text:
|Publication number
|Publication type
|Application number
|PCT number
|Publication date
|Jan 2, 2007
|Filing date
|Oct 5, 1998
|Priority date
|May 14, 1996
|Fee status
|Also published as
|Publication number
|Warren P. Williamson, IV, Stephen Whitlach, Dominic DiNovo, Douglas Allen, Thomas Ward
|Original Assignee
|Biopath Automation, L.L.C.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (59), Non-Patent Citations (1), Referenced by (111), Classifications (17), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
The instant application is a continuation-in-part of application Ser. No. 08/645,750, filed on May 14, 1996, and presently pending. All of the material of this application is incorportated by reference into the present application.
The present invention relates to the general art of analysis of tissue samples, and to the particular field of obtaining, handling and processing tissue biopsy samples.
When disease is suspected in a living being, the physician must arrive at a specific diagnosis. Some disease processes, particularly tumors, require a histologic and/or cytologic diagnosis. While radiologic tools are useful in detecting the presence of a tumor, the cell type of the tumor can only be determined by a pathologist's examination of a histologic or cytologic sample of the tumor. There are a number of devices that have been fashioned to actually perform the act of taking tissue samples. These devices may obtain tissue for histology or in the case of needle aspiration biopsies, samples for cytology and histology. In many cases, these samples are very small and difficult to retrieve and process. These small tissue fragments may originate from a punch, or similar biopsy procedure devices or from Fine Needle Aspiration Biopsy (FNAB) biopsies. FNAB is typical and produces single cells, small cell clumps and fragments which are immediately smeared onto a glass slide (direct smears) or rinsed into a container with preservative fluid. After being transported to the laboratory, these samples are centrifuged onto a glass slide (cytospin smears). In some cases needle aspiration biopsy produces tissue fragments which are large enough to process histologically. If successfully retrieved, these fragments are submitted in blood clot or agar in a technique known as cell block preparation which are then immobilized in wax for sectioning and slide preparation.
FNAB is one example of the tissue collection techniques used and the problems which are of interest to the present invention. Fine Needle Aspiration Biopsy techniques have been practiced for many years and the literature contains many studies on technique and comparison of various improved devices for same. There exists two different kinds of biopsy needles. Those with active or movable cutting elements and those that are passive or non-moving. Active needles have two basic problems, which are cost and complexity. The needles that are of interest to this invention are most often 22 gauge which is 0.028″ OD with a standard wall of 0.006″. This leaves only 0.016″ ID. Some prior art designs use an active element down the ID bore to sever and capture tissue. 0.016″ does not provide a great deal of clearance for these elements and thus these prior art needles are inefficient. If it is desired to further suck tissue fragments up the needle bore further reducing the bore, the bore will be further reduced because a second element must be added, which is counter productive.
Other methods of obtaining samples are also discussed in the literature and also have problems. Each is characterized by tissue size and number of pieces generally available as well as whether orientation in the eventual sectioning plane is critical for example:
Fine Needle Aspiration Biopsy—very small pieces of tissue taken from the core of a fine needle; usually transported in fixative solution;
GI biopsy—characterized by a few small tissue pieces; it is desirable to concentrate the tissue pieces in close proximity to each other;
Prostate chips—orientation is irrelevant for these samples;
Endometrial Curettings—characterized by varying size samples; orientation is irrelevant;
Vessel—orientation is critical; sections need to be transverse;
Core Biopsy—i.e. from the prostate—orientation is critical; the tissue should lie flat all in the same plane;
Gall bladder—orientation is critical—the tissue should be embedded on edge;
Uterine Wall, breast or large tumors—orientation is not critical—sample lies flat in a plane.
Some of these methods are characterized by the possibility of supplying extremely small tissue samples. Some samples can be as small as a few cells, and extremely small samples can create problems. These problems include loss of the sample, dehydration of the sample, and contamination of the sample during harvesting, storage and transport. Still further, as will be more evident from the following discussion, small samples are extremely difficult and time consuming to process in the laboratory.
Still further, in many cases, a tissue sample is mixed with effluent. Prior art devices and methods account for collection of effluent only and do not provide devices and methods for trapping tissue specimens. The prior art collects effluent, but does not provide devices or methods for the separation of tissue from the effluent. Therefore, there is a need for apparatus and a method for handling effluent as well as tissue samples and for efficiently separating tissue from effluent.
Once a tissue sample is harvested it must be transported to the pathology lab for processing. Currently, handling and processing of small biopsies in the histology laboratory is a tedious task and requires multiple manual manipulations of the specimen. Fine Needle Aspiration Biopsy (FNAB) is typical. Therefore, there is a need to handle and process very small samples of tissue in an expeditious manner.
In addition to the above problems, a further problem with currently used apparatus and methods is associated with the orientation of samples. Currently, in a pathology lab, the pathologist will gross-in the tissue samples, cut them into appropriate size specimens, if necessary, and place them into a tissue cassette for processing. Herein lies one of the biggest problems of the existing art. When the tissue sample is placed into the tissue cassette, the pathologist orients the sample so that any surface in which he or she desires to see sectioned is placed face up in the cassette. The histotech who retrieves the tissue from the cassette after processing knows through training that when opening the cassette the tissue surface that faces up when first opened is then placed face down into the wax mold, which in turn will become the first surface to be sectioned by a microtome blade. This is an established protocol which is observed in most pathology labs today. This process then necessitates human involvement and redundant handling. In addition, sometimes special sponge materials must be packed into the cassette to keep a sample oriented or to prevent loss from the cassette if it is too small and may turn or lose its orientation during the tissue processing. Sometimes, notes and drawings accompany tissue samples to show how they should be oriented in the wax.
No current system or method provides the ability to maintain critical tissue orientation throughout these steps and eliminate human errors in the associated manual steps and procedures. Therefore, there is a need for a system and a process that can maintain the preferred orientation of the tissue sample from the time of initial gross-in throughout the tissue processing procedure and continuing through the wax embedding stage with no human involvement required beyond initial gross in.
Yet another problem associated with harvesting and handling of tissue samples for biopsy analysis is associated with the analysis process itself. In the analysis procedure, the sample is exposed to heat and chemicals which can cause the tissue and/or its support to change shape and/or move. The sample-holding structure should account for this or there may be a risk of damaging the sample or the sample holder. Accordingly, there is a need for an apparatus for holding a harvested biopsy sample in a manner that accommodates the tissue analysis process.
Another problem encountered with presently available systems is the lack of integration and multiple handling steps required to produce a sectioned sample for pathological examination. Therefore, there is a need for an approach which reduces the time and handling of biopsy samples.
By way of background, a review of the standard procedure that each sample must undergo to get from harvest to a prepared histologic slide is necessary. First, the sample must be taken with the appropriate instrument. The tissue is then retrieved from the instrument and deposited into some sort of specimen container, usually with a fixative such as 10% formalin. The container is labeled and transported to the pathology lab. Herein lies the first problem with the prior art. With no way to control where the sample lodges in the container, the sample may stick to the lid or sides of the container and become dried out before it reaches the pathology lab; rendering it difficult, if not impossible to interpret. In addition, the samples may be extremely small and may be hard to locate and retrieve from the container.
When the pathology laboratory receives the container, the specimen is logged into the manual or computerized anatomic pathology system and is assigned a unique surgical pathology accession number. This number is placed on the specimen container and is subsequently used to label histology slides, cassettes and the final surgical pathology report. The specimen is logged into the paperwork system and physically described in an appropriate medium, such as dictation or the like, by a pathologist or assistant. This is the description portion of the process known as "grossing-in" the specimen. The grossing in continues when the pathologist or assistant manually retrieves the specimen and views the specimen, and then sections the specimen into appropriate size morsels, if necessary, and places them into a plastic tissue cassette. If very tiny or multiple, the pieces of tissue must be immobilized within some device such as two layers of sponge or a tea bag to prevent them from escaping from the cassette during processing. Many times a surgeon will have taken diffuse biopsy samples or scrapings from the mucosal lining of an organ, such as an endocervical biopsy. Often these samples are very small and multiple such as is the case with tissue fragments from Fine Needle Aspiration Biopsy (FNAB). Other times a doctor will deposit the sample in filter paper which resembles a tea bag. All of these various tissue specimens end up in a tissue cassette. As used herein, the term "grossing-in" includes both the description of the tissue sample and the preparation of the tissue sample for further processing.
At the end of the day all of the cassettes are put into a tissue processor where the tissue is subjected to a sequence of solutions and heat. These solutions gradually replace water in the cells with alcohol, followed by xylene, and ultimately by wax. This gives the wax-impregnated tissue a similar consistency to the wax surrounding the tissue in the next step. After the tissue processing is complete, usually the following morning, the sample is again handled to remove it from the cassette where it is placed and oriented in a mold. At this point if a tea bag or sponge was used to immobilize the sample, the pathology lab is then faced with trying to extract or scrape the wax-impregnated specimen from the paper, before placing the specimen in the wax mold.
An embedding medium such as hot (molten) paraffin wax is poured into the mold to immobilize the tissue in a solid block of wax. Wax or parrifin can be used as an embedding medium; however, agar or even chemically setting resins such as polyester can be used. Harder resins can also be sectioned with a saw blade and then ground and polished to a thin film. After cooling, the wax block is removed from the mold, placed into a microtome and sectioned into thin slices approximately 4-6 microns thick. These sections are floated onto glass slides, stained, cover-slipped, and are then ready for microscopic examination. In this process, samples are handled or transferred many times. Each handling process takes time and human involvement.
Therefore, there is a need for apparatus and method to improve the harvesting of tissue samples. There is also a need for handling and processing those harvested tissue samples in an efficient and reliable manner that lends itself to automation and removes the need for a human to find, handle and orient a tissue sample before analysis of that sample can be performed.
Some long thin tissue samples are difficult to align and orient. The parent application discloses walls and pegs between which tissue is placed.
While in many instances those configurations work well, such as for fallopian tubes, in other instances, such as for gallbladder, it is difficult to place the tissue between the posts. Most often because the tissue sample varies in dimension from one end to the other. It is difficult to accommodate the many different sizes of tissue that are encountered in preparing biopsy samples. Therefore, there is a need for an orientation device which can be self accommodating to the differing dimensions of tissue samples. In addition, it is much easier to hold the tissue upright and place the orienting device over the tissue.
Once the tissue is properly supported by the orientation device, the device and the tissue are both subjected to the analysis process. Therefore, in addition to being easy to use in connection with biopsy samples, the orientation device must be able to withstand the analysis process and be sectionable as well.
It is a main object of the present invention to provide apparatus and method for handling harvested tissue samples in an efficient manner which lends itself to automation.
It is another object of the present invention to provide a system and a process that can maintain the preferred orientation of the tissue sample from the time of initial gross-in throughout the tissue processing procedure and continuing through the wax embedding stage with no human involvement required beyond initial gross-in.
