a separate container or a segmented container that keeps samples from different lobes separated. In this procedure, cores are taken from the four lobes of the prostate, most core procedures call for multiple cores per lobe. The anatomical position (lobe) of each sample may be noted and transferred with the sample to the pathology laboratory and labeled throughout the procedure. If cancer is found in one side or one lobe then staging, surgery, or treatment may be designed around this information. Therefore, it is important to be certain that the cassette holding a particular sample be marked and that the anatomical position be tracked by each cassette. Furthermore, it is important to be certain that the corresponding tracking appear in each slide as confirmation. While the state of the art tracks the cassettes, the ability to identify the tissue sample on a slide is lost without the sectionable indicia. By including a unique sectionable indicia in each cassette used for the biopsy cores, such as a prostate procedure, the ability to track each anatomical position of the core is achievable. This provides the ability to identify the tissue sample all the way through to each microscope slide produced.

[0088] A large part of the total production of cassettes may be divided into two cassette designs: (1) the standard large cassette and (2) the micro biopsy cassette. These two cassette designs currently make up approximately 80% of the total yearly volume of cassettes produced. The remaining 20% is made up of a plurality of different specialty cassette designs totaling as many as a dozen different configurations. Each different configuration requires expensive multicavity tooling and inserts that result in the capital expenditure to create this 20% of specialty cassette designs to far exceed the capital expenditure of the other 80% of cassette designs produced. Thus, timing and customization for changing customer needs are impaired due to the high capital expenditure required.

[0089] Another possible benefit of this disclosure is directed towards a cassette design which can utilize as many relatively high-volume production processes as possible to keep capital expenditures low. These high-volume production methods allow mass production of cassettes. This cassette design includes adding customized features, that meet customer’s needs, to an existing cassette preform produced by high- volume production. The combination of these two creates a cassette which can be easily customized with interchangeable features while still utilizing as much high-volume production as possible.

[0090] Furthermore, this disclosure discusses several different types of possible cassettes, where part of the cassette is mass produced in a high-volume manufacturing (“HVM”) process, such as injection molding, which allow mass production with a mold and a separate part of the tissue cassette is made in a low volume manufacturing (“LVM”) process, such as 2D printing or 3D printing, where a mold is not involved. These two types of manufacturing (HVM and LVM) are combined to make a finished workable customized tissue cassette. HVM methods will be understood as those that involve mass producing one or more portions of a cassette (i.e., a preform, preform body, or base unit) in volumes at least ten times higher than the LVM method(s) used to manufacture custom features on those preforms, preform bodies, or base units. Often, the production volumes of the preforms, preform bodies, or base units will be at levels even higher than the resulting complete cassette produced after implementation of a given LVM production.

[0091] Tissue cassettes may be configured at the point of use, or elsewhere, for anatomy specific orientation needs. For example, during the gross-in step when the case is logged into the histopathology case computer database, recording the type of case selected may allow the histotechnician or pathologist to choose the custom cassette features that are best suited for the pathology needs that are specific to that case. This enables customization of cassette or device features as the case is configured at gross-in. Once the desired cassette / d evice features are selected, the manufacturing station may process the type and number of cassettes needed for that case. If required, different types of cassette features could be ordered for the same case. Manufacturing on-demand customization of case specific cassette features for immediate use may be prepared during the gross-in, or pre-embedding stage of sample preparation.

[0092] Another possible benefit of this disclosure is the ability to simplify the supply chain of cassettes to the customer. Because pathology laboratories use high volumes of cassettes, they must store significant numbers of cassettes in inventory so they do not run out during the normal course of use. This puts a large burden on the supplier of the cassettes to make certain that the inventory can be quickly replenished from stock in all countries or specific locations where product is sold. Any interruption in the supply chain can be catastrophic for the pathology laboratory delaying cases from being completed. By reducing inventory to only a few standard types of preforms or base units, the supply chain simplifies for the manufacturer. Currently, cassettes are made in such high volume for worldwide supply that they are manufactured by processes that require substantial investment in tooling, quality control, packaging and shipment logistics. Each new cassette design requires expensive tooling to manufacture these parts and have the quality and availability that is always consistent.

[0093] Because the highest volume cassettes are made in multicavity tools it presents quite a challenge to provide a cassette that is not consumed in significant volumes. Therefore, the manufacture of each type of cassette, be it one that is used for large tissue samples or ones that helps align smaller or specific types of tissue samples for proper orientation, requires individual manufacturing tools. In order to supply the high volumes of cassettes that are required for worldwide distribution, tools that have alarge multicavity design are required. These large multicavity tools are designed so that every time the tool is “shot” or injected with hot plastic it makes many copies of the same cassette. This is known as a multicavity tool. Multicavity tools are very expensive to make, but once the investment is made, they produce a lower cost part as the time to run the injection molding machine is a fixed cost, so the more cavities you can fill in a “shot” the part cost per shot is less.

[0094] The problem with this is that to make any changes to the multicavity tool (or the design of the cassette) all of the cavities must get the exact same changes. This makes the investment in multicavity tooling very high. In addition, all of the R&D should be rigorously vetted as the cost of rebuild mistakes is prohibitive. This usually mandates that a single cavity mold be made first and rigorously tested before committing hundreds of thousands of dollars to build a multicavity tool. In this industry there are further costs to validate the changes and process parameters to be certain the product performs as intended. It is a substantial undertaking to supply tens of millions of cassettes each year to customers. It is not uncommon for it to take several years of R&D to produce just one new cassette design.

[0095] When a new cassette is designed millions of dollars must be spent in retooling to manufacture the new product regardless of how many might be sold. In one aspect, this disclosure allows for new cassettes to be designed, prototyped and rolled out to customers with speed and cost savings never before achieved. Now, via instructions sent to the manufacturing system, a custom cassette feature can be made on site at the laboratory or elsewhere, bypassing the need to retool the multicavity tool for that cassette. In addition, this substantially reduces the lead time in getting new and innovative cassette features to end users.

[0096] As one can understand from the above discussion even minor changes to a cassette design can be very disruptive and expensive to the manufacturing process. This leads to a general reluctance to provide customers with custom needs. What may seem to be simple requests by customers for cassette features in the cassette design are often left unanswered. For many years customers have had to make do with a limited number of cassette features to meet their needs. The combination of manufacturing and specialized access to the cassette during case preparation, enablesnew and useful customization of histopathology cassette features. By utilizing a manufacturing system, customers can now utilize on-demand or otherwise custom cassette features that can be added to high volume cassette preforms.

[0097] Another advantage of this disclosure is that in some cases one particular type of cassette may not have enough volume to warrant being supplied over a wide distribution region, but yet a customer such as a research laboratory may require a very specific cassette feature. The research laboratory cannot obtain the cassette feature it needs because it is too expensive to make a multicavity tool for the particular need of one customer. With this disclosure, a customer may now ask for their specific cassette design. As shown in FIGS. 3A and 3B, a cassette design is shown that might accommodate specific tissue 122a, 122b, 122c, 122d used in research like a specific mouse tissue sample or other laboratory animal tissue. The cassette supplier could customize a cassette feature for that anatomical part and send the instructions to the manufacturing system for it to make a very specific type of cassette. This may allow the production of highly customized cassettes that meet the anatomy requirements that the customer needs to align and orient tissue for the best slide preparation.

