HK1162661B - Methods and apparatuses for heating slides carrying specimens - Google Patents

Description

Method and apparatus for heating specimen-carrying slides

Cross Reference to Related Applications

According to 35u.s.c. § 119(e), the present application claims priority from united states provisional patent application No. 61/113,964, filed 11, 12, 2008. This provisional application is incorporated herein by reference in its entirety.

Technical Field

The present invention relates generally to a method and apparatus for processing specimen-bearing slides. More particularly, the present invention relates to attaching specimens to microscope slides.

Background

Tissue analysis is a diagnostic tool used by physicians, such as pathologists, for diagnosing different types of diseases and by medical researchers for obtaining information about pathology, organization and tissue structure. In order to prepare a tissue sample for tissue analysis, various methods are commonly used. Many types of tissue are relatively soft and pliable and are therefore not suitable for use in slicing. Techniques for preparing tissue samples include fixing the tissue, tissue embedding in material, sectioning the embedded tissue, and transferring the tissue sections onto microscope slides for subsequent processing and analysis (e.g., staining, immunohistochemistry, or in situ hybridization). To slice a tissue sample for examination by an optical microscope, a thin strip of tissue may be cut from a large tissue sample so that light may be transmitted through the thin strip of tissue. The average thickness of the tissue strips is approximately about 2 microns to about 8 microns.

The thin tissue strips are typically transferred onto microscope slides using water. Residual water droplets trapped between the microscope slide and the thin tissue strip will cause the thin tissue strip to float on the slide. The tissue sections floating on the wet slide are sensitive to movement along the front surface of the microscope slide. If the tissue sample moves too far, the sample may detach from the microscope slide. If the physician does not perceive the sample as being detached from the microscope slide, a diagnosis may be made based on the incomplete test results, eventually resulting in a misdiagnosis. For example, if a set of tissue samples float on residual water on a slide, one of the tissue samples may detach from the slide during the drying process. The detached tissue sample may be the tissue sample necessary for proper diagnosis.

Horizontal hotplates and convection ovens are often used to heat and dry wet microscope slides. If a horizontal heating plate is used, it may take a longer period of time to evaporate the water below the tissue sample horizontally positioned on the slide. In addition, the contact angle between the water and the slide is typically increased when the embedding material of the specimen dissolves and reaches the front surface of the slide. If the microscope slide moves or is not flat during this drying process, the tissue sample may move a significant distance relative to the slide and, in some cases, may detach from the microscope slide. If spaced apart tissue samples (e.g., a row of evenly spaced tissue samples) move a significant distance relative to one another during the drying process, the physician may be interested in one or more tissue samples that are detached from the microscope slide. The physician may discard that sample carrier slide and prepare an entirely new sample carrier slide to ensure that the entire set of tissue samples is analyzed. Additional tissue samples may need to be obtained from the subject. Convection ovens take longer to dry the slides. Conventional convection ovens may dry vertically positioned slides in about 30 minutes to 2 hours.

Disclosure of Invention

At least some embodiments disclosed herein include an apparatus configured to dry a specimen on a microscope slide. The apparatus controls the temperature of a microscope slide carrying a specimen. The apparatus heats the specimen while supporting the microscope slide so that movement of the specimen (relative to the microscope slide, if any) can be controlled, even for adhesion between the specimen and the slide.

In certain embodiments, the apparatus supports the microscope slide in a near vertical orientation to limit, minimize, or substantially prevent movement of the specimen relative to the microscope slide. The specimen may be held in substantially the same position relative to the microscope slide prior to or during the drying process. In certain embodiments, the specimen is attached to the region of the slide where the specimen was originally placed. In addition, residual transfer fluid between the specimen and the slide is drained to physically contact the specimen with the slide, thereby reducing drying time. The specimen may be heated to couple the back surface of the specimen with the front surface of the slide.

In certain embodiments, the dryer is adapted to support the carrier in a vertical position to allow residual transfer fluid between the specimen and the carrier to be removed from an interface between the specimen and the carrier. The conductive heater of the dryer is capable of generating sufficient heat to conductively heat at least a portion of the specimen to the melting point. The specimen includes a biological sample of tissue and another material (e.g., an embedding material having a lower melting point). The melted embedding material can be cooled to fixedly couple the specimen to the carrier. In a particular embodiment, the carrier is a slide, such as a microscope slide.

The conductive heater maintains and transfers thermal energy to the rear surface of the carrier, thereby transferring thermal energy through the thickness of the carrier to the specimen on the front surface of the carrier. Melting at least a portion of the embedding material. The melted portion of the embedding material allows the specimen to be in direct contact with the front surface of the carrier. When cooled, the specimen reliably adheres to the front surface of the carrier.

In certain embodiments, an apparatus for processing specimen-bearing microscope slides includes a slide dryer. The specimen may include a biological sample and an embedding material. The slide dryer can dry the specimen and embedding material without unnecessary movement of the biological specimen. In certain embodiments, the slide dryer is configured to support the microscope slide in a substantially vertical orientation. The slide dryer includes a controller and a thermally conductive slide heater communicatively coupled to the controller. The conductive slide heater is adapted to generate sufficient heat in response to a signal from the controller to conductively heat the specimen on the microscope slide to the melting point of the embedding material. The slide dryer can effectively dry microscope slides even when the ambient temperature (e.g., room temperature) is low.

In certain embodiments, the slide dryer is configured to support the microscope slide in a vertical orientation while drying water on the microscope slide. The conductive slide heater selectively heats the microscope slide and the biological specimen carried thereon to adhere the biological specimen to the microscope slide.

In other embodiments, the slide dryer includes a conductive slide heater having a contact surface and a tilt angle of about at least 75 degrees. The conductive slide heater is adapted to heat the interface to a temperature equal to or greater than about 50 degrees celsius.