It is another object of the present invention to provide apparatus and a method for efficiently harvesting tissue samples for biopsy.
It is another object of the present invention to provide apparatus and method for handling harvested tissue samples in an efficient manner with a minimum of human intervention.
It is another object of the present invention to provide a tissue trap and support that can retain tissue samples and facilitate easy transfer of the specimen without having to individually retrieve small tissue fragments from a sample container.
It is another object of the present invention to provide a tissue trap or stage that is sectionable and that is constructed of a material that is able to be sectioned in a microtome and appears non-distracting in the histologic sections and does not stain with tissue stains applied to the sections.
It is another object of the present invention to provide a tissue trapping platform that is constructed of a material that is impervious to the harsh chemical and temperature environment of a tissue wax processor machine.
It is another object of the present invention to provide a tissue trapping platform that is constructed of a material that is impervious to the chemical and temperature environment of a tissue wax embedding machine and may have a surface modification improving wettability on the filter or stage of the platform. The stages may be sectionable or not.
It is another object of the present invention to provide a biopsy container that holds the specimen sectionable trap for easy placement of tissue samples, and assures that the tissue remains continually submerged in the fixative solution and further allows the removal of the tissue trap and support and specimen with ease.
It is another object of the present invention to provide a method for immobilizing the tissue on a trapping platform to facilitate automation of the embedding medium process.
It is another object of the present invention to provide a method of automating the cell block tissue preparation, processing and wax embedding procedures.
It is another object of the present invention to provide for a tissue trapping platform which includes some sectionable tissue management features.
It is another object of the present invention to provide a tissue trapping platform which includes a method of assuring that the tissue will be oriented in the desired sectioning plane in the embedding media and will be pressed down into the wax embedding material so as to be close to the sectioning surface.
It is another object of the present invention is to automate the front end of a biopsy sample analysis procedure by providing a method to place the harvested tissue appropriately onto the sectionable filter or stage or on a non-sectionable stage prior to tissue processing.
It is another object of the present invention to automate the paraffin embedding process once the tissue has passed through the processor.
It is another object of the present invention to provide a method for automating the gross in process.
It is another object of the present invention to provide a fine needle aspiration biopsy device which includes a detachable tissue trapping sectionable support means specifically adapted for the needs of specimen processing in pathology.
It is another object of the present invention to provide a surgical biopsy device which includes a detachable tissue trapping microtome-sectionable support specifically adapted for the needs of specimen processing in pathology.
It is another object of the present invention to provide a cassette that traps tissue and maintains a stable orientation and spacing between samples through tissue processing and embedding procedures.
It is another object of the present invention to provide a system that accommodates dimensional changes of the cassette during processing.
It is another object of the present invention to provide a cassette system that allows the cassette to be securely retained in the frame during processing, yet allows for easy release of the cassette when desired.
It is another object of the present invention to provide a cassette system having a lid that can securely retain various sizes of tissue.
It is another object of the present invention to provide a cassette system having a lid that is hingeably connected to the cassette and can accommodate and hold different tissue sizes in the cassette.
It is another object of the present invention to provide a cassette that permits material held therein to be sectioned.
It is another object of the present invention to provide a cassette system that is not likely to become separated during handling.
It is another object of the present invention to provide a cassette system that is highly resistant to chemical solvent effects that are encountered during processing.
It is another object of the present invention to provide a small cassette which can yield a large number of tissue slices on a slide.
It is another object of the present invention to provide a cassette system that retains tissue in a single plane while accommodating tissue of various thicknesses within the same cassette well.
It is another object of the present invention to provide a cassette system that has a special device which can be installed on tissue samples and which maintains their orientation during processing.
It is another object of the present invention to provide a cassette system that can accommodate tissues having various sizes.
It is another object of the present invention to maintain orientation of a tissue sample and accommodates various tissue sizes which can be embedded and sectioned.
It is another object of the present invention to provide a cassette system that has a tissue trap where the tissue is not removed from the cassette after processiing.
It is a more spectific object of the present invention to provide a cassette system that is made more sectionable during the analysis process.
These, and other, objects are achieved by providing a multipurpose tissue trap and support. The tissue trap is formed so it can be cleanly sectioned using a microtome and which is constructed to survive the harsh chemical environment of the tissue preparation process and to be visually non-apparent when viewed during microscopic examination of the tissue structure during tissue analysis. For the purposes of this disclosure, a platform assembly includes a cassette frame and either a sectionable immobilizing platform or a non-sectionable immobilizing platform. By "sectionable," this disclosure means sectionable in a microtome. The cassette frame is adapted to accept stages or platforms with movable features and is adapted for us in a microtome. Thuse a tissue suport may be used in conjunction with a cassette frame, a platform and a cassette, and may be used to capture tissue samples and to keep them in good condition during transportation to the pathology lab and to manage the tissue specimen during the preparation, wax medium embedding and sectioning of the tissue.
The tissue trap can be used in or in close association with the harvesting apparatus, such as a Fine Needle Aspiration Device, or the like, and will support the harvested tissue in a manner that promotes automation of the handling process, even if the samples are extremely small.
Broadly, the invention includes a tissue trap and support that can include a porous member. For ease of discussion, this porous member will often be referred to as being a filter because it traps certain material (tissue) while permitting liquid to pass through it. The main purpose of the filter is to trap and hold material, such as harvested tissue samples. The filter is formed so that the tissue samples received directly from harvesting techniques can be placed directly onto the filter and can remain on that filter throughout the entire process, including microtome sectioning and mounting on a slide for analysis. The filter is microtomable, that is, it can be cleanly sectioned in a mictrotome. In this manner, the handling of the tissue samples can be entirely carried out in an automated manner because the tissue sample does not have to be handled.
More specifically, the invention includes various sectionable cassettes also referred to herein as tissue trapping platforms, that reduce the amount of sample handling required by either the pathologist or technician and make possible an automated system. A sectionable cassette includes a filter or stage in a cassette frame. The tissue trapping platforms can have a movable sample surface. The movable sample surface facilitates sample loading, confers protection from crushing of the tissue samples during the processing steps and allows the sample surface to be pushed into the wax mold for embedding.
By being placed inside the cassette, tissue is trapped and cannot be cross-contaminated with another sample. Therefore, the cassette is in a configuration with a bottom and four sides and a hinged lid. The cassette is placed into a frame, which holds the cassette during the tissue processing procedure. The frame also carries the sample identification surface on it. Many different types of sectionable cassettes can be interchangeably installed in the frame. It therefore could be characterized as being a "universal frame." One of the key components to making this system work is to be able to support the cassette properly during the tissue processing procedure. The tissue processing chemistry and heat make the sectional cassette very soft and in addition sometimes makes the cassette swell. Therefore in order to avoid distortion of the cassette, the cassette must be properly supported during processing. In addition, it must be very easy for the histotech to install the cassette into the frame.
One of the sectionable cassettes described in this disclosure contains a sectionable immobilization stage which enables the pathologist or technician to orient and fix tissue samples such as gall bladder, prostate chips or transverse vessel samples. The term "sectionable" as used herein means the item can be cleanly sectioned into extremely thin sections using a microtome to cut the embedding medium, tissue sample and any sectionable platform, so the layers can be mounted on a slide for further analysis. The tissue sample can be stretched or "pinned" into an appropriate orientation to provide for the proper plane of sectioning. This orientation process can take place at initial gross in and only has to be done one time to ensure appropriate positioning for sectioning. The prior art requires handling of the samples before processing and then orienting of the samples after tissue processing. The design of the sectionable immobilization stage and cassette frame combination allows for the vertical translation of the sample surface, so the samples can be automatically pressed down into the wax mold base and positioned close to the sectioning surface of the wax.
Another type of sectionable cassette contains a sectionable filter design which can be used to collect biopsy samples from various biopsy containers or devices. These sectionable filters are device specific. One such filter has particular application to the handling of Fine Needle Aspiration Biopsy samples. This filter can be manufactured in various pore sizes. One application for this filter is to include it with a biopsy sample container. The trapping filter is detachably retained on the cap of the container and can be removed with a single-handed motion. It is intended that the filter be placed directly into the cassette frame thereby eliminating the step of retrieving the samples from the sample container. In addition, this particular filter is constructed in such a way as to allow the filter to remain in the cassette frame while it is in the tissue processor. An immobilization technique which permanently affixes the tissue to the stage, filter or platform could be used with this type of filter prior to tissue processing. The filter when removed from the cassette frame can also be placed directly into the mold for paraffin block preparation without further manipulation since it can be successfully sectioned once embedded in the wax.
When biopsy samples are small (1 mm3 or less) it can be hard to locate and position a sample properly in the wax mold and this handling can be time consuming. By retaining the samples on the sectionable filter from initial collection to the final embedding procedure these problems are avoided.
Another type of sectionable cassette, also referred to as the sectionable filter cassette, is designed as a screen in a cassette frame with a vertically translatable sample surface. This type of sectionable cassette might be coupled with an immobilization technique and then would allow for the automatic gross-in of Fine Needle Aspiration Biopsy samples as well as mucosal scrapings, endometrial curettes, GI biopsies scrapings, etc. This sectionable filter cassette could be manufactured in different pore sizes to accommodate different applications.
A fourth type of sectionable cassette contains a non-sectionable stage which can accommodate large pieces of tissue which do not change orientation during processing just because of their size. These samples also protrude far enough off the surface of the stage so that once embedded in wax, enough sample is available in the microtomed sections so that the non-sectionable stage itself never interferes with the microtome blade.
The non-sectionable cassette with its movable sample surface can remain in a cassette frame through tissue processing, wax embedding and microtome sectioning.
The invention includes apparatus to immobilize the tissue samples on a filter or stage to reduce the number of manipulations required and to enable the automation of the whole histologic section preparation process. The immobilization technique does not alter the tissue composition in any way, nor does it interfere with the normal interactions of the tissue and the processor and wax embedder as well as the appearance of the final section and can be efficiently used on long, thin samples. Immobilization techniques, from the very simple to more complex are disclosed hereinafter.
In addition, one element of the present invention provides a novel tissue separation system and allows for the recovery of tissue samples from the effluent in a surgical suction device. The combined features of this invention reduces the transfer and handling requirements of the samples throughout the entire process.
Additionally, there is provided elements to immobilize the tissue on a platform which can then be passed through the tissue processor and wax embedder. The prior art requires the histotech-nologist to spend a major proportion of a work day removing tissue from cassettes after processing and orienting them in the wax mold. The present invention discloses a novel method for eliminating these steps by automating this process.
