An application system for applying at least one sample of at least one body fluid to at least one slide

Abstract

An application system (110) for applying at least one sample of at least one body fluid to at least one slide (112) is disclosed. The application system (110) comprises: i. at least one slide holder (114) for holding the at least one slide (112) during application of the sample of the body fluid; and ii. at least one application device (116) for depositing a sample liquid of the body fluid onto an application side (118) of the slide (112) held by the slide holder (114), wherein the slide holder (114) comprises at least one receptacle (126) for receiving the slide (112), wherein the slide holder (114) comprises three reference elements (128), each reference element (128) having an abutment tip (130), wherein the slide holder (114) further comprises at least one pressure application element (132) configured for applying pressure onto an opposite side (134) of the slide (112) opposite to the application side (118), thereby pressing the application side (118) of the slide (112) onto the abutment tips (130) of the reference elements (128).

Description

Technical Field

[0001] This invention relates to an application system and method for applying at least one sample of at least one bodily fluid to at least one glass slide. The invention further relates to an analytical system and method for analyzing samples of at least one bodily fluid. The invention further relates to computer programs and computer-readable storage media for performing these methods. As an example, the methods and apparatus can be used in the field of hematology for applying and analyzing samples of bodily fluids (e.g., blood) to at least one glass slide. However, other applications are also possible. Background Technology

[0002] In medical or diagnostic laboratories, specifically in the fields of hematology or cytology, the processing of body fluid samples may include one or more sample processing operations and one or more sample analysis operations. For example, a body fluid sample may be applied onto one or more glass slides. Sample processing and / or analysis may include one or more of spotting, staining, and / or imaging. Apparatus and methods for automating sample application are known. For example, US 10,073,015 B2 discloses a sample smear apparatus comprising: a slide feeder for supplying glass slides prior to processing; a smear processor for smearing samples onto the glass slides; and a slide transporter including a slide support mechanism having a transfer mechanism for holding the upper surface of the glass slides and for moving the slide support mechanism in vertical and horizontal directions. The slide transporter is movably arranged between the slide feeder and the smear processor.

[0003] EP 1 261 852 B2 discloses an automated system for preparing multiple cytological samples from multiple fluid samples in vials. The system includes apparatus for collecting a monolayer of cells from each sample and transferring the cells to microscope slides for fixation, staining, and examination. The system includes a first loading station for receiving sample vials, a second loading station for receiving consumables such as filter membranes, a slide dispenser, and an unloading area for removing completed sample slides. To maintain a one-to-one correspondence between the samples and the samples produced therefrom, the system includes a subsystem for identifying each sample and permanently labeling each slide with a corresponding marker before transferring the samples to the slides.

[0004] US 2005 / 0136534 A1 describes the automated collection and deposition of fluid, semi-solid, and solid samples of biological or chemical materials. More specifically, it describes microarrayers, which are devices for autonomously depositing tiny droplets of biological or chemical fluid samples in an ordered array onto a substrate. Further, it describes tissue arrayers, which are devices for collecting and depositing solid and semi-solid tissue samples in an ordered array. Further still, it describes fluid dynamics robots, which are devices for autonomously collecting, dispensing, and processing biological or chemical fluid samples.

[0005] WO 2023 / 172670 A2 describes a method, system, and apparatus for capturing an analyte from a sample. A first substrate including the sample is mounted on a first member of a sample processing apparatus, and a second substrate including a capture probe array is mounted on a second member of the sample processing apparatus. A first reagent medium is applied to the first substrate and / or the second substrate, and the first member and / or the second member are moved to fluidly couple the sample and the capture probe array through the first reagent medium. The sample and the capture probe array are fluidly decoupled by moving the first member and / or the second member, and a second reagent medium is applied to the first substrate and / or the second substrate, and the first member and / or the second member are moved to fluidly couple the sample and the capture probe array through the second reagent medium.

[0006] US 2019 / 0317310 A1 describes probe handling in digital pathology. A slide holder for digital pathology is provided, comprising a tray base, multiple mounting devices, and multiple slide holder positioning points. The tray base is configured to hold multiple slides to be imaged by a digital pathology system, and for this purpose, the tray base provides multiple slide receiving positions. Multiple mounting devices are arranged on the tray base to mount multiple slides on the tray base at the multiple slide receiving positions, thereby imaging each slide at separate imaging positions. The slide holder positioning points include multiple interacting portions that provide mechanical positioning of the tray base with respect to the digital pathology system at each imaging position.

[0007] Despite the advantages of known methods and apparatus, several technical challenges remain in automating sample application. Specifically, the positioning and / or alignment of the glass slide may still be technically challenging. For example, a glass slide may be placed on a metal surface and held there by a vacuum. Bodily fluid samples (e.g., blood) can be spotted onto the other side of the glass slide using a spotting probe. The distance between the spotting probe and the glass slide can range from 10 µm to 20 µm. The thickness of the glass slide can be 0.991 ± 0.051 mm. Therefore, the tolerance of the glass slide thickness may be much larger than the spotting gap, and thus must be compensated for during spotting. The flatness of the glass slide can be less than 1 µm. To maintain a constant spotting gap, the position of the glass slide can be sensed optically, for example, at three locations on each glass slide. A theoretical surface plane can be calculated, and this theoretical surface plane can be used to adjust the height of the spotting probe according to a preset x or y position on the glass slide. However, this method is generally time-consuming because level sensing of the glass slides must be performed on each individual slide.

[0008] Problems to be solved Therefore, it is desirable to provide methods and apparatus that at least partially avoid the drawbacks of known methods and apparatus. Specifically, an application system and method for applying at least one sample of at least one bodily fluid to at least one glass slide, and an analytical system and method for analyzing at least one bodily fluid sample, which facilitates the application of the sample to the glass slide, should be provided. Summary of the Invention

[0009] This problem is solved by an application system and method having the features of the independent claims for applying at least one sample of at least one bodily fluid to at least one glass slide, and an analytical system and method for analyzing at least one bodily fluid sample. Advantageous embodiments that can be implemented individually or in any combination are set forth in the dependent claims and throughout the specification.

[0010] As used below, the terms “have,” “contain,” or “include,” or any grammatical variations thereof, are used in a non-exclusive manner. Thus, these terms can refer either to a situation where no other features exist in the entity described in this context besides those introduced by these terms, or to a situation where one or more other features exist. For example, the statements “A has B,” “A includes B,” and “A contains B” can refer to a situation where no other elements exist in A besides B (i.e., where A is solely and uniquely composed of B); or to a situation where one or more other elements (such as element C, element D, or even other elements) exist in entity A besides B.

[0011] Furthermore, it should be noted that the terms "at least one," "one or more," or similar expressions indicating that a feature or element may exist once or more are generally used only once when the corresponding feature or element is introduced. In the following text, in most cases, when referring to the corresponding feature or element, the expressions "at least one" or "one or more" will not be used repeatedly, even though the corresponding feature or element may exist only once or more.

[0012] Furthermore, as used below, the terms “preferredly,” “more preferably,” “particularly / specifically,” “more particularly / more specifically,” “specifically,” “more specifically,” or similar terms are used in combination with optional features without limiting the possibility of alternatives. Therefore, features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. As those skilled in the art will recognize, the invention can be carried out by using alternative features. Similarly, features or similar expressions introduced by “in one embodiment of the invention” are intended to be optional features without limiting alternative embodiments of the invention, without limiting the scope of the invention, and without limiting the possibility of combining features introduced in this way with other optional or non-optional features of the invention.

[0013] In a first aspect of the invention, an application system is disclosed for applying at least one sample of at least one bodily fluid to at least one glass slide. As used herein, the term "system" is a broad term and will be given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, an arbitrary set of interacting or interdependent component parts forming a whole. Specifically, the components may interact with each other to achieve at least one common function. At least two components may be processed independently, or may be coupled or connectable.