In certain embodiments, an apparatus for processing a microscope slide includes a drying station, a processing station, and a transport device. In certain embodiments, the drying station includes a slide dryer configured to support the microscope slide in a substantially vertical orientation and to generate heat that conductively heats at least one specimen held by the microscope slide during a cycle (e.g., a drying cycle). The processing station is adapted to process a specimen on a microscope slide after a drying cycle. The transport device is configured to transport the microscope slide between the slide dryer and the processing station.

In certain embodiments, a method for processing a specimen on a microscope slide is provided. The method includes placing the specimen on a microscope slide such that the residual transfer fluid is located between the specimen and the microscope slide. The microscope slide is supported in a substantially vertical orientation to expel residual transfer fluid from between the specimen and the microscope slide. The microscope slide is conductively heated while the microscope slide is positioned in a substantially vertical orientation using a thermally conductive slide heater that physically contacts the microscope slide.

In other embodiments, a method for processing a specimen carried by a microscope slide includes positioning a specimen-carrying microscope slide in a substantially vertical orientation. The specimen floats above the residual transfer fluid trapped on the microscope slide. The residual transfer fluid is drained from between at least a portion of the floating specimen and the microscope slide. A microscope slide is conductively heated using a conductive slide heater.

In certain embodiments, the slide dryer generally dries microscope slides independent of the temperature of the ambient air. Heat can be conductively transferred to the microscope slide to rapidly heat the microscope slide, typically independent of ambient air temperature. The user can easily enter the slide dryer to manually load the microscope slides onto the slide dryer and remove the microscope slides after the drying cycle. In some embodiments, the slide dryer can have a controller programmed to implement different types of drying processes.

Brief description of the drawings

Non-limiting and non-exhaustive embodiments are described with reference to the following figures. Unless otherwise specified, like reference numerals refer to like parts or acts in the various figures.

FIG. 1 is a diagram of a slide dryer for heating microscope slides, according to one embodiment;

FIG. 2 is a side elevational view of the slide dryer of FIG. 1 supporting a plurality of specimen-bearing microscope slides;

FIG. 3 is a front elevational view of the slide dryer of FIG. 2 with a specimen-carrying microscope slide;

FIG. 4 is a partial cross-sectional view of the slide dryer and elements of a specimen-bearing microscope slide;

FIG. 5 is a flow chart of one method of processing a biological sample;

FIG. 6 is an elevational view of a specimen and residual transfer fluid on a microscope slide supported by a thermally conductive slide heater;

FIG. 7 is an elevational view of a microscope slide carrying a specimen before the rear surface of the specimen is attached to the front face of the slide;

FIG. 8 is an elevational view of the specimen of FIG. 7 attached to a microscope slide;

FIG. 9 is a pictorial view of a slide dryer having a housing and a thermally conductive slide heater capable of supporting a thermally conductive slide dryer with a plurality of microscope slides spaced apart from one another;

FIG. 10 is a pictorial view of a thermally conductive slide heater for supporting two rows of microscope slides;

FIG. 11 is a diagram of an apparatus for processing microscope slides, according to one illustrated embodiment;

FIG. 12 is a side elevational view of the apparatus of FIG. 11;

fig. 13 is a cross-sectional view of the apparatus of fig. 11 taken along line 13-13 of fig. 12.

Detailed Description

Fig. 1 illustrates a slide dryer 100 capable of drying one or more specimen-bearing microscope slides. The slide dryer 100 may heat the microscope slide and the specimen carried thereon to dry the slide and/or specimen, couple the specimen to the slide, and/or perform any other desired thermal treatment. The microscope slides carrying the specimen are supported in an orientation that accelerates the elimination of residual transfer fluid between the specimen and the respective microscope slide while limiting, minimizing, or substantially eliminating unwanted movement of the specimen. The specimen-bearing slides are dried to fixedly couple the specimen to the respective slide. After the specimen is fixedly coupled to the slide, the slide holding the specimen is removed from the slide dryer 100 for subsequent processing and tissue analysis (e.g., staining, immunohistochemistry, in situ hybridization, or other processing). The slide dryer 100 shown is portable and can be easily carried (e.g., by hand) by a user. In a laboratory environment, the slide dryer 100 may be manually transported between workstations.

The microscope slide can be supported in a substantially vertical orientation to speed up the removal of residual transfer fluid trapped under the specimen and thereby shorten drying times. By draining the flowable residual transfer fluid from the specimen, the region of the slide under the specimen can be quickly dried. Likewise, only a portion of the remaining transfer fluid is evaporated to dry the region of the slide facing the specimen. The slide dryer 100 generates heat to dry the slides and to facilitate coupling the specimen to the slides. Specimens can include, but are not limited to, biological samples (e.g., tissue samples) and materials in which the samples are embedded (e.g., embedded materials).

At least a portion of the embedding material is melted, contacted with the slide, and solidified to attach the biological sample directly to the slide. The embedding material can be moved toward the microscope slide and eventually placed on the slide. If this material is more hydrophobic than the slide material and the residual transfer fluid (e.g., water), the embedding material can accelerate fluid beading. Because the embedding material is coated onto the slide, the contact angle between the fluid and the slide will be increased. Because the microscope slide is in a vertical orientation, residual transfer fluid due to gravity will tend to collect at the lower end of the specimen. The upper end of the specimen may directly contact the front of the slide and minimize, limit, or substantially prevent unwanted movement of the specimen. After a sufficient amount of residual transfer fluid has accumulated, it can drain downward away from the specimen, leaving the specimen on the front face of the slide. The process can be carried out on a variety of wet microscope slides.

The slide dryer 100 shown in fig. 1 includes a conductive slide heater 110, a controller 114, and a body 118 that houses the internal components of the slide dryer 100. The conductive slide heater 110 can physically contact and support one or more microscope slides. The body 118 includes a slide support 120 proximate the conductive slide heater 110.