The present invention provides a reduction in handling by immobilizing the tissue onto or along with a sectionable cassette that can travel through the entire tissue preparation and mounting process. The immobilization can be mechanical whereby the tissue is hooked or pinned or otherwise mechanically bound to the platform. Alternatively, the immobilization can take on a much more active roll such as adhesives, coatings, gels or covering materials. The immobilization also permits automation of the entire process. By fixing the tissue to a sectionable cassette that can be machine manipulated, the tissue can be moved and oriented through use of machine components that would otherwise crush or be unable to manipulate tissue samples. By further making the sectionable cassettes of the sectionable cassettes a material that can be embedded in the final wax process with no ill effects on the sectioning process or to the diagnostic pathological review of the stained tissue, the cycle can be completed with labor savings and accuracy of tissue specimen preparation.
Automation of the histologic section preparation process is a significant way of consolidating manpower requirements in the histology laboratory. In today's hospitals there are consolidation efforts underway to reduce or combine services of area health care providers. In addition, mergers and takeovers have forced some histology labs to go to extreme measures to keep up with the demand for processed and sectioned histologic slides. In the prior art, one of the most time-consuming tasks in the laboratory is the manual handling of biopsy samples. By reducing the handling requirements and redundant steps significant reductions in labor-related costs can be achieved with this invention. The present invention includes apparatus and methods to manually load or automatically dispense specimens, automatically gross in specimens, automatically immobilize specimens and automatically wax embed specimens. Use of any of these automated procedures substantially improves the work flow in the histology laboratory and potentially provides the pathologists with their sections for review in a more timely and efficient manner.
The sectionable cassettes of the present invention provide a surface to which the tissue will become attached at or before gross-in. Elements are disclosed for immobilizing the tissue sample to the filter or stage of the sectionable cassette prior to introducing it into the processor. The tissue remains attached to the cassette through the tissue processor without effect on the tissue or processor. This further allows that once through the processor the cassette and tissue could be handled by mechanical apparatus through the wax embedding procedure and does not necessar-ily require further manipulation by a technician.
A description of the process with the biopsy container system with integral sectionable filter will now be presented. The tissue is placed or deposited on the sectionable filter at the time of harvest in the surgical setting. The sectionable filter and tissue are then immersed in a fixative solution for transport to the pathology lab. Once in the lab the pathologist or clinician removes the sectionable filter from the container. The tissue is trapped on the sectionable filter so there is no need to probe around inside the container looking for tissue particles. The sectionable filter and specimen are grossed in (described for record) and placed in a filter cassette frame. If necessary, at this point a tissue immobilization technique can be applied in order to affix the tissue to the sectionable filter.
The sectionable filter is constructed to survive the harsh chemical environment of the processor. After the cassette has emerged from the processor, the sectionable filter/specimen is placed in the embedding mold, tissue side down. Since the sectionable filter of the present invention has been specially formulated from a material that allows it to be sectioned in the microtome, the sectionable filter itself becomes embedded in the wax along with the tissue specimen. This eliminates the further step of finding and individually placing each tissue fragment in the embedding waxing mold. After the sectionable filter is placed in the mold, the mold is filled with molten paraffin. When chilled, the paraffin with embedded specimen and sectionable filter (paraffin block) is removed from the mold and is ready for sectioning to make histologic slides. Again, the term "wax medium" is used to describe one form of embedding medium. This is not intended to be limiting since one skilled in the art could use other embedding media based on the teaching of the present disclosure.
Still further, because the filter eliminates the need to manually handle a tissue sample, the automated process could also include an automated gross-in station. In some cases where specific tissue orientation is not critical, an additional automated step can empty the contents of a biopsy container onto a sectionable platform, depositing the larger samples on the filter surface of the platform. This is applicable to samples from Fine Needle Aspiration Biopsy and GI biopsies, in particular. Upon arrival at the histology lab the sample containers are placed into the automated gross-in station where the machine removes the lid of the container and decants the fluid containing the samples onto a sectionable filter cassette (assuming a sectionable filter does not come with the container as disclosed herein). This process will work well for samples such as GI biopsy that do not need to be oriented in any special way for the section.
A surgical pathology accession number, unique to each specimen, is obtained when the specimen is accessioned into the laboratory's anatomic pathology computer system. A barcode can be generated at this time and placed on the specimen container thus uniquely identifying the specimen with its accession number. By interfacing an automated computer system, the surgical pathology accession number can be printed on each specimen cassette and video image. The number can be human readable and/or computer readable. The samples that are trapped on the sectionable filter are then recorded with a single digital image or infrared or other scan which could have a 1 mm (or other scale) reticule grid in front of the lens to aid in sizing the tissue pieces. The image, surgical accession number, date and other pertinent information are stored on a write optical computer drive or other magnetic media for archive purposes. Once scanned, the platform with sample is fed into the immobilization device.
Currently, state-of-the art preparation of tissue samples for microscopic examiination is a very labor-intensive and sequential-step dependent process. While this current process works well, it is merely the result of a combination of very old non-integrated processes, which have evolved into standard practice. Small improvements have been made over the last twenty years in such areas as tissue processing machines (e.g., vacuum infiltration) and automated (e.g., computerized) record keeping. However, very little has been done to integrate and reduce the steps that are required from the time the tissue is harvested to the final preparation of a diagnostic slide. Within the present disclosure the inventors have disclosed a cradel-to-grave system in which all components are designed to eliminate steps and to provide the users with a fully integrated system that will provide for a more efficient overall process.
In today's lab, tissue samples are handled numerous times before a final slide can be prepared. This constant involvement of the human hand is inefficient and costly. In addition, the current healthcare environment has created enourmous incentives to cut costs. For many pathology labs this has meant a consolodation of smaller lab facilities that are now shared between hospitals. This then creates larger central facilities that must process enormous quantities of tissue samples all the while demanding higher efficiencies from employees. There has been a long-felt, and heretofore unfufilled, need for a less labor intensive process.
The inventive system disclosed herein has been designed to move the biopsy samples with the least amount of operator involvement, while maintaining at least the current standards for preparing slides. For instance, numerous methods are disclosed which take advantage of the invention's ability to capture tissue samples at the site of harvest, thus eliminating the steps of transferring the samples form one container to another. The inventive material goes on to encompass the entire record keeping, tissue processing and wax embedding procedures. Therefore, a larger number of samples can be processed by a fewer number of individuals. This is accomplished by utilizing the inventive tissue handling components, combined with automated machinery to transport tissue samples through the various stages creating a final slide for pathological examination.
Tissue Trapping Platforms
A platform includes a filter or stage assembled in a filter cassette frame or a stage cassette frame.
Microtome Sectionable Tissue Support
Sectionable filter A′ shows a fine � mm filter grid and sectionable filter A″ shows a 1 mm filter grid. Preferred pore sizes are 1 mm, � mm and 180 microns to 200 microns for use with FNAB. However, other pore sizes can be used based on the teaching of the present disclosure as will occur to those skilled in the art. The sectionable filter grid can be manufactured in many other sizes as will be understood by those skilled in the art based on the teaching of this disclosure.
In general, the filter is one form of a tissue support used in an overall apparatus for supporting histologic tissue biopsy samples. In general, the overall apparatus comprises a microtome sectionable tissue support such as filters A′ and A″ for supporting tissue samples during tissue processing, embedding and microtomy including a means for permitting the tissue supporting means to be successfully sectioned in a microtome. Successful microtome sectioning means, as used herein, sliced in a microtome without damaging the microtome or the tissue, or without tearing or cleaving the tissue or the tissue support. The tissue supporting means includes a means for resisting histological stains, a means for resisting degredation from solvents and chemicals used to fix, process and stain the tissue and a means for maintaining the tissue support, also referred to herein as tissue supporting means, non-distracting during tissue processing and slide preparation. As used herein, the term "degredation" is defined to mean softening, discoloring or any kind of unfitness for use in all processes associated with the analysis of the tissue.
The sectionable filter or stage is made from a special low density thermoplastic which is molded into a porous filter or screen. The filter is specially selected to resist the chemical and heat environments in the tissue preparation processor. At the same time the material must be of similar density to both the tissue and the paraffin embedding materials. It must further be able to be sectioned using a standard laboratory microtome (microtomy) without dulling or nicking the blade. The material must section just as if it were part of the wax without tearing or cleaving. If the filter material tears during microtome sectioning, it may destroy the fragile tissue section. The material must also not stain when the tissue is prepared with various histologic stains. It should not become soft, discolored or dissolved in the solvents and chemicals used to stain the tissue. Still further the material must appear non-distracting, such as window clear, in the section so as not to distract or confuse the pathologist during microscopic examination. As used herein, the term "non-distracting" means that the material will be readily identifiable as being filter material as opposed to tissue when viewed during analysis of the tissue specimen. Thus, a "non-distracting" material will not be confused with tissue being analyzed during tissue analysis. The preferred form of a non-distracting material appears window clear or at least translucent when viewed during tissue analysis; whereas, the tissue has a color or appearance that is readily identifiable as being tissue. One such material is a low density polyethylene homopolymer such as Quantum Chemical Co. Petrothene� NA 601-04. Other sectionable materials could be used that appear cloudy or take a bit of stain. So long as the pathologist is not distracted by a cellular structure of the sectionable material that is herein referred to as non-distracting.
Since the sectionable filter will be used to separate small tissue particles from suspended liquids it may be necessary to modify the surface tension or wetting characteristics of the plastic to allow the fluid to pass rapidly through the filter screen while retaining samples. Surface treatments such as Plasma etching, Corona Discharge, Ion beam, Hydrogels, Photolink™ surface modifications can be used. These surface treatments may also be used to attract or retain tissue on any of the filters or stages. As will occur to those skilled in the art, there may be a need to have an affinity coating to attract mucosal tissue fragments as an example.
Stage Cassette Configurations
Sectionable Filter Cassette Configuration
Sectionable Immobilization Stage
Additional hooks 24, pins and gripping elements can be provided on these stages to allow the pathologist to select the most appropriate immobilizing method and orientation for each tissue sample. As shown in
Non-sectionable Stage
The tissue trapping platforms have numerous applications for use. Specific applications of the invention are discussed herein.
These are shown as examples of methods to trap and transport tissue samples to the histology lab. It should be noted that there may be many more uses for this technology so as not to limit the tissue trapping platform concepts and applications to the disclosed applications.
In general, the invention includes a method for preparing biopsy tissue samples for histological examination comprising:
removing a tissue sample from a patient; placing the tissue sample onto a suport; immobilizing the tissue sample on the support; subjecting both the support and the tissue sample immobilized thereon to a process for replacing tissue fluid with wax and impregnating the tissue sample with wax, embedding the tissue sample in a wax mold to form a solid block of wax, using a microtome, slicing the solid block of wax into thin slices; and mounting at least one of the thin slices on a support member for examination. It is also noted that one form of the invention includes a tissue support that can be successfully mictrotomed, while another form of the invention includes a support that is porous. In that case, the tissue support will be embedded with the tissue sample in the wax and both the sample and the support will be sectioned using a microtome.
