Application system for applying at least one sample of at least one bodily fluid to at least one slide

Abstract

An application system (110) for applying at least one sample of at least one bodily 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 bodily fluid; and ii. at least one application device (116) for liquid deposition of the sample of the bodily 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 exerting element (132), the pressure exerting element (132) being configured for exerting a pressure onto a reverse side (134) of the slide (112) opposing 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

[0001] Roche Diagnostics International AG

[0002] Application system for applying at least one sample of at least one bodily fluid to at least one slide

[0003] Technical Field

[0004] The present invention refers to an application system and an application method for applying at least one sample of at least one bodily fluid to at least one slide. The invention further refers to an analytical system and an analytical method for analyzing samples of at least one bodily fluid. The invention further refers to computer programs and computer-readable storage media for performing the methods. The methods and devices may, as an example, be used in the field of hematology for applying and analyzing samples of a bodily fluid, e.g. blood, to at least one slide. However, further uses are also feasible.

[0005] Background art

[0006] In medical or diagnostic laboratories, in particular in the field of hematology or cytology, handling of samples of a bodily fluid may comprise one or more sample processing operations and one or more sample analysis operations. For example, the sample of the bodily fluid may be applied to one or more slide. The processing and / or the analysis of the samples may comprise one or more of printing, staining and / or imaging. Devices and methods for automated sample application are known. For example, US 10,073,015 B2 discloses sample smear apparatus including a slide feeder that feeds a slide glass before processing; a smear processor that smears a sample on the slide glass; and a slide transporter including a slide holder mechanism with an upper surface where to hold the slide glass and a transfer mechanism that moves the slide holder mechanism in a vertical direction and in a horizontal direction. The slide transporter is arranged movably to the slide feeder and the smear processor. EP 1 261 852 B2 discloses an automated system for preparing a plurality of cytological specimens from a plurality of fluid samples in vials. The system includes an apparatus for collecting a monolayer of cells from each sample and transferring the cells to a microscope slide for fixing, staining, and inspection. The system includes a first loading station for receiving the sample vials, a second loading station for receiving consumables such as filter membranes, a slide dispenser, and an unloading area for removing completed specimen slides. To maintain one-to-one correlation between the samples and specimens produced therefrom, the system includes a subsystem for identifying each sample and permanently marking each slide with corresponding indicia prior to transferring the specimen thereto.

[0007] US 2005 / 0136534 Al describes the automated collection and deposition of fluid, semi-solid, and solid samples of biological or chemical materials. More specifically, microarrayers are described, which are devices for autonomously depositing minute droplets of biological or chemical fluid samples in ordered arrays onto substrates. Further, tissue arrayers are described, which are devices for the collection and deposition of solid and semi-solid tissue samples in ordered arrays. Further, fluidics robots are described, which are devices for the autonomous collection, dispensing and processing of biological or chemical fluid samples.

[0008] WO 2023 / 172670 A2 describes a method, and systems and apparatuses of capturing analytes from a sample. A first substrate including a sample is mounted on a first member of a sample handling device and mounting a second substrate including an array of capture probes on a second member of the sample handling device. A first reagent medium is applied to the first and / or second substrate and moving the first member and / or the second member to fluidi- cally couple the sample and the array of capture probes via the first reagent medium. The sample and the array of capture probes are fluidically decoupled by moving the first member and / or the second member and a second reagent medium is applied to the first and / or second substrate and moving the first member and / or the second member to fluidically couple the sample and the array of capture probes via the second reagent medium.

[0009] US 2019 / 0317310 Al describes handling of probes in digital pathology. A slide-holder for digital pathology is provided that comprises a tray basis, a plurality of mounting means and a plurality of slide-holder registration points. The tray basis is configured to carry a plurality of slides to be imaged by a digital pathology system, for which the tray basis provides a plurality of slide-receiving positions. The plurality of mounting means are arranged on the tray basis to mount the plurality of slides on the tray basis in a plurality of slide-receiving positions to image each slide in a separate imaging position. The slide-holder registration points comprise a plurality of interacting portions that provide a mechanical registration of the tray basis with a digital pathology system for each of the imaging positions.

[0010] Despite the advantages achieved by known methods and devices, several technical challenges remain for automated sample application. Specifically, positioning and / or aligning of slides may still be technically challenging. For example, glass slides may be placed on a metal surface and held there by vacuum. A sample of a bodily fluid, e.g. blood, may be printed onto the other side of the glass slide by a print probe. A distance between the print probe and the glass slide may be in the range of 10 to 20 pm. A thickness of the glass slide may be 0.991 ±0.051 mm. Thus, the tolerance in the thickness of the glass slide may be much bigger than the print gap and therefore must be compensated while printing. A flatness of the glass slide may be less than 1 pm. In order to keep a constant print gap, a level of the glass slide may be sensed, e.g. on three positions of each glass slide, by optical means. A theoretical surface plane may be calculated and may be used to adjust a height of the print probe in accordance with the preset x- or y-position on the glass slide. However, this approach is generally time consuming since the sensing of the level of the glass slide has to be performed on every single slide.

[0011] Problem to be solved

[0012] It is therefore desirable to provide methods and devices which at least partially avoid the disadvantages of known methods and devices. Specifically, an application system and an application method for applying at least one sample of at least one bodily fluid to at least one slide as well as an analytical system and an analytical method for analyzing samples of at least one bodily fluid shall be proposed which facilitate sample application to the slide.

[0013] Summary

[0014] This problem is addressed by an application system and an application method for applying at least one sample of at least one bodily fluid to at least one slide as well as by an analytical system and an analytical method for analyzing samples of at least one bodily fluid with the features of the independent claims. Advantageous embodiments which might be realized in an isolated fashion or in any arbitrary combinations are listed in the dependent claims as well as throughout the specification.

[0015] As used in the following, the terms “have”, “comprise” or “include” or any arbitrary grammatical variations thereof are used in a non-exclusive way. Thus, these terms may both refer to a situation in which, besides the feature introduced by these terms, no further features are present in the entity described in this context and to a situation in which one or more further features are present. As an example, the expressions “A has B”, “A comprises B” and “A includes B” may both refer to a situation in which, besides B, no other element is present in A (i.e. a situation in which A solely and exclusively consists of B) and to a situation in which, besides B, one or more further elements are present in entity A, such as element C, elements C and D or even further elements.

[0016] Further, it shall be noted that the terms “at least one”, “one or more” or similar expressions indicating that a feature or element may be present once or more than once typically will be used only once when introducing the respective feature or element. In the following, in most cases, when referring to the respective feature or element, the expressions “at least one” or “one or more” will not be repeated, non-withstanding the fact that the respective feature or element may be present once or more than once.

[0017] Further, as used in the following, the terms "preferably", "more preferably", "particularly", "more particularly", "specifically", "more specifically" or similar terms are used in conjunction with optional features, without restricting alternative possibilities. Thus, features introduced by these terms are optional features and are not intended to restrict the scope of the claims in any way. The invention may, as the skilled person will recognize, be performed by using alternative features. Similarly, features introduced by "in an embodiment of the invention" or similar expressions are intended to be optional features, without any restriction regarding alternative embodiments of the invention, without any restrictions regarding the scope of the invention and without any restriction regarding the possibility of combining the features introduced in such way with other optional or non-optional features of the invention.

[0018] In a first aspect of the present invention, an application system for applying at least one sample of at least one bodily fluid to at least one slide is disclosed. The term “system” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary set of interacting or interdependent components parts forming a whole. Specifically, the components may interact with each other in order to fulfill at least one common function. The at least two components may be handled independently or may be coupled or connectable.

[0019] The term “applying” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a process of contacting the at least one sample of the bodily fluid with the slide, in particular with a surface of the slide. The applying may specifically comprise bringing the at least one sample of the bodily fluid in contact with the slide, specifically such that at least a part of the sample of the bodily fluid at least partially coheres with the slide. The applying of the at least one sample of the bodily fluid to the slide may specifically comprise printing the at least one sample of the bodily fluid to the slide. The applying of the at least one sample of the bodily fluid may comprise attaching at least a part of the at least one sample of the bodily fluid to the slide, specifically in the form of a thin film. Consequently, the term “application system”, as used herein, may refer, without limitation, to a system configured for applying the at least one sample of the bodily fluid to the slide. The application system may specifically be a slide printer comprising at least one print probe to print the sample of the bodily fluid to the slide, e.g. to print a sample of blood on a glass slide. The process of applying the at least one sample of the bodily fluid to the slide may be referred to as “application”.