[0014] As used herein, the term "apply" is a broad term and will be given its common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, the process of bringing at least one bodily fluid sample into contact with a glass slide, particularly with the surface of the glass slide. Applying may specifically include bringing at least one bodily fluid sample into contact with a glass slide, specifically causing at least a portion of the bodily fluid sample to adhere at least partially to the glass slide. Applying at least one bodily fluid sample to a glass slide may specifically include spotting at least one bodily fluid sample onto the glass slide. Applying to at least one bodily fluid sample may include adhering at least a portion of at least one bodily fluid sample to the glass slide, specifically in the form of a thin film. Therefore, as used herein, the term "applying system" may refer to, but is not limited to, a system configured for applying at least one bodily fluid sample to a glass slide. An applying system may specifically be a slide spotter that includes at least one spotting probe for spotting a bodily fluid sample onto a glass slide, such as spotting a blood sample onto a glass slide. The process of applying at least one body fluid sample to a glass slide can be referred to as "application".

[0015] As used herein, the term "body fluid" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. The term may specifically refer to, but is not limited to, any fluid generally present in the body or body tissues of a human or animal. Body fluids may be selected from the group consisting of blood, specifically whole blood, plasma, serum, and interstitial fluid. However, additionally or alternatively, one or more other types of body fluids may be used, such as cerebrospinal fluid, bone marrow aspirate, saliva, tears, urine, or other body fluids.

[0016] As used herein, the term "body fluid sample" is a broad term and will be given a meaning common and customary to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, any divisible or non-divisible portion of a biological fluid that is directly a body fluid as defined above or derived from a body fluid, such as by one or more pretreatment steps, such as by transferring the body fluid to at least one sampling solution, by diluting the body fluid, by centrifuging the body fluid, etc. As an example, the body fluid may contain blood, such as human blood, such as the blood of a patient suffering from a disease or undergoing a medical examination. A body fluid sample may contain an aliquot of blood obtained by venipuncture and collected in a sample tube. Alternatively or additionally, a body fluid sample may contain at least one body fluid collected via at least one swab or brush, such as via at least one nasopharyngeal swab, for example, a swab from at least one anterior nasal cavity and / or throat, such as by applying a swab to the surface of the anterior nasal cavity and / or throat. The collected body fluid sample can be transferred at least to a sampling solution or reagent solution by immersing the swab in the sampling solution or reagent solution. The sampling solution or reagent solution may specifically contain lysis reagents. Other examples of body fluid samples are also possible. Body fluid samples may also be referred to simply as samples.

[0017] As used herein, the term "slide" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, a substrate configured to receive at least one bodily fluid sample, specifically for receiving at least one bodily fluid sample on the surface of a slide. The slide can be mechanically stable. The slide can specifically include any material that provides sufficient mechanical stability for the application of automated processing by the system. The slide can be configured to hold the bodily fluid sample during processing without any change. The slide can exhibit at least one surface compatible with biological materials, particularly bodily fluid samples. For example, the slide can be a glass slide. Specifically, glass is known to provide both sufficient mechanical stability and compatibility with biological materials. However, other types of materials for slides are also feasible. The slide can be a plate having a two-dimensional extension and thickness. The two-dimensional extension of the plate can exhibit a rectangular or circular form. The thickness of the plate can be smaller than the size of the extension, for example, 20%, 10%, or 5%, or less than a measure of the linear range of the two-dimensional extension of the plate.

[0018] The application system includes: i. At least one slide holder for holding the at least one slide during the application of a body fluid sample; and ii. At least one application device for depositing the body fluid sample onto the application side of a glass slide held by the slide holder.

[0019] As used herein, the term "slide holder" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, a device configured to receive at least one slide and maintain the position and / or orientation of said at least one slide. Thus, as used herein, the term "hold" can refer to the process of holding a slide in a certain position and / or orientation. A slide holder may be specifically configured to receive, support, and / or hold one or more individual slides during the application of a bodily fluid sample. A slide holder may be further configured to control the position and / or orientation of the slide held by the slide holder, specifically for actively controlling the position and / or orientation of the slide held by the slide holder. For example, a slide holder may include one or more actuators, such as one or more linear actuators, for changing the position and / or orientation of the slide held by the slide holder. A slide holder may be configured to hold a slide in a substantially horizontal orientation. The basic horizontal orientation can refer to the orientation of a slide, specifically at least one surface of the slide, or more specifically the surface of a two-dimensional extension of the slide, having an orientation with a tilt angle of 10° or less, specifically 5° or less, more specifically 1° or less, and most specifically 0.1° or less relative to the ground.

[0020] As used herein, the term "application device" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, a device configured to direct fluid onto a glass slide. Specifically, an application device may be configured to direct a bodily fluid sample onto a glass slide, such as from one or more containers or sample tubes containing the bodily fluid sample. The application device may include at least one application tip for controlling liquid deposition of the bodily fluid sample onto the application side of the glass slide. For example, the application device may include at least one nozzle system having at least one nozzle. Further, the application device may include at least one pump and / or at least one tubing system for supplying the bodily fluid sample to the nozzle system. Alternatively or additionally, the application device may include at least one pipetting system having at least one pipette tip comprising one or more pipettes, such as a single-channel pipette or a multi-channel pipette. Alternatively or additionally, the application device may include at least one spotting probe for spotting the bodily fluid sample onto the glass slide.

[0021] As used herein, the term "liquid deposition" is a broad term and will be given the common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. The term may specifically refer to, but is not limited to, the process of directing a body fluid sample onto a glass slide, specifically onto the surface of the slide. Liquid deposition may specifically be an active, controlled process of bringing a body fluid sample into contact with a glass slide, such as by controlling one or more of the amount of body fluid sample deposited on the slide and / or the location of the body fluid sample deposition on the slide.

[0022] As used herein, the term "application side" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. The term specifically refers to, but is not limited to, the side of a glass slide on which a bodily fluid sample is applied. Specifically, the application side may include the surface of the glass slide on which the liquid deposition of the bodily fluid sample is performed by the application device. For example, as outlined above, the glass slide may be a plate having a two-dimensional extension and thickness. The two-dimensional extension of the plate may define a first surface or upper surface and a second surface or lower surface. The first surface of the plate may be defined by a surface facing the application device. The second surface of the plate may be defined by a surface facing the sample holder. The application side may include the first surface of the plate facing the application device.

[0023] For example, as outlined above, the application device may include at least one spotting probe for spotting a body fluid sample onto a glass slide. As used herein, the term "spotting" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, the process of spatially controlling liquid deposition. Spotting a body fluid sample onto a glass slide, specifically onto the application side of the slide, may include spatially controlling the liquid deposition of the body fluid sample on the glass slide, specifically on the application side of the glass slide. Spatial control may be performed at least partially simultaneously with liquid deposition. Therefore, as used herein, the term "spotting probe" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, a device configured for spotting, i.e., for spatially controlling liquid deposition. The spotting probe may be specifically configured to simultaneously control the amount and location of the body fluid sample applied to the glass slide. Spotting probes can be configured to move relative to a glass slide during the deposition of bodily fluid samples onto the slide.

[0024] The slide holder includes at least one receiving portion for receiving a slide, wherein the slide holder includes three reference elements, each reference element having an adjacent tip, and wherein the slide holder further includes at least one pressure applying element configured to apply pressure to an opposite side of the slide opposite to the applying side, thereby pressing the applying side of the slide against the adjacent tip of the reference element.

[0025] As used herein, the term "receiving portion" is a broad term and will be given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, a device or element of a device configured to at least partially receive the at least one slide. Thus, as used herein, the term "receiving" can refer to the process of at least partially receiving a slide in a receiving portion of a slide holder. The receiving portion can specifically be at least one recess in a slide holder, wherein, specifically, the recess can be adjustable according to the size of the slide. Additionally or alternatively, the receiving portion may include at least one slot for receiving the at least one slide. The receiving portion can specifically be configured to receive slides individually, such as for receiving slides one after another.

[0026] As used herein, the term "reference element" is a broad term and will be given its common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. The term may specifically refer to, but is not limited to, any element having a known or predetermined position. A reference element may specifically provide a known or predetermined position relative to a slide held by a slide holder and specifically received in a receiving portion of the slide holder. The position of the reference element may be known or predetermined, such as during calibration, for example, by calibrating the position of the reference element using a first slide received in the slide holder. The position of the reference element relative to a slide held by a slide holder and specifically received in a receiving portion of the slide holder may be specifically constant during the application of a body fluid sample to the slide. Furthermore, the position of the reference element relative to a slide held by a slide holder and specifically received in a receiving portion of the slide holder may be constant during the application of a body fluid sample to one or more subsequent slides. The reference element provides a constant relative position to multiple glass slides, received one after another in the sample holder and specifically in the receiving portion. The reference element may be made of at least one conductive material, such as a metal.