The invention also, broadly, includes a tissue analysis automation process which includes placing tissue on a machine manupulable support; immobilizing the tissue on the support to maintain a selected orientation of the tissue on the support; and processing the immobilized tissue along with the support to replace tissue fluids with wax, as well as a method of conducting analysis of tissue biopsy samples comprisng: harvesting tissue samples from a patient; placing the harvested tissue samples onto a machine manipulable tissue support; immobilizing the tissue samples on the tissue support; and processing the tissue samples and the tissue support to replace tissue fluids with wax.
Automation of Tissue Processing and Histologic Section Preparation
Automated Dispensing of Samples in Fixative Solution
Step 1 of
In Step 2, cap gripper 406 powered by cap removal servo 407 removes and discards the standard biopsy container cap 405. Cap grippers, as well as the other mechanical equipment necessary to carry out the steps and to practice the invention disclosed herein, will be known to those skilled in the art of creating automated machines, see, for example catalogs such as published by Techno Sommer Automatic of 2101 Jericho Turnpike, New Hyde Park, N.Y. Many standard off-the-shelf components exist as standard catalog items, such as Transfer and Pick-n-Place mechanisms can be esaily modified to interface with the tissue handling invention disclosed herein. In addition, off-the-shelf catalog items such as programmagle logic controllers are available to control a multitude of environmental variables, drive systems, and timing issues to create automated machines of the complexity required to carry out the invention disclosed herein based on the teaching of this disclosure. Accordingly, details of such equipment will not be presented.
In Step 3, the container is tilted and the contents are dispensed into a funnel stage 413 directing the contents first through sectionable filter 400. Again, as discussed above, such elements which hold and manipulate containers such as element 406 which then dispense the contents of the container would be modifications of off-the-shelf components from companies that supply such parts to those skilled in the art of creating automated machines. As depicted, this is a sectionable filter but could alternatively configured as a sectionable filter cassette. The filtrate is normally discarded as waste, however, the filtrate can be directed into a cytospin container 414. When a cytology test has been ordered, it is indicated by the technologist or pathologist by placing a special cytospin indicator 427 on the biopsy container. Such an indicator is machine readable in order to direct a machine to retrieve additional fluid samples dispensed from a container or to command additional testing. These examples illustrate that separate machine-readable indicators are used in conjunction with the sample containers and platforms. However, these indicators could be combined into one machine-readable code. Such indications can be either hand applied or could be coded into a pre-processed or in-process labels. These examples merely illustrate the possibilities of indicating to the machine the pathologist's request for different tests to be applied to the sample. Bar or any other machiine-readable code cold be used to enable this invention and are included to illusrate how the machine designer will process instructions about how to handle individual samples within machine environments. In addition, such machine-readable codes would also need to be compatible with existing machine-readable code in the current pathoogy laboratories. Bar-code reader 402 notes the indicator and directs the appropriate pore size sectionable filter to be automatically installed along with cytospin container 414. The cytospin container is automatically labeled with the biopsy sample's unique accession number with printer head 424 (machine and/or human readable). The funnel 413 could be a single use device which is disposed of after use to prevent cross contamination of specimens.
Whether or not a cytospin container is used, a rinse cycle is initiated after the biopsy container is emptied. Washing wand 409 dispenses rinse solution from reservoir 411 controlled by rinse valve 410. The rinse solution will clean out the biopsy container of any particulate that will then, if large enough, be trapped on sectionable filter 400. The smaller cellular components of the biopsy flow through filter 400 and are either discarded or captured in cytospin container 414 for further processing.
Automated Gross in of Samples
In Step 4, filter stage 400 moves into a gross in station where an image capturing device such as a digital camera or video camera 415 records an image 416 of the tissue samples on sectionable filter 400. A 1 mm (or other gradation) grid reticule on the camera lens may be used for a size calibration. Traditionally, the number and size of tissue samples in a cassette are described at gross in for future reference. With the present invention, the digital picture contains a record of this information, that may be printed on the surgical pathology report, or may be accessed sometime in the future if questions arise. The digital picture is displayed for the histotech to verify that a record has been created for the particular biopsy sample. The information is digitally compressed by CPU 417 and stored on an optical disk or other data storage media 418. In addition, given the information in the digital image, the processor can determine if too much tissue is present on a given platform and reject it for further treatment by the histotech. Additional scanners such as infra red could be used as a diagnosis tool.
In addition, the digital image can be used to transcribe an appropriate gross description of the surgical pathology report of the specimen. One such requirement of the system might include a physical record of the number and sizes of the tissue samples present on the tissue platform. Information gathered by the digitized video image could be stored and analyzed a suitable computer program in order to determine the number and size of the samples present in the tissue container. Digital systems are particularly well suited for this applicaion. The image area can be divided into small coordinate areas, such as the pixels which make up the imaging device. Through a simple computer program, each pixel can be converted to a known physical size, and groups of pixels can be lumped together to create calculated surface areas. Again, this is an area in which a sub-speciality such as pattern recognition and video imaging is integrated into this invention to enable new combinations that were not previously known. In addition, one should not limit the automated gross in procedure to video only. Scanning sonar or radar could be employed to give a more three-dimensional record of the tissue samples. Such a system would involve a scanning head, which would transmit and receive electromagnetic signals that would use a reflected signal to reconstruct a non-contact picture of the tissue samples, much the same way as sonar has mapped the bottom of the ocean surfaces but in a much smaller scale. The digitized image is analyzed by CPU 417 to determine the number and size range of the pieces of tissue in the specimen. This information is passed through an interface to the laboratory anatomic pathology computer system. Through appropriate programming, such as macros similar to ones which are presently in use in the word processing systems of most laboratory systems, the system transcribes an appropriate gross description of each specimen for incorporation into the surgical pathology report.
This system uses a combination of electronic imaging which was captured in the previous step, and in combination with computer matching systems allows printed text to be recorded along with the video image. For instance, in the pattern recognition system described above, the computer would determine that for instance three tissue samples were obtained, each three square millimeters in area. The computer would write a file that stores the proper code for each tissue sample recorded and its individual size. The computer would then print out a written text report with a prerecorded description matching that of three individual samples each with their own respective sizes given in square millimeters. Thus, there would be both a visual record and a text record of the samples obtained and recorded. This would replace the current practice whereby the pathologist dictates a spoken description of the tissue samples onto magnetic tape, which is subsequently listened to by a transcriber who types a written description for the pathology report. This would reduce the cost for each written description of the pathology report. CPU 417 controls all of the stations in steps 1 through 5 and records all events, tracking numbers on digital storage media 418. An accession or tracking number 423 (see
Immobilization of Tissue on Platform
The tissue immobilization process on the filter or stage will now be discussed. Both manual and automated immobilization techniques have been proposed. The pathologist or technician is able to properly orient samples as required for sectioning by placing the samples on an appropriate tissue trapping platform just prior to gross in. The immobilizing process maintains the pathologist-specified orientation of the tissue throughout the histology preparation process. No further treatment is required for samples placed on a sectionable immobilizing platform since its gripping features act to hold the tissue in place throughout the histology preparation process. The tissue on a non-sectionable platform or sectionable filter cassette may require further immobilization treatment.
Tissue immobilizing adhesives or the like such as adhesive BIS indicated in
Step 5 of
Although the preferred embodiment is shown as ballistic particle deposition of material, many other ways could accomplish the same result such as the thermal bonding of a net material over the tissue (Dry Net, see
In the Dry Net technique the tissue on a platform is then placed into an immobilizing fixture seen in
Two methods for use of a wet adhesive process to immobilize the tissue on a filter or stage are disclosed whereby either an adhesive is sprayed onto the sample surface of the filter or stage prior to loading with the tissue sample; or the adhesive is applied after the tissue has been placed on the filter or stage. In order to be effective, the latter method requires the adhesive to wick underneath the edges of the tissue and thereby hold down the tissue throughout processing. Adhesives such as cyanoacrylates are well suited for this application since moisture sets off the rapid curing process. Tests have shown that the cyanoacrylate tissue bond is impervious to the chemical and temperature environments of the tissue processor and the wax embedder. It does not interfere with the sectioning or staining of the samples nor does it interfere with the tissue histology.
Any substance which does not interfere with the histologic sample preparation, as described above, can be used to immobilize and affix the tissue to the platform. The immobilization process depicted in
If the tissue sample has been loaded onto a sectionable immobilizing stage which does not require an extra process to secure the tissue to its surface, a machine readable code on the platform could identify the platform type and allow for this specific type to bypass the immobilization step and continue on to the tissue processor.
Once the tissue is immobilized on the filter or stage, the platform can be placed in a standard storage rack or automatically introduced into the tissue processor. If the filter or stage is not already in a platform configuration, it will be automatically placed into the appropriate four sided cassette frame before progressing to the tissue processor.
The teaching of the present inventors has also shown that immobilization can be carried out in a variety of ways, including glues, nets and the like. However, tissue immobilization can also be achieved in other ways as well, including capturing the tissue sample in a special container. To keep the tissue from being cross-contaminated and properly oriented and spaced during processing and embedding, the container can be closed and sealed. To gain access to the tissue after embedding, the container can be formed of sectionable material so the container can be sectioned along with the tissue. Since those skilled in the art are used to working with containers, using a container in this manner will permit them to use familiar items.
Therefore, by adapting the herein-disclosed teaching to containers, the present invention can be made into a form that will be acceptable to those skilled in the art who wish to continue working with familiar items.
Automated Wax Embedding Process
In general, the automated process prepares the tissue sample for embedding in wax, and embeds the tissue sample in wax. Then, the tissue sample can be sliced into thin slices using a microtome and at least one of the slices mounted for microscopic examination. Broadly, the method of preparing biopsy tissue samples for histological examination comprises: removing a tissue sample from a patient; storing the tissue sample in a container; dispensing the contents of the container onto a support; immobilizing the tissue sample on the support; subjecting both the support and the tissue sample immobilized thereon to a process for replacing tissue fluid with wax and impregnating the tissue sample with wax, and embedding the tissue sample in a wax mold to form a solid block of wax. As above discussed, one form of the invention includes a porous tissue support while another form of the invention includes a tissue support that can be successfully sectioned by a microtome. A microtome is then used to slice the solid block of wax into thin sections which can be used for further examination. If the tissue support is microtomable, it, or part of it, can also be embedded in the wax block.
More specifically as shown in
Setting head 454 (
Once the platform and tissue samples are set in the pre-fill layer of paraffin, the pick and place head is raised and the mold base is again translated laterally to the paraffin dispensing station 460. In Step 4 16 the mold is automatically filled to the final level. Mold base 432 dwells at this station for a period of time (Step 5 16) post filling during which time the sub base is chilled to set the newly added paraffin.