[0020] The term “bodily fluid” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary liquid, which is typically present in a body or a body tissue of a human being or an animal. The bodily fluid may be selected from the group consisting of blood, specifically whole blood, blood plasma, serum and interstitial fluid. However, additionally or alternatively, one or more other types of bodily fluids may be used, such as cerebrospinal fluid, bone marrow aspirate, saliva, tear fluid, urine or other body fluids.

[0021] The term “sample of a bodily fluid” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary aliquot part or aliquant part of a biological fluid which directly is a bodily fluid as defined above or which is derived from a bodily fluid, such as by one or more preprocessing steps, e.g. g. by transferring a bodily fluid to at least one sampling fluid, by diluting a bodily fluid, by centrifugation a bodily fluid or the like. As an example, the bodily fluid may comprise blood, e.g. blood of a human being, such as patient suffering from a disease or a person under medical investigation. The sample of the bodily fluid may comprise an aliquot of blood obtained by venipuncture and collected in a sample tube. Alternatively or additionally, the sample of the bodily fluid may comprise at least one bodily fluid collected via at least one swab or brush, such via at least one nasopharyngeal swab, e.g. at least one swab of the anterior nares or from saliva, such by applying a cotton swab to a surface of the anterior nares and / or the throat. The collected sample of bodily fluid may be transferred to at least sampling or reagent fluid by immersing the cotton swab in the sampling or reagent fluid. The sampling or reagent fluid may specifically comprise lysis reagents. Other examples of the sample of the bodily fluid are also feasible. The sample of bodily fluid may also be simply referred to as the sample.

[0022] The term “slide” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a substrate configured for receiving the at least one sample of a bodily fluid, specifically for receiving the at least one sample of a bodily fluid on a surface of the slide. The slide may be mechanically stable. The slide may specifically comprise any material which provides sufficient mechanical stability for being automatically handled by the application system. The slide may be configured for carrying the sample of the bodily fluid without any changes during the processing of the slide. The slide may exhibit at least one surface which is compatible with biological material, specifically with the sample of the bodily fluid. By way of example, the slide may be a glass slide. Specifically, glass may be known to provide both sufficient mechanical stability and compatibility with biological material. However, further kinds of materials for the slides may also be feasible. The slide may be a plate having a two-dimensional extension and a thickness. The two-dimensional extension of the plate may exhibit a rectangular or circular form. The thickness of the plate may be small compared to a size of the extension, for example 20 %, or 10 %, or 5 %, or less than a measure for a linear extent of the two-dimensional extension of the plate.

[0023] The application system comprises: i. at least one slide holder for holding the at least one slide during application of the sample of the bodily fluid; and ii. at least one application device for liquid deposition of the sample of the bodily fluid onto an application side of the slide held by the slide holder.

[0024] The term “slide holder” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a device configured for receiving at least one slide and for maintaining a position and / or an orientation of the at least one slide. Consequently, the term “holding”, as used herein, may refer to the process of maintaining the slide in a position and / or orientation. The slide holder may specifically be configured for one or more of receiving, supporting and / or holding a single slide during application of the sample of the bodily fluid. The slide holder may further be configured for controlling 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, the slide holder may comprise one or more actuators, such as one or more linear actuators, for varying the position and / or the orientation of the slide held by the slide holder. The slide holder may be configured for holding the slide in an essential horizontal orientation. The essential horizontal orientation may refer to an orientation in which the slide, specifically at least one surface of the slide, more specifically a surface of the two- dimensional extension of the slide, has an inclination angle to ground of 10° or less, specifically of 5° or less, more specifically of 1° or less, most specifically of 0.1° or less.

[0025] The term “application device” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a device configured for directing fluid to the slide. Specifically, the application device may be configured for directing the sample of the bodily fluid to the slide, such as from one or more containers or sample tubes comprising the sample of the bodily fluid to the slide. The application device may comprise at least one application tip for controlling liquid deposition of the sample of the bodily fluid onto the application side of the slide. For example, the application device may comprise at least one nozzle system having at least one nozzle. Further, the application device may comprise at least one pump and / or at least one piping system for providing the sample of the bodily fluid to the nozzle system. Alternatively or additionally, the application device may comprise at least one pipetting system having at least one pipetting head comprising one or more pipettes, such as single pipettes or multichannel pipettes. Alternatively or additionally, the application device may comprise at least one print probe for printing the sample of the bodily fluid to the slide.

[0026] The term “liquid deposition” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a process of directing the sample of the bodily fluid to the slide, specifically to a surface of the slide. The liquid deposition may specifically be an actively controlled process of contacting the sample of the bodily fluid to the slide, such as by controlling one or more of an amount of the sample of the bodily fluid deposited on the slide and / or a position on the slide to which the sample of the bodily fluid is deposited. The term “application side” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a side of the slide to which the sample of the bodily fluid is applied. Specifically, the application side may comprise a surface of the slide where the liquid deposition of the sample of the bodily fluid is performed by the application device. For example, as outlined above, the slide may be a plate having a two-dimensional extension and a thickness. The two-dimensional extension of the plate may define a first or upper surface and a second or lower surface. The first surface of the plate may be defined by the surface facing the application device. The second surface of the plate may be defined by the surface facing the sample holder. The application side may comprise the first surface of the plate facing the application device.

[0027] For example, as outlined above, the application device may comprise at least one print probe for printing the sample of the bodily fluid to the slide. The term “printing” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a process of spatially controlling liquid deposition. The printing of the sample of the bodily fluid to the slide, specifically to the application side of the slide, may comprise spatially controlling the liquid deposition of the sample of the bodily fluid on the slide, specifically on the application side of the slide. The spatial controlling may be performed at least partially simultaneously to the liquid deposition. Consequently, the term “print probe” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a device configured for printing, i.e. for spatially controlling liquid deposition. The print probe may specifically be configured for simultaneously controlling an amount and a position of the sample of the bodily fluid applied to the slide. The print probe may be configured for moving relatively to the slide during liquid deposition of the sample of the bodily fluid to the slide.

[0028] The slide holder comprises at least one receptacle for receiving the slide, wherein the slide holder comprises three reference elements, each reference element having an abutment tip, wherein the slide holder further comprises at least one pressure exerting element, the pressure exerting element being configured for exerting a pressure onto a reverse side of the slide opposing the application side, thereby pressing the application side of the slide onto the abutment tips of the reference elements. The term “receptacle” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a device or an element of a device configured for at least partially accommodating the at least one slide. Consequently, the term “receiving”, as used herein, may refer to the process of at least partially accommodating the slide in the receptacle of the slide holder. The receptacle may specifically be at least one recess in the slide holder, wherein, specifically, the recess may be adjustable to the dimensions of the slide. Additionally or alternatively, the receptacle may comprise at least one slot for receiving the at least one slide. The receptacle may specifically be configured for individually receiving the slide, such as for receiving one slide after another.

[0029] The term “reference element” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element of known or predetermined position. The reference element may specifically provide a known or predetermined position relative to the slide held by the slide holder, specifically received in the receptacle of the slide holder. The position of the reference element may be either known or predetermined, such as in a calibration process, e.g. by calibrating the position of the reference element with a first slide received in the slide holder. The position of the reference element relative to the slide held by the slide holder, specifically received in the receptacle of the slide holder, may specifically be constant during application of the sample of the bodily fluid to the slide. Further, the position of the reference element relative to the slide held by the slide holder, specifically received in the receptacle of the slide holder, may be constant during application of the sample of the bodily fluid to one or more subsequent slides. The reference element may provide constant relative position to a plurality of slides received in the sample holder, specifically in the receptacle, one after another. The reference element may be made from at least one conductive material, e.g. a metal.