[0027] As used herein, the term "adjacent tip" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, any element providing a stop point. An adjacent tip may specifically provide the intended endpoint of the path of movement of a slide held and specifically received in the receiving portion of a slide holder. An adjacent tip may include a sharply formed element to provide a single stop point for a slide held and specifically received in the receiving portion of a slide holder. An adjacent tip may specifically include a tapered element, such as a cone or a regular pyramid, wherein the apex of the tapered element may form the adjacent tip. An adjacent tip may contact a slide held and specifically received in the receiving portion of a slide holder. An adjacent tip may be made of at least one material suitable for contacting the slide. For example, an adjacent tip may be made of at least one metallic material.

[0028] The slide holder may include a frame extending along at least three edges of a slide received in a receiving portion. Three reference elements may be disposed on the frame extending along these three edges. For example, at least one of the three reference elements may be disposed on the frame, located at each edge of the slide. Alternatively or additionally, the three reference elements may be partially disposed on the frame, located at a first edge of the slide, specifically at a short edge of the slide. The slide holder may further include a rod extending across the slide received in the receiving portion. The three reference elements may be partially disposed on this rod. As an example, one of the three reference elements may be disposed on the frame, located at a first edge of the slide, specifically at a short edge of the slide. Two of the three reference elements may be disposed on the rod.

[0029] Furthermore, the slide holder may include at least one temperature-regulating element for heating and / or cooling the slide received in the receiving portion. As used herein, the term "temperature-regulating element" is a broad term and will be given its common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, means configured to control the temperature of the slide received in the receiving portion. The temperature-regulating element may be specifically configured to adjust the temperature of the slide received in the receiving portion according to at least one temperature setpoint, such as by actively increasing and / or decreasing the temperature of the slide received in the receiving portion. The temperature-regulating element may include at least one of a resistance heating element or a Peltier element. The temperature-regulating element may be disposed on the opposite side of the slide received in the receiving portion. Specifically, the temperature-regulating element may be disposed on the opposite side of the receiving portion. The temperature-regulating element may be configured to heat and / or cool the receiving portion, thereby heating and / or cooling the slide received in the receiving portion. The pressure application element can be at least partially integrated into the temperature control element.

[0030] As outlined above, the slide holder further includes at least one pressure-applying element configured to apply pressure to the opposite side of the slide. As used herein, the term "pressure" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, a physical quantity indicating a force applied perpendicular to the surface of an object. Specifically, the pressure of the pressure-applying element may include a force applied perpendicular to the surface of the slide held by the slide holder, specifically received in the receiving portion. When pressure is applied to the slide, the slide may be forced to move toward an adjacent tip and / or may be held in close contact with the adjacent tip.

[0031] As used herein, the term "pressure applying element" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. The term specifically refers to, but is not limited to, any element configured to apply pressure to a component. Specifically, a pressure applying element may be configured to apply pressure to the reverse side of a slide held by a slide holder and specifically received in a receiving portion. The pressure applying element may be or may include a single element of the slide holder, and / or may be at least partially constituted by another element of the slide holder. For example, the pressure applying element may be or may include a spring pin for applying pressure to the reverse side of the slide. The spring pin may extend at least partially through the receiving portion for applying pressure to the slide received in the receiving portion. Alternatively or additionally, the pressure applying element may be or may include a raised region of the receiving portion of the slide holder.

[0032] As used herein, the term "reverse side" is a broad term and will be given its common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. The term may specifically refer to, but is not limited to, the side of the slide opposite to the application side.

[0033] The pressure-applying element may include three pressure-applying tips, each having an adjacent protrusion for applying pressure to the opposite side of the slide. The pressure-applying tips may be positioned on the opposite side of the slide relative to their corresponding adjacent tips. Three pairs of tips may be provided. Each pair may include one adjacent tip and one pressure-applying tip. As an example, in each pair, the adjacent tip and the pressure-applying tip may be positioned on the opposite side of the slide such that the connecting line between the adjacent tip and the pressure-applying tip is substantially perpendicular to the application-side orientation of the slide. The term "substantially perpendicular" as used herein may refer to, but is not limited to, two elements or objects having an orientation of tilt angle in the range of 80° to 100°, specifically in the range of 85° to 95°, more specifically in the range of 89° to 91°. Additionally or alternatively, in each pair, the adjacent tip and the pressure-applying tip may be aligned relative to each other.

[0034] The application system may further include: iii. At least one control device, wherein the control device may be configured to control the liquid deposition of a body fluid sample by an application device.

[0035] As used herein, the term "control device" is a broad term and will be given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, any logical circuit system configured to perform basic operations of a computer or system; and / or, generally, a device configured to perform computation or logical operations. A control device may include one or more processors. In particular, a control device may be configured to process basic instructions that drive and apply to the system. As an example, a control device may include at least one arithmetic logic unit (ALU), at least one floating-point unit (FPU) (such as a math coprocessor or numerical coprocessor), multiple registers (specifically registers configured to provide operands to the ALU and store the results of operations), and memory (such as L1 and L2 caches). In particular, a control device may be a multi-core processor. Specifically, a control device may be or may include a central processing unit (CPU). Additionally or alternatively, a control device may be or may include a microprocessor, and thus, specifically, the elements of the control device may be contained within a single integrated circuit (IC) chip. Additionally or alternatively, the control device may be or may include one or more application-specific integrated circuits (ASICs) and / or one or more field-programmable gate arrays (FPGAs) and / or one or more tensor processing units (TPUs) and / or one or more chips, such as dedicated machine learning optimization chips. Specifically, the control device may be configured (e.g., through software programming) to perform one or more control operations.

[0036] The control device may be configured to control the distance between at least one application tip of the application device and the application surface of a slide on the application side during liquid deposition of a body fluid sample onto the application side. The control device may be configured to perform a calibration procedure. In the calibration procedure, the application surface of a calibration slide received in the receiving portion, specifically a first slide received in the receiving portion, may be determined. As used herein, the term "calibration slide" may refer to, but is not limited to, a separate slide used to perform the calibration procedure, or a first slide received in the receiving portion. A calibration slide may specifically be a standard slide, such as that used for applying a body fluid sample.

[0037] The control device may be further configured to perform subsequent application of a body fluid sample to the application side of a subsequent slide held by a slide holder by determining a reference surface based on the application surface of a calibration slide and using the reference surface to control the distance between the at least one application tip of the application device and the application surface of the subsequent slide during subsequent application of the body fluid sample to the application side of the subsequent slide.

[0038] The calibration slide may specifically be a slide received in the receiving section. The control device may be configured to perform a calibration routine for each slide received in the receiving section.

[0039] The control device can be configured to determine the positions of at least three points on the application surface of a calibration slide received in the receiving portion during a calibration routine, and to calculate the reference surface as a virtual plane defined by these three points. Alternatively or additionally, the control device can be configured to determine the positions of a grid of multiple points on the application surface of a calibration slide received in the receiving portion during a calibration routine. This grid of multiple points can form a surface grid on the application surface of the calibration slide. The control device can be configured to use this surface grid as a reference surface. The surface grid allows for the generation of the morphology of the application surface on the application side of the slide. The surface grid allows for the consideration of irregularities on the application surface on the application side of the slide.

[0040] Additionally or alternatively, the control device may be configured to control a measurement routine for determining, directly or indirectly, the position of a point on the application surface of a slide received in the accommodating portion of a slide holder by using at least one measuring device. The measuring device may be selected from the group consisting of: optical measuring devices; electrical measuring devices, specifically at least partially integrated into the application device, and more specifically at least partially integrated into a controller for controlling the distance between at least one application tip of the application device and the application surface of the slide, such as capacitive measuring devices, resistive measuring devices, and / or inductive measuring devices; and ultrasonic measuring devices. For example, the measuring device may include at least one resistive measuring device integrated into the application device, specifically into the application tip of the application device, for example, into a spotting probe of the application device. The position of the application surface of the slide relative to the application device, specifically relative to the application tip of the application device, can be obtained by determining the positions of three reference elements. The position of the reference element can be determined by moving the application device, specifically the application tip of the application device, toward the reference element, and detecting the contact between the application device (specifically the application tip of the application device) and the reference element via resistance measurement. As summarized above, the reference element provides a known or predetermined position relative to the slide held and specifically received in the receiving portion of the slide holder. Therefore, the position of the application surface of the slide relative to the application device can be derived using the position of the reference element. A control device can be configured to control this measurement routine to determine the position of a point on the application surface of the slide received in the receiving portion of the slide holder using a resistance measuring device. However, other examples are also possible.