[0098] Specifically, FIG. 3A shows a histologic tissue sample support device 100 according to one illustrative embodiment and in an open position. The device 100 includes a cassette body 110, a frame 112, and a lid 114. The cassette body 110 defines an interior or recess 111 surrounded by at least one sidewall 110a and a bottom wall 110b. The cassette body 110 is carried within the frame 112. The connection of the cassette body 110 to the frame 112 may be accomplished in many different manners, such as any of the manners described in the above-incorporated patent and patent applications. As illustrative examples, any of the configurations, features, characteristics and materials disclosed for the tissue supports (e.g., cassettes) and frames in the above-incorporated patent and patent applications may be employed for cassette body 110 and frame 112. In the illustrative embodiment shown, the cassette body 110 is porous or perforated 126, 128 and is releasably retained in the frame 112 and the frame 112 is further configured to be releasably secured within a microtome chuck (not shown), such as is generally done in the industry. The perforations 126, 128, 130 in different areas of the cassette body 110 and / or different areas of the lid 114may have different physical characteristics, such as size, numbers, etc., for example, to accommodate needs of the tissue samples(s) 122a, 122b, 122c, 122d. Although a generally rectangular recess 111 is shown (see FIG. 3A), it will be appreciated that any other shape, such as any polygon (e.g., square) or any rounded shape (e.g., oval or circular) or shapes with troughs or alignment features may be used instead. The frame 112 generally includes an interior 112a defined between surrounding outer walls 112b, 112c, 112d, 112e, a bottom edge 112f, and a top edge 112g. The frame 112 also includes stop members 124 (such as four total in number) configured to prevent the cassette body 110 and lid 114 from moving beyond the stop members 124 when staged (discussed in more detail below). In this illustrative embodiment, the lid 114 of device 100 is coupled to the cassette body 110 by hinges 118a and 118b. In alternative embodiments, the lid 114 may be coupled to the cassette body by a single hinge 118. Further, in another alternative embodiment, the lid 114 may be coupled to the frame 112 by a hinge 118, depending on the cassette design. The cassette body 110 and the lid 114 may be sized and configured to frictionally or "snap" fit and move within the interior 112a between at least first and second positions, again, as generally discussed in the above-incorporated patent properties and for the same purposes.

[0099] In this illustrative embodiment, the lid 114 includes customized cassette features 120a, 120b, and 120c that may secure, align, orient, and / or bias the tissue sample 122a, 122b, 122c, 122d. While three customized features are shown, it will be appreciated that any number of customized features may be formed. The customized features 120a, 120b, 120c may be added to the lid 114 depending on the needs or desires of the user. For example, in any given case a laboratory technician may need four customized features instead of three. In such case, an additive manufacturing device such as a 3D printer may add four customized features to the lid 114. In alternative embodiments, subtractive or reductive manufacturing may be used to add the customized features to the lid 114. It will also be appreciated that customized features 120a, 120b, 120c may be configured or arranged in any suitable manner. In this illustrative embodiment, the customized features 120a, 120b, 120c are configured to orient the tissue samples 122a, 122b, 122c. Specifically, customized features 120a, 120b include posts that are attached to the underside of the lid 114 which areconfigured to orient the tissue samples 122a, 122b. The customized feature 120c includes a structure to orient tissue samples 122c, 122d. The customized features 120a, 120b, 120c may be formed of the same material as the lid 114, which may be capable of successful sectioning in a microtome. In an alternative illustrative embodiment, the customized features may be manufactured first and then added to a lid or cassette by HVM.

[0100] Another example of where this disclosure may be particularly useful is when a laboratory processes a significant number of research animals to do drug screening. For instance, many laboratories use mice as screening models to see if tumors grow in several target organs. Current cassette designs require two different types of cassettes to process each anatomy specimen (organ) from the same animal. Using the eyes and brain stem, or liver and skin as examples, each of these anatomy sections require dissimilar cassette features. This results in requiring two cassettes for each animal, one for each type of cassette feature required. Because of the high volume of cassettes that a research laboratory uses, it may warrant a special manufactured design, however, there are not enough additional customers that may use their design to justify a large investment in new multicavity tooling. For example, with the manufacturing technology of the current disclosure, the eyes and brain stem can have custom cassette features added into the same cassette preform. This presents a unique opportunity not only for the manufacturer to control tooling costs, but to provide unprecedented customization of cassette features that can be changed, updated, and innovated without the cost and lead times associated with traditional manufacturing methods. In addition to the above, a research laboratory can order a custom cassette feature for their laboratory processes that can be designed and sent out via web update or site visit file transfer. This novel improvement bridges the gap between tooling costs and customer needs making it possible to provide customers with a customized cassette feature tailored to their specific needs.

[0101] All modern histopathology laboratories have some sort of computer database to track cases through the various stages of slide preparation and diagnosis. This includes a 2D printer which may indelibly mark a cassette frame for identifying the tissue sample, cassettes and slides created for that case. The 2D printer is typically adot matrix printer, however, the 2D printer may be an inkjet printer or any other suitable devices. These printers are fast and can print ink that sticks to the plastic surfaces of the cassette and will not become unreadable due to exposure to solvents and heat used in the processing of the tissue or embedding materials. Manufacturing which is performed in this manner will be referred to in this disclosure as 2D printing or as a 2D printer to distinguish it from a three dimensional (3D) printer which is a form of an additive manufacturing device.

[0102] Referring now to FIG. 4, a schematic diagram view of the incorporation of custom manufacturing processes in histopathology tissue sample preparation is shown. The first step to incorporate custom manufacturing is market evaluation and pricing 50. Market evaluation and pricing 50 includes determining whether there is a need in the histopathology tissue sample market for the specific manufacturing. Determining pricing for the manufacturing is also determined. Then market evaluation and pricing 50 leads to research and development (R&D) 52 including the design and testing of manufactured products. R&D 52 allows for users to test manufactured histopathology tissue sample devices before mass production to ensure viability and a solution to the need identified in market evaluation and pricing 50. Lab verification 54 is undertaken to test manufacturing in an actual lab setting. Lab verification 54 allows pathologists and histotechnicians to test in an actual lab setting. After lab verification 54 a new product or update, or customer accounts are then available for use by the user. A new product or updates, or customer accounts 56 allows the user to utilize manufacturing that has been researched, designed, and lab verified. The user may receive the new product, updates, or customer accounts through the world wide web (WWW), cloud storage 62 or through the use of a universal serial bus (USB) or flash drive 58, etc., and a tech service 60 to a printer 64. Larger files may need to be transferred through a flash drive 58 to a tech service 60 that can download the new product, update, or customer account on to the printer 64. Other files may easily travel over WWW or cloud storage 62 to the printer 64 with an online application. The printer 64 may be a 3D printer or a 2D printer that receives and may create the new product or update from a customer account 56. The printer 64 may also be any additive manufacturing or subtractive manufacturing device. Additionally the printer 64 may be a combination 2D printer andcustom feature manufacturing device. This enables configuring of the type of tissue orientation, placement, and security needed for the exact type of biopsy. By incorporating a custom feature manufacturing device with a 2D printer, the laboratory printer becomes a cassette configuration station. This combination of 2D printing with cassette configuration customization greatly enhances automation of cassette configuration and tracking. However, in some applications a stand-alone printer could be used to build up inventory of a custom cassette that could be stored in the customer’s inventory for use when needed. Deployment of new ideas may go from validation to customer in short time frames as compared to current practice.

[0103] Referring now to FIGS. 5, 6, and 7, implementation of this technology can be as a stand-alone manufacturing system 200. The stand-alone manufacturing system 200 could be configured to manufacture the sectionable cassette features 210 into already accessioned 2D printed cassette preforms or base units 212. The manufacturing print head 224 and envelope may be a reduced size from what might be expected because it has a very small envelope compared to what is commercially available. For this embodiment, the X and Y axes of the manufacturing system 200 may be determined by how many cassettes 212 are to be inserted in the manufacturing system 200 at a single session. This illustrative embodiment shows a two cassette type stand-alone manufacturing system 200, however, it will be appreciated that any type of stand-alone manufacturing system may be used for the same purpose. For example, a four cassette type stand-alone manufacturing system may be used. This illustrative embodiment shows a knob 214 and a display 216 for use with choosing a customized cassette feature. The display 216 may display any character (i.e. numeric or alphabetic) or combination thereof and knob 214 is used to allow a user to select the customized feature being added to the cassettes 212.