[0030] The term “abutment tip” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element providing a stop point. The abutment tip may specifically provide an intended end of a movement path of the slide being held by the slide holder, specifically received in the receptacle of the slide holder. The abutment tip may comprise a sharply formed element to provide a single stop point to the slide held by the slide holder, specifically received in the receptacle of the slide holder. The abutment tip may specifically comprise a tapered element, such as a cone or a regular pyramid, wherein a peak of the tapered element may form the abutment tip. The abutment tip may be in contact with the slide held by the slide holder, specifically received in the receptacle of the slide holder. The abutment tip may be made from at least one material compatible for being in contact with the slide. For example, the abutment tip may be made from at least one metallic material.

[0031] The slide holder may comprise a frame extending along at least three edges of the slide received in the receptacle. The three reference elements may be disposed on the frame extending along the three edges. For example, at least one of the three reference elements may be disposed on the frame on each edge of the slide. Alternatively or additionally, the three reference elements may be partially disposed on the frame on a first edge of the slide, specifically on a short edge of the slide. The slide holder may further comprise a bar extending across the slide received in the receptacle. The three reference elements may be partially disposed on the bar. As an example, one of the three reference elements may be disposed on the frame on the first edge of the slide, specifically on the short edge of the slide. Two of the three reference elements may be disposed on the bar.

[0032] Further, the slide holder may comprise at least one tempering element for heating and / or cooling the slide received in the receptacle. The term “tempering element” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a device configured for controlling a temperature of the slide received in the receptacle. The tempering element may specifically be configured for adjusting a temperature of the slide received in the receptacle according to at least one temperature set point, such as by actively increasing and / or decreasing the temperature of the slide received in the receptacle. The tempering element may comprise at least one of a resistive electrical heating element or a Peltier element. The tempering element may be disposed on the reverse side of the slide received in the receptacle. Specifically, the tempering element may be disposed on a reverse side of the receptacle. The tempering element may be configured for heating and / or cooling the receptacle thereby heating and / or cooling the slide received in the receptacle. The pressure exerting element may be at least partially integrated into the tempering element.

[0033] As outlined above, the slide holder further comprises the at least one pressure exerting element configured for exerting a pressure onto a reverse side of the slide. The term “pressure” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a physical quantity indicating a force applied perpendicular to a surface of an object. Specifically, the pressure of the pressure exerting element may comprise a force applied perpendicular to a surface of the slide held by the slide holder, specifically received in the receptacle. Upon application of pressure to the slide, the slide may be forced to move towards the abutment tips and / or may be held in close contact with the abutment tips.

[0034] The term “pressure exerting element” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element configured for applying pressure onto an element. Specifically, the pressure exerting element may be configured for applying the pressure onto the reverse slide held by the slide holder, specifically received in the receptacle. The pressure exerting element may be or may comprise a separate element of the slide holder and / or may be at least partially comprised by another element of the slide holder. For example, the pressure exerting element may be or may comprise a spring-loaded pin for exerting the pressure onto the reverse side of the slide. The spring-loaded pin may at least partially extend through the receptacle for applying the applying the pressure onto the slide received in the receptacle. Alternatively or additionally, the pressure exerting element may be or may comprise elevated areas of the receptacle of the slide holder.

[0035] The term “reverse side” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a side of the slide opposing the application side.

[0036] The pressure exerting element may comprise three pressure exerting tips, each pressure exerting tip having an abutment protrusion for exerting the pressure onto the reverse side of the slide. The pressure exerting tips may be positioned on opposing sides of the slide with respect to corresponding abutment tips. Three pairs of tips may be provided. Each pair of tips may comprise one abutment tip and one pressure exerting tip. As an example, in each pair, the abutment tip and the pressure exerting tip may be positioned on opposing sides of the slide, such that a connecting line connecting the abutment tip and the pressure exerting tip is oriented essentially perpendicular to the application side of the slide. The term “essentially perpendicular”, as used herein, may refer, without limitation, to an orientation of two elements or objects having an inclination 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 abutment tip and the pressure exerting tip may be aligned with respect to each other.

[0037] The application system may further comprise: iii. at least one control device, wherein the control device may be configured for controlling the liquid deposition of the sample of the bodily fluid by the application device.

[0038] The term “control device” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary logic circuitry configured for performing basic operations of a computer or system, and / or, generally, to a device which is configured for performing calculations or logic operations. The control device may comprise one or more processors. In particular, the control device may be configured for processing basic instructions that drive the application system. As an example, the control device may comprise at least one arithmetic logic unit (ALU), at least one floating-point unit (FPU), such as a math co-processor or a numeric co-processor, a plurality of registers, specifically registers configured for supplying operands to the ALU and storing results of operations, and a memory, such as an LI and L2 cache memory. In particular, the control device may be a multi-core processor. Specifically, the control device may be or may comprise a central processing unit (CPU). Additionally or alternatively, the control device may be or may comprise a microprocessor, thus specifically the elements of the control device may be contained in one single integrated circuitry (IC) chip. Additionally or alternatively, the control device may be or may comprise 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 unit (TPU) and / or one or more chip, such as a dedicated machine learning optimized chip, or the like. The control device specifically may be configured, such as by software programming, for performing one or more control operations.

[0039] The control device may be configured for controlling a distance between at least one application tip of the application device and an application surface of the slide on the application side during liquid deposition of the sample of the bodily fluid onto the application side. The control device may be configured for performing a calibration routine. In the calibration routine, the application surface of a calibration slide received in the receptacle, specifically of a first slide received in the receptacle, may be determined. The term “calibration slide”, as used herein, may refer, without limitation, to a separate slide for performing the calibration routine or to a first slide received in the receptacle. The calibration slide may specifically be a standard slide as used for applying the sample of the bodily fluid.

[0040] The control device may further be configured for performing subsequent applications of samples of bodily fluids onto application sides of subsequent slides held by the slide holder by determining a reference surface from the application surface of the calibration slide and by using the reference surface for controlling the distance between the at least one application tip of the application device and the application surfaces of the subsequent slides during the subsequent applications of the samples of bodily fluids onto the application sides of the subsequent slides.

[0041] The calibration slide may specifically be the slide received in the receptacle. The control device may be configured for performing the calibration routine for each slide received in the receptacle.

[0042] The control device may be configured for determining, in the calibration routine, the position of at least three points on the application surface of the calibration slide received in the receptacle and for calculating the reference surface to be a virtual plane determined by the three points. Alternatively or additionally, the control device may be configured for determining, 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 receptacle. The grid of the plurality of points may form a surface mesh on the application surface of the calibration slide. The control device may be configured for using the surface mesh as the reference surface. The surface mesh may allow for generating a topography of the application surface on the application side of the slide. The surface mesh may allow for accounting for irregularities on the application surface on the application side of the slide.

[0043] Additionally or alternatively, the control device may be configured for controlling a measurement routine for directly or indirectly determining positions of points on the application surface of a slide received in the receptacle of the slide holder by using at least one measurement device. The measurement device may be selected from the group consisting of an optical measurement device; an electrical measurement device, specifically an electrical measurement device at least partially integrated into the application device, more specifically an electrical measurement device at least partially integrated into a control for controlling a distance between at least one application tip of the application device and an application surface of the slide, such as an electrical capacitive measurement device, an electrical resistive measurement device and / or an electrical inductive measurement device; an ultrasonic measurement device. For example, the measurement device may comprise at least one electrical resistive measurement device integrated into the application device, specifically into the application tip of the application device, e.g. into the print probe of the application device. The positions of the application surface of the slide relative to the application device, specifically to the application tip of the application device, may be obtained by determining the positions of the three reference elements. The positions of the reference elements may be determined by moving the application device, specifically the application tip of the application device, towards the reference elements and detecting contact of the application device, specifically of the application tip of the application device, with the reference elements via a resistive measurement. As outlined above, the reference elements may provide a known or predetermined position relative to the slide held by the slide holder, specifically received in the receptacle of the slide holder. Thus, the positions of the application surface of the slide relative to the application device may be derived by using the positions of the reference elements. The control device may be configured for controlling the measurement routine for determining positions of points on the application surface of the slide received in the receptacle of the slide holder by using the electrical resistive measurement device. Other examples, however, are also feasible.