[0041] In a further aspect of the invention, an analytical system for analyzing samples of at least one bodily fluid is disclosed. As used herein, the term "analytical system" is a broad term and will be given its common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, a system configured to perform at least one analytical function on at least one bodily fluid sample. The process of performing the at least one analytical function may also be referred to as "analysis". The analytical system may be specifically configured to automatically analyze the at least one bodily fluid sample, for example by performing the at least one analytical function without manual support. The analytical system may be configured to analyze multiple bodily fluid samples. Specifically, the analytical system may be configured to analyze bodily fluid samples one by one, such as analyzing bodily fluid samples one after another, in batches, or continuously. The analytical system may be part of an automated laboratory automation system (LAS). The analytical system may specifically be a modular analytical system. Alternatively or additionally, the analytical system may be a standalone system specifically configured to independently perform the at least one analytical function. As an example, the analytical system may be configured to analyze blood cells in a bodily fluid sample. The analytical system may be configured to analyze one or more of the following: the presence of blood cells in a body fluid sample, the number of blood cells in a body fluid sample, the concentration of blood cells in a body fluid sample, the identity of blood cells in a body fluid sample, the shape of blood cells in a body fluid sample, the size of blood cells in a body fluid sample, the staining of blood cells in a body fluid sample, the shape of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in a body fluid sample, the size of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in a body fluid sample, and / or the staining of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in a body fluid sample.

[0042] The analysis system includes: I. At least one application system according to the present invention, such as any of the embodiments disclosed above and / or any of the embodiments further detailed below; and II. At least one detector for detecting at least one characteristic of a body fluid sample disposed on at least one glass slide by an application system.

[0043] For the terminology definitions and possible embodiments of the application system, refer to the description of the application system above.

[0044] As used herein, the term "detector" is a broad term and will be given its common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, any device configured to quantitatively or qualitatively determine at least one property of a bodily fluid sample. A detector may be or may include at least one hematology analyzer, specifically at least one automated hematology analyzer.

[0045] As used herein, the term "detection" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, the process of quantitatively and / or qualitatively determining at least one characteristic of a bodily fluid sample. As an example, detection results may include at least one detection piece of information that quantitatively and / or qualitatively indicates at least one characteristic of the bodily fluid sample, such as a detection piece of information indicating the presence and / or concentration of a compound or parameter in the bodily fluid sample.

[0046] As used herein, the term "characteristics of a body fluid sample" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, any measurable parameter of a body fluid sample. The characteristics of a body fluid sample may include the presence and / or concentration of at least one analyte in the sample. For example, a body fluid sample may contain blood cells, such as a whole blood sample. The characteristics of a body fluid sample may include at least one parameter selected from the group consisting of: the presence of blood cells in the body fluid sample; the number of blood cells in the body fluid sample; the concentration of blood cells in the body fluid sample; the identity of blood cells in the body fluid sample; the shape of blood cells in the body fluid sample; the size of blood cells in the body fluid sample; the staining of blood cells in the body fluid sample; the shape of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in the body fluid sample; the size of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in the body fluid sample; and / or the staining of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in the body fluid sample.

[0047] The detector may be an optical detector, specifically an optical microscope, comprising at least one light source and at least one photosensitive element, specifically at least one camera. As used herein, the term "light source" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, any element configured to emit electromagnetic radiation within an optical spectral range. The optical spectral range may include one or more of the visible spectral range, the infrared spectral range, and / or the ultraviolet spectral range. In this document, the term "ultraviolet spectral range" generally refers to electromagnetic radiation with wavelengths from 1 nm to 380 nm, preferably from 100 nm to 380 nm. Further, in part according to the ISO-21348 standard, which was in effect at the date of this document, the term "visible spectral range" generally refers to a spectral range from 380 nm to 760 nm. The term "infrared spectral range" (IR) generally refers to electromagnetic radiation from 760 nm to 1000 µm. The light source may include at least one element selected from the group consisting of: incandescent light source, discharge light source, light-emitting diode (LED), laser.

[0048] As used herein, the term "photosensitive element" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to any particular or customary meaning. The term may specifically refer to, but is not limited to, any device configured for detecting electromagnetic radiation within an optical spectrum. A photosensitive element may include at least one photosensitive region configured to generate at least one detector signal when illuminated. A photosensitive element may be configured to determine at least one optical parameter, such as the intensity and / or power of light illuminating at least one photosensitive region of the photosensitive element. A photosensitive element may include at least one element selected from the group consisting of: a photodiode; a photovoltaic cell; a photoresistor; a phototransistor; a thermopile sensor; a photoacoustic sensor; a pyroelectric sensor; a photomultiplier tube; and a calorimeter. Alternatively or additionally, a photosensitive element may include at least one camera chip, such as at least one CCD chip and / or at least one CMOS chip configured for imaging.

[0049] The analysis system may further include: Ⅲ. At least one transfer device for transferring a glass slide from an application system to a detector.

[0050] As used herein, the term "transfer device" is a broad term and will be given the common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, any device configured to change one or more of the position and orientation of a slide. A transfer device may be configured to change one or more of the position and orientation of a slide such that a slide on which a body fluid sample is applied can be analyzed by a detector. A transfer device may include at least one gripping unit for holding the slide and at least one actuator for moving the gripping unit with the slide from the application system to the detector. For example, a transfer device may be or may include a Delta robot for transferring a slide from the application system to the detector. However, other options are also possible.

[0051] In a further aspect of the invention, an application method is disclosed for applying at least one sample of at least one bodily fluid to at least one glass slide. This application method uses an application system according to the invention, such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below. For definitions of the terminology used in the application system and possible embodiments, refer to the description of the application system above.

[0052] The method includes the following steps, which may be performed in a specific order. However, it should be noted that different orders are also possible. Furthermore, one or more method steps may be performed once or repeatedly. Further, two or more method steps may be performed simultaneously or in a manner that overlaps as appropriate. The method may include other method steps not listed.

[0053] The method includes: a. Receiving a slide in a slide holder; and b. Liquid deposition of the body fluid sample is performed by using an application device, and the sample is applied to the application side of a glass slide held by a slide holder.

[0054] The application method may include subsequently applying a sample of at least one bodily fluid to a plurality of slides. The application method may include at least one calibration routine. In the calibration routine, an application surface of a calibration slide received in a receiving portion may be determined. The method may further include: determining a reference surface from the application surface of the calibration slide, and using this reference surface to control the distance between at least one application tip of the application device and the application surface of a subsequent slide during subsequent application of the bodily fluid sample to the application side of a subsequent slide held by a slide holder, thereby performing subsequent application of the bodily fluid sample to the application side of a subsequent slide held by a slide holder.

[0055] In this application method, at least step b, and optionally, the calibration routine, may be computer-controlled, specifically performed by at least one control device of the application system. As used herein, the term "computer-controlled" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, a process wholly or partially controlled by the use of a data processing device (such as a data processing device including at least one processor).

[0056] In a further aspect of the invention, a computer program is disclosed comprising instructions that, when executed by a control device of an application system according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below), cause the control device to perform at least step b of an application method according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below), and optionally, a calibration routine.

[0057] In a further aspect of the invention, a computer-readable storage medium is disclosed, specifically a non-transitory computer-readable storage medium comprising instructions that, when executed by a control device of an application system according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below), cause the control device to perform at least step b of an application method according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below), and optionally, a calibration routine.

[0058] As used herein, the term "computer-readable storage medium" specifically refers to a non-transitory data storage device, such as a hardware storage medium having computer-executable instructions stored thereon. A computer-readable data carrier or storage medium can specifically be or may include storage media such as random access memory (RAM) and / or read-only memory (ROM). The computer-readable storage medium can be or may include at least one computer-readable data carrier.