[0104] Each cassette 212 is placed on a nest or receiving structure 218 presented by the slide out receptacle 220. Each cassette 212 includes a cassette basket 228 and lid 230. As shown in this illustrative embodiment, the nests 218 should have accurate repeatable positioning of each cassette 212 in relation to the X-Y motion of the manufacturing system 200, and to be capable of moving the cassettes 212 in the Z axis. As shown in FIGS. 6 and 7, both nests 214 are moved on one Z axisstepper / leadscrew 222 with a screw 246 towards the manufacturing print head 224. It is also possible to have a Z axis motion control with each Z axis stepper / leadscrew 222 on each nest 218. The Z axis stepper / leadscrew 222 moves the center of both nests 218 while collars 240, 242 move along shafts 238. Each shaft 238 is positioned at two of the corners of each nest 218. The collars 240, 242 prevent the nests 218 from sliding and allow the use of only one Z axis stepper / leadscrew 222. This may allow the manufacturing system 200 to work on one cassette 212 with the manufacturing print head 224 while another cassette 212 is preheating, cooling, or 2D printing. The manufacturing print head 224 may be a 3D printer or any other suitable device. The manufacturing print head 224 includes a housing 250 with a nozzle 248. The housing 250 moves the manufacturing print head 224 in the X axis and the Y axis and along rails 234 and 236. The nozzle 248 delivers material on to the cassette 212 creating a customized feature 210. While one nozzle 248 is shown, more than one nozzle 248 may be used to deliver several different materials through the manufacturing print head 224.

[0105] Referring now to FIG. 7, the nests 218 may also be equipped with thin metal or high temperature flex plates 226 under the basket 228 and / or lid 230. The term “basket”, when in reference to the cassette 212, is used throughout this disclosure as a term to describe the tissue cassette 212 and, as mentioned, may take any desired shape or configuration. As shown in this illustrative embodiment, there may be times when substantial portions of the lid 230 or cassette basket 228 are manufactured in place. By flexing or otherwise moving the flex plate 226 with ejection solenoids 232, the manufactured areas may be readily removed from the nest 218. Each ejection solenoid 232 includes a screw or electrically actuated plunger, for example, that pushes against the cassette basket 228 and the lid 230 of the cassette 212 to flex the flex plates 226. Taking the manufactured areas off the nest 218 may prevent a finished cassette 212 from getting stuck in the nest 218. A solid state heater / chiller Peltier device could be placed near the flex plate 226 to assist ejection.

[0106] A Peltier device is a solid-state thermoelectric heater / cooler that uses electricity to move electrons in one direction across joined dissimilar materials to create heat on one side and cold on the other side. This is called the "Peltier effect." ThePeltier effect allows one side of the substrate to absorb heat and the other to radiate heat, so the hot and cold sides switch depending on the current direction.

[0107] As shown in FIG. 7, some customizations of the manufacturing device 200 may be necessary to manufacture into the narrow confines of the cassette preform 212. This makes the customized features 210 manufactured on the lid 230 to be the easiest to implement. One of the hallmarks of the manufacturing technology is its adaption to the many kinds of thermoplastic polymers available. While many of these polymers are off the shelf, they may not be usable in this application. However, some polymers, like Acrylonitrile Butadiene Stryene (ABS) or Nylon, and others, may be usable in this manufacturing technology. Significant research has gone into the polymer selection for sectionable cassettes and the research has shown that these polymers may be usable in manufacturing. Furthermore, custom polymers can be extruded and supplied as filament for use as manufacturing material for additive manufacturing devices such as 3D printers.

[0108] In use, for example, a material may be loaded into a manufacturing device, either HVM or LVM, to create a customized feature of a cassette. The customized feature is then manufactured out of the material. Once the customized feature of the cassette is manufactured, a material is loaded into a separate manufacturing device that is either HVM or LVM. The customized feature is inserted into the separate manufacturing device and the material is used to finish the cassette. These various steps may or may not be performed by a direct step by step manufacturing method. Furthermore, several of the steps may be separated in time. For example, several people may be involved in creating the finished workable cassette. For example, the customized features or a cassette preform may be mass produced and held in storage until they are needed.

[0109] One of the unique advantages provided by the present disclosure is to be able to change the material properties of the manufacturing filament used to make the sectionable customized features. A tissue cassette preform / base unit may be made of a different material than the cassette feature. The tissue cassette preform may also be made with the same material as the cassette feature or a combination of materials. In a specific example, a custom manufacturing resin is extruded into filament from the samematerial as the sectionable cassette preform to allow homogeneous sectioning.However, it is envisioned that other resins may be developed which further enhance the nature of the sectionable part of the cassette. This material may flow easily and have all the characteristics of a sectionable cassette polymer. It is desirable to keep the manufacturing parts as light as possible so that the acceleration and deceleration of the manufacturing parts can happen quickly without causing significant jerk or shake of the entire manufacturing system. Most of this has to do with the control and torque specifications of the stepper motors used to move the print heads in X, Y and Z directions. The Z direction is also used in conjunction with a linear actuator. The Z actuator allows the manufacturing nest to be moved into position out of the way of the 2D printing path. The 3D print is done in a detour of line fashion. One embodiment of this is when the 3D nest is moved up the Z axis and the ink path is restored below it. In a second embodiment, the 3D nest is moved laterally out of the 2D printing path and a second Z axis is used to move the nest. This allows the creation of the Z level changes as the layers of plastic are extruded from additive manufacturing.

[0110] An existing 2D printing center commonly uses an inline track based design to manage the flow of cassettes through the printer. In more automated models, the unprinted cassettes are stacked in vertical magazines for storage. Mechanisms move the unprinted cassettes from pre-stacked magazines to be 2D printed. Then they are moved on to be exposed to ultraviolet (UV) which cures the ink. By making accommodations for several magazines to feed into the printing mechanism, the printer can store several types of cassettes (e.g., large , small, extra small, etc.). For specialty cassettes the magazine can be removed, and a different type of cassette fed via that feeder. Once an accessioned case is entered into the laboratory database and the number and type of cassettes in the case are chosen, the manufacturing device picks the correct supply magazine to pull an unprinted cassette from. Using the manufacturing type X-Y axis print head above the cassette and the Z axis nest configuration described previously, the instantly configurable manufacturing technology can be incorporated into the 2D printing type machine.

[0111] FIG. 8 is a top view diagrammatic design of one illustrative embodiment showing the movement and production of a finished cassette. In this illustrativeembodiment, 3D printing is used in conjunction with 2D printing on the outside surfaces of the cassette. The system 300 utilizes a cassette preform 310 selected from one of MAG 1 312a, MAG 2 312b, or MAG 3 312c. Once the cassette preform 310 is selected a shuttle motor 330 moves the cassette preform 310 to one of two nests that move along one of a 2D print path or a 3D print path. This illustrative embodiment shows the cassette preform 310 moving in a nest along the 3D print path. Both the 2D print path and the 3D print path have a production line 318. The cassette preform 310 moves along the production line 318 with the shuttle motor 330. The 3D print path includes a Z axis stepper / leadscrew 324 that moves the cassette preform 310 into contact with a 3D print head. The 3D print head adds a customized feature to the cassette preform 310 making a finished cassette 324. Once the cassette preform 310 leaves the production line 318, it enters the output track 322 where the cassette 324 is ready for use. Further, a 2D printing head can move above the two nests. The 3D printing nest is configured to interface with an existing 2D printing machine, either by direct incorporation, or as an add on at the output feed.