In Step 1 16 again mold base 432 translates back to the center position where the pick and place head 457 comes down and removes the platform from mold sub base 429. In order to facilitate easy removal of the hardened paraffin block and attached platform 426 from the mold sub base, the mold sub base is pivotally mounted on the mold base with actuating mechanisms 431 that are operated and controlled by computer controlled motors (not shown). Mold sub base 429 is preferably made of a flexible material such as urethane, which allows the mold to be flexed, popping the hardened paraffin block out as shown in
The automated process will allow the completed paraffin block to be transferred directly to the microtomy station where it is sectioned, applied to a glass slide and stained.
Any or all of the above described automated stations could be configured into a package to best meet the needs of a particular laboratory. Automation of every step would not be a requirement.
1 10. automated sample dispensing and platform selection
2 10. printing and video gross in unit
3 10. immobilization
4 10. tissue processing (prior art technology) and
5 10. automated wax embedding.
Additionally, biopsy container storage 6 10 is located adjacent to a gross in location.
In the first station, automated sample dispensing and platform selection, biopsy sample containers C10 are stored in a rack awaiting automated dispensing. Blank platforms and cytospin containers are stored in an area 7 10. Sample containers are brought into the automated processing system. A bar code reader deciphers the machine readable code on the container, which indicates whether a cytospin container is required for this particular sample. The sample container is automatically opened and the contents are decanted onto a sectionable filter. If required, the eluate is collected in a cytospin container for further processing. There is also a single container entry tray which can be used to accommodate a sample which needs to be processed immediately; samples entered there are given priority over samples that may already be in storage.
In the second station a printer head prints a laboratory accession number A10 from the laboratory log records onto the cassette frame and cytospin container if one was required. The platform is moved for digital or video gross in and display on screen 8 10 by video camera 9 10 and a single digital or video image is recorded of the tissue samples on the platform, capturing the identifying accession number as well. A manual loader 10 10 can also be used.
A single entry tray 11 10 can be provided at this station as well to allow entry of platforms which are loaded manually such as the sectionable or non-sectionable stage platforms or a sectionable filter cassette that has been manually prepared. The printing and video gross in functions are performed on these samples as well.
The platforms are then moved individually into the third station 3 10 for immobilization of the tissue samples. The immobilizing technique is applied to the tissue and filter or stage and current sample number is displayed on screen 14 10.
The platforms with immobilized tissue samples are transferred into a holding tank 15 10 for batch processing or are sent directly into the tissue processor for continuous processing.
From the tissue processor, the platforms move into the automated wax embedding station (station 4 10). They may also be held in storage there and processed in a batch, if required. The automated wax embedding system described in
Finished paraffin block storage trays are provided in which the system will store finished embedded platforms awaiting sectioning.
In Step 1 other samples are manually loaded onto the appropriate tissue trapping platforms. The printing station 113 then prints the accession number assigned by the automation CPU form accession log data base 115. This is printed both onto the cassette frame and the cytospin container if one was required. The cytospin container is exited from the system in Step 2.
Automated gross in 117 is performed and the information is stored on storage media 118. Decision process 119 determines whether further immobilization of the sample is required. For example, sectionable immobilization stages which have been manually prepared will not require application of additional immobilization techniques. A machine readable feature on the stage determines whether the immobilization station should be bypassed or not. If immobilizing is required, the platform is treated with the appropriate technique at box 120.
After immobilization, the platforms are held in batch in a process holding tank awaiting tissue processing or are sent continuously through the processor. Step 4 is tissue processing which relies on standard prior art technology.
After processing another decision block determines whether the platforms will be held for batch wax embedding or will be embedded as available from the processor. Step 5, box 125 is the automated wax embedding process.
Tissue Specimen Container with Integral Sectionable Filter
The object of the container embodiment (shown in
In general, one form of a tissue sample container 200 is shown in
The sectionable filter ring is adapted to have an outer ring 211 and spider ribs 212 (
Yet another feature of the container is the fixative fluid displacement apparatus, such as cylinder 215 on cap 203. The cap has an elongated cylinder which extends below attachment section 216 which is shown as threaded, but could take on any of a number of configurations, such as: � turn locking; friction or snap fit. The displacement cylinder 215 acts to raise the fixative level 210 above the sectionable filter 202 inside the container when the cap 203 is installed.
To facilitate the removal of the sectionable filter from the container, retention ridges 207 on fingers 205 and grooves 217 are fashioned on the inside diameter of displacement cylinder 215. As shown in
Alternately the displacement cylinder would have no grooves to engage the sectionable filter. This would be necessary case one wants to inspect the filtered contents before removing the sectionable filter from the container. In that case, it is envisioned that the sectionable filter would reside above the lip of the container to facilitate access to the edge of the sectionable filter with forceps for easy removal of the sectionable filter. The cap would retain the fixative displacement ring but would not include the retaining grooves.
Fine Needle Aspiration Biopsy Device.
In general, the invention includes a tissue sample container comprising: a means for supporting histologic tissue biopsy samples which includes a tissue support for supporting tissue samples during tissue processing and embedding and micotomy including, means for permitting the tissue supporting means to be successfully sectioned in a microtome, means for resisting histological stains, means for resisting degredation from solvents and chemicals used to process and stain the tissue, and means for maintaining the tissue supporting means non-distracting during tissue preparation and slide preparation. As before, one form of the invention includes the tissue supporting means being porous as well.
In order to provide tissue specimens for histologic exam one must first obtain sufficient quantity and size from the biopsy. As prior art has shown many attempts have been made at providing fine needle aspiration biopsy needle configurations that provide improved sample harvesting properties. Yet in most cases physicians continue to use standard three bevel grind venipuncture needles such as is shown in
If one looks at a venipuncture needle tip under magnification, it will be found that the tip has three flat faces 510, 511, 512, two of which 510, 511 create the sharp tip and a third 512 which is transverse to the axis at a very acute angle usually 18–20 degrees. The two tip bevels are very finely ground and produce exceptionally sharp edges 513, 514 that part the tissue on insertion. Third surface 512 is less fine and in fact has one serious flaw that creates problems for the cutting of biopsy samples. Edge 515 which is created from the inside bore and the third surface is not well controlled and most often is found to have been treated by an abrasive grit blast to de-burr the edge. For venipuncture this is advantageous since it is not desirable to cut holes in a blood vessel which would cause trauma and bleeding. But when it is desired to take tissue samples, it produces poor and unpredictable results. It might be assumed that just honing the third surface to produce a fine sharp edge would produce better results, and while this is partially true, the inventors have discovered that the tissue tends to "tent" upon passage through tissue.
When creating a design for FNAB, it must be kept in mind that although standard venipuncture needles are less than optimal, they are inexpensive. Therefore, it is desirable to make the FNAB needle of the present invention inexpensive to manufacture. The four bevel grind is relatively inexpensive to manufacture. However, it is very aggressive and cuts on the entry stroke. The entry stroke leads to tissue samples from the path to the target site in addition to the target. Another configuration allows for sampling on the removal stroke.
In yet another improvement the inventors have discovered that any ledges or interstices in a syringe will create traps where the tissue samples may become lodged and therefore become trapped and not retrieved from the device for examination. One such area in the standard needle and syringe is the luer fitting. A prior art needle NP is shown in
In still another way to implement the sectionable filter technology there is provided an improved tissue harvesting fine needle such as the ones described above, but which deletes the sectionable filter in the syringe body. This then allows the physician to use a better method of ensuring complete capture of the harvested biopsy samples. Since many times the physician will request cell cytology and cell block preparation for histology, it must be assured that all sample material is collected and preserved in fixative immediately after harvest.
Since this sectionable filter fits into the smallest inner dimension of the wax mold form, it is not necessary for this particular platform to have the vertically translatable sample surface feature of the inventive filter cassette frame. When the sectionable filter is removed from the cassette frame and placed into the wax mold form, the sample surface will be automatically oriented in the sectioning plane close to the sectioning surface of the wax mold.
Surgical Biopsy Devices with Sectionable Filter
Shaft 804 which connects handle 802 to jaws 806 actuates the biopsy jaws and allows for a hollow central channel to transport the biopsy sample from the patient's body at the biopsy jaws to the filter surface where it is trapped. Filter assembly 810 is shown in
A suction trigger 816 couples to a suction port 818 for controlling suction, with the port 818 being a source of suction for device 800. When the suction trigger is pulled back, the suction port opens. When the suction port is connected to a vacuum source 819 the suction is coupled through the filter and hollow shaft to the biopsy jaws. This transports any loosened tissue pieces from the biopsy jaws back to and trapping them in the filter. Any fluid that is suctioned into the hollow shaft will pass through filter 820 into the filter housing and out through the suction port. Once the sample has been deposited on the filter, the filter housing is rotated up and opened. The surgeon can then remove valve cap 822 and the filter (the filter assembly) from the filter housing. This filter assembly is placed into a container for transport to the pathology laboratory. Another filter assembly can be inserted into the filter housing to collect more samples. The valve cap has a one-way valve, such as duck bill valve 824, preferably made of silicone, which allows for one way passage of suction from the biopsy jaws onto the filter. Once the filter assembly is placed into the container for transport, the contents of the container cannot leak out through the one way valve.
Sectionable Filter adapted for histological laboratory use and manual loading.
Additional uses for the sectionable filter are shown in
The sectionable lab filter or cassette configuration as shown in
Sectioned Paraffin Block
In general, the finished product is a sample of a tissue for analysis comprising: means for supporting histologic tissue biopsy samples including a microtome sectionable tissue supporting means for supporting tissue samples during tissue processing, embedding and microtomy including means for permitting said tissue supporting means to be successfully sectioned in a microtome, means for resisting histological stains, means for resisting degredation from solvents and chemicals used to process and stain the tissue, and means for maintaining the tissue supporting means non-distracting during tissue preparation and slide preparation; and a supporting surface for supporting the sample for microscopic examination. One form of the invention includes a porous tissue supporting means.
A finished product is specifically illustrated in
Slicing the wax embedded tissue and tissue support (filter) is indicated in
In summary, some of the components and advantages of the present invention include the following.
1. The invention of tissue trapping filters or stages including those that are microtome sectionable or not and those that act as filters as well as those that act as immobilizing stages; all can have a vertically translatable sample surface within a cassette frame which facilitates sample loading, confers protection from crushing of the tissue samples during the processing steps and allows the sample surface to be pushed into the wax mold; use of the tissue trapping platforms (filter or stage in combination with a cassette frame) allows the tissue processing and wax embedding procedures to be automated.
2. An immobilization process, whereby the tissue is secured to a filter or stage by various apparatus (Dry Net, Ballistic Net, etc.) allowing it to be properly oriented for sectioning at the initial gross in, which eliminates the need for further handling of the samples during tissue processing and wax embedding and therefore makes automation of these processes possible.
3. Proper orientation of tissue samples is assured throughout the process.
4. The invention of sample trapping containers which contain a sectionable filter and help to preserve the quality of the sample from collection to gross in and again reduce the amount of handling required for the samples.