[0059] Referring to the computer implementation aspects of the present invention, one or more method steps, or even all method steps, of the methods according to one or more embodiments disclosed herein can be performed and / or controlled using a computer or computer network. Therefore, in general, any method steps, including providing and / or manipulating data, can be performed and / or controlled using a computer or computer network. Generally, these method steps can include any method steps that typically require manual work, such as providing samples and / or performing actual measurements.

[0060] In another aspect of the invention, an analytical method for analyzing samples of at least one bodily fluid is disclosed. This analytical method uses an analytical system according to the invention, such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below. For definitions of analytical systems and possible embodiments, refer to the description of the analytical systems above.

[0061] The method includes the following steps, which may be performed in a specific order. However, it should be noted that different orders are also possible. Furthermore, one or more method steps may be performed once or repeatedly. Further, two or more method steps may be performed simultaneously or in a manner that overlaps as appropriate. The method may include other method steps not listed.

[0062] The analytical method includes: A. Applying a body fluid sample to a glass slide using an application method according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below); and B. By using the detector, at least one characteristic of the body fluid sample placed on the glass slide is detected.

[0063] This analysis method can be computer-controlled.

[0064] In a further aspect of the invention, a computer program is disclosed that includes instructions that, when executed by a control device of an application system of an analysis system according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below), cause the control device to perform steps of an analysis method according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below).

[0065] In a further aspect of the invention, a computer-readable storage medium is disclosed, specifically a non-transitory computer-readable storage medium comprising instructions that, when executed by a control device of an application system of an analysis system according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments involving the analysis system disclosed in more detail below), cause the control device to perform steps of an analysis method according to the invention (such as any of the embodiments disclosed above and / or any of the embodiments disclosed in more detail below).

[0066] The apparatus and method according to the invention offer numerous advantages over known methods and apparatus of the same kind. Specifically, the application system according to the invention facilitates the application of a sample to a glass slide because the three reference elements allow the glass slide to be consistently positioned relative to the application device. Therefore, the application system eliminates the need for individual sensing of the level in each of the multiple glass slides.

[0067] Furthermore, the application system can be configured to determine the position of a point on the application surface of a slide received in the receiving portion of a slide holder by using a measuring device, particularly a resistance measuring device. Resistance measurement, in particular, can provide a precise signal for determining the position of a point on the application surface of the slide. The requirement for control current may be lower compared to other measuring devices (e.g., optical measuring devices). Resistance measurement may be faster than optical measurement. Furthermore, since the slide received in the receiving portion of the slide holder may not be contacted by the application device during the sensing of the slide's level, the risk of damage is reduced.

[0068] The application system specifically provides a simple and time-saving method for aligning the application side of a slide with the application device. The slide may have a flat surface with a thickness variation of less than 0.1 mm, specifically less than 0.5 mm. The slide, received in the slide receiving portion, can be pressed against three adjacent tips, which specifically support the slide on the application side. Tolerances in the slide thickness do not affect the position of the slide relative to the application device. Slide level sensing can be performed using a first slide, for example during a calibration routine, and can be used on subsequent slides on which body fluid samples can be applied using the same theoretical surface. This method can reduce the time required for sample application. Additionally, slide level recalibration can be performed periodically to correct for thermal expansion of components of the application system. The frequency of slide level sensing can be adjustable based on temperature drift detected in the application system. Alternatively or additionally, slide level sensing can be performed by optically detecting the reflection of the application device (e.g., a spotting probe). Alternatively or additionally, the sensing of the slide level can be performed using force detection. An application device, such as a spotting probe, can be moved toward the application side of the slide. Impact can be detected by an increase in the z-axis current. This method may require precise control of the current and rapid cessation of the z-axis movement to avoid damaging the slide, since the current only begins to increase after the slide comes into contact with the application device.

[0069] Slide level sensing can be performed via resistance measurement using three reference elements, specifically three reference elements made at least partially of a conductive material such as metal. During the calibration routine, the slide is received in the receiving portion of a slide holder and pressed against the adjacent tips of the reference elements. Using the level sensing function, the distance between the slide and the upper side of the reference element can be measured at each reference element. These distances can be saved to the calibration file and used for subsequent slides. These distances are almost unaffected by heat because only one component, the reference element, is involved, and these distances are very small, ranging from 1 mm to 10 mm. By measuring this distance during calibration, the actual value can be determined, where, specifically, all tolerances can be included. This distance may be insensitive to thermal expansion.

[0070] During sample application to the slide, the distance to the application side of the slide can be controlled using the upper side of a reference element. The reference element can be easily detected using a resistance measuring device. Resistance detection occurs instantaneously upon contact, specifically contrasting with the resistive movement used for force detection, and thus provides a clearer signal than a slight increase in current. The resistance signal is independent of the driving parameters and is not accidentally triggered by locally increased frictional forces on the vertical axis. Combined with calibration measurements, the theoretical sample placement plane of the slide can be calculated.

[0071] The application device may include a pressure application element. As an example, the pressure application element may be or may include a spring pin. Alternatively or additionally, the slide holder of the application device may include the at least one temperature regulating element. As an example, the temperature regulating element may be or may include a heating foil configured to heat the slide to a temperature setpoint. Alternatively or additionally, the temperature regulating element may include a Peltier element configured to cool and heat the slide to a temperature setpoint. In a later example, the pressure application element may be or may include a raised region of the receiving portion of the slide holder. To heat the slide quickly and uniformly, the slide holder may be configured to hold the slide in close contact with the heating foil. The application system can compensate for slide non-parallelism by moving and / or pivoting the slide holder using the gap between the vertical rod and the guide sleeve.

[0072] Alternatively or additionally, the level of the glass slide can be sensed by using force measurements to detect the positions of the three reference elements. This method prevents any damage to the glass slide, but may require very precise control of the current and rapid stopping of the z-axis movement to avoid damaging the application device.

[0073] Alternatively or additionally, the level of the slide can be sensed by a designated level-sensing probe mounted parallel to the application device (e.g., a spotting probe of the application device). This method eliminates the risk of damage or blockage to the application device (e.g., the spotting probe) in cases where an object (such as dust) is located on the reference element or where force control is problematic. A calibration process can be used to compensate for the length difference between the level-sensing probe and the application device.

[0074] In summary, and without excluding other possible embodiments, the following embodiments are conceivable.

[0075] Example 1: An application system for applying at least one sample of at least one bodily fluid to at least one glass slide, the application system comprising: i. At least one slide holder for holding the at least one slide during the application of a body fluid sample; and ii. At least one application device for depositing the body fluid sample onto the application side of a glass slide held by the slide holder. The slide holder includes at least one receiving portion for receiving a slide, and the slide holder includes three reference elements, each reference element having an adjacent tip. The slide holder further includes at least one pressure applying element configured to apply pressure to the opposite side of the slide opposite to the applying side, thereby pressing the applying side of the slide against the adjacent tip of the reference element.

[0076] Example 2: The application system according to the foregoing embodiment, wherein the pressure application element includes three pressure application tips, each pressure application tip having an adjacent protrusion for applying pressure to the opposite side of the slide.

[0077] Example 3: The application system according to the foregoing embodiments, wherein these pressure application tips are positioned on the opposite side of the slide relative to the corresponding adjacent tips, wherein three pairs of tips are provided, each pair of tips including an adjacent tip and a pressure application tip.

[0078] Example 4: According to the application system described in the foregoing embodiments, in each pair, the adjacent tip and the pressure application tip are positioned on opposite sides of the slide such that the connecting line between the adjacent tip and the pressure application tip is substantially perpendicular to the application side orientation of the slide.

[0079] Example 5: An application system according to any one of the preceding two embodiments, wherein, in each pair, the adjacent tip and the pressure application tip are aligned relative to each other.

[0080] Example 6: The application system according to any one of the foregoing embodiments further includes: iii. At least one control device, wherein the control device is configured to control the liquid deposition of the body fluid sample by the application device.

[0081] Example 7: An application system according to the foregoing embodiments, wherein the control device is configured to control the distance between at least one application tip of the application device and the application surface of the glass slide on the application side during liquid deposition of the body fluid sample onto the application side.