The conductive slide heater 110 and the slide support 120 can cooperate to support a microscope slide in a substantially vertical orientation to transfer heat generated by the conductive slide heater 110 to the microscope slide for a desired period of time (e.g., a drying period). The conductive slide heater 110 can generate sufficient heat in response to a signal from the controller 114 to conductively heat the specimen to a desired temperature. Residual transfer fluid may flow away from the specimen, evaporate, and/or otherwise be removed from the specimen-carrying microscope slide. The heated specimen is brought into physical contact with a microscope slide. The specimen may be raised to a temperature that facilitates adhesion between the specimen and the microscope slide, as discussed in fig. 6-9.

Fig. 2 and 3 show microscope slides 130a, 130b, 130c (collectively 130) resting against the conductive slide heater 110 and on the upper surface 136 of the slide support 120. The microscope slide 130 is a substantially flat, transparent substrate that carries a specimen 132, which specimen 132 is examined using equipment such as optical equipment (e.g., a microscope). For example, each microscope slide 130 may be a generally rectangular piece of transparent material (e.g., glass) having a front face for receiving specimens and a rear face for attaching the slide dryer 100. The microscope slide 130 can be loaded or unloaded according to the application, and the microscope slide 130 can have different sizes. In certain embodiments, the slide 130 has a length of about 3 inches (75 millimeters) and a width of about 1 inch (25 millimeters), and in certain embodiments may include a label (e.g., a barcode). In certain embodiments, the slide has a length of about 75 millimeters, a width of about 25 millimeters, and a thickness of about 1 millimeter. The microscope slide 130 can be in the form of a standard microscope slide. The microscope slide 130 is shown carrying an uncovered specimen 132 (e.g., without a coverslip). In certain embodiments, the dimensions of the slide support 120 are such that: the label on the slide 130 is located on the side of the slide opposite the slide support and above the slide portion, i.e., in contact with the slide support. In this way, heating of the label during the drying process can be avoided.

The body 118 rests on a generally horizontal support surface 140 so that the microscope slide 130 is supported generally vertically. The user can conveniently access the controller 114 to control the operation of the slide dryer 100. Fig. 1-3 illustrate a controller 114 communicatively coupled to the conductive slide heater 110, which includes a housing 146, a display 150, and an input device 154. The display 150 may be a screen or other display device. Input devices 154 may include, but are not limited to: one or more buttons, keyboards, input pads, buttons, control modules, or other suitable input elements. The input device 154 is shown in the form of an input pad (e.g., a touchpad) for programming the slide dryer 100.

The controller 114 generally includes, but is not limited to: one or more central processing units, processing devices, microprocessors, digital signal processors, central processing units, processing devices, microprocessors, Digital Signal Processors (DSPs), Application Specific Integrated Circuits (ASICs), readers and the like. To store information (e.g., a drying program), the controller 114 may also include, but is not limited to: one or more memory elements, such as volatile memory, non-volatile memory, Read Only Memory (ROM), Random Access Memory (RAM), and the like. The controller 114 can be programmed based on the desired processing of the specimen-bearing slide. In the fixed temperature mode of operation, the controller 114 can be used to maintain the conductive slide heater 110 at a substantially constant temperature. In the variable temperature mode of operation, the controller 114 is used to adjust the temperature of the conductive slide heater 110. The controller 114 can store one or more programs for controlling the operation of the heat carrier heater 110. The input device 154 may be used to switch between different programs, modes of operation, etc.

Referring to fig. 1-3, heat can be efficiently transferred through the thickness of the microscope slide 130. The conductive slide heater 110 shown in fig. 2 has a height H that is greater than or equal to the length of the specimen seating area of the slide 130. The longitudinal length L of each microscope slide 130_sMay be in contact with the conductive slide heater 110 to facilitate substantially even heat distribution throughout the mounting region. In certain embodiments, the height H is at least about 2.5 inches (63.5 millimeters), about 2.75 inches (70 millimeters), or about 2.9 inches (74.7 millimeters), and ranges encompassing these heights. The upper ends 139a, 139b, 139c of the slides 130a, 130b, 130c, respectively, can extend upwardly beyond the slide dryer 100 to facilitate gripping of the slides 130.

The longitudinal length L of the conductive slide heater 110 can be selected based on the desired number of microscope slides 130 being processed. The length L is increased or decreased in order to increase or decrease the number of microscope slides that can be processed, the pitch of the microscope slides, and the like. The embodiment shown in fig. 3 has three spaced apart microscope slides 130. In certain embodiments, the length L is at least 6 inches (152 millimeters) to allow for simultaneous processing of at least three microscope slides 130. Other dimensions may also be used.

The conductive slide heater 110 can be a plate having a generally rectangular shape when viewed from the side (see fig. 3). The thermal characteristics of the thermally conductive slide heater 110 can be selected based on desired processing criteria (e.g., desired processing temperature, temperature distribution, heating/cooling rates, etc.). For example, the contact face 160 of the slide heater 110 has a relatively low thermal mass and a high thermal conductivity to rapidly transfer heat across the entire face 160. The contact surface 160 can have a substantially uniform heat distribution to ensure that all or a substantial portion of the slides 130 are maintained at substantially the same temperature.

The conductive slide heater 110 can be made, in whole or in part, of one or more thermally conductive materials (e.g., such as copper, steel, aluminum, iron, combinations thereof, and the like). In certain embodiments, the contact surface 160 is made primarily of steel (e.g., stainless steel) and is particularly resistant to wear and corrosion. In other embodiments, the contact surface 160 is made primarily of copper to quickly transfer heat between the internal heating element and the slide 130. Advantageously, the number of internal heating elements (e.g., resistive heating wires of the heater 110) may be reduced due to rapid heat transfer. The conductive slide heater 110 can have a multi-layer structure to enhance wear and thermal performance. For example, the contact face 160 may be a thin steel sheet, and an inner layer of copper in the heater 110 may help distribute and transfer heat to the face 160. In other embodiments, the conductive slide heater 110 has a single layer structure.