5. The invention of a Fine Needle Aspiration Device and needle configurations which can be used with the sectionable filter;
6. The invention of a surgical biopsy device with integral tissue trapping sectionable filter.
7. The automation of the gross in procedure.
8. The automation of the tissue processing and wax embedding processes together.
9. The automation of the dispensing of Fine Needle Aspiration Biopsy as well as mucosal scrapings, endometrial curettes, bristle brush scrapings etc., with collection of larger tissue pieces onto a sectionable filter and if desired the collection of eluate into a cytospin container for cytology.
10. A method for conducting tests on histology tissue biopsy samples comprising: removing a tissue sample from a patient; placing the tissue sample onto a support, which can be microtomable if desired and which can, in one form of the invention, be porous; immobilizing the tissue sample on the support; subjecting both the support and the tissue sample immobilized thereon to a process for replacing tissue fluid with wax and impregnating the tissue sample with wax, embedding the tissue sample in a wax mold to form a solid block of wax, using a microtome, slicing the solid block of wax into thin slices; and mounting at least one of the thin slices on a support member for examination. If the tissue support is microtomable, then this element, along with the tissue sample, can be embedded in the wax, and both the sample and the support can be sliced by the microtome when the microtome slices the block of wax.
By way of example, the above-discussed methods of obtaining tissue samples is repeated herein along with the preferred form of tissue support:
Fine Needle Aspiration Biopsy—very small pieces of tissue taken from the core of a fine needle; usually transported in fixative solution; decant off fixative solution through a sectionable filter (180 μm filter);
GI biopsy—characterized by a few small tissue pieces; it is desirable to concentrate the tissue pieces in close proximity to each other—decant off fixative solution through a sectionable filter (� mm filter);
Prostate chips—orientation is irrelevant for these samples—sectionable filter (1 mm filter);
Endometrial Curettings—characterized by varying size samples; orientation is irrelevant—sectionable immobilization stage (� mm filter);
Vessel—orientation is critical; sections need to be transverse—sectionable immobilizing stage—manually position over vertical pegs;
Core Biopsy—i.e. from the prostate—orientation is critical; the tissue should lie flat all in the same plane—sectionable immobilization stage;
Gall bladder—orientation is critical—the tissue should be embedded on edge—sectionable immobilization stage;
Uterine Wall, breast or large tumors—orientation is not critical—sample lies flat in a plane—non-sectionable stage.
As discussed above, the cassette is subject to heat and chemicals during the tissue processing. Such heat and chemicals can cause the cassette to change shape. In order to accommodate the changing size of a cassette during tissue processing, a cassette frame interface can be used which accommodates the cassette in both the swelled and the un-swelled configurations. In the unsewelled configuration, the cassette has extra room to move around inside the frame. However, as the cassette grows from heat and exposure to chemicals, its size changes due to swelling.
Still further, as discussed above, it is an object of the present invention to provide a histologic tissue biopsy sample support comprising a microtome sectionable tissue support for supporting tissue samples during tissue processing, embedding and microtomy including means for permitting said tissue supporting means to be successfully sectioned in a microtome, means for resisting histological stains, means for resisting degradation from solvents and chemicals used to fix, process and stain the tissue and means for maintaining said tissue supporting means non-distracting during tissue processing and slide preparation. The above-discussed means achieves this object. However, to achieve this object as well as the just-stated object of accommodating a changing size, the present invention also teaches additional cassettes. These additional cassettes achieve the just-stated objective as well as for cassettes that can accommodate changing shapes as well as including means for resisting chemicals used in replacing tissue fluids with wax, and means for resisting molten wax used to embed the tissue sample and a low density thermoplastic material. The means discussed above in relation 35′ to these functions also applies to the following disclosure as well.
Shown in
As can be seen in
Once a tissue sample has been processed, the cassette can be removed from the frame by pressing on the cassette in a direction indicated in
Unit 500 is one form that will accommodate swelling of the cassette, another unit 550 is shown in
A cassette 570 is shown in
As shown in
Lid 574 cooperates with bottom portion 572 to capture tissue inside the sectionable cassette. The lid not only prevents tissue loss but also maintains the orientation and placement of tissue in the cassette once the lid is closed. Because tissues of different thicknesses will be used in the cassette, the cassette must accommodate such different sized samples, and lid 574 achieves this. Lid 574 is attached to bottom portion 572 by hinge 576 that is movable in several directions, including a direction that permits the lid to move toward and away from the bottom portion as well as a direction that permits the lid to move in directions 592 and 594. Hinge 576 is a double hairpin which can be stretched to permit the lid to be placed over, or into, the bottom portion while tissue is located in the bottom portion. Movement of the lid on the hinge with respect to the bottom portion will accommodate tissue of a thickness that differs from a tissue that is accommodated prior to movement of the lid with respect to the bottom portion. The lid also has a multiplicity of slots, such as slot 600, that are organized in four quadrants, such as quadrant 602, and are elongated to have the long axis thereof extend parallel to a diagonal of the lid. The lid is held in place on the bottom portion by a friction fit between the walls of the lid and the walls of the bottom portion. Ladder like elements on the sides of the cassette can also be included.
The lid can include tissue-retaining projections, such as projection 604, which hold tissue in place in the cassette.
The lid can thus be moved with respect to the bottom portion to be positioned to accommodate tissue samples of nearly any thickness and such samples will be securely held in the cassette. Thus, once tissue is captured in the cassette, the tissue need not be manipulated again after tissue processing. The tissue will not move around inside the cassette and will thus maintain its spacing and orientation throughout the embedding process. The lid is locked to the bottom portion by a lip or projection 605 on the lid engaging grooves, such as bump or groove 606 shown in
As shown in
Another form of the frame is shown as frame 611 in
Yet another form of the cassette is shown in
In addition, the cassette can be colored to provide a histotech with an indicator during the facing operation of microtomy. During the facing operation, the histotech will cut through the bottom surface of the cassette to obtain access to the tissue inside the cassette. If the cassette is colored, the histotech will be signalled when to stop facing the paraffin block, and when the colored plastic disappears, to begin cutting thin ribbons for slide. The color of the cassette can be chosen so tissue stains will not be interfered with. Such tissue stain interference would be distracting to the pathologist.
The material of the cassette can be manipulated to further control the swelling of the cassette thereby making the cassette compatible with a wide variety of processing chemicals. For example, different types of plastics can be alloyed together to create a material which is both easy to cut in a microtome and which survives a variety of chemicals. By melt blending high molecular weight and low molecular weight plastics together, the ease of cutting certain materials is maintained while the chemical resistance of other materials is also established. Fluorination of the plastic cassette can be carried out to further modify the material of the cassette to meet the desired goals. Blending filler materials, such as finely ground talc, with the material will alter the properties of the material to reduce swelling from the processing solvents while maintaining the ability of the material to be cut in a microtome.
Chemical solvents such as acetone, xylene, D-Limonene, Aliphtic hydrocarbons, Formalin, Methyl Alchol, ethanol, Isopropanol, and hot pariffin, and the like are some of the most commonly used reagents for tissue processing. This creates a challenge to find a polymer that will withstand each or combinations of these reagents while still maintaining the mechanical integrity of the cassette. In addition, materials which are highly resistant to different chemicals used to process tissue are desirable to use. Flouropolymers which are injection moldable such as FEP are desirable as the chemicals used for processing become more aggressive. Other materials include PTFE, FEP, PFA, ETFE, ECTFE, PCTFE and PVDF which are commercially available through Complex Plastics, Inc as of the date of this application, TEFLON� PFA 340, FEP 100, TEFZEL HT-2181, HYTREL G5544 and HYTREL G4774, all trademarked products of DuPont, and all available from DuPont.
Biopsy Cassette
A biopsy cassette 650 is shown in
As shown in
Orientation Device
Shown in
As indicated in
Other forms of the orientation device can also be used, and two alternative forms are shown in
Device 680″ is X-shaped and has locks 7241 on each end, with a crossbar 740 supporting the portions 722′ and 734′. Other configurations can also be used without departing from the scope of the present disclosure as will occur to those skilled in the art based on the teaching of this disclosure.
Thus, it is seen that a system and method for harvesting and handling tissue samples is provided. One skilled in the art will appreciate that the present invention can be practiced by other than the preferred embodiments which are presented in this description for purposes of illustration and not of limitation, and the present invention is limited only by the claims which follow. It is noted that equivalents for the particular embodiments discussed in this description may practice the invention as well.
|Cited Patent
|Filing date
|Publication date
|Sep 21, 1954
|Jun 12, 1956
|Biopsy knife
|Nov 6, 1962
|Dec 21, 1965
|Waldemar Medical Res Foundatio
|Cell collector
|Jul 31, 1962
|Jun 21, 1966
|Philip Schain
|Water-soluble medium for tissue infiltrating and embedding
|Nov 25, 1964
|Sep 8, 1970
|Brunswick Corp
|Tissue infiltrant
|Sep 4, 1969
|Nov 30, 1971
|Schain Philip
|Water-soluble tissue infiltrating and embedding compositions
|Mar 16, 1970
|Jul 25, 1972
|Roy Nutt
|Biopsy method
|Jun 15, 1970
|Sep 12, 1972
|Du Pont
|Uniform composite structures of catalyst and fibrous refractory
|Apr 26, 1972
|Jun 4, 1974
|Miles Lab
|Test article for use in microbiology
|Nov 15, 1973
|Apr 1, 1975
|Robert John Wilkins
|Method and apparatus for the detection of microfilariae
|Oct 28, 1971
|Jun 1, 1976
|Gravlee Jr Joseph F
|Method of preparing tissue for microscopic examination
|Apr 9, 1975
|Dec 7, 1976
|Sherwood Medical Industries Inc.
|Method of embedding a histology specimen
|Aug 16, 1976
|May 24, 1977
|Arnold David Studer
|Process and apparatus for heartworm microfilariae detection
|Apr 3, 1978
|Apr 22, 1980
|Shandon Southern Products Limited
|Tissue processing method
|Mar 3, 1978
|Aug 26, 1980
|Battelle-Institut E. V.
|Polymer carrier and method for carrying out scientific, analytical and diagnostic examinations
|Aug 27, 1979
|Sep 2, 1980
|Miles Laboratories, Inc.
|Biological specimen process apparatus
|Apr 24, 1978
|Sep 23, 1980
|Boehringer Mannheim Gmbh
|Coated slides and apparatus for coating same
|Nov 1, 1979
|Apr 14, 1981
|Cohen Milton J
|Filter device for injectable fluids
|Feb 1, 1980
|Jul 20, 1982
|Sherwood Medical Industries Inc.