[0082] Example 8: An application system according to the foregoing embodiments, wherein the control device is configured to perform a calibration routine, wherein, in the calibration routine, the application surface of a calibration slide received in the accommodating portion, specifically a first slide received in the accommodating portion, is determined, wherein the control device is further configured to perform subsequent application of body fluid samples to the application side of subsequent slides held by the slide holder by: determining a reference surface from the application surface of the calibration slide, and using the reference surface to control the distance between at least one application tip of the application device and the application surfaces of the subsequent slides during the subsequent application of these body fluid samples to the application sides of these subsequent slides.

[0083] Example 9: The application system according to the foregoing embodiments, wherein the calibration slide is the slide received in the receiving portion, and wherein the control device is configured to perform the calibration routine for each slide received in the receiving portion.

[0084] Example 10: An application system according to any one of the preceding two embodiments, wherein the control device is configured to determine the positions of at least three points on the application surface of the calibration slide received in the receiving portion in the calibration routine, and to calculate the reference surface as a virtual plane determined by the three points.

[0085] Example 11: An application system according to any one of the preceding three embodiments, wherein the control device is configured to determine, in the calibration routine, the position of a grid of points on the application surface of the calibration slide received in the receiving portion, the grid of the multiple points forming a surface grid on the application surface of the calibration slide, and to use the surface grid as the reference surface.

[0086] Example 12: An application system according to any one of the preceding five embodiments, wherein the control device is configured to control a measurement routine for determining, directly or indirectly, the position of a point on the application surface of a slide received in the receiving portion of the slide holder by using at least one measuring device.

[0087] Example 13: The application system according to the foregoing embodiments, wherein the measuring device is selected from the group consisting of: optical measuring devices; electrical measuring devices, specifically at least partially integrated into the application device, more specifically at least partially integrated into a controller for controlling the distance between at least one application tip of the application device and the application surface of the slide, such as capacitive measuring devices and / or inductive measuring devices; ultrasonic measuring devices.

[0088] Example 14: An application system according to any of the preceding embodiments, wherein the slide holder includes a frame extending along at least three edges of the slide received in the receiving portion, wherein the three reference elements are disposed on the frame extending along the three edges.

[0089] Example 15: The application system according to the foregoing embodiments, wherein at least one of the three reference elements is disposed on the frame and located on each edge of the slide.

[0090] Example 16: An application system according to any one of the preceding two embodiments, wherein the three reference elements are partially disposed on the frame, located on the first edge of the slide, specifically on the short edge of the slide, wherein the slide support further includes a rod extending across the slide received in the receiving portion, wherein the three reference elements are partially disposed on the rod.

[0091] Example 17: The application system according to the foregoing embodiment, wherein one of the three reference elements is disposed on the frame, on the first edge of the slide, specifically on the short edge of the slide, and two of the three reference elements are disposed on the rod.

[0092] Example 18: An application system according to any one of the foregoing embodiments, wherein the slide holder further includes at least one temperature regulating element for heating and / or cooling the slide received in the receiving portion.

[0093] Example 19: The application system according to the foregoing embodiments, wherein the temperature regulating element includes at least one of a resistance heating element or a Peltier element.

[0094] Example 20: An application system according to any one of the foregoing two embodiments, wherein the temperature regulating element is disposed on the reverse side of the glass slide received in the receiving portion.

[0095] Example 21: An application system according to any one of the three preceding embodiments, wherein the pressure application element is at least partially integrated into the temperature control element.

[0096] Example 22: An analytical system for analyzing samples of at least one bodily fluid, comprising: I. At least one application system according to any one of the foregoing embodiments; and II. At least one detector for detecting at least one characteristic of a body fluid sample disposed on at least one glass slide by an application system.

[0097] Example 23: The analysis system according to the foregoing embodiments further includes: Ⅲ. At least one transfer device for transferring a glass slide from an application system to a detector.

[0098] Example 24: An analytical system according to any one of the foregoing embodiments relating to an analytical system, wherein the analytical system is configured to analyze blood cells in the body fluid sample.

[0099] Example 25: An analysis system according to any one of the foregoing embodiments relating to an analysis system, wherein the detector is an optical detector, specifically an optical microscope, which includes at least one light source and at least one photosensitive element, specifically at least one camera.

[0100] Example 26: An application method for applying at least one sample of at least one bodily fluid to at least one glass slide, the application method using an application system according to any one of the foregoing embodiments relating to an application system, the method comprising: a. Receiving a slide in a slide holder; and b. Liquid deposition of the body fluid sample is performed by using an application device, and the sample is applied to the application side of a glass slide held by a slide holder.

[0101] Example 27: An application method according to the foregoing embodiments, wherein the method includes subsequently applying a sample of at least one bodily fluid to a plurality of glass slides, wherein the method includes at least one calibration routine, wherein in the calibration routine, the application surface of a calibration glass slide received in the receiving portion is determined, wherein the method further includes: determining a reference surface from the application surface of the calibration glass slide, and using the reference surface to control the distance between at least one application tip of the application device and the application surfaces of the subsequent glass slides during subsequent application of the bodily fluid sample to the application sides of the subsequent glass slides held by the glass slide holder, thereby performing subsequent application of the bodily fluid sample to the application sides of the subsequent glass slides held by the glass slide holder.

[0102] Example 28: The application method according to any one of the foregoing embodiments, wherein at least step b., and optionally, the calibration routine, is computer-controlled, specifically performed by at least one control device of the application system.

[0103] Example 29: A computer program including instructions that, when executed by a control device of an application system according to any of the preceding embodiments, cause the control device to perform at least step b of the application method according to any of the preceding embodiments, and optionally, a calibration routine.

[0104] Example 30: A computer-readable storage medium, specifically a non-transitory computer-readable storage medium, comprising instructions that, when executed by a control device of an application system according to any of the preceding embodiments, cause the control device to perform at least step b of the application method according to any of the preceding embodiments, and optionally, a calibration routine.

[0105] Example 31: An analytical method for analyzing a sample of at least one bodily fluid, the analytical method using an analytical system according to any one of the foregoing embodiments, the analytical method comprising: A. Applying the body fluid sample to the glass slide using the application method according to any one of the foregoing embodiments; and B. By using the detector, at least one characteristic of the body fluid sample placed on the glass slide is detected.

[0106] Example 32: The analysis method according to the foregoing examples, wherein the method is computer-controlled.

[0107] Example 33: A computer program including instructions that, when executed by a control device of an application system of an analysis system according to any one of the foregoing embodiments, cause the control device to perform the steps of an analysis method according to any one of the foregoing embodiments.

[0108] Example 34: A computer-readable storage medium, specifically a non-transitory computer-readable storage medium, includes instructions that, when executed by a control device of an application system of an analysis system according to any of the preceding embodiments, cause the control device to perform the steps of the analysis method according to any of the preceding embodiments. Attached Figure Description

[0109] Other optional features and embodiments will be disclosed in more detail in the following description of embodiments, in conjunction with the dependent claims. As those skilled in the art will recognize, each optional feature can be implemented individually and in any feasible combination. The scope of the invention is not limited to the preferred embodiments. Embodiments are schematically depicted in the accompanying drawings. In these drawings, the same reference numerals refer to the same or functionally equivalent elements.

[0110] In the attached diagram: Figures 1A and 1B show a perspective view (Figure 1A) and a side sectional view (Figure 1B) of an embodiment of an application system for applying at least one sample of at least one body fluid to at least one glass slide. Figure 2 shows a perspective view of a further embodiment of the slide holder of the application system; Figures 3A and 3B show a perspective view (Figure 3A) and a side sectional view (Figure 3B) of a further embodiment of the slide holder of the application system. Figures 4A and 4B show a perspective view (Figure 4A) and a side sectional view (Figure 4B) of a further embodiment of the slide holder of the application system. Figure 5 shows a schematic diagram of an embodiment of an analytical system for analyzing at least one body fluid sample; Figure 6 shows a flowchart of an embodiment of an application method for applying at least one sample of at least one bodily fluid to at least one glass slide; and Figure 7 shows a flowchart of an embodiment of an analytical method for analyzing at least one body fluid sample. Detailed Implementation

[0111] Figures 1A and 1B show, in perspective view (Figure 1A) and side sectional view (Figure 1B), a first exemplary embodiment of an application system 110 for applying at least one sample (not shown) of at least one bodily fluid to at least one glass slide 112.