[0044] In a further aspect of the present invention, an analytical system analytical system for analyzing samples of at least one bodily fluid is disclosed. The term “analytical system” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a system configured for performing at least one analysis function with at least one sample of the bodily fluid. The process of performing the at least one analysis function may also be referred to as “analyzing”. The analytical system may specifically be configured for automatically analyzing the at least one sample of the bodily fluid, e.g. by performing the at least one analysis function without manual support. The analytical system may be configured for analyzing a plurality of sample of the bodily fluid. Specifically, the analytical system may be configured for analyzing the samples of the bodily fluid singly, such as one sample 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 stand-alone system which, specifically, may be configured for performing the at least one analytical function independently. As an example, the analytical system may be configured for analyzing blood cells in the sample of the bodily fluid. The analytical system may be configured for analyzing one or more of a presence of blood cells in the sample of the bodily fluid, a number of blood cells in the sample of the bodily fluid, a concentration of blood cells in the sample of the bodily fluid, an identity of blood cells in the sample of the bodily fluid, a shape of blood cells in the sample of the bodily fluid, a size of blood cells in the sample of the bodily fluid, a coloration of blood cells in the sample of the bodily fluid, a shape of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”, a size of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”, and / or a coloration of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”.

[0045] The analytical system comprises:

[0046] I. at least one application system according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further detail below; and

[0047] II. at least one detector for detecting at least one property of the sample of the bodily fluid disposed on at least one slide by the application system.

[0048] For definitions of terms and possible embodiments of the application system, reference is made to the description of the application system above.

[0049] The term “detector” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary device configured for quantitatively or qualitatively determining at least one property of the sample of the bodily fluid. The detector may be or may comprise at least one hematology analyzer, specifically at least one automatic hematology analyzer.

[0050] The term “detecting” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a process of quantitatively and / or qualitatively determining at least one property of the sample of the bodily fluid. The result of the detection, as an example, may comprise at least one item of detection information quantitatively and / or qualitatively indicating the at least one property of the sample of the bodily fluid, such as an item of detection information indicating a presence and / or a concentration of compounds or parameters in the sample of the bodily fluid. The term “property of the sample of the bodily fluid” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to any measurable parameter of the sample of the bodily fluid. The property of the sample of the bodily fluid may comprise a presence and / or a concentration of at least one analyte in the sample of the bodily fluid. For example, the sample of the bodily fluid may comprise blood cells, such as a sample of whole blood. The property of the sample of the bodily fluid may comprise at least one parameter selected from the group consisting of a presence of blood cells in the sample of the bodily fluid; a number of blood cells in the sample of the bodily fluid; a concentration of blood cells in the sample of the bodily fluid; an identity of blood cells in the sample of the bodily fluid; a shape of blood cells in the sample of the bodily fluid; a size of blood cells in the sample of the bodily fluid; a coloration of blood cells in the sample of the bodily fluid, a shape of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”, a size of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”, and / or a coloration of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”.

[0051] The detector may be an optical detector, specifically an optical microscope, comprising at least one light source and at least one light-sensitive element, specifically at least one camera. The term “light source” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element configured for emitting electromagnetic radiation in an optical spectral range. The optical spectral range may comprise one or more of the visible spectral range, the infrared spectral range and / or the ultraviolet spectral range. Herein, the term “ultraviolet spectral range”, generally, refers to electromagnetic radiation having a wavelength of 1 nm to 380 nm, preferably of 100 nm to 380 nm. Further, in partial accordance with standard ISO- 21348 in a valid version at the date of this document, the term “visible spectral range”, generally, refers to a spectral range of 380 nm to 760 nm. The term “infrared spectral range” (IR) generally refers to electromagnetic radiation of 760 nm to 1000 pm. The light source may comprise at least one element selected from the group consisting of an incandescent light source; an electric discharge light source; a light-emitting diode (LED); a laser. The term “light-sensitive element” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary device configured for detecting electromagnetic radiation in the optical spectral range. The light-sensitive element may comprise at least one light-sensitive area which may be configured for generating at least one detector signal upon illumination by light. The light-sensitive element may be configured for determining at least one optical parameter, such as an intensity and / or a power of light by which at least one light-sensitive area of the light-sensitive element is irradiated. The light-sensitive element may comprise at least one element selected from the group consisting of a photodiode; a photocell; a photosensitive resistor; a phototransistor; a thermophile sensor; a photoacoustic sensor; a pyroelectric sensor; a photomultiplier; a bolometer. Alternatively or additionally, the light-sensitive element may comprise at least one camera chip, such as at least one CCD chip and / or at least one CMOS chip configured for imaging.

[0052] The analytical system may further comprise:

[0053] III. at least one transfer device for transferring slides from the application system to the detector.

[0054] The term “transfer device” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary device configured for changing one or more of a position and an orientation of the slide. The transfer device may be configured for changing one or more of a position and an orientation of the slide such that the slide having the sample of the bodily fluid applied thereto can be analyzed by the detector. The transfer device may comprise at least one gripping unit for gripping the slide and at least one actuator for moving the gripping unit with the slide from the application system to the detector. For example, the transfer device may be or may comprise a delta robot for transferring slides from the application system to the detector. Other options, however, are also feasible.

[0055] In a further aspect of the present invention, an application method for applying at least one sample of at least one bodily fluid to at least one slide is disclosed. The application method uses the application system according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further detail below. For definitions of terms and possible embodiments of the application system, reference is made to the description of the application system above. The method comprises the following steps which, specifically, may be performed in the given order. It shall be noted, however, that a different order is also possible. Further, it is also possible to perform one or more of the method steps once or repeatedly. Further, it is possible to perform two or more of the method steps simultaneously or in a timely overlapping fashion. The method may comprise further method steps which are not listed.

[0056] The method comprises: a. receiving the slide in the slide holder; and b. applying the sample onto the application side of the slide held by the slide holder by liquid deposition of the sample of the bodily fluid using the application device.

[0057] The application method may comprise subsequently applying samples of the at least one bodily fluid to a plurality of slides. The application method may comprise at least one calibration routine. In the calibration routine, the application surface of a calibration slide received in the receptacle may be determined. The method may further comprise performing subsequent applications of samples of bodily fluids onto application sides of subsequent slides held by the slide holder by determining a reference surface from the application surface of the calibration slide and by using the reference surface for controlling the distance between at least one application tip of the application device and the application surfaces of the subsequent slides during the subsequent applications of the samples of bodily fluids onto the application sides of the subsequent slides.

[0058] In the application method, at least step b., and, optionally, the calibration routine, may be computer-controlled, specifically by at least one control device of the application system. The term “computer-controlled” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a process which is fully or partially controlled by using a data processing means, such as data processing means comprising at least one processor.

[0059] In a further aspect of the present invention, a computer program is disclosed, comprising instructions which, when the program is executed by a control device of an application system according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below, cause the control device to perform at least step b., and, optionally, the calibration routine, of the application method according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below.

[0060] In a further aspect of the present invention, a computer-readable storage medium, specifically a non-transient computer-readable storage medium, is disclosed, comprising instructions which, when the instructions are executed by a control device of an application system according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below, cause the control device to perform at least step b., and, optionally, the calibration routine, of the application method according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below.

[0061] As used herein, the term “computer-readable storage medium” specifically may refer to non- transitory data storage means, such as a hardware storage medium having stored thereon computer-executable instructions. The computer-readable data carrier or storage medium specifically may be or may comprise a storage medium such as a random-access memory (RAM) and / or a read-only memory (ROM). The computer-readable storage medium may be or may comprise at least one computer-readable data carrier.

[0062] Referring to the computer-implemented aspects of the invention, one or more of the method steps or even all of the method steps of the method according to one or more of the embodiments disclosed herein may be performed and / or controlled by using a computer or computer network. Thus, generally, any of the method steps including provision and / or manipulation of data may be performed and / or controlled by using a computer or computer network. Generally, these method steps may include any of the method steps, typically except for method steps requiring manual work, such as providing the samples and / or certain aspects of performing the actual measurements.