[0112] Referring now to FIG. 9, a top view diagrammatic design of another illustrative embodiment is shown. Like elements of structure and function in this illustrative embodiment are denoted with like reference numerals to those previously shown and described (FIG. 8), while like reference numerals having prime marks (‘) refer to like elements of the first embodiment but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art and / or described herein. Further description of such like elements is not given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative system 300’ is for higher throughput manufacturing devices, where additional integration into the 2D printer may detour an offline manufacturing process to free up manufacturing. Two 3D printing nests 334 are shown as detour points in the track. Once a cassette preform 310 is selected, it is placed into one of two nests. Each nest is connected to actuators 330’ that move the nests into position while the 2D printer mechanism 316 advances the nests to a position on the manufacturing device 300’. The cassette preform 310 is then translated out of the production track 318 by actuator 336 to the 3D print track. The Z-axis steppers 314’move the cassette preforms 310 in and out of contact with the 3D printer and allow the requested / selected custom cassette feature 320 to be manufactured. If necessary, a second operation, such as adding bias foam with a bias pad placer 326, is performed at this point in the process. When this point of the process is complete the manufactured cassette 324 can be moved back in the production line 318 to the output track 322. While the manufacturing device 300 is manufacturing one cassette 324, the 2D printer 316 can be performing the 2D prints and staging to output on the second side of the manufacturing system 300.

[0113] Some materials that are printed in manufacturing situations need to have hot environments to prevent significant shrinkage of the parts. However, this does not seem to be an overriding consideration as most of the parts are very small and shrinkage may not be significant enough to warrant complete environmental enclosure. If the material would require a hot print environment it is known art to enclose the printer in a hot environment chamber. It may be sufficient enough to include a solid-state heating and cooling element, such as a Peltier heater / cooler discussed above, in the nest. This may allow for rapid heating of the base material in the cassette and may also allow for better bonding between the manufactured product and the base cassette material. In addition, flex plates may be incorporated into the nest to help prevent the manufactured product from sticking to the nest. The manufactured product may stick to the nest when the material used oozes through the existing basket openings into the nest. Flex plates are common in standalone manufacturing systems. There are various different nonstick surfaces or textured surfaces that can prevent the manufactured product from sticking to the print bed.

[0114] The customized features can be printed on the lid or on the inside of the cassette body. They might also be printed partially or wholly on each lid and cassette, making customized features which can secure the tissue sample from the top and bottom. The customized features manufactured on a lid and connected cassette body may operate together or may operate independent of each other. These types of customized features are typically difficult to produce in standard cassette designs due to complicated slides or impossible to make undercuts in the draft needed to eject parts from the mold at each cycle.

[0115] Referring now to FIGS. 10A, 10B, 10C, 10D, and 10E, a histologic tissue sample support device according to another illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A and 3B) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art or described herein. Further description of such like elements is not given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment shows a histologic tissue sample support device 400 including a biasing feature 410 added to the lid 114 and a customized features 412 manufactured on top of the biasing feature 410. The biasing feature 410 may be made from open cell reticulated urethane foam or any other suitable material. Biasing feature 410, such as foam, can be magazine fed to a pick and place arm which shuttles the biasing feature 410 onto the lid 114. The manufacturing system secures the biasing feature 410 locking it down onto the lid 114. Once the biasing feature 410 is secured, the Z axis is staged up to the surface of the biasing feature 410 and the customized features 412 are manufactured onto the surface of the biasing feature 410. This allows the addition of customized features 412 on the biasing feature 410. The customized feature 412 further acts to compress the tissue 414 down against the bottom wall of the cassette body 110b ensuring that the tissue is flattened against the sectioning surface of the cassette body 110. Customized feature 412 may be additively and / or subtractively manufactured, as with other customized features contemplated by this disclosure. In addition biasing features 410 need not be custom manufactured and may be added to the device 400. Then the customized feature 412 can be manufactured on top of the biasing feature 410.

[0116] Further, FIG. 10D shows the cassette body 110 and lid 114 of the device 400 in the first position with respect to the frame 112 while the second, “staged” position is shown in FIG. 10E. FIG. 10D also shows the lid 114 in the closed position. In the second position, the lower portion of the cassette body 110 including the bottom wall 110b and at least a portion of the sidewall 110a is exposed below the bottom edge 112f of the frame 112 for allowing an embedded tissue sample to be sectioned in a microtome while the frame 112 is held in the microtome chuck. The cassette body 110and lid 114 are prevented from moving beyond this second position with down stops 124. The general procedure for processing, embedding, and sectioning is discussed in the above-incorporated patent and patent applications. The cassette body 110 and other microtome sectionable structures described herein may be formed from perfluoroalkoxyethylene (PFA) in accordance with the above-incorporated patents and patent applications. Alternatively, the microtome sectionable structure may be formed from any other suitable material capable of performing the necessary or desired functions. The biasing feature 410 biases the tissue samples 414 against the bottom wall 110b of the cassette body 110. The customized feature 412 may orient, bias, secure, or provide indicia to identify the tissue sample.

[0117] Referring to FIGS. 11A, 11 B, and 11C, another alternative, illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 10E) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment shows a histologic tissue sample support device 500 with customized features 510 as being cantilever springs made from sectionable manufacturing material placed on the lid 114. The cantilever springs 510 bias extended trough-like structures 512 configured to hold tissue sample 516, 518. Each extended trough-like structure 512 has two cantilever structures 510. The extended trough-like structure 512 includes a plate 513 with recessed portions 514 extending towards the tissue sample 516, 518. This illustrative embodiment shows five recessed portions 514 on the plate 513, however, the plate 513 may be manufactured to suit any number of recessed portions 514. While two sets of two cantilever springs 510 and one trough-like structure 512 are shown with tissue samples 516, 518, the lid 114 may have more or fewer cantilver springs 510 and trough-like structures 512 to hold any number of tissue samples. As the manufacturing system becomes more accepted in the pathology laboratory, additional steps could lead to more creative implementation that combines cassette preforms with sectionable customized features. Core biopsies are positionedin the elongated trough-like structure 512 and the device 500 is closed by holding the lid 114 stationary and placing the cassette body 110 and frame 112 on top of the lid 114 to trap the core biopsy against the bottom wall of the cassette 110b. The manufactured bias springs 510 ensure that the core biopsy is biased or retained securely against the bottom wall of the cassette 110b, assuring that all core biopsies are in the same sectioning plane. The bias springs 510 and elongated trough-like structures 512 may be used for any of the illustrative embodiments throughout.

[0118] Referring to FIGS. 12A and 12B, another alternative, illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 11C) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art and / or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment includes a histologic tissue sample support device 600 with customized features requiring manufacturing for both the lid 614 and the cassette body 616. The entire cassette body 616 may be manufactured and inserted into the frame 112 and an entire lid 616 may be manufactured and inserted into a lid frame 610. The cassette body 616 includes an interior or recess 611 with at least one sidewall 610a and a bottom wall 616b. The lid frame 610 is coupled to the frame 612 by a hinge 118. This illustrative embodiment shows the cassette body 616 being manufactured and inserted into the frame 112. The cassette body 616 includes frame-cassette connectors 618 configured to slide inside slots 624 in the frame 612. Slots 624 extend from the top edge 612g to the bottom edge 612f of the frame 612. The lid frame 610 includes an open area 614 where a manufactured lid may be manufactured and snap fit into pockets 622 in the lid frame 610.