The contact face 160 can be substantially flat to increase the contact area between the slide 130 and the face 160. The contact surface 160 can be a highly polished surface that is very flat so as to contact most or substantially all of the covered portion of the slide 130. In certain embodiments, the contact face 160 is configured to minimize, limit, or substantially prevent relative displacement of the microscope slide 130. For example, anti-migration features (e.g., protrusions, channels, segmentation, texturing, etc.) may be integrated into the face 160.

The body 118 of fig. 1-3 has a base 170 that rests on the surface 140. The body 118 protects the internal components even if the slide dryer 100 is used in harsh environments including, but not limited to, corrosive environments or other test sites often found in laboratories. The slide support 120 is integrally formed with the body 118. In the illustrated embodiment, the upper surface 136 extends generally perpendicularly relative to the contact surface 160. When the lower end of the microscope slide 130 is placed on the upper surface 136, the back surface 141 (see FIG. 2) of the slide 130 is flat against the contact surface 160.

Fig. 4 shows the controller 114, the power supply 200, the wires 202 that deliver power to the conductive slide heater 110, and the sensors 212 that evaluate the operation of the slide heater 110. A line 220 communicatively couples the controller 114 to the sensor 212. The illustrated conductive slide heater 110 includes an exterior 210 and a thermoelectric element 204. The term "thermoelectric element" is a broad term that includes, but is not limited to, one or more electrical devices capable of generating heat and/or absorbing heat.

Substantially all or most of the contact surface 160 may have substantially the same temperature when the element 204 is activated. For example, substantially all or most of the contact surface 160 may be within a temperature range of about 10 degrees celsius. In one embodiment, the contact surface 160 is maintained at approximately the same temperature. For example, the average temperature of the contact face 160 may be in the range of about 5 degrees celsius. In other embodiments, different portions of the contact surface 160 can be maintained at different temperatures to provide for drying of slides that support different types of tissue and different embedding materials that embed the tissue.

In certain embodiments, including the embodiment shown in fig. 4, the outer portion 210 is a hollow core plate and the thermoelectric element 204 is a heating element that converts electrical energy to thermal energy. When the heating element 204 generates heat, heat is transferred through the portion 210 and the microscope slide 130 absorbs heat. Heat is ultimately transferred from the slide 130 to the specimen 132. The amount of electrical energy delivered to the element 204 can be increased or decreased to increase or decrease the temperature of the specimen 132.

The heating element 204 may be a resistive heating element. Various different types of resistive heating elements (e.g., plate resistive heaters, coil resistive heaters, ribbon heaters, etc.) may be selected based on desired operating parameters. Other types of thermal elements (e.g., cooling elements, heating/cooling elements, etc.) may also be used. As used herein, the term "cooling element" is a broad term that includes, but is not limited to, one or more elements capable of actively absorbing heat such that at least a portion of the conductive slide heater 110 cools. For example, the cooling element may be a cooling tube or a fluid channel through which the cooled fluid flows. In certain embodiments, the conductive slide heater 110 includes a heating element that generates heat during a heating period and a cooling element that absorbs heat during a cooling period.

In certain embodiments, the element 204 is a heating/cooling element, such as a Peltier (Peltier) device. A peltier device may be a solid state element that generates heat on one side and cools on the opposite side depending on the direction of current passing therethrough. By simply selecting the direction of the current, the peltier device 204 can be used to heat the contact surface 160 for a desired length of time. By switching the direction of the current, the device 204 cools the contact surface 160. In other embodiments, heating/cooling element 204 may be in the form of a channel through which a working fluid passes. Heated fluid may pass through the channels during the heating period, and cooled fluid may pass through the channels during the cooling period. The location, number, and type of heating/cooling elements 204 can be selected based on the desired temperature profile of the conductive slide heater 210.

The thermal characteristics of the portion 210 may be selected to achieve a desired temperature distribution along the wall 211 of the interface 160. For example, the portion 210 may be made, in whole or in part, of a highly thermally conductive material (e.g., copper or other suitable material that is sufficiently thermally conductive) to reduce or limit any significant localized temperature non-uniformity associated with the discrete heating elements 204. The element 204 can constantly generate a constant flow rate because heat is lost to the surrounding air (e.g., air at room temperature). The interior portion of the slide heater 110 can be hotter than the periphery of the heater 110, and heat can dissipate more quickly from the periphery of the slide heater 110 due to the exposed edges of the slide heater 110. In some embodiments, an array of closely spaced heating elements 204 is used to maintain approximately the same temperature on surface 160. Other configurations may also be used.

Sensor 212 is a temperature sensor that senses the temperature of heater 110 and sends one or more signals indicative of the temperature. The sensor 212 can be mounted on the back surface 217 of the conductive slide heater 110, embedded in the heater 110, mounted on the contact surface 160 or embedded in the contact surface 160, or positioned at any other suitable location that measures the temperature of any portion of the slide heater 110 and/or the microscope slide 130. The sensors 212 may include, but are not limited to, one or more thermocouples, thermometers (e.g., IR thermometers), pyrometers, Resistance Temperature Detectors (RTDs), thermistors, and the like.