[0063] In a further aspect of the present invention, an analytical method for analyzing samples of at least one bodily fluid is disclosed. The analytical method uses the analytical system according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below. For definitions of terms and possible embodiments of the analytical system, reference is made to the description of the analytical system above. The method comprises the following steps which, specifically, may be performed in the given order. It shall be noted, however, that a different order is also possible. Further, it is also possible to perform one or more of the method steps once or repeatedly. Further, it is possible to perform two or more of the method steps simultaneously or in a timely overlapping fashion. The method may comprise further method steps which are not listed.

[0064] The analytical method comprises:

[0065] A. applying the sample of the bodily fluid to the slide by using the application method according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below; and

[0066] B. detecting at least one property of the sample of the bodily fluid disposed on the slide by using the detector.

[0067] The analytical method may be computer-controlled.

[0068] In a further aspect of the present invention, a computer program is disclosed, comprising instructions which, when the program is executed by a control device of an application system of an analytical system according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below, cause the control device to perform the steps of the analytical method according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below.

[0069] In a further aspect of the present invention, a computer-readable storage medium, specifically a non-transient computer-readable storage medium, is disclosed, comprising instructions which, when the instructions are executed by a control device of an application system of an analytical system according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below referring to an analytical system, cause the control device to perform the steps of the analytical method according to the present invention, such as according to any one of the embodiments disclosed above and / or according to any one of the embodiments disclosed in further details below. The devices and methods according to the present invention provide a large number of advantages over known methods and devices of similar kind. Specifically, the application system according to the present invention may facilitate sample application to the slide since the three reference elements enable constant positioning of the slide relative to the application device. Thus, the application system may avoid the necessity of individually sensing the level for each of multiple slides.

[0070] Further, the application system may be configured for determining positions of points on the application surface of the slide received in the receptacle of the slide holder by using the measurement device, specifically by using the electrical resistive measurement device. The resistive measurement, in particular, may provide a precise signal for determining positions of points on the application surface of the slide. The requirement for controlling electric current may be lower compared with other measurement devices, e.g. optical measurement devices. The resistive measurement may be faster than optical measurements. Further, the risk of damages may be reduced since the slide received in the receptacle of the slide holder may not be contacted by the application device during sensing of the level of the slide.

[0071] The application system may specifically provide an easy and time-effective approach of aligning the application side of the slide to the application device. The slide may have a flat surface with thickness variations of less than 0.1 mm, specifically of less than 0.5 mm. The slide received in the receptacle of the slide may be pushed to the three abutment tips which, specifically, support the slide on the application side. The tolerance of the thickness of the slide may not affect the position of the slide relative to the application device. The sensing of the level of the slide may be performed using the first slide, e.g. during a calibration routine, and may be used for multiple subsequent slides on which the sample of the bodily fluid may be applied using the same theoretical surface. This approach may shorten the time necessary for sample application. Additionally, in order to correct for thermal expansions of parts of the application system, re-calibration of the level of the slide may be performed on a regular basis. The frequency of the sensing of the level of the slide may be adjustable according to a temperature drift detected in the application system. Alternatively or additionally, the sensing of the level of the slide may be performed by optically detecting the reflection of the application device, e.g. of the print probe. Alternatively or additionally, the sensing of the level of the slide may be performed by force detection. The application device, e.g. the print probe, may be moved towards the application side of the slide. A collision may be detected via a rise in current of the z-axis. This approach may require a precise control of the current and a fast stop of the z-movement in order to not damage the slide since the current starts to rise only after contact between slide and application device. By using the three reference elements, specifically three reference elements at least partially made from a conductive material such as a metal, the sensing of the level of the slide may be performed via a resistive measurement. During the calibration routine, a slide may be received in the receptacle of the slide holder and may be pressed against the abutment tips of the reference elements. With the level sense function, the distance between the slide and the upper side of the reference element may be measured at each of the reference elements. The distances may be saved into a calibration file and may be used for subsequent slides. The distances may be hardly affected by thermal influences because there is only one part involved, i.e. the reference elements, and the distances are very small in the range of 1 to 10 mm. By measuring this distance during the calibration, the actual value may be determined, wherein, specifically all tolerances may be included. This distance may be insensitive to thermal expansion.

[0072] During sample application to the slide, the distance to the application side of the slide may be controlled using the upper side of the reference elements. The reference elements may be easily detected using the electrical resistive measurement device. A resistive detection may happen at the moment of contact, specifically in contrast to an inhibited move for force detection and, thus, may provide a clearer signal than a slight increase in current. The resistive signal may be independent of drive parameters and cannot accidentally be triggered by locally increased friction of the vertical axis. In combination with the calibration measurement, the theoretical print plane of the slide may be calculated.

[0073] The application device may comprise the pressure exerting elements. The pressure exerting element, as an example, may be or may comprise spring-loaded pins. Alternatively or additionally, the slide holder of the application device may comprise the at least one tempering element. The tempering element, as an example, may be or may comprise a heat foil configured for heating the slide to a temperature set point. Alternatively or additionally, the tempering element may comprise a Peltier element configured for cooling and heating the slide to a temperature set point. In the latter examples, the pressure exerting element may be or may comprise elevated areas of the receptacle of the slide holder. In order to heat the slide quickly and evenly, the slide holder may be configured for holding the slide in close contact to the heat foil. The application system may compensate unparallelism of the slide by moving and / or pivoting the slide holder using the play between vertical rods and guide bushes.

[0074] Alternatively or additionally, the level of the slide may be sensed by using a force measurement to detect the positions of the three reference elements. This approach may prevent any damages to the glass slides but may require a very precise control of the current and a fast stop of the z-movement in order to not damage the application device.

[0075] Alternatively or additionally, the level of the slide may be sensed by a designated level sense probe being mounted parallel to the application device, e.g. to the print probe of the application device. This approach may eliminate the risk of a damaged or clogged application device, e.g. damaged or clogged print probes, in case an object, such as dust, was lying on the reference element or if the force control had a problem. A calibration process may be used to compensate the difference in length between level sense probe and application device.

[0076] Summarizing and without excluding further possible embodiments, the following embodiments may be envisaged:

[0077] Embodiment 1 : An application system for applying at least one sample of at least one bodily fluid to at least one slide, the application system comprising: i. at least one slide holder for holding the at least one slide during application of the sample of the bodily fluid; and ii. at least one application device for liquid deposition of the sample of the bodily fluid onto an application side of the slide held by the slide holder, wherein the slide holder comprises at least one receptacle for receiving the slide, wherein the slide holder comprises three reference elements, each reference element having an abutment tip, wherein the slide holder further comprises at least one pressure exerting element, the pressure exerting element being configured for exerting a pressure onto a reverse side of the slide opposing the application side, thereby pressing the application side of the slide onto the abutment tips of the reference elements.

[0078] Embodiment 2: The application system according to the preceding embodiment, wherein the pressure exerting element comprises three pressure exerting tips, each pressure exerting tip having an abutment protrusion for exerting the pressure onto the reverse side of the slide.

[0079] Embodiment 3 : The application system according to the preceding embodiment, wherein the pressure exerting tips are positioned on opposing sides of the slide with respect to corresponding abutment tips, wherein three pairs of tips are provided, each pair of tips comprising one abutment tip and one pressure exerting tip. Embodiment 4: The application system according to the preceding embodiment, wherein, in each pair, the abutment tip and the pressure exerting tip are positioned on opposing sides of the slide, such that a connecting line connecting the abutment tip and the pressure exerting tip is oriented essentially perpendicular to the application side of the slide.

[0080] Embodiment 5: The application system according to any one of the two preceding embodiments, wherein, in each pair, the abutment tip and the pressure exerting tip are aligned with respect to each other.

[0081] Embodiment 6: The application system according to any one of the preceding embodiments, further comprising: iii. at least one control device, wherein the control device is configured for controlling the liquid deposition of the sample of the bodily fluid by the application device.