[0119] Here, manufacturing is used to make a cassette feature in the form of a tissue cradle on the bottom wall of the tissue cassette 616b. The tissue cradle is created by posts 626 extending up from the bottom wall of the cassette 616b. For example, The posts 626 are offset to cradle tissue 620, 621 in the cassette body 616. Any number of posts 626 may be used to cradle the tissue 620, 621. In alternativeembodiments, a biasing feature, such as foam, may be manufactured or coupled on a lid and coupled to the lid frame 610. This ensures the tissue 620, 621 is retained or biased towards the bottom wall of the tissue cassette 616b. These customized features prevent the tissue 620, 621 from being dislodged from the customized features and ensure that it is flattened against the bottom wall or sectioning surface of the tissue cassette 616b. In alternative embodiments, the posts 626 may be added to a lid 614 and foam may be added to the bottom wall 616b of the cassette body 616.

[0120] Referring to FIGS. 13A through 13D, another alternative, illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 12B) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment shows histologic tissue sample support device 700 with holes 716 in the lid 714. The cassette body 710 includes an interior or recess 711 with at least one sidewall 710a and a bottom wall 710b. One or more of these holes 716 can be used as anchor points to secure customized feature (not shown) to the lid 714. Any other structure or element may be used instead of or in addition to the holes for coupling a customized feature to the lid 714, as these holes 716 are only illustrative examples. In addition, the customized feature may be formed separately and then coupled to the lid 714, or may be formed in-situ, such as using additive manufacturing or another method. For example, the customized feature may be extruded into the holes 716 and then onto a surface of the lid 714. This may create a “locked-in” base to continue manufacturing a customized feature into the device 700. Many types of customized features can be used with these same concepts. They can be simple customized features like orientation pins or walls or more complex customized features like a skin orientation feature.

[0121] In this illustrative embodiment, a skin orientation feature 720 may have tissue clamp plates 726 that can clamp the skin 718 in an upright position. As best shown in FIGS. 13C and 13D, the tissue clamp plates 726 hold the skin sample 718 inthe correct orientation. The tissue clamp plates 726 are attached to supports 728. Supports 728 deliver torsion from torsion bars 722 to the clamp plates 726. Clamp plates 726 may have protrusions that extend towards the tissue sample 718. While three clamp plates 726 are shown on each skin orientation feature 720, any number of clamp plates 726 may be used to clamp the tissue 718. The torsion bars 722 are supported by rigid supports 730 and may be used to attach the skin orientation feature 720 to the bottom wall 710b of the cassette body 710. Rigid supports 730 may attach to the bottom wall 710b by a dovetail docking feature, for example, and / or may include any other type of mechanical connection suitable for this application. While one set of skin orientation features 720 are shown with one tissue sample 718, it will be appreciated that any number of skin orientation features 720 may be used to orient as many tissue samples as desired by the user. In an alternative illustrative embodiment, the skin orientation features 720 may be manufactured so as to be coupled to the lid 714.

[0122] Referring to FIGS. 14A and 14B, another alternative, illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 13D) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art and / or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. In this illustrative embodiment another histologic tissue sample support device 800 may be a version which would look mostly like an existing sectionable cassette but has at least a portion of the bottom wall 810b of the cassette body 810 omitted thereby creating an opening 812. The cassette body 810 includes an interior or recess 811 with at least one sidewall 810a and a bottom wall 810b. This may allow the entire bottom wall 810b to be manufactured into the device 800 to essentially complete the bottom wall 810b or fill the opening 812. This illustrative embodiment shows a portion of the bottom wall 810b to support a customized cassette feature. This effectively makes an enclosed device 800 with a bottom, except the bottom may be customized with various cassette features. Special dovetail docking features 816 may be molded into the walls of the cassette, or otherwise coupled to the cassette, and the custom cassette featuremay lock into place and attach to the bottom, or even become the bottom of the cassette. In alternative embodiments, these dovetail docking features may be molded into the lid 114. These dovetail docking features 816 may be used in any of the illustrative embodiments throughout, or may be substituted by, or complemented by other types of connectors.

[0123] The manufacturing device may manufacture extremely thin layers of material on the order of 0.1mm thick. A feature on any part of the tissue sample support device, such as a cassette similar to those shown and described herein, may also be manufactured much flatter than can be molded since it may be manufactured directly onto a flat surface. One advantage of this is that less time is required when opening up the cassette to gain access to the tissue sample to be sectioned. This operation is referred to in this disclosure as “facing” or “to face”. Facing tends to be a time consuming operation in the microtome when using sectionable cassettes. Any reduction in bottom thickness of the cassette is welcome as it reduces the time taken to face the cassette during a microtome or slicing operation, and remove all of the bottom structure before making slides comprised of hardened paraffin and the tissue sample.

[0124] Referring to FIG. 15, another alternative, illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 14B) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art and / or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment shows histologic tissue sample support device 900 with a frame 912, a sectionable breakaway cassette body 910, and a lid 914. The cassette body 910 includes an interior or recess 911 with at least one sidewall 910a and a bottom wall 910b. The device 900 could be utilized with a separate lid 914 or lid frame including a lid structure and a lid feature 922, that secures, aligns, orients, and / or biases a tissue sample. The lid feature is coupled with biasing feature 920, such as foam, and similar to the biasing feature discussed in detail above. The lid 914 or lid frame may be coupled with the cassette preform. The lid 914 includes cutters 918 to break the^0-breakaway connectors 910c on the cassette body 910. The cutters 918 may be utilized by a user pressing against the lid 914 or by machine staging 916, shown in this illustrative embodiment. Machine staging 916 helps the user break the breakaway connections 910c and to stage the cassette to the second position for sectioning as discussed previously. This may be used for any of the illustrative embodiments throughout.

[0125] Referring to FIG. 16, another alternative, illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 15) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art and / or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment shows a histologic tissue sample support device 1000 with a cassette body 1010, a frame 112, a frame peripheral portion 1016, and a lid peripheral portion 1014. The cassette body 1010 includes an interior or recess 1011 with at least one side wall 1010a and a bottom wall 1010b. The frame 112 may be made of non-sectionable material. The frame peripheral portion 1016 and the lid peripheral portion 1014 are coupled together by breakaway connectors 1018. The lid peripheral portion 1014 includes docking features 1020 configured to hold a customized lid feature 1022 that is manufactured in accordance with this disclosure, such as through additive or subtractive manufacturing processes. The customized lid feature 1022 includes a base 1024 with perforations 1028. The base includes posts 1026 to bias, orient, and / or secure tissue against the bottom wall 1010b of the cassette body 1010. The breakaway connectors are broken in any suitable manner as the lid peripheral portion 1014 and the customized lid feature 1022 are staged to a second position for sectioning as previously described. The cassette body 1010 may be a customized feature held in the frame 112 by breakaway connectors 1012. The cassette body 1010 includes customized cassette features 1030 to bias, orient, and / or secure tissue inside the cassette body 1010. The cassette body 1010 and the customized lid feature 1022 may be made out ofsectionable material, and like any of the customized features mentioned herein, may be formed via rapid techniques such as additive or subtractive manufacturing.

[0126] Referring to FIG. 17, another alternative, illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 16) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art and / or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment shows a histologic tissue sample support device 1100 with a cassette body 1110 and an integrated frame 112. The cassette body 1110 includes an interior or recess 1111 with at least one sidewall 1110a and a bottom wall 1110b. The cassette body 1110 and lid 1114 are manufactured and added to the frame 112. The cassette body 1110 and lid 1114 are coupled together by a hinge 118. The lid 1114 includes a biasing feature 1116 with a customized lid feature 1118 manufactured, such as with additive or subtractive manufacturing, to hold a tissue sample 1120. The cassette body 1110 and lid 1114 snap fit into the frame 112. This allows for the mass production of frame 112 and the ability for a user or other facility to rapidly manufacture the customized, sectionable parts of the device 1100, such as via additive or subtractive manufacturing techniques. Additive manufacturing and subtractive manufacturing may be used for any of the embodiments throughout this disclosure and in any combination.