[0112] The application system 110 includes at least one slide holder 114 for holding the at least one slide 112 during application of a bodily fluid sample. The application system 110 further includes at least one application device 116 for depositing the bodily fluid sample onto an application side 118 of the slide 112 held by the slide holder 114. As shown in FIG1A, the application device 116 may include at least one application tip 120 for controlling the liquid deposition of the bodily fluid sample onto the application side 118. In this example, the application system 110 may specifically be a slide spotter 122, which includes at least one spotting probe 124 for spotting a bodily fluid sample onto the slide 112, such as spotting a blood sample onto a glass slide. As indicated by the arrows in FIG1A, the application device 116, specifically the spotting probe 124, is movable in at least one of the x, y, and z directions, specifically in all x, y, and z directions, and more specifically independently of each other. Alternatively, in another embodiment (not shown in the figure), the slide holder 114 may be movable relative to the static application device 116 and / or the spotting probe 124 in at least one of the x, y and z directions, and specifically in all of these directions.

[0113] The slide holder 114, shown in more detail in a side sectional view in Figure 1B, includes at least one receiving portion 126 for receiving a slide 112. The slide holder 114 further includes three reference elements 128, each having an abutment tip 130. The slide holder 114 further includes at least one pressure applying element 132 configured to apply pressure to the opposite side 134 of the slide 112, opposite to the applying side 118, thereby pressing the applying side 118 of the slide 112 against the abutment tip 130 of the reference element 128.

[0114] In the examples of Figures 1A and 1B, the pressure applying element 132 may include three pressure applying tips 136, each pressure applying tip 136 having an adjacent protrusion 138 for applying pressure to the opposite side 134 of the slide 112. The pressure applying tip 136 may be positioned on the opposite side of the slide 112 relative to a corresponding adjacent tip 130. Thus, as exemplarily shown in Figure 1A, three pairs of tips may be provided. Each pair of tips may include one adjacent tip 130 and one pressure applying tip 136. As an example, in each pair, the adjacent tip 130 and the pressure applying tip 136 may be positioned on the opposite side of the slide 112 such that the connecting line between the adjacent tip 130 and the pressure applying tip 136 is oriented substantially perpendicular to the applying side 118 of the slide 112.

[0115] The slide holder 114 may include a frame 140 extending along at least three edges of a slide 112 received in the receiving portion 126. Three reference elements 128 may be disposed on the frame 140 extending along these three edges. The three reference elements 128 may be partially disposed on the frame 140, located on a first edge of the slide 112, specifically on the short edge of the slide 112. The slide holder 114 may further include a rod 142 extending across the slide 112 received in the receiving portion 126. The three reference elements 128 may be partially disposed on the rod 142. As shown in FIG1A, in this exemplary embodiment, one of the three reference elements 128 may be disposed on the frame 140, located on a first edge of the slide 112, specifically on the short edge of the slide 112. Two of the three reference elements 128 may be disposed on the rod 142.

[0116] An alternative arrangement of the three reference elements 128 is shown in FIG. 2. FIG. 2 shows a further embodiment of the slide holder 114 of the application system 110 in perspective view. The slide holder 114 in this exemplary embodiment largely corresponds to the slide holder 114 shown in FIG. 1A and FIG. 1B. Therefore, for a detailed description of the slide holder 114, refer to the description of FIG. 1A and FIG. 1B. As can be seen in FIG. 2, in this exemplary embodiment, at least one of the three reference elements 128 may be disposed on the frame 140, located at each edge of the slide 112. Specifically, one reference element 128 may be disposed on the frame 140, located at each edge of the slide 112.

[0117] Returning to Figure 1A, the application system 110 may further include at least one control device 143, wherein the control device 143 may be configured to control the liquid deposition of the body fluid sample by the application device 116. The control device 143 may be configured to control the distance between the application tip 120 of the application device 116 and the application surface of the slide 112 on the application side 118 during liquid deposition of the body fluid sample onto the application side 118. The control device 143 may be configured to perform a calibration routine. In the calibration routine, the application surface of the calibration slide received in the receiving portion 126, specifically the first slide received in the receiving portion 126, may be determined. The control device 143 may be further configured to perform subsequent application of a body fluid sample to the application side 118 of a subsequent slide 112 held by the slide holder 114 by determining a reference surface from the application surface of the calibration slide and using the reference surface to control the distance between the at least one application tip 120 of the application device 116 and the application surface of the subsequent slide 112 during the subsequent application of the body fluid sample to the application side 118 of the subsequent slide 112.

[0118] Figures 3A and 3B show a further embodiment of the slide holder 114 of the application system 110 in perspective view (Figure 3A) and side sectional view (Figure 3B). The slide holder 114 in this exemplary embodiment largely corresponds to the slide holder 114 shown in Figures 1A and 1B. Therefore, for a detailed description of the slide holder 114, reference is made to the description of Figures 1A and 1B. In the exemplary embodiment of Figures 3A and 3B, the pressure application element 132 may be or may include the raised region 144 of the receiving portion 126 of the slide holder 114.

[0119] Further, as seen in FIG3B, the slide holder 114 may include at least one temperature regulating element 146 for heating and / or cooling the slide 112 received in the receiving portion 126. The temperature regulating element 146 may specifically be configured to adjust the temperature of the slide 112 received in the receiving portion 126 according to at least one temperature setpoint, such as by actively increasing and / or decreasing the temperature of the slide 112 received in the receiving portion 126. In this exemplary embodiment, the temperature regulating element 146 may include at least one resistance heating element 148, for example, in the form of an electric heating foil. Figure 3BAs shown, the temperature regulating element 146 may be disposed on the opposite side of the receiving portion 126. Specifically, the temperature regulating element 146 may be configured to heat the receiving portion 126, thereby heating the glass slide 112 received in the receiving portion 126.

[0120] Figures 4A and 4B show a further embodiment of the slide holder 114 of the application system 110 in perspective view (Figure 4A) and side sectional view (Figure 4B). The slide holder 114 in this exemplary embodiment largely corresponds to the slide holder 114 shown in Figures 3A and 3B. Therefore, for a detailed description of the slide holder 114, refer to the description of Figures 3A and 3B. In this exemplary embodiment, the temperature regulating element 146 may alternatively or additionally include at least one Peltier element 150. Thus, in this example, the temperature regulating element 146 may be configured for heating and cooling the slide 112 received in the receiving portion 126, specifically indirectly heating and cooling the slide 112 via the receiving portion 126 as outlined above. Additionally or alternatively, the temperature regulating element 146 may include at least one heat sink 152.

[0121] Figure 5 schematically illustrates one embodiment of an analytical system 154 for analyzing at least one bodily fluid sample. The analytical system 154 includes at least one application system 110 according to the invention, such as any of the embodiments disclosed in Figures 1A through 4B and / or any other embodiments disclosed herein. Therefore, for a detailed description of the application system 110, reference is made to the description of Figures 1A through 4B.

[0122] The analysis system 154 further includes at least one detector 156 for detecting at least one characteristic of a bodily fluid sample disposed on at least one slide 112 by the application system 110. For example, the detector 156 may be an optical detector 158, specifically an optical microscope, which includes at least one light source 160 and at least one photosensitive element 162, specifically at least one camera.

[0123] The analysis system 154 may further include at least one transfer device 164 for transferring the slide 112 from the application system 110 to the detector 156.

[0124] As an example, the analysis system 154 may be configured to analyze blood cells in a body fluid sample. The analysis system 154 may be configured to analyze one or more of the following: the presence of blood cells in the body fluid sample, the number of blood cells in the body fluid sample, the concentration of blood cells in the body fluid sample, the identity of blood cells in the body fluid sample, the shape of blood cells in the body fluid sample, the size of blood cells in the body fluid sample and / or the staining of blood cells in the body fluid sample, the shape of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in the body fluid sample, the size of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in the body fluid sample, and / or the staining of cellular structures or organelles (e.g., nuclei or cell surface structures, such as differentiation clusters, also known as "CD markers") in the body fluid sample. However, other examples are also possible.

[0125] Figure 6 shows a flowchart of one embodiment of an application method for applying at least one sample of at least one bodily fluid to at least one glass slide 112. This application method uses an application system 110 according to the invention, such as any of the embodiments disclosed in Figures 1A to 4B and / or any other embodiments disclosed herein. Therefore, for a detailed description of the application system 110, reference is made to the description of Figures 1A to 4B.