|Medical device for collecting a body sample
|Sep 26, 1980
|Oct 12, 1982
|Hoechst Aktiengesellschaft
|Process and embedding system for embedding tissue samples
|Oct 14, 1982
|Jan 24, 1984
|Imperial Chemical Industries Plc
|3-Hydroxybutyric acid polymers
|Jun 30, 1981
|Mar 6, 1984
|Stenkvist Bjoern G
|Process and device for preparation of cell samples for cytological tests
|Jul 16, 1982
|Mar 27, 1984
|Rock John G
|Receptacle for the collection of medical specimens and the like
|Dec 18, 1981
|Feb 5, 1985
|Sherwood Medical Company
|Specimen embedding composition
|Sep 13, 1982
|Oct 8, 1985
|The Mount Sinai School Of Medicine
|Method for transferring a thin tissue section
|Sep 16, 1983
|Dec 10, 1985
|Pelam, Inc.
|Apparatus for preparing and embedding tissue samples for histological examination
|Mar 6, 1986
|Apr 7, 1987
|Kok Lanbrecht P
|Rapid method for cell block preparation
|Oct 3, 1986
|Sep 22, 1987
|Rada David C
|Method for preparing tissue sections
|Sep 21, 1987
|Jun 21, 1988
|Rada David C
|Apparatus for preparing tissue sections
|Jun 25, 1987
|Jan 31, 1989
|Stephen Owen
|Methods of and apparatus for preparing tissue specimens
|Nov 30, 1987
|Apr 4, 1989
|Schnepp Pesch Wolfram
|Method for removing tissue from a body
|Feb 6, 1987
|Apr 11, 1989
|City Of Hope
|Multi-specimen tissue blocks and slides
|Jul 5, 1985
|Jun 13, 1989
|Bone Diagnostic Center
|Methods of preparing tissue samples
|Jul 24, 1987
|Jul 18, 1989
|Chang Mao Kuei
|Excrement examination unit
|Jul 5, 1988
|Oct 3, 1989
|Scott Cronk
|Suction canister assembly for the collection of body fluids and tissue specimens
|Apr 27, 1988
|Dec 19, 1989
|Esco Precision, Inc.
|Endoscopic biopsy forceps
|Jan 10, 1989
|Oct 9, 1990
|Cancer Diagnostics, Inc.
|Modular fluid sample preparation assembly
|Sep 25, 1987
|Oct 9, 1990
|Ceskoslovenska Akademie Ved
|Microorganism determination with a sorbent packed column
|Nov 22, 1982
|Nov 20, 1990
|The University Of Va Alumni Patents Foundation
|Tissue processing for immunofluorescence microscopy
|Jul 14, 1987
|Nov 20, 1990
|Technicon Instruments Corporation
|Apparatus and method for the separation of immiscible liquids
|Aug 9, 1988
|Jun 18, 1991
|The Board Of Regents, The University Of Texas
|Method for cryopreparing biological tissue for ultrastructural analysis
|Oct 27, 1989
|Sep 10, 1991
|Storz Instrument Company
|Vitrectomy probe
|Apr 9, 1990
|Dec 31, 1991
|La Mina Ltd.
|Device for detecting disease markers
|Jan 24, 1991
|May 26, 1992
|Peter F. Lee, Inc.
|Single-hand controlled fine needle aspiration device
|Feb 9, 1989
|Jul 21, 1992
|Hitachi, Ltd.
|Semiconductor device and manufacturing method thereof
|Jul 10, 1990
|Aug 11, 1992
|Shandon Scientific Limited
|Cell block preparation
|Dec 27, 1991
|Dec 15, 1992
|Symbiosis Corporation
|Hermaphroditic endoscopic claw extractors
|Sep 17, 1990
|Dec 22, 1992
|C. R. Bard, Inc.
|Disposable biopsy forceps
|Feb 14, 1991
|Jun 8, 1993
|Linvatec Corporation
|Surgical cutting instrument
|Aug 31, 1992
|Jul 6, 1993
|Neuffer Francis H
|Biopsy needle with extendable cutting means
|Jan 15, 1993
|Feb 8, 1994
|Neuro Probe, Inc.
|Multiple-site chemotactic test apparatus and method
|Oct 9, 1992
|May 3, 1994
|Tufts University
|Method and apparatus for study of gas-phase and gas-borne agents
|Sep 5, 1990
|May 17, 1994
|Oy Sed-Par-Sed Ab
|Method and device for combined enrichment, processing and embedding of cytological specimens according to histological principles
|Apr 15, 1992
|Jun 7, 1994
|Microsurge, Inc.
|Surgical instrument for endoscopic surgery
|May 14, 1996
|Oct 6, 1998
|Biopath Automation Llc.
|Means and method for harvesting and handling tissue samples for biopsy analysis
|Apr 14, 1998
|Jul 27, 1999
|Mccormick; James B.
|Apparatus and method for preparing small tissue samples for histological examination
|Feb 1, 1996
|Oct 19, 1999
|Takezaki; Teiji
|Method of fixedly supporting biopsy specimen and embedding cassette
|Apr 9, 1999
|May 14, 2002
|Culterra, Llc
|Apparatus and method for automatically producing tissue slides
|Title not available
|Title not available
|European Patent Office, Supplementary European Search Report in corresponding EP 02776027, Jul. 7, 2006.
|Citing Patent
|Filing date
|Publication date
|Feb 10, 2004
|Jun 2, 2009
|University Of Massachusetts
|Method and apparatus for preparing cells for microtome sectioning and archiving nucleic acids and proteins
|Dec 13, 2004
|May 25, 2010
|Biopath Automation, Llc
|Apparatus and methods for automated handling and embedding of tissue samples
|Aug 17, 2010
|Biopath Automation, L.L.C.
|Cassette and embedding assembly for handling and holding tissue samples during processing, embedding and microtome procedures, staging devices therefore, and methods therefor
|Mar 15, 2011
|University Of Massachusetts
|Method and apparatus for biopsy sample processing
|Aug 15, 2007
|Mar 29, 2011
|Cytyc Corporation
|Methods for processing cell block
|Oct 11, 2011
|Biopath Automation Llc
|Apparatus and methods for automated handling and embedding of tissue samples
|Nov 1, 2011
|University Of Massachusetts
|Method and apparatus for preparing cells for microtome sectioning and archiving nucleic acids and proteins
|Nov 10, 2008
|Feb 21, 2012
|Cytyc Corporation
|Method and apparatus for spacing cellular matter in a cell block
|Jan 22, 2010
|Dec 11, 2012
|Biopath Automation, L.L.C.
|Microtome sectionable biopsy support for orienting tissue samples
|Mar 15, 2011
|Dec 11, 2012
|University Of Massachusetts
|Method and apparatus for biopsy sample processing
|Feb 26, 2013
|Biopath Automation, L.L.C.
|Biopsy support with sectionable resilient cellular material
|Apr 23, 2008
|Apr 30, 2013
|Leica Biosystems Nussloch Gmbh
|Tissue embedding apparatus, and method for operating a tissue embedding apparatus
|May 25, 2006
|Jun 11, 2013
|Sakura Finetek U.S.A., Inc.
|Fluid dispensing apparatus
|Jun 18, 2013
|Endochoice, Inc.
|Tissue collection and separation device
|May 13, 2010
|Jul 23, 2013
|Ethicon Endo-Surgery, Inc.
|Method and apparatus for morcellating tissue
|Sep 21, 2011
|Nov 12, 2013
|Sakura Finetek U.S.A., Inc.
|Traceability for automated staining system
|Jul 17, 2008
|Feb 18, 2014
|Histologics, LLC
|Frictional trans-epithelial tissue disruption and collection apparatus and method of inducing and/or augmenting an immune response
|Mar 16, 2009
|Apr 8, 2014
|C. R. Bard, Inc.
|Biopsy device having rotational cutting
|Apr 29, 2011
|Apr 22, 2014
|C.R. Bard, Inc.
|Quick cycle biopsy system
|Aug 10, 2011
|Apr 22, 2014
|C.R. Bard, Inc.
|Quick cycle biopsy system
|Apr 15, 2009
|Apr 29, 2014
|Bard Peripheral Vascular, Inc.
|Biopsy apparatus having integrated fluid management
|Mar 12, 2013
|Apr 29, 2014
|Bard Peripheral Vascular, Inc.
|Biopsy apparatus having integrated fluid management
|Mar 13, 2013
|Apr 29, 2014
|Bard Peripheral Vascular, Inc.
|Biopsy apparatus having integrated fluid management
|Aug 28, 2012
|May 13, 2014
|C. R. Bard, Inc.
|Single-insertion, multiple sample biopsy device with integrated markers
|Aug 28, 2012
|May 20, 2014
|C.R. Bard Inc.
|Single insertion, multiple sample biopsy device with integrated markers
|Apr 12, 2012
|May 20, 2014
|C.R. Bard, Inc.
|Biopsy needle system having a pressure generating unit
|Mar 14, 2011
|May 27, 2014
|Biopath Automation, L.L.C.
|Tissue cassette for automated handling and embedding of tissue samples
|Feb 1, 2011
|Jun 17, 2014
|Sakura Finetek U.S.A., Inc.
|Fluid dispensing system
|Aug 22, 2012
|Jul 8, 2014
|C.R. Bard, Inc.
|Single insertion, multiple sampling biopsy device with linear drive
|Sep 22, 2011
|Jul 15, 2014
|University Of Massachusetts
|Method and apparatus for preparing cells for microtome sectioning and archiving nucleic acids and proteins
|Mar 28, 2011
|Aug 5, 2014
|Histologics, LLC
|Frictional trans-epithelial tissue disruption collection apparatus and method of inducing an immune response
|Nov 16, 2012
|Aug 5, 2014
|Biopath Automation, L.L.C.
|Method for orienting tissue samples on a microtome sectionable biopsy support
|Mar 14, 2013
|Aug 19, 2014
|Bard Peripheral Vascular, Inc.
|Biopsy driver assembly having a control circuit for conserving battery power
|Nov 7, 2013
|Oct 14, 2014
|C. R. Bard, Inc.
|Biopsy device
|Jul 8, 2005
|Oct 21, 2014
|Bard Peripheral Vascular, Inc.
|Transport system for biopsy device
|Apr 20, 2011
|Oct 21, 2014
|Eric J. Seibel
|Optical projection tomography microscopy (OPTM) for large specimen sizes
|Jan 2, 2007
|Nov 4, 2014
|Biopath Automation, L.L.C.
|Cassette for handling and holding tissue samples during processing, embedding and microtome procedures, and methods therefor
|Feb 27, 2011
|Nov 11, 2014
|Board Of Trustees Of The University Of Arkansas
|Apparatus, system, and method of processing biopsy specimen
|Mar 27, 2012
|Jan 6, 2015
|Bard Peripheral Vascular, Inc.
|Tissue sample flushing system for biopsy device
|Sep 21, 2011
|Jan 13, 2015
|Sakura Finetek U.S.A., Inc.