[0127] In some modern manufacturing systems, the use of sensors are incorporated to produce first layer compensation to the build plate. A sensor may include a scanner, for example a lidar unit or other similar devices. Before the manufacturing system starts a build, it may scan the build plate for any irregularities in the X-Y plane in relationship to the fixed sensor position on the manufacturing device. Any irregularities of the build plate may then be offset by a thin printed element between the build plate and the first layer of the part to be manufactured. The sensor unit may be a very small device which may be installed on the manufacturing system. In the novel application of this technology for use in securely trapping or retaining the tissue to the cassette, the sensor scans the tissue which has been positioned on or in thecassette. Then the sensor may be used to create a 3D contour map of the tissue in the orientation intended for sectioning. Digital processing may be required in order to determine the boundary of the biopsy perimeter and contour map. That information may be used to create code to provide for a customized feature for each individual biopsy sample.

[0128] As this is somewhat of a change to the existing way in which grossing in is traditionally done, this type of customized feature may be performed at a separate manufacturing station. This separate manufacturing station could be dedicated to retaining the tissue samples to the cassette almost instantaneously at the gross in stage. This represents a new way to orient and retain a tissue sample in a sectionable cassette. In this manner the operator needs to do very little other than to place the tissue loosely on the cassette in the desired orientation. The manufacturing system may do the rest of the securing and retaining of the tissue in that predetermined orientation.

[0129] Referring to FIGS. 18A through 18C, another alternative, illustrative embodiment is shown. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 17) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art and / or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment shows a histologic tissue sample support device 1200 with a large tissue sample 1224 positioned on the lid 1214. The lid 1214 includes perforations 1216. The tissue sample 1224, cassette body 110, lid 1214, and frame 112 may be inserted into the manufacturing device. Then the manufacturing device may scan the tissue sample 1224 on the lid 1214, determine the best way to secure and retain the tissue sample 1224, and then manufacture a securing feature 1218 to secure the tissue sample 1224 against the lid 1214. This illustrative embodiment includes ten of the securing features 1218 to secure the tissue sample 1224, however, any number may be used. Each securing feature 1218 includes a base 1220 to secure the securing feature 1218 to the lid 1214 and a finger 1222 that contacts and secures the tissuesample 1224. Once each securing feature 1218 is manufactured, a matrix 1226 secures the rest of the tissue sample 1224 to the lid 1214. More specifically, FIG. 18A shows tissue 1224 secured to the lid 1214 with the matrix 1226 and ten securing features 1218. Each of the securing features 1218 and matrix 1226 may be manufactured by additive manufacturing, such as 3D printing. While one tissue sample 1224 is shown, several tissue samples may be secured to the lid 1214 with the securing features 1218 and matrix 1226. FIGS. 18B shows the tissue sample 1224 secured against the lid 1214 with the securing features 1218 and the matrix 1226. FIG. 18C shows the tissue sample 1224 held against the lid 1214 with each securing feature 1218 and without the matrix 1226. In alternative illustrative embodiments, a tissue sample may be added to the cassette body 110 with a securing feature added. In another alternative illustrative embodiment, a securing feature may be added to the lid or cassette body before the tissue sample is placed.

[0130] In addition to creating customized features, it is important to note that the concept of having a first incomplete frame base and doing secondary finishing is not limited only to using additive manufacturing methods. The term “frame base” or “base unit” is used throughout this disclosure and refers to a preform, as discussed above. Just as additive manufacturing methods, such as 3D printing, have been revolutionized in the last few years, so too have reductive or, in other words, subtractive manufacturing methods been impacted by advances in computer numerical control (CNC) motion control and software / firmware breakthroughs. Now small desktop machine centers have taken advantage of the machining precision and ease of programming that was, until lately, only available in large heavy industrial machine tools. Therefore, it will be understood that “additive manufacturing” and like terminology may be enabled through 3D printing, while “subtractive”, “reductive” or similar manufacturing techniques may be enabled through machining such as CNC machining techniques.

[0131] If one applies subtractive manufacturing to create unique sectionable customized features on an incomplete cassette and / or frame preform, many of the features of the additive manufacturing process can be replaced by the subtractive manufacturing process. The spindle cutter and axis drives replace the additive manufacturing apparatus discussed above with a subtractive manufacturing center.The cassette and / or frame preform may look somewhat similar to the additive manufacturing cassette preform. However, this type of preform or base unit will have one or more sectionable area(s) which may be modified or changed to suit the needs of the customer by machining away material to create features to secure, align, orient, bias and / or provide indicia to identify a tissue sample just as the additive manufacturing system may have done. However, with subtractive or reductive manufacturing, the starting point may be a rough sectionable pad or area. Then, unneeded material is removed, leaving behind the desired feature(s). This subtractive or reductive manufacturing process may have advantages over the additive manufacturing method. For example, machining away or otherwise removing material may be faster than adding and building certain structures with an additive manufacturing device.

[0132] FIGS. 19A and 19B show an alternative illustrative embodiment. In this embodiment, like reference numerals are used to refer to like elements and function as between the different embodiments (FIGS. 3A, 3B, and 10A through 18C) but having slightly different structure and / or function which will be either apparent to those of ordinary skill in the art and / or described herein. Further description of such like elements may not be given hereinbelow so as to reduce redundancy, except as necessary or desirable in describing this illustrative embodiment. This illustrative embodiment shows a histologic tissue sample support device 1300 with a machineable portion 1322 on the lid 1314 that may be subtractively manufactured to add a customized feature. The machineable portion 1322 in or on the lid 1314 may be made from sectionable material so that once subtractively manufactured, the newly formed customized feature is sectionable. The machineable portion 1322 is similar to the biasing features, discussed above, and may be added to the lid 1314 in the same manner. More specifically, FIGS. 19A and 19B show a frame peripheral portion 1316 connected to the frame 112 by a hinge 118. The lid 1314 includes perforations 1324. The lid peripheral portion 1316 is coupled to the lid 1314 by breakaway connectors 1318, similar to those discussed above. The breakaway connectors 1318 may be broken in any suitable manner such as by a user or machine during staging of the lid and the cassette body 1310 to a second position suitable for the sectioning process, as previously described. The cassette body 1310 includes an interior or recess 1311 withat least one side wall 1310a and a bottom wall 1310b. The cassette body 1310 is connected to the frame 112 by breakaway connectors 1320, similar to those discussed above.

[0133] FIG. 20 shows a subtractive manufacturing device 1330, such as a CNC machine, with device 1300. The subtractive manufacturing device 1330 removes material from the machineable portion 1322 to add customized features 1326 to the lid 1314. The subtractive manufacturing device 1330 includes a cutting tool 1332 held in place by a spindle 1334. The spindle 1334 rotates the cutting tool 1332 to cut material. Several cutting tools 1332 may be used including end mills, drills, and lathe tools. The solenoid 1336 moves the cutting tool 1332 and spindle 1334 in the Z axis as necessary to cut material. The housing 1338 is capable of moving the subtractive manufacturing device 1330 in the X axis and the Y axis by moving along rails 1340 and 1342. Tube 1346 encases the power cables for powering the subtractive manufacturing device. The subtractive manufacturing device 1330 is supported by at least one post 1344. Different customized features 1326 may require different sizes and types of subtractive manufacturing devices 1330. The subtractive manufacturing device 1330 may produce customized features that bias, orient, secure, and / or bias a tissue sample.

[0134] The next iteration of this technology utilizes a process where the customized features are preproduced and stored in bulk in preparation to be inserted into a cassette preform. These customized features may be parts that complete the cassette body or the lid. The reason for this may be that all the customized features produced by HVM are those which are common to high volume cassette designs and features. Furthermore, this allows a preproduced customized feature to be inserted into the high volume cassette design process prior to completion. This may allow a quickly configurable customized feature to be switched out or selected to be inserted into an otherwise HVM product.