[0082] Embodiment 7: The application system according to the preceding embodiment, wherein the control device is configured for controlling a distance between at least one application tip of the application device and an application surface of the slide on the application side during liquid deposition of the sample of the bodily fluid onto the application side.

[0083] Embodiment 8: The application system according to the preceding embodiment, wherein the control device is configured for performing a calibration routine, wherein, in the calibration routine, the application surface of a calibration slide received in the receptacle, specifically of a first slide received in the receptacle, is determined, wherein the control device is further configured for performing subsequent applications of samples of bodily fluids onto application sides of subsequent slides held by the slide holder by determining a reference surface from the application surface of the calibration slide and by using the reference surface for controlling the distance between the at least one application tip of the application device and the application surfaces of the subsequent slides during the subsequent applications of the samples of bodily fluids onto the application sides of the subsequent slides.

[0084] Embodiment 9: The application system according to the preceding embodiment, wherein the calibration slide is the slide received in the receptacle, wherein the control device is configured for performing the calibration routine for each slide received in the receptacle.

[0085] Embodiment 10: The application system according to any one of the two preceding embodiments, wherein the control device is configured for determining, in the calibration routine, the position of at least three points on the application surface of the calibration slide received in the receptacle and for calculating the reference surface to be a virtual plane determined by the three points.

[0086] Embodiment 11 : The application system according to any one of the three preceding embodiments, wherein the control device is configured for determining, 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 receptacle, the grid of the plurality of points forming a surface mesh on the application surface of the calibration slide and for using the surface mesh as the reference surface.

[0087] Embodiment 12: The application system according to any one of the five preceding embodiments, wherein the control device is configured for controlling a measurement routine for directly or indirectly determining positions of points on the application surface of a slide received in the receptacle of the slide holder by using at least one measurement device.

[0088] Embodiment 13: The application system according to the preceding embodiment, wherein the measurement device is selected from the group consisting of: an optical measurement device; an electrical measurement device, specifically an electrical measurement device at least partially integrated into the application device, more specifically an electrical measurement device at least partially integrated into a control for controlling a distance between at least one application tip of the application device and an application surface of the slide, such as an electrical capacitive measurement device and / or an electrical inductive measurement device; an ultrasonic measurement device.

[0089] Embodiment 14: The application system according to any one of the preceding embodiments, wherein the slide holder comprises a frame extending along at least three edges of the slide received in the receptacle, wherein the three reference elements are disposed on the frame extending along the three edges. Embodiment 15: The application system according to the preceding embodiment, wherein at least one of the three reference elements is disposed on the frame on each edge of the slide.

[0090] Embodiment 16: The application system according to any one of two preceding embodiments, wherein the three reference elements are partially disposed on the frame on a first edge of the slide, specifically on a short edge of the slide, wherein the slide holder further comprises a bar extending across the slide received in the receptacle, wherein the three reference elements are partially disposed on the bar.

[0091] Embodiment 17: The application system according to the preceding 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, wherein two of the three reference elements are disposed on the bar.

[0092] Embodiment 18: The application system according to any one of the preceding embodiments, wherein the slide holder further comprises at least one tempering element for heating and / or cooling the slide received in the receptacle.

[0093] Embodiment 19: The application system according to the preceding embodiment, wherein the tempering element comprises at least one of a resistive electrical heating element or a Peltier element.

[0094] Embodiment 20: The application system according to any one of the two preceding embodiments, wherein the tempering element is disposed on the reverse side of the slide received in the receptacle.

[0095] Embodiment 21 : The application system according to any one of the three preceding embodiments, wherein the pressure exerting element is at least partially integrated into the tempering element.

[0096] Embodiment 22: An analytical system for analyzing samples of at least one bodily fluid, comprising:

[0097] I. at least one application system according to any one of the preceding embodiments; and II. at least one detector for detecting at least one property of the sample of the bodily fluid disposed on at least one slide by the application system.

[0098] Embodiment 23 : The analytical system according to the preceding embodiment, further comprising:

[0099] III. at least one transfer device for transferring slides from the application system to the detector.

[0100] Embodiment 24: The analytical system according to any one of the preceding embodiments referring to an analytical system, wherein the analytical system is configured for analyzing blood cells in the sample of the bodily fluid.

[0101] Embodiment 25: The analytical system according to any one of the preceding embodiments referring to an analytical system, wherein the detector is an optical detector, specifically an optical microscope, comprising at least one light source and at least one lightsensitive element, specifically at least one camera.

[0102] Embodiment 26: An application method for applying at least one sample of at least one bodily fluid to at least one slide, the application method using the application system according to any one of the preceding embodiments referring to an application system, the method comprising: a. receiving the slide in the slide holder; and b. applying the sample onto the application side of the slide held by the slide holder by liquid deposition of the sample of the bodily fluid using the application device.

[0103] Embodiment 27: The application method according to the preceding embodiment, wherein the method comprises subsequently applying samples of the at least one bodily fluid to a plurality of slides, wherein the method comprises at least one calibration routine, wherein, in the calibration routine, the application surface of a calibration slide received in the receptacle is determined, wherein the method further comprises performing subsequent applications of samples of bodily fluids onto application sides of subsequent slides held by the slide holder by determining a reference surface from the application surface of the calibration slide and by using the reference surface for controlling the distance between at least one application tip of the application device and the application surfaces of the subsequent slides during the subsequent applications of the samples of bodily fluids onto the application sides of the subsequent slides. Embodiment 28: The application method according to any one of the preceding embodiments referring to an application method, wherein at least step b., and, optionally, the calibration routine, are computer-controlled, specifically by at least one control device of the application system.

[0104] Embodiment 29: A computer program comprising instructions which, when the program is executed by a control device of an application system according to any one of the preceding embodiments referring to an application system, cause the control device to perform at least step b., and, optionally, the calibration routine, of the application method according to any one of the preceding embodiments referring to an application method.

[0105] Embodiment 30: A computer-readable storage medium, specifically a non-transient computer-readable storage medium, comprising instructions which, when the instructions are executed by a control device of an application system according to any one of the preceding embodiments referring to an application system, cause the control device to perform at least step b., and, optionally, the calibration routine, of the application method according to any one of the preceding embodiments referring to an application method.

[0106] Embodiment 31 : An analytical method for analyzing samples of at least one bodily fluid, the analytical method using the analytical system according to any one of the preceding embodiments referring to an analytical system, the analytical method comprising:

[0107] A. applying the sample of the bodily fluid to the slide by using the application method according to any one of the preceding embodiments referring to an application method; and

[0108] B. detecting at least one property of the sample of the bodily fluid disposed on the slide by using the detector.

[0109] Embodiment 32: The analytical method according to the preceding embodiment, wherein the method is computer-controlled.

[0110] Embodiment 33: A computer program comprising instructions which, when the program is executed by a control device of an application system of an analytical system according to any one of the preceding embodiments referring to an analytical system, cause the control device to perform the steps of the analytical method according to any one of the preceding embodiments referring to an analytical method.

[0111] Embodiment 34: A computer-readable storage medium, specifically a non-transient computer-readable storage medium, comprising instructions which, when the instructions are executed by a control device of an application system of an analytical system according to any one of the preceding embodiments referring to an analytical system, cause the control device to perform the steps of the analytical method according to any one of the preceding embodiments referring to an analytical method.

[0112] Short description of the Figures

[0113] Further optional features and embodiments will be disclosed in more detail in the subsequent description of embodiments, preferably in conjunction with the dependent claims. Therein, the respective optional features may be realized in an isolated fashion as well as in any arbitrary feasible combination, as the skilled person will realize. The scope of the invention is not restricted by the preferred embodiments. The embodiments are schematically depicted in the Figures. Therein, identical reference numbers in these Figures refer to identical or functionally comparable elements.