FIG. 5 is a flow chart of a method of preparing and analyzing a specimen. Typically, thin tissue sections are used to deliver a fluid (e.g., water) to place the specimen on a microscope slide. The specimen-bearing microscope slide is loaded into a slide dryer and dried to adhere the specimen to the microscope slide. The slide dryer 100 dries slides quickly while minimizing, limiting, or substantially eliminating unnecessary movement of the specimen relative to the microscope slides. During the drying process, the specimen may be held in substantially the same position relative to the microscope slide. If multiple specimens are mounted on the slide, the spacing between the specimens may be maintained throughout the drying process. This may reduce or eliminate the concern of the physician regarding the tissue specimen becoming detached from the microscope slide. Various diagnostic techniques and equipment are used so that specimen-bearing slides can be conveniently transported and analyzed. This process will be discussed in detail below.

Biological samples (e.g., tissue samples) are processed to preserve their properties, such as tissue structure, cellular structure, and the like. The tissue may be any collection of cells that may be mounted on a microscope slide, including but not limited to organ sections, tumor sections, body fluids, smears, frozen sections, cell sheets, or cell lines. For example, the tissue sample may be a sample obtained using an excisional biopsy, core biopsy, excisional biopsy, needle biopsy, hollow needle biopsy, stereotactic biopsy, incisional biopsy, surgical biopsy, or the like.

At 250, a fixative is used to fix and preserve the sample. The fixative may fix and preserve cellular structure, inhibit or substantially stop enzymatic action that may lead to tissue purification or autolysis, etc. The fixation process may increase the rigidity of the tissue, thereby making it more convenient to slice, as described in more detail below. Formaldehyde, ethanol, acetone, paraformaldehyde, or other types of fixatives may be used. The type and amount of fixative is selected based on the desired treatment to be performed (e.g., staining, cell staining, immunohistochemistry, or in situ hybridization). After the tissue sample is fixed, the tissue sample is stored for a desired length of time.

In 260, the sample is embedded in a material having mechanical properties that can facilitate sectioning. Embedding materials include, but are not limited to, paraffin, resins (e.g., plastic resins), polymers, agarose, nitrocellulose, gelatin, mixtures thereof, and the like. In certain embodiments, the embedding material comprises primarily or entirely paraffin wax. Paraffin is a white or substantially colorless solid substance insoluble in water and resistant to many agents. For example, paraffin wax may be a mixture of hydrocarbons of the basic series obtained mainly from petroleum. Paraffins may be made from a variety of different mixtures of similar hydrocarbons, and these mixtures may be solid, semi-solid, and/or oily. In certain embodiments, the paraffin wax is a wax.

Various conventional infusion processes are used to at least partially embed materials into tissue samples. The tissue sample is mixed or otherwise combined with a material that can infiltrate the tissue sample to impart properties that facilitate the cutting process. In this manner, the tissue sample is embedded. If the tissue sample is sectioned using a microtome or similar device, the tissue sample may be embedded in paraffin or other suitable material (e.g., plastic resin). If the embedding material is paraffin, the paraffin may be heated and melted. The hot fluid paraffin is at least partially injected into the biological sample and then solidifies.

At 270, the specimen is sliced into mountable sections, placed on microscope slides, and then dried. The microtome may cut the specimen into thin sections, for example, slices of approximately 5-6 microns in thickness. Each section may include a portion of the tissue sample with some embedded material.

Different techniques may be used to transfer the tissue specimen onto a microscope slide at 280, and in some embodiments, the slide is floated on water to spread or flatten the slide. If the section is a paraffin sheet of embedded tissue, the section may float on a warm bath (wall bath) to support the section in a generally flat configuration, thereby reducing or preventing folding, twisting, or bending. The microscope slide was inserted into the warm channel. The front surface of the slide is used to pick up the tissue specimen. To use one slide to examine multiple tissue samples (e.g., a set of tissue samples, each taken from a different location of the subject), multiple tissue samples may be sequentially floated on the slide. The wet slides are dried using a slide dryer 100.

Fig. 6 shows a specimen 286 positioned on a droplet of the transport fluid 282. The droplets of the transport fluid 282 may be water or other suitable fluids (including aqueous media) with or without any additives (e.g., wetting agents, reagents, dyes, etc.). If water is used, the water may be deionized water, double distilled deionized water, purified water, or the like. When the slide 130 is removed from the slot (bath) as described above, a droplet of the transfer fluid 282 can be formed. Alternatively, the droplet 282 is placed by dripping the transport fluid directly onto the front surface 284, and thereafter the specimen is placed on top of the droplet. The droplet placed directly on surface 284 then acts to allow placement of the specimen on front surface 284. The contact angle between the transfer fluid 282 and the slide 130 is small so that the specimen 286 is held in substantially the same position even if the slide 130 is moved, such as between workstations or different devices.

The surface tension of the transfer fluid 282 helps maintain the generally flat configuration of the specimen 286 to limit, reduce, or substantially prevent unwanted irregularities, such as folds, twists, protrusions, buckles, etc., of the specimen 286. Because the fluid 282 is trapped between the specimen 286 and the microscope slide 130, the specimen 286 is distal from the front surface 284.

The microscope slide 130 is held in a substantially vertical orientation to speed the draining of the fluid 282 to reduce drying time. The slide 130 is shown at an oblique angle α defined by an imaginary, generally horizontal plane 291 (e.g., an imaginary plane generally parallel to the support surface of fig. 2 and 3) and the contact surface 160. Because the slide 130 is flat against the conductive slide heater 110, the slide 130 maintains approximately the same tilt angle. The illustrated conductive slide heater 110 extends generally along an imaginary plane 283, the imaginary plane 283 defining an angle β with the imaginary horizontal plane 291 that is greater than about 70, 80, 85, or 90 degrees. The longitudinal axis 295 of the slide 130 is substantially parallel to the imaginary plane 283. The angle β may be equal to or greater than about 80 degrees to maintain the microscope slide 130 at an angle of inclination α of about 80 degrees. Other angles may be used as needed or desired.