[0135] LVM may produce sectionable tissue cassettes in a small batch. In addition, the small batch processes of the LVM methods allow production to stockpile seldom called for features and only produce the finished assembly of parts on an as needed basis. The stored LVM features can then be stored and later fed into assembly machines which can install them into a frame produced by HVM. Overall, the keybenefit is the ability to create, test, and implement new cassette designs and get to the marketplace faster and with less capital expenditure.

[0136] Another similar concept may be to position a LVM tool, like a 3D printing head, which can slide into an opened HVM machine, like an injection molding machine, between a hot and a cold half of a mold base. The 3D print head may be positioned on a sliding track which may bring the 3D print head into position where it may make a customized feature onto a movable core inside the opened HVM machine. The movable core may then close, producing an open cavity between the hot half and the cold half of the mold. The open cavity may then be filled with a HVM grade thermoplastic such as those used to make a rigid frame and a sectionable tissue cassette. This may mitigate or be in place of changing out the multicavity tooling inserts, as discussed above.

[0137] Since LVM methods require no specific tooling to create parts, new designs can be conceived, prototype tested and implemented extremely quickly compared to the long lead times and expense that it takes to create multicavity tooling. Many ways have been described throughout this disclosure in which that may be accomplished. The advent of LVM devices and the ability to tailor the polymer used in the LVM device’s extruding process may allow a cassette designer to only design what needs to change between desirable features of the cassette. These novel concepts enable the manufacturer of cassettes to have the ability to provide a nimble customer driven portfolio of products that may serve smaller markets and niche embedding requirements. This portfolio of products may not otherwise be financially possible.

[0138] While the present disclosure has been illustrated by the description of specific embodiments thereof, and while the embodiments have been described in considerable detail, it is not intended to restrict or in any way limit the scope of the appended claims to such detail. The various features discussed herein may be used alone or in any combination within and between the various embodiments. Additional advantages and modifications will readily appear to those skilled in the art. The invention in its broader aspects is therefore not limited to the specific details, representative apparatus and methods and illustrative examples shown and described. azAccordingly, departures may be made from such details without departing from the scope or spirit of the general inventive concept.

Claims

What is claimed is:

1. A histologic tissue sample support device for carrying a tissue sample, the device comprising: a tissue cassette configured to hold the tissue sample, the tissue cassette including at least one side wall, the tissue cassette formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue; a cassette feature coupled to the tissue cassette, the cassette feature including at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, the cassette feature formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue; wherein the tissue cassette and the cassette feature are capable of moving from a first position to a second position with respect to the frame and, in the second position, at least a portion of the cassette feature and at least a portion of the side wall extend beyond the bottom edge of the frame for sectioning in the microtome.

2. The device of claim 1 , wherein the device further comprises: a lid coupled to at least one of the frame or the tissue cassette, the lid being capable of moving from the first position to the second position with respect to the frame.

3. The device of claim 2, wherein the device further comprises: a lid feature coupled to the lid, the lid feature including at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, the lid feature formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.

4. The device of claim 2, wherein the device further comprises: a biasing feature coupled to the lid, the biasing feature configured to bias a tissue sample against the bottom wall of the tissue cassette, the biasing feature formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process, and stain tissue; and a customized feature coupled to the biasing feature, the customized feature including at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, the biasing feature formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.

5. A histologic tissue sample support device for carrying a tissue sample, the device comprising: a tissue cassette configured to hold the tissue sample, the tissue cassette including at least one side wall, the tissue cassette formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue; a frame including a bottom edge, the tissue cassette being movably coupled to the frame; a lid coupled to at least one of the frame or tissue cassette; and a lid feature coupled to the lid, the lid feature including at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, the lid feature formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue; wherein the lid, the lid feature and the tissue cassette are capable of moving from a first position to a second position with respect to the frame and, in the second position, at least a portion of the lid feature and at least a portion of the side wall extend beyond the bottom edge of the frame for sectioning in the microtome.

6. A histologic tissue sample support device for carrying a tissue sample, the device comprising: a tissue cassette configured to hold the tissue sample, the tissue cassette including at least one side wall, the tissue cassette formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue; a frame including a bottom edge, the tissue cassette being movably coupled to the frame; a lid coupled to at least one of the frame or tissue cassette; a biasing feature coupled to the lid, the biasing feature including an element to bias a tissue sample; and a customized feature coupled to the biasing feature, the customized feature including at least one element to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, the customized feature formed of material that can be successfully sectioned in the microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue; wherein the lid, the customized feature, the biasing feature and the tissue cassette are capable of moving from a first position to a second position with respect to the frame and, in the second position, at least a portion of the biasing feature and at least a portion of the side wall extend beyond the bottom edge of the frame for sectioning in the microtome.

7. A method for making a device for holding a histologic tissue sample while sectioning the tissue sample, the method comprising: loading a cassette preform into a manufacturing device; manufacturing a cassette feature on the cassette preform, the cassette feature being configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, and being formed of material that can be successfully sectioned in a microtome, the cassette feature further being resistant to degradation from solvents and chemicals used to fix and process the tissue sample during a histologic procedure.

8. The method of claim 7, wherein manufacturing the cassette feature further comprises making the cassette feature using at least one of additive manufacturing or subtractive manufacturing.

9. The method of claim 7, wherein the method further comprises: manufacturing a lid feature on the cassette preform, the lid feature being configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, and being formed of material that can be successfully sectioned in a microtome, the lid feature further being resistant to degradation from solvents and chemicals used to fix and process the tissue sample during a histologic procedure.

10. The method of claim 9, manufacturing the lid feature further comprises making the cassette feature using at least one of additive manufacturing or subtractive manufacturing.

11. A method for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device, the method comprising: loading a cassette preform into a manufacturing device; manufacturing a cassette from the cassette preform using the manufacturing device, including the formation of a cassette feature on the cassette preform, the cassette feature being formed of material that can be successfully sectioned in a microtome, and the cassette feature further being resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure; and securing the tissue sample to the cassette, at least in part by using the cassette feature.

12. The method of claim 11 , wherein manufacturing the cassette and formation of the cassette feature further comprises making the cassette, including the cassette feature, using at least one of additive manufacturing or subtractive manufacturing.

13. The method of claim 11 , wherein the method further comprises: closing a lid when a tissue cassette is positioned within a frame and in a first position relative to the frame.

14. The method of claim 13, wherein the method further comprises: moving the lid and the tissue cassette into a second position within the frame where at least a portion of the tissue cassette and at least a portion of the cassette feature extend beyond a bottom edge of the frame for sectioning in the microtome.

15. The method of claim 11 , wherein the method further comprises: manufacturing a lid feature on the cassette preform using the manufacturing device, the lid feature being formed of material that can be successfully sectioned in a microtome, and the lid feature further being resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histological procedure.

16. The method of claim 15, wherein manufacturing the cassette, including formation of the cassette feature, and manufacturing the lid feature further comprises making the cassette, including the cassette feature, and manufacturing the lid feature using at least one of additive manufacturing or subtractive manufacturing.

17. The method of claim 16, wherein the method further comprises: securing the tissue sample to the cassette, at least in part by using the lid feature.

18. A method for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device including a lid, the method comprising: loading a lid preform into a manufacturing device; manufacturing the lid from the lid preform using the manufacturing device, including the formation of a lid feature on the lid preform, the lid feature being formed of a material that can be successfully sectioned in a microtome, the lid feature further being resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure; securing the tissue sample to the lid at least in part by using the lid feature; positioning the support device within a frame and in a first position relative to the frame; closing the lid while the tissue sample is secured to the lid with the lid feature; and moving the lid and the lid feature into a second position within the frame where at least a portion of the lid feature extends beyond a bottom edge of the frame for sectioning in the microtome.