|Automated staining system and reaction chamber
|Aug 13, 2012
|Feb 10, 2015
|C. R. Bard, Inc.
|Self-contained handheld biopsy needle
|Apr 18, 2012
|Feb 10, 2015
|C. R. Bard, Inc.
|Biopsy device and insertable biopsy needle module
|Sep 10, 2012
|Feb 24, 2015
|C.R. Bard, Inc.
|Single-insertion, multiple sampling biopsy device usable with various transport systems and integrated markers
|Oct 28, 2009
|Mar 3, 2015
|Covidien LLP
|Device for needle biopsy with integrated needle protection
|Dec 18, 2008
|Mar 3, 2015
|University Of Massachusetts
|Method and apparatus for preparing cells for microtome sectioning and archiving nucleic acids and proteins
|Sep 26, 2011
|Mar 31, 2015
|Bard Peripheral Vascular, Inc.
|Length detection system for biopsy device
|May 9, 2014
|Mar 31, 2015
|Rushabh Instruments, Inc.
|Tissue processor
|May 23, 2014
|Apr 7, 2015
|Biopath Automation, L.L.C.
|Method for automated processing and embedding of tissue samples
|Oct 18, 2013
|Apr 14, 2015
|Sakura Finetek U.S.A., Inc.
|Traceability for automated staining system
|Jun 5, 2014
|Apr 28, 2015
|Sakura Finetek U.S.A., Inc.
|Fluid dispensing system
|Mar 28, 2011
|Jun 2, 2015
|Histologics, LLC
|Frictional tissue sampling and collection method and device
|Mar 11, 2014
|Jun 9, 2015
|Leica Biosystems Nussloch Gmbh
|Method for processing and embedding tissue
|Dec 29, 2011
|Jul 7, 2015
|C. R. Bard, Inc.
|Disposable biopsy unit
|Mar 11, 2014
|Aug 4, 2015
|Leica Biosystems Nussloch Gmbh
|Tissue cassette with retractable member
|Apr 21, 2014
|Oct 20, 2015
|C. R. Bard, Inc.
|Quick cycle biopsy system
|Aug 12, 2009
|Nov 3, 2015
|C. R. Bard, Inc.
|Biopsy apparatus having integrated thumbwheel mechanism for manual rotation of biopsy cannula
|Oct 1, 2008
|Nov 17, 2015
|Covidien Lp
|Needle biopsy device
|Mar 10, 2015
|Nov 24, 2015
|Biopath Automation, L.L.C.
|Method for automated processing and embedding of tissue samples
|Oct 26, 2012
|Dec 29, 2015
|Endochoice, Inc.
|Tissue collection and separation device
|Dec 17, 2013
|Feb 2, 2016
|Uc-Care Ltd.
|Mold and molding apparatus for embedding biological specimen in a block and related methods
|Sep 28, 2012
|Mar 15, 2016
|Bard Peripheral Vascular, Inc.
|Charging station for battery powered biopsy apparatus
|Apr 25, 2014
|Mar 15, 2016
|Histologics, LLC
|Frictional trans-epithelial tissue disruption collection apparatus and method of inducing an immune response
|Nov 16, 2011
|May 10, 2016
|Covidien Lp
|Needle biopsy device with exchangeable needle and integrated needle protection
|Jan 10, 2013
|May 17, 2016
|Uc-Care Ltd.
|Device and method for handling biological tissues
|Oct 7, 2014
|May 24, 2016
|Bard Peripheral Vascular, Inc.
|Transport system for biopsy device
|Mar 11, 2014
|Jul 12, 2016
|Leica Biosystems Nussloch Gmbh
|Tissue cassette with biasing element
|May 25, 2006
|Nov 29, 2007
|Sakura Finetek, U.S.A., Inc.
|Fluid dispensing apparatus
|Jul 10, 2007
|Jan 10, 2008
|Jeda Technologies
|System and Method for Thread Creation and Memory Management In An Object-Oriented Programming Environment
|Aug 15, 2007
|Apr 3, 2008
|Cytyc Corporation
|Methods for processing cell block
|Dec 11, 2007
|Jun 12, 2008
|Biopath Automation, L.L.C.
|Biopsy support with sectionable resilient cellular material
|Mar 7, 2008
|Sep 18, 2008
|Nightingale Stephen D
|Tissue sample support and orientation device
|May 23, 2008
|Nov 13, 2008
|University Of Massachusetts
|Method and apparatus for preparing cells for microtome sectioning and archiving nucleic acids and proteins
|Jul 2, 2007
|Jan 8, 2009
|University Of Massachusetts
|Method and apparatus for biopsy sample processing
|Dec 18, 2008
|Apr 16, 2009
|University Of Massachusetts
|Method and apparatus for preparing cells for microtome sectioning and archiving nucleic acids and proteins
|Nov 13, 2008
|May 14, 2009
|Mayo Foundation For Medical Education And Research
|Biopsy sample mount and processing method
|Nov 10, 2008
|Jul 2, 2009
|Cytyc Corporation
|Method and apparatus for spacing cellular matter in a cell block
|Sep 29, 2008
|Apr 1, 2010
|Searete Llc, Alimited Liability Corporation Of The State Of Delaware
|Histological facilitation systems and methods
|Sep 29, 2008
|Apr 1, 2010
|Searete Llc, A Limited Liability Corporation Of The State Of Delaware.
|Histological facilitation systems and methods
|Apr 1, 2010
|Searete Llc, A Limited Liability Corporation Of The State Of Delaware
|Histological facilitation systems and methods
|Apr 1, 2010
|Searete Llc, A Limited Liability Corporation Of The State Of Delaware
|Histological facilitation systems and methods
|Sep 29, 2008
|Apr 1, 2010
|Searete Llc, A Limited Liability Corporation Of The State Of Delaware
|Histological facilitation systems and methods
|Apr 1, 2010
|Searete Llc, A Limited Liability Corporation Of The State Of Delaware
|Histological Facilitation systems and methods
|Oct 1, 2008
|Apr 1, 2010
|John Mugan
|Needle biopsy device
|Oct 28, 2009
|May 13, 2010
|Boston Endoscopic Engineering Corporation
|Device for needle biopsy with integrated needle protection
|Jul 17, 2008
|Aug 19, 2010
|Histologics Llc
|Frictional trans-epithelial tissue disruption and collection apparatus and method of inducing and/or augmenting an immune response
|Apr 23, 2008
|Sep 30, 2010
|Leica Biosystems Nussloch Gmbh
|Tissue Embedding Apparatus, And Method For Operating A Tissue Embedding Apparatus
|Aug 26, 2009
|Jan 13, 2011
|Morales Azorides R
|Pathology grossing tool, cassette, and board
|Apr 21, 2009
|Apr 7, 2011
|Steffen Kraus
|Device for removal of excess embedding medium
|Jul 7, 2011
|University Of Massachusetts
|Method and apparatus for biopsy sample processing
|Jul 14, 2011
|Histologics Llc
|Frictional trans-epithelial tissue disruption collection apparatus and method of inducing an immune response
|Aug 29, 2011
|Mar 1, 2012
|William Parks
|Tissue collection and separation device
|Apr 15, 2009
|Mar 15, 2012
|Videbaek Karsten
|Biopsy apparatus having integrated fluid management
|Apr 20, 2011
|Aug 2, 2012
|Eric J. Seibel
|Optical Projection Tomography Microscopy (OPTM) for Large Specimen Sizes
|Jan 24, 2013
|Aug 1, 2013
|Western Michigan University Research Foundation (WMURF)
|Tissue cassette assembly
|Mar 13, 2013
|Aug 1, 2013
|Bard Peripheral Vascular, Inc.
|Biopsy apparatus having integrated fluid management
|Oct 26, 2012
|May 1, 2014
|Endochoice, Inc.
|Tissue Collection and Separation Device
|May 23, 2014
|Sep 11, 2014
|Biopath Automation, L.L.C.
|Method for automated processing and embedding of tissue samples
|Mar 10, 2015
|Jul 16, 2015
|Biopath Automation, L.L.C.
|Method for automated processing and embedding of tissue samples
|Mar 25, 2015
|Jul 1, 2015
|Device for analyzing interaction between microorganisms of specific categories under natural conditions
|Aug 28, 2013
|Aug 19, 2015
|Microtome sectionable gel support structure and methods
|May 8, 2007
|Nov 13, 2008
|Leica Biosystems Nussloch Gmbh
|Gewebeeinbettvorrichtung und Verfahren zum Betreiben einer Gewebeeinbettvorrichtung
|Mar 15, 2013
|Sep 18, 2014
|Leica Biosystems Nussloch Gmbh
|Gewebekassette mit Vorspannung
|Mar 15, 2013
|Sep 18, 2014
|Leica Biosystems Nussloch Gmbh
|Verfahren zum Bearbeiten von Gewebeproben
|Mar 15, 2013
|Sep 18, 2014
|Leica Biosystems Nussloch Gmbh
|Gewebekassette mit zur�ckziehbarem Bauteil
|Mar 13, 2014
|Sep 17, 2014
|Leica Biosystems Nussloch GmbH
|Tissue cassette with biasing element
|Mar 13, 2014
|Sep 17, 2014
|Leica Biosystems Nussloch GmbH
|Method for treating a tissue sample
|Mar 13, 2014
|Sep 17, 2014
|Leica Biosystems Nussloch GmbH
|Tissue cassette with retractable member
|Mar 7, 2008
|Sep 18, 2008
|Quickmbed, Inc.
|Tissue sample support and orientation device
|Sep 10, 2009
|Mar 18, 2010
|Quickmbed, Inc.
|Scaffold for tissue sample orientation
|Jan 22, 2010
|Jul 29, 2010
|Biopath Automation, L.L.C.
|Microtome sectionable biopsy support for orienting tissue samples
|Aug 28, 2013
|Mar 20, 2014
|Biopath Automation, L.L.C.
|Microtome sectionable gel support structure and methods
|U.S. Classification
|600/562, 435/305.1, 435/297.5, 435/40.52
|International Classification
|Cooperative Classification
|European Classification
|Jan 3, 2002
Owner name: SAKURA FINETEK U.S.A. INC., CALIFORNIA
Free format text: DEVELOPMENT AND LICENSE AGREEMENT;ASSIGNOR:BIOPATH AUTOMATION, LLC;REEL/FRAME:013625/0190
Effective date: 19971020
|Jan 7, 2002
Owner name: BIOPATH AUTOMATION, L.L.C., OHIO
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WILLIAMSON IV, WARREN P.;WHITLATCH, STEPHEN P.;DINOVO, DOMINIC;AND OTHERS;REEL/FRAME:012422/0292;SIGNING DATES FROM 20010820 TO 20010827
|Nov 13, 2007
|Certificate of correction
|Jun 22, 2010
|Fee payment
Year of fee payment: 4
|Jun 24, 2014
|Fee payment
Year of fee payment: 8