The contact surface 160 is maintained at or above the melting point of the embedding material of the specimen 286 in order to conductively heat the specimen 286. If the embedding material is paraffin wax having a melting point between about 50 degrees Celsius and 57 degrees Celsius, the surface 160 is maintained at a temperature of about 50 degrees Celsius or above. Arrow 277 represents the amount of heat transferred from the heater 110 to the specimen 286. When the embedding material melts, the molten substance may float along the upper surface of the transfer fluid 282 and rest on the front surface 284. If the embedding material is more hydrophobic than the microscope slide 130, the contact angle of the interface of the transfer fluid 282 with the surface 284 may increase, causing the fluid 282 to form as an unstable droplet that is sensitive to movement along the surface 284. The tilted slide 130 accelerates the accumulation of the transfer fluid 282 proximate the lower portion 287 of the specimen 286. The fluid 282 collects in the gap 285 between the specimen 286 and the microscope slide 130 such that the fluid 282 eventually drains below the front surface 284.

FIG. 6 also shows a location 296 (shown in phantom) of the fluid 282 after the contact angle has been increased, assuming the microscope 130 is in a horizontal orientation rather than a vertical orientation. Because the microscope slide 130 is shown in a vertical orientation, the fluid 282 tends to collect at the gap 285 due to gravity, as shown in fig. 7. An upper portion 293 of the specimen 286 may directly contact the heating surface 284 to limit, minimize, or substantially prevent movement of the specimen 286. For example, the upper portion 293 may be adhered to the surface 284.

After a sufficient amount of fluid has been collected, there is a tendency to drain downwardly from the specimen 286, as indicated by arrow 297. The fluid 282 flows downward from the specimen 286 and down through the surface 284. In this manner, at least a portion or substantially all of the fluid 282 trapped between the specimen 286 and the surface 284 is removed. The specimen 286 thus covers and directly contacts the surface 284. The fluid 282 can eventually flow down the entire surface 284 to the bottom end of the slide 130.

The tilt angle of fig. 7 is shown to be greater than about 70 degrees so that after a sufficient amount of embedding material has melted, the beaded transfer fluid 282 drains to significantly increase the contact angle between the fluid 282 and the surface 284. In certain embodiments, the tilt angle is greater than about 75 degrees. This embodiment is particularly well suited for allowing residual transfer fluid to be expelled from smaller specimens, such as specimens containing tissue samples obtained using a hollow core needle punch biopsy. Residual transfer fluid, including larger or smaller samples, is expelled at different rates from different types and sizes of samples. In a certain embodiment, the tilt angle is greater than about 75 degrees to accelerate the rapid accumulation of the transfer fluid 282 when heating the specimen 286. Once the embedding material is heated to its melting point, the transport fluid rapidly condenses into a water droplet and is expelled therefrom.

Fig. 8 shows the specimen-bearing slide 130 after the drying cycle is complete. The contact surface 160 may be maintained at a temperature equal to or greater than about 50 degrees celsius and the ambient air may be less than 30 degrees celsius (e.g., a temperature of about 21 degrees celsius). The slide 130 is placed against the heater 110. The contact surface 160 heats the slide 130 so that the specimen 286 is adhered to the surface 284 for a short period of time, such as less than or equal to about 5 minutes, 1 minute, 45 seconds, 30 seconds, 20 seconds, or a range including such a period of time. Most of the transfer fluid 282 is expelled from the specimen 286 to avoid drying time associated with evaporating the entire droplet. The length of the drying period may depend on the amount of fluid delivered, the characteristics of the tissue of the specimen 286, the characteristics of the embedding material, etc.

The contact face 160 of fig. 7 may be maintained at a temperature at or above about 50 degrees celsius, 55 degrees celsius, or 65 degrees celsius, and within a range including such temperatures (e.g., a range of about 50 degrees celsius to about 65 degrees celsius). This temperature is particularly well suited for melting paraffin or other materials with a lower melting point. In certain embodiments, the specimen 286 is attached to the surface 284 in less than about 1 minute. For example, the specimen 286 is attached to the surface 284 in less than about 1 minute. In certain embodiments, the contact face 160 is maintained at a temperature of about 65 degrees celsius or greater. In particular embodiments, the contact surface 160 may be at a temperature less than, greater than, or equal to about 65 degrees celsius, 70 degrees celsius, 80 degrees celsius, or a range of such temperatures. The temperature of the contact surface 160 is measured using an infrared thermometer to maintain accuracy. Feedback from the thermometer can be used to increase or decrease the temperature of the contact surface 160 to decrease or increase the drying time.

The contact surface 160 is maintained at a somewhat constant temperature during heating to dry stably. The slide heater 110 is thus able to dry the slides without significant temperature variation. For example, the contact surface 160 may be maintained at a temperature at or above the substantially constant melting point of the embedding material to ensure a reduced drying time. In certain embodiments, the temperature of the contact surface 160 is maintained within an operating temperature range above the melting point. The operating temperature range may be 50 to 60 degrees celsius, 55 to 65 degrees celsius, or 60 to 70 degrees celsius. Other ranges may also be used.

The contact surface 160 can be preheated so that heat is immediately transferred to the slide 130 upon contact. Preheating is used to avoid ramp up times associated with the heat treatment cycle. Slides can be repeatedly loaded onto the slide dryer 100 without waiting for the interface 160 to reach a particular temperature. Of course, the temperature of the interface 160 may decrease slightly as the slide 130 absorbs heat. These effects can be minimized or avoided by continuously generating heat by the slide heater 110.