[0114] In the Figures:

[0115] Figures 1A and IB show an embodiment of an application system for applying at least one sample of at least one bodily fluid to at least one slide in a perspective view (Figure 1 A) and in a side cut view (Figure IB);

[0116] Figure 2 shows a further embodiment of a slide holder of an application sys- tern in a perspective view;

[0117] Figures 3 A and 3B show a further embodiment of a slide holder of an application system in a perspective view (Figure 3 A) and in a side cut view (Figure 3B);

[0118] Figures 4 A and 4B show a further embodiment of a slide holder of an application system in a perspective view (Figure 4A) and in a side cut view (Figure 4B); Figure 5 shows an embodiment of an analytical system for analyzing samples of at least one bodily fluid in a schematic view;

[0119] Figure 6 shows a flow chart of an embodiment of an application method for applying at least one sample of at least one bodily fluid to at least one slide; and

[0120] Figure 7 shows a flow chart of an embodiment of an analytical method for analyzing samples of at least one bodily fluid.

[0121] Detailed description of the embodiments

[0122] Figures 1 A and IB show a first exemplary embodiment of an application system 110 for applying at least one sample of at least one bodily fluid (not shown in the Figures) to at least one slide 112 in a perspective view (Figure 1 A) and in a side cut view (Figure IB).

[0123] The application system 110 comprises at least one slide holder 114 for holding the at least one slide 112 during application of the sample of the bodily fluid. The application system 110 further comprises at least one application device 116 for liquid deposition of the sample of the bodily fluid onto an application side 118 of the slide 112 held by the slide holder 114. As shown in Figure 1 A, the application device 116 may comprise at least one application tip 120 for controlling liquid deposition of the sample of the bodily fluid onto the application side 118. In this example, the application system 110 may specifically be a slide printer 122 comprising at least one print probe 124 to print the sample of the bodily fluid to the slide 112, e.g. to print a sample of blood on a glass slide. As indicated by the arrows in Figure 1 A, the application device 116, specifically the print probe 124, may be movable in at least one of a x-direction, a y-direction and a z-direction, specifically in all of the x-direction, the y- direction and the z-direction, more specifically independently from each other. Alternatively, in another embodiment (not shown in the figures), the slide holder 114 may be movable in at least one of, specifically in all of, the x-direction, the y-direction, and the z-direction relative to a static application device 116 and / or print probe 124.

[0124] The slide holder 114, which is shown in further detail in a side cut view in Figure IB, comprises at least one receptacle 126 for receiving the slide 112. The slide holder 114 further comprises three reference elements 128, each reference element 128 having an abutment tip 130. The slide holder 114 further comprises at least one pressure exerting element 132, the pressure exerting element 132 being configured for exerting a pressure onto a reverse side 134 of the slide 112 opposing the application side 118, thereby pressing the application side 118 of the slide 112 onto the abutment tips 130 of the reference elements 128.

[0125] In the example of Figures 1 A and IB, the pressure exerting element 132 may comprise three pressure exerting tips 136, each pressure exerting tip 136 having an abutment protrusion 138 for exerting the pressure onto the reverse side 134 of the slide 112. The pressure exerting tips 136 may be positioned on opposing sides of the slide 112 with respect to corresponding abutment tips 130. Thus, as exemplarily shown in Figure 1A, three pairs of tips may be provided. Each pair of tips may comprise one abutment tip 130 and one pressure exerting tip 136. As an example, in each pair, the abutment tip 130 and the pressure exerting tip 136 may be positioned on opposing sides of the slide 112, such that a connecting line connecting the abutment tip 130 and the pressure exerting tip 136 is oriented essentially perpendicular to the application side 118 of the slide 112.

[0126] The slide holder 114 may comprise a frame 140 extending along at least three edges of the slide 112 received in the receptacle 126. The three reference elements 128 may be disposed on the frame 140 extending along the three edges. The three reference elements 128 may be partially disposed on the frame 140 on a first edge of the slide 112, specifically on a short edge of the slide 112. The slide holder 114 may further comprise a bar 142 extending across the slide 112 received in the receptacle 126. The three reference elements 128 may be partially disposed on the bar 142. As shown in Figure 1 A, in this exemplary embodiment, one of the three reference elements 128 may be disposed on the frame 140 on the 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 bar 142.

[0127] An alternative arrangement of the three reference elements 128 is shows in Figure 2. Figure 2 shows a further embodiment of the slide holder 114 of the application system 110 in a perspective view. The slide holder 114 in this exemplary embodiment widely corresponds to the slide holder 114 shown in Figures 1 A and IB. Thus, for a detailed description of the slide holder 114, reference is made to the description of Figures 1A and IB. As can be seen in Figure 2, in this exemplary embodiment, at least one of the three reference elements 128 may be disposed on the frame 140 on each edge of the slide 112. Specifically, one reference element 128 may be disposed on the frame 140 on each edge of the slide 112.

[0128] Turning back to Figure 1A, the application system 110 may further comprise at least one control device 143, wherein the control device 143 may be configured for controlling the liquid deposition of the sample of the bodily fluid by the application device 116. The control device 143 may be configured for controlling a distance between the application tip 120 of the application device 116 and an application surface of the slide 112 on the application side 118 during liquid deposition of the sample of the bodily fluid onto the application side 118. The control device 143 may be configured for performing a calibration routine. In the calibration routine, the application surface of a calibration slide received in the receptacle 126, specifically of a first slide received in the receptacle 126, may be determined. The control device 143 may further be configured for performing subsequent applications of samples of bodily fluids onto application sides 118 of subsequent slides 112 held by the slide holder 114 by determining a reference surface from the application surface of the calibration slide and by using the reference surface for controlling the distance between the at least one application tip 120 of the application device 116 and the application surfaces of the subsequent slides 112 during the subsequent applications of the samples of bodily fluids onto the application sides 118 of the subsequent slides 112.

[0129] Figures 3 A and 3B show a further embodiment of the slide holder 114 of the application system 110 in a perspective view (Figure 3 A) and in a side cut view (Figure 3B). The slide holder 114 in this exemplary embodiment widely corresponds to the slide holder 114 shown in Figures 1A and IB. Thus, for a detailed description of the slide holder 114, reference is made to the description of Figures 1 A and IB. In the exemplary embodiment of Figures 3A and 3B, the pressure exerting element 132 may be or may comprise elevated areas 144 of the receptacle 126 of the slide holder 114.

[0130] Further, as can be seen in Figure 3B, the slide holder 114 may comprise at least one tempering element 146 for heating and / or cooling the slide 112 received in the receptacle 126. The tempering element 146 may specifically be configured for adjusting a temperature of the slide 112 received in the receptacle 126 according to at least one temperature set point, such as by actively increasing and / or decreasing the temperature of the slide 112 received in the receptacle 126. In this exemplary embodiment, the tempering element 146 may comprise at least one resistive electrical heating element 148, e.g. in the form of an electrical heating foil. As shown in Figure 3B, the tempering element 146 may be disposed on a reverse side of the receptacle 126. Specifically, the tempering element 146 may be configured for heating the receptacle 126 thereby heating the slide 112 received in the receptacle 126.

[0131] Figures 4A and 4B show a further embodiment of the slide holder 114 of the application system 110 in a perspective view (Figure 4A) and in a side cut view (Figure 4B). The slide holder 114 in this exemplary embodiment widely corresponds to the slide holder 114 shown in Figures 3 A and 3B. Thus, for a detailed description of the slide holder 114, reference is made to the description of Figures 3 A and 3B. In this exemplary embodiment, the tempering element 146, alternatively or additionally, may comprise at least one Peltier element 150. Thus, in this example, the tempering element 146 may be configured for heating and cooling the slide 112 received in the receptacle 126, specifically indirectly heating and cooling the slide 112 via the receptacle 126, as outlined above. Additionally or alternatively, the tempering element 146 may comprise at least one heat sink 152.

[0132] Figure 5 shows an embodiment of an analytical system 154 for analyzing samples of at least one bodily fluid in a schematic view. The analytical system 154 comprises at least one application system 110 according to the present invention, such as according to any one of the embodiments disclosed in Figures 1 A to 4B and / or according to any other embodiment disclosed herein. Thus, for a detailed description of the application system 110, reference is made to the description of Figures 1 A to 4B.

[0133] The analytical system 154 further comprises at least one detector 156 for detecting at least one property of the sample of the bodily fluid disposed on the 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, comprising at least one light source 160 and at least one light-sensitive element 162, specifically at least one camera.