19. The method of claim 18, wherein manufacturing the lid and formation of the lid feature further comprises making the lid, including the lid feature, using at least one of additive manufacturing or subtractive manufacturing.

20. The method of claim 18, wherein the method further comprises: closing the lid when support device is positioned within a frame and in a first position relative to the frame.21 . The method of claim 20, wherein the method further comprises: moving the lid and the support device into a second position within the frame where at least a portion of the lid feature extends beyond a bottom edge of the frame for sectioning in the microtome.

22. The method of claim 19, wherein the method further comprises: securing the tissue sample to the support device, at least in part by using the lid feature.

23. A method for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device including a cassette, the method comprising: loading a cassette preform into a manufacturing device; manufacturing the cassette from the cassette preform using the manufacturing device, including the formation of a lid feature on the cassette preform, the lid feature being formed of material that can be successfully sectioned in a microtome, and the lid feature further being resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure; and securing the tissue sample to the cassette, at least in part by using the lid feature.

24. The method of claim 23, wherein the formation of the lid feature further comprises making the lid feature on the cassette preform using at least one of additive manufacturing or subtractive manufacturing.

25. The method of claim 23, wherein the method further comprises: manufacturing a cassette feature on the cassette preform using the manufacturing device, the cassette feature being formed of material that can be successfully sectioned in a microtome, and the lid feature further being resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure.

26. The method of claim 25, wherein manufacturing the cassette feature further comprises making the cassette, including the cassette feature, using at least one of additive manufacturing or subtractive manufacturing.

27. The method of claim 26, wherein the method further comprises: securing the tissue sample to the cassette by using the lid feature and / or the cassette feature.

28. A cassette preform device, the device comprising: a cassette preform body configured to form a portion of a tissue cassette for holding a tissue sample; and a cassette preform element coupled with the cassette preform body configured to allow for providing a manufactured cassette feature configured to secure, align, orient, bias, and / or provide indicia to identify the tissue sample.

29. The device of claim 28, wherein the cassette preform body is further configured to form a portion of a lid.

30. The device of claim 28, wherein the device further comprises: a second cassette preform element coupled with the cassette preform body configured to allow for providing a manufactured lid feature, the lid feature configured to secure, align, orient, bias, and / or provide indicia to identify the tissue sample.31 . A cassette preform device, the device comprising: a cassette preform body configured to form a portion of a lid for holding a tissue sample; and a cassette preform element coupled with the cassette preform body configured to allow for providing a manufactured lid feature to secure, align, orient, bias, and / or provide indica to identify the tissue sample.

32. An apparatus for making a tissue sample support device, the apparatus comprising: a sensor configured to detect at least a portion of a preform; and a manufacturing unit configured to provide a feature on the preform based at least in part on the detected portion of the preform, the feature configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample.

33. The apparatus of claim 32, wherein the apparatus further comprises: an actuator configured to assist with providing the feature to the preform.

34. The apparatus of claim 32, wherein the apparatus further comprises: a receptacle configured to hold the preform.

35. The apparatus of claim 32, wherein the apparatus further comprises: an actuator configured to move the preform.

36. The apparatus of claim 32, wherein the sensor is a scanner.

37. The apparatus of claim 32, wherein the sensor is a 3D scanner.

38. A method for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device, the support device including a surface, the method comprising: positioning a tissue sample on the surface; scanning at least a portion of the surface with a sensor, creating a contour map based at least in part on the scanned surface; and manufacturing a microtome sectionable surface feature such that the surface feature is coupled to the surface, the surface feature being manufactured based at least in part on the contour map, the surface feature being configured to secure, orient, align, bias, and / or provide indicia to identify the biopsy tissue sample.

39. The method of claim 38, wherein the surface is coupled with a frame, the frame including a bottom edge.

40. The method of claim 38, wherein the surface is formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.41 . The method of claim 38, wherein the surface feature is formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.

42. The method of claim 38, wherein the sensor is a scanner.

43. The method of claim 38, wherein the sensor is a 3D Scanner.

44. A method for preparing a biopsy tissue sample for histological examination using a histologic tissue sample support device, the support device including a surface, the method comprising: positioning the tissue sample on the surface; scanning at least a portion of the surface and / or the tissue sample with a sensor; creating a first contour map based at least in part on the scanned surface; manufacturing a sectionable surface feature such that the surface feature is coupled to the surface, the surface feature being manufactured based at least in part on the contour map, the surface feature being configured to secure, orient, align, bias and / or provide indicia to identify the tissue sample; scanning at least a portion of the surface feature and / or the surface with the sensor; creating a second contour map based at least in part on the scanned surface feature and / or the scanned surface; and manufacturing a sectionable securing feature coupled to the surface feature and / or the surface, the securing feature being manufactured based at least in part on the second contour map, the securing feature being configured to retain the tissue sample against the surface feature and / or the surface.

45. The method of claim 44, wherein the surface is coupled with a frame, the frame including a bottom edge.

46. The method of claim 44, wherein the surface is formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.

47. The method of claim 44, wherein the surface feature is formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.

48. The method of claim 44, wherein the securing feature is formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue.

49. The method of claim 44, wherein the sensor is a scanner.

50. The method of claim 44, wherein the sensor is a 3D scanner.51 . A method for manufacturing a cassette preform, the method comprising: loading a material into a manufacturing device; and manufacturing the cassette preform, the cassette preform manufactured to have a cassette preform feature.

52. The method for manufacturing a cassette preform of claim 51 , further comprising: manufacturing the cassette preform feature using at least one of additive manufacturing or subtractive manufacturing with the cassette preform feature being configured to secure, orient, align, bias, and / or provide indicia to identify a biopsy tissue sample.

53. A method for making a biopsy tissue sample cassette, the method comprising: loading a first material into a first manufacturing device; manufacturing a customized feature out of the material by using the first manufacturing device, the customized feature configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample, the customized feature further being resistant to degradation from solvents and chemicals used to fix and process a tissue sample during a histologic procedure; inserting the customized feature into a second manufacturing device; loading second material into the second manufacturing device; and manufacturing at least a portion of the cassette with the second manufacturing device in a manner coupling the second material to the customized feature.

54. The method of claim 53, wherein the first and second materials are the same material.

55. The method of claim 53, wherein the first and second materials are different materials.

56. The method of claim 53, wherein the first manufacturing device is an additive manufacturing device or a subtractive manufacturing device.

57. The method of claim 53, wherein one of the first or second manufacturing devices is a mold and the other of the first or second manufacturing devices is an additive manufacturing device or a subtractive manufacturing device.

58. Apparatus for making a tissue sample support device, the apparatus comprising: an additive manufacturing device configured to manufacture at least a portion of a feature configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample on a cassette; and a mold configured to manufacture one or more portions of the cassette other than the portion of the feature configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample on the cassette.

59. Apparatus for making a tissue sample support device, the apparatus comprising: a subtractive manufacturing device configured to manufacture at least a portion of a feature configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample on a cassette; and a mold configured to manufacture one or more portions of the cassette other than the portion of the feature configured to secure, align, orient, bias, and / or provide indicia to identify a tissue sample on the cassette.

60. A biopsy tissue sample indicia device, comprising: an element including a plurality of recesses, the element being formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue; and a detectable substance located in at least some of the plurality of recesses; wherein the detectable substance in at least some of the plurality of recesses provides information regarding the tissue sample.61 . A method for providing information regarding a biopsy tissue sample, comprising: providing an element including a plurality of recesses and including a detectable substance located in at least some of the recesses, the element formed of material that can be successfully sectioned in a microtome and is resistant to degradation from solvents and chemicals used to fix, process and stain tissue; and detecting information regarding the tissue sample based on a pattern produced by the detectable substance in at least some of the plurality of recesses.

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