In other embodiments, the contact surface 160 is heated after the slide 130 is placed against the contact surface 160. To reduce energy consumption, the interface 160 may be maintained at a low temperature, such as about room temperature or a temperature between room temperature and a desired drying temperature. In certain embodiments, the low temperature is a standby temperature. For example. The contact surface 160 may be maintained at a standby temperature in a range of about 25 degrees celsius to 50 degrees celsius. During or after loading the slide 130, the temperature of the interface 160 is increased to at least about 50 degrees celsius. After drying, the contact surface 160 returns to the standby temperature. Various different types of heating periods may be used to reduce or limit the energy used during the drying process.

After drying, the slide 130 is removed from the slide dryer 100. To increase the cooling rate of the specimen 286 and thus reduce processing time, the thermally conductive slide heater 110 can also include a cooling element (e.g., a peltier element) for rapidly absorbing heat from the dried specimen-carrying slide 130. Once the specimen-bearing slide 130 is sufficiently cooled, it can be removed from the slide dryer 100.

At step 289, the specimen 286 is stained for examination. The specimen may also be baked, dewaxed, deparaffinized, etc. In certain embodiments, after performing the de-paraffin process, a stain is applied to the specimen 286. The microscope slide is then covered with a coverslip for subsequent optical examination.

At step 290, the specimen 286 may be examined using optical equipment (e.g., a microscope), optical tools, etc. Different types of study implementations may be employed to perform a variety of different tissue analyses for obtaining information about pathology, tissue composition, and tissue structure. Physicians use this information to diagnose different types of diseases and conduct various medical studies.

Referring to fig. 9, the slide dryer 300 includes a conductive slide heater 310, a base 312, and a housing 314. The base 312 includes a controller 320 for controlling the operation of the conductive slide heater 310. The housing 314 may surround and enclose the conductive slide heater 310 to prevent unwanted contamination from falling onto the specimen-carrying microscope slide. The base 312 includes a collector 337 surrounding the slide conductive heater 310. The collector 337 can collect residual transfer fluid or other material removed from the slide.

The illustrated conductive slide heater 310 includes a plurality of heat-generating support elements 330a-h (collectively 330) spaced apart from one another. The support elements 330 may operate independently or together and be oriented at the same or different inclinations. The illustrated elements 330 are generally parallel to each other and are spaced apart to allow insertion of at least one generally vertically positioned microscope slide between a pair of adjacent elements 330. Each support element 330 may include one or more electrical heating devices (e.g., electrical heating elements). In other embodiments, the back plate 441 extends between support elements 330 having thermal devices (e.g., internal thermal devices) capable of generating heat that is conducted through the support elements 330.

In operation, a microscope slide can rest on the respective support element 330. The housing 314 can be moved toward the slide heater 310 as indicated by arrow 339. The conductive slide heater 310 can dry an entire row of vertically positioned specimen-carrying microscope slides. After processing the microscope slide, the housing 314 can be removed to access and remove the microscope slide.

Fig. 10 illustrates a heating apparatus 360 including a frame 361 and a plurality of conductive slide heaters 362, 364 coupled to the frame 361. The conductive slide heaters 362, 364 can be substantially similar to the slide conductive heater 310 of fig. 9. The heating device 360 can be incorporated into different types of slide processing systems, such as an automated slide processing system or a separate slide dryer, and can include a controller, power supply, and the like.

Fig. 11 shows an apparatus 400 comprising a drying station 402 and a plurality of treatment stations 404, 406, 408. The controller 410 controls the operation of the drying station 402 and one or more of the processing stations 404, 406, 408. A controller 410 is shown communicatively coupled to and commands each of the stations 402, 404, 406, 408. Microscope slides can be automatically processed (e.g., via substantially non-human intervention processing) using the apparatus 400. For example, the controller 410 may control the amount of heat generated by the slide dryer 401 at the station 402 (fig. 13), the rate of drying, the length of the drying cycle, or other processing parameters, preferably while maintaining the thermal loss of the tissue sample at or below a desired level.

As used herein, the term "processing station" includes, but is not limited to, a baking station, a material removal station (e.g., a dewaxing station, etc.), a staining station, a cover station, and the like. For example, processing stations 404, 406, 408 are a paraffin removal station, a staining station, and a coversheet station, respectively.

The transport 418 transports specimen-bearing microscope slides between the drying station 402 and the other stations 404, 406, 408. The transport 418 can include, but is not limited to, one or more elevators, slide handlers, slide trays, slide holders, and the like. The slide handler may include, but is not limited to, a slide robot, an X-Y-Z transfer system, a robotic system, or other automated system capable of receiving and transferring slides. The robotic system may include, but is not limited to, one or more pick-and-place robots, robotic arms, and the like.

Referring to fig. 11-13, the drying station 402 includes a slide dryer 401 and a slide handler 420, as shown in a robotic slide handler. The slide dryer 401 generates heat that conductively heats the specimen-carrying microscope slides. The robotic slide handler 420 includes an arm 421 and an end effector 423 capable of lifting and carrying slides between the conductive slide heater 401 and the slide transporter 424, shown schematically in fig. 13. The slide dryer 401 may be substantially similar to the slide dryer 100 of fig. 1-3 or the slide dryer 300 of fig. 10. Other various types of automated slide processing systems may also have slide dryers and other features disclosed herein. For example, U.S. application No. 10/414,804 (U.S. publication No. 2004/0002163) discloses various types of slide carriers, processing stations, etc., which may be used or combined with the features disclosed herein by this embodiment.

A wet microscope slide carrying a freshly cut tissue specimen can be processed using apparatus 400. The access port 430 may be opened and the user may load the specimen-bearing slide into the transfer device 418. The conveyor 418 may load the slides into the drying station 402. After drying the specimen-carrying slides, the slides are sequentially transferred to the stages 404, 406, 408. The transfer device of fig. 13 includes an elevator system 430 and a movable platform 434 that is shown holding the slide transporter 424. The elevator system 430 moves the conveyor 424 up and down along rails 440.