[0126] The method includes the following steps, which may be performed in a specific order. However, it should be noted that different orders are also possible. Furthermore, one or more method steps may be performed once or repeatedly. Further, two or more method steps may be performed simultaneously or in a manner that overlaps as appropriate. The method may include other method steps not listed.

[0127] The method includes: a. (Indicated by reference numeral 166) Receiving a slide 112 in a slide holder 114; and b. (Indicated by reference numeral 168) The body fluid sample is applied to the application side 118 of the slide 112 held by the slide holder 114 by liquid deposition of the body fluid sample using the application device 116.

[0128] The application method may include subsequently applying a sample of at least one bodily fluid to a plurality of slides 112. The application method may include at least one calibration routine. In the calibration routine, an application surface of a calibration slide received in the receiving portion 126 may be determined. The method may further include: determining a reference surface from the application surface of the calibration slide, and using this reference surface during subsequent application of the bodily fluid sample to the application side 118 of the subsequent slide 112, controlling the distance between at least one application tip 120 of the application device 116 and the application surface of the subsequent slide 112, thereby performing subsequent application of the bodily fluid sample to the application side 118 of the subsequent slide 112 held by the slide holder 114.

[0129] Figure 7 illustrates a flowchart of one embodiment of an analytical method for analyzing at least one bodily fluid sample. This analytical method uses an analytical system 154 according to the invention, such as the exemplary embodiments disclosed in Figure 5 and / or any other embodiments disclosed herein. Therefore, for a detailed description of the analytical system 154, reference is made to the description of Figure 5.

[0130] The method includes the following steps, which may be performed in a specific order. However, it should be noted that different orders are also possible. Furthermore, one or more method steps may be performed once or repeatedly. Further, two or more method steps may be performed simultaneously or in a manner that overlaps as appropriate. The method may include other method steps not listed.

[0131] The analytical method includes: A. (Indicated by reference numerals 166, 168) Applying a body fluid sample to a glass slide 112 using an application method according to the invention (such as the exemplary embodiments disclosed in FIG. 6 and / or other embodiments disclosed herein); and B. (Indicated by reference numeral 170) At least one characteristic of a body fluid sample placed on a glass slide 112 is detected by using detector 156.

[0132] List of reference numerals 110 Application System 112 glass slides 114 Slide Holder 116 Application device 118 Application side 120 Apply tip 122 Slide Spotting Instrument 124 Spotting Probe 126. Storage Unit 128 reference elements 130 Adjacent tip 132 Pressure application element 134 Reverse side 136 Pressure application tip 138 Adjacent protrusions 140 Frame 142 strokes 143 Control device 144 Rising Area 146 Temperature control element 148 Electric heating element 150 Peltier elements 152 Radiator 154 Analysis System 156 detectors 158 Optical Detectors 160 light source 162 Photosensitive element 164 Transfer device 166 Receiving slides in a slide holder 168. Apply the sample to the application side of the glass slide. 170. Detect at least one characteristic of a body fluid sample.

Claims

1. An application system (110) for applying at least one sample of at least one bodily fluid to at least one glass slide (112), said application system (110) comprising: i. At least one slide holder (114) for holding the at least one slide (112) during the application of the body fluid sample; as well as ii. At least one application device (116) for depositing a sample liquid of the body fluid onto the application side (118) of the slide (112) held by the slide holder (114), The slide holder (114) includes at least one receiving portion (126) for receiving the slide (112), the slide holder (114) includes three reference elements (128), each reference element (128) having an adjacent tip (130), and the slide holder (114) further includes at least one pressure applying element (132) configured to apply pressure to a reverse side (134) of the slide (112) opposite to the applying side (118), thereby pressing the applying side (118) of the slide (112) against the adjacent tip (130) of the reference element (128), wherein the pressure applying element (132) includes three pressure applying tips (136), each pressure applying tip (136) having a function for applying pressure to the slide (112). The adjacent protrusion (138) on the opposite side (134) wherein the pressure applying tip (136) is positioned on the opposite side of the slide (112) relative to the corresponding adjacent tip (130), wherein three pairs of tips are provided, each pair of tips including an adjacent tip (130) and a pressure applying tip (136).

2. The application system (110) according to the preceding claim further comprises: iii. At least one control device (143), wherein the control device (143) is configured to control the liquid deposition performed by the application device (116) on the sample of the body fluid.

3. The application system (110) according to the preceding claim, wherein the control device (143) is configured to control the distance between at least one application tip (120) of the application device (116) and the application surface of the slide (114) on the application side (118) during the deposition of a sample liquid of the body fluid onto the application side (118), wherein the control device (143) is configured to perform a calibration routine, wherein, In the calibration routine, the application surface of the calibration slide received in the receiving portion (126) is determined, wherein the control device (143) is further configured to perform the subsequent application of a sample of body fluid to the application side (118) of a subsequent slide (112) held by the slide holder (114) by: determining a reference surface from the application surface of the calibration slide, and using the reference surface to control the distance between at least one application tip (120) of the application device (116) and the application surface of the subsequent slide (112) during the subsequent application of the sample of body fluid to the application side (118) of the subsequent slide (112).

4. The application system (110) according to the preceding claim, wherein the control device (143) is configured to determine the positions of at least three points on the application surface of the calibration slide received in the receiving portion (126) in the calibration routine, and is configured to calculate the reference surface as a virtual plane determined by the three points.

5. The application system (110) according to any one of the preceding two claims, wherein the control device (143) is configured to determine, in the calibration routine, the position of a grid of a plurality of points on the application surface of the calibration slide received in the receiving portion (126), the grid of the plurality of points forming a surface grid on the application surface of the calibration slide, and is configured to use the surface grid as the reference surface.

6. The application system (110) according to any one of the preceding three claims, wherein the control device (143) is configured to control a measurement routine for determining, directly or indirectly, the position of a point on the application surface of a slide (112) received in the receiving portion (126) of the slide holder (114) by using at least one measuring device.

7. The application system (110) according to any one of the preceding claims, wherein the slide holder (114) includes a frame (140) extending along at least three edges of the slide (112) received in the receiving portion (126), wherein the three reference elements (128) are disposed on the frame (140) extending along the three edges.

8. The application system (110) according to the preceding claim, wherein at least one of the three reference elements (128) is disposed on the frame (140) on each edge of the slide (112).

9. The application system (110) according to any one of the preceding two claims, wherein the three reference elements (128) are partially disposed on the frame (140) on a first edge of the slide (112), wherein the slide holder (114) further includes a rod (142) extending across the slide (112) received in the receiving portion (126), wherein the three reference elements (128) are partially disposed on the rod (142).

10. The application system (110) according to any one of the preceding claims, wherein the slide holder (114) further comprises at least one temperature regulating element (146) for heating and / or cooling the slide (112) received in the receiving portion (126).

11. An analytical system (154) for analyzing samples of at least one bodily fluid, comprising: I. At least one application system (110) according to any one of the preceding claims; as well as II. At least one detector (156) for detecting at least one characteristic of a sample of the body fluid disposed on at least one glass slide (112) by the application system (110).

12. The analysis system (154) according to the preceding claim, further comprising: III. At least one transfer device (164) for transferring a glass slide (112) from the application system (110) to the detector (156).

13. An application method for applying at least one sample of at least one bodily fluid to at least one glass slide (112), said application method using an application system (110) according to any one of the preceding claims relating to an application system (110), said method comprising: a. The slide (112) is received in the slide holder (114); as well as b. The sample is applied to the application side (118) of the slide (112) held by the slide holder (114) by liquid deposition of the sample of the body fluid using the application device (116).

14. The application method according to the preceding claim, wherein the method comprises subsequently applying a sample of the at least one bodily fluid to a plurality of glass slides (112), wherein the method comprises at least one calibration routine, wherein, In the calibration routine, the application surface of the calibration slide received in the receiving portion (126) is determined, wherein the method further includes performing the subsequent application of a sample of body fluid to the application side (118) of a subsequent slide (112) held by the slide holder (114) by: determining a reference surface from the application surface of the calibration slide, and using the reference surface to control the distance between at least one application tip (120) of the application device (116) and the application surface of the subsequent slide (112) during the subsequent application of the sample of body fluid to the application side (118) of the subsequent slide (112).

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