In one method of using the apparatus 400, specimen-bearing microscope slides are loaded onto slide trays located on the platform 434. The slide handler 420 loads the specimen-bearing microscope slides into the slide dryer 401. The slide dryer 401 dries the specimen-carrying microscope slide. After the specimen-bearing microscope slides are sufficiently dried, the slide handler 420 transfers the slides back to the conveyor 424.

The conveyor 242 is lowered vertically and the conveyor 242 is brought close to the treatment station 404 for deparaffinization. The stage 404 is capable of removing at least a portion of the embedding material of the specimen. The stone removal station 404 may be a trough type stone removal station or a jet type stone removal station. The illustrated stone removal station 404 includes a modular chamber 414 and includes one or more direct downward flush dispensing nozzles 416. The de-paraffinized material is delivered to the specimen using the nozzle 416. After removal of the embedding material (e.g., paraffin), the slide can be rinsed with a substance such as deionized water to remove its paraffin substance and additional paraffin attaches the exposed tissue sample to the microscope slide.

Various de-paraffinizing substances may be used at station 404. For example, the paraffin-depleted material may be a fluid, such as a water-based fluid that facilitates separation of paraffin from tissue specimens, such as disclosed in U.S. Pat. No. 6,855,559 published at 2/15/2005 and U.S. Pat. No. 6,544,798 published at 4/8/2003, the fluids including deionized water, citrate buffer (pH6.0-8.0), tris-HCI buffer (pH6-10), phosphate buffer (pH6.0-8.0), acidic buffer or solvent (pH1-6.9), basic buffer or solvent (pH7.1-14), and the like. The material may also comprise one or more ionic or non-ionic surfactants. The paraffin-depleted material may be heated. For example, the substance (e.g., fluid) may be heated to a temperature greater than the melting point of the embedding material, such as between 60-70 degrees Celsius. United states patent No. 7,303,725, published 12-4-2007, discloses various elements (e.g., probes, filters, sprayers, etc.) for use in de-waxing substances.

In certain embodiments, the station 404 also includes one or more heating elements for baking the embedding material. The slide may be heated to soften the embedding material in order to facilitate the elimination of the material.

After the stage 404 has processed the specimen-bearing slide, the transfer system 424 transfers the specimen-bearing slide to the stage 406 for staining. The desired stain is applied to the tissue sample. The stain may be a biological or chemical substance that, when applied to a target molecule in the tissue, allows the tissue to be detected by the tool. Stains include, but are not limited to, detectable nucleic acid probes, antibodies, hematoxylin, tetrabromofluorescin, and dyes (e.g., iodine, methylene blue, reiter white blood cell stain, etc.).

After staining the specimen, the specimen-bearing slide is transferred to the coverslipping station 408. In other embodiments, the station 408 is a drying station. Stage 408 dries the stained slide and prepares the slide for coverslipping. In certain embodiments, the drying station 408 conductively heats the stained specimen using a slide dryer (e.g., as discussed in fig. 1-10). In other embodiments, the drying station 408 is in the form of a convection oven or microwave oven.

The device 400 may also include other types of processing stations. The number, configuration and type of processing stations may be selected based on the type of processing to be performed. For example, U.S. Pat. No. 7,396,508 discloses an apparatus for staining and processing tissue. U.S. Pat. No. 7,396,508 is incorporated herein by reference in its entirety. In certain embodiments, the processing station 406 comprises a carousel-type system, such as the carousel system disclosed in U.S. Pat. No. 7,396,508.

The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the application data sheet, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments.

These and other changes can be made to the described embodiments in light of the above detailed description. In general, in the claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments that are equivalent to the full scope of the claims. The claims are not, therefore, to be limited by this disclosure.

Claims (9)

1. An apparatus for processing a microscope slide carrying a specimen, the specimen comprising a biological sample and embedding material, the apparatus comprising:

a slide dryer configured to hold an uncovered specimen carrying a microscope slide in a substantially vertical orientation, the slide dryer including a controller and a thermally conductive slide heater communicatively coupled to the controller, the thermally conductive slide heater adapted to generate sufficient heat to conductively heat the specimen on the microscope slide to a melting point of the embedding material in response to a signal from the controller;

a processing station adapted to dispense a fluid for contacting the specimen held by the microscope slide after the slide dryer has dried the specimen; and

a transfer device that transfers a specimen-carrying microscope slide between the slide dryer and the processing stage,

wherein the conductive slide heater includes a contact surface that is inclined upwardly at an angle of inclination greater than about 75 degrees.

2. The apparatus of claim 1, wherein the slide dryer is adapted to hold the microscope slide in the substantially vertical orientation to promote accumulation of fluid proximate a gap between a periphery of the specimen and the microscope slide.

3. The apparatus of claim 1, wherein the conductive slide heater includes a contact surface that is at a temperature greater than about 50 degrees celsius when the conductive slide heater generates heat.

4. The apparatus of claim 1, wherein the conductive slide heater comprises a selectively heatable plate sized to support a plurality of substantially vertically oriented microscope slides spaced apart from one another.

5. The apparatus of claim 1, wherein the conductive slide heater includes a plurality of heat generating support elements spaced apart from one another to allow at least one microscope slide to be positioned between a respective pair of adjacent support elements.

6. The apparatus of claim 1, wherein the conductive slide heater comprises at least one resistive heating element.

7. The apparatus of claim 1, wherein the processing station is a deparaffinization station configured to deliver at least one deparaffinization fluid to the specimen.

8. The apparatus of claim 1, wherein the controller is communicatively coupled to at least one of the processing station and the transfer device.

9. The apparatus of claim 1, wherein the conductive slide heater extends along an imaginary plane that is at an angle greater than about 75 degrees from an imaginary horizontal plane.