[0134] The analytical system 154 may further comprise at least one transfer device 164 for transferring slides 112 from the application system 110 to the detector 156.

[0135] As an example, the analytical system 154 may be configured for analyzing blood cells in the sample of the bodily fluid. The analytical system 154 may be configured for analyzing one or more of a presence of blood cells in the sample of the bodily fluid, a number of blood cells in the sample of the bodily fluid, a concentration of blood cells in the sample of the bodily fluid, an identity of blood cells in the sample of the bodily fluid, a shape of blood cells in the sample of the bodily fluid, a size of blood cells in the sample of the bodily fluid and / or a coloration of blood cells in the sample of the bodily fluid, a shape of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”, a size of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”, and / or a coloration of cell structures or organelles in the sample of the bodily fluid, e.g. of cell nuclei or cell surface structures, such as clusters of differentiation, also referred to as “CD-markers”. Other examples, however, are also feasible. Figure 6 shows a flow chart of an embodiment of an application method for applying at least one sample of at least one bodily fluid to at least one slide 112. The application method uses the application system 110 according to the present invention, such as according to any one of the embodiments disclosed in Figures 1 A to 4B and / or according to any other embodiment disclosed herein. Thus, for a detailed description of the application system 110, reference is made to the description of Figures 1 A to 4B.

[0136] The method comprises the following steps which, specifically, may be performed in the given order. It shall be noted, however, that a different order is also possible. Further, it is also possible to perform one or more of the method steps once or repeatedly. Further, it is possible to perform two or more of the method steps simultaneously or in a timely overlapping fashion. The method may comprise further method steps which are not listed.

[0137] The method comprises: a. (denoted by reference number 166) receiving the slide 112 in the slide holder 114; and b. (denoted by reference number 168) applying the sample onto the application side 118 of the slide 112 held by the slide holder 114 by liquid deposition of the sample of the bodily fluid using the application device 116.

[0138] The application method may comprise subsequently applying samples of the at least one bodily fluid to a plurality of slides 112. The application method may comprise at least one calibration routine. In the calibration routine, the application surface of a calibration slide received in the receptacle 126 may be determined. The method may further comprise performing subsequent applications of samples of bodily fluids onto application sides 118 of subsequent slides 112 held by the slide holder 114 by determining a reference surface from the application surface of the calibration slide and by using the reference surface for controlling the distance between at least one application tip 120 of the application device 116 and the application surfaces of the subsequent slides 112 during the subsequent applications of the samples of bodily fluids onto the application sides 118 of the subsequent slides 112.

[0139] Figure 7 shows a flow chart of an embodiment of an analytical method for analyzing samples of at least one bodily fluid. The analytical method uses the analytical system 154 according to the present invention, such as according to the exemplary embodiments disclosed in Figure 5 and / or according to any other embodiment disclosed herein. Thus, for a detailed description of the analytical system 154, reference is made to the description of Figure 5. The method comprises the following steps which, specifically, may be performed in the given order. It shall be noted, however, that a different order is also possible. Further, it is also possible to perform one or more of the method steps once or repeatedly. Further, it is possible to perform two or more of the method steps simultaneously or in a timely overlap- ping fashion. The method may comprise further method steps which are not listed.

[0140] The analytical method comprises:

[0141] A. (denoted by reference numbers 166, 168) applying the sample of the bodily fluid to the slide 112 by using the application method according to the present invention, such as according to the exemplary embodiment disclosed in Figure 6 and / or according to other embodiment disclosed herein; and

[0142] B. (denoted by reference number 170) detecting at least one property of the sample of the bodily fluid disposed on the slide 112 by using the detector 156.

[0143] List of reference numbers application system slide slide holder application device application side application tip slide printer print probe receptacle reference element abutment tip pressure exerting element reverse side pressure exerting tip abutment protrusion frame bar control device elevated area tempering element electrical heating element

[0144] Peltier element heat sink analytical system detector optical detector light source light-sensitive element transfer device receiving the slide in the slide holder applying the sample onto the application side of the slide detecting at least one property of the sample of the bodily fluid

Claims

Claims1. An application system (110) for applying at least one sample of at least one bodily fluid to at least one slide (112), the application system (110) comprising: i. at least one slide holder (114) for holding the at least one slide (112) during application of the sample of the bodily fluid; and ii. at least one application device (116) for liquid deposition of the sample of the bodily 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 exerting element (132), the pressure exerting element (132) being configured for exerting a pressure onto a reverse side (134) of the slide (112) opposing the application side (118), thereby pressing the application side (118) of the slide (112) onto the abutment tips (130) of the reference elements (128), wherein the pressure exerting element (132) comprises three pressure exerting tips (136), each pressure exerting tip (136) having an abutment protrusion (138) for exerting the pressure onto the reverse side (134) of the slide (112), wherein the pressure exerting tips (136) are positioned on opposing sides of the slide (112) with respect to corresponding abutment tips (130), wherein three pairs of tips are provided, each pair of tips comprising one abutment tip (130) and one pressure exerting tip (136).

2. The application system (110) according to the preceding claim, further comprising: iii. at least one control device (143), wherein the control device (143) is configured for controlling the liquid deposition of the sample of the bodily fluid by the application device (116).

3. The application system (110) according to the preceding claim, wherein the control device (143) is configured for controlling a distance between at least one application tip (120) of the application device (116) and an application surface of the slide (114)on the application side (118) during liquid deposition of the sample of the bodily fluid onto the application side (118), wherein the control device (143) is configured for performing a calibration routine, wherein, in the calibration routine, the application surface of a calibration slide received in the receptacle (126) is determined, wherein the control device (143) is further configured for performing subsequent applications of samples of bodily fluids onto application sides (118) of subsequent slides (112) held by the slide holder (114) by determining a reference surface from the application surface of the calibration slide and by using the reference surface for controlling the distance between the at least one application tip (120) of the application device (116) and the application surfaces of the subsequent slides (112) during the subsequent applications of the samples of bodily fluids onto the application sides (118) of the subsequent slides (112).

4. The application system (110) according to the preceding claim, wherein the control device (143) is configured for determining, in the calibration routine, the position of at least three points on the application surface of the calibration slide received in the receptacle (126) and for calculating the reference surface to be a virtual plane determined by the three points.

5. The application system (110) according to any one of the two preceding claims, wherein the control device (143) is configured for determining, 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 receptacle (126), the grid of the plurality of points forming a surface mesh on the application surface of the calibration slide and for using the surface mesh as the reference surface.

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

7. The application system (110) according to any one of the preceding claims, wherein the slide holder (114) comprises a frame (140) extending along at least three edges of the slide (112) received in the receptacle (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 two preceding 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 comprises a bar (142) extending across the slide (112) received in the receptacle (126), wherein the three reference elements (128) are partially disposed on the (142) bar.

10. The application system (110) according to any one of the preceding claims, wherein the slide holder (114) further comprises at least one tempering element (146) for heating and / or cooling the slide (112) received in the receptacle (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; andII. at least one detector (156) for detecting at least one property of the sample of the bodily fluid disposed on at least one slide (112) by the application system (110).

12. The analytical system (154) according to the preceding claim, further comprising:III. at least one transfer device (164) for transferring slides (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 slide (112), the application method using the application system (110) according to any one of the preceding claims referring to an application system (110), the method comprising: a. receiving the slide (112) in the slide holder (114); and b. applying the sample onto the application side (118) of the slide (112) held by the slide holder (114) by liquid deposition of the sample of the bodily fluid using the application device (116).

14. The application method according to the preceding claim, wherein the method comprises subsequently applying samples of the at least one bodily fluid to a plurality ofslides (112), wherein the method comprises at least one calibration routine, wherein, in the calibration routine, the application surface of a calibration slide received in the receptacle (126) is determined, wherein the method further comprises performing subsequent applications of samples of bodily fluids onto application sides (118) of subse- quent slides (112) held by the slide holder (114) by determining a reference surface from the application surface of the calibration slide and by using the reference surface for controlling the distance between at least one application tip (120) of the application device (116) and the application surfaces of the subsequent slides (112) during the subsequent applications of the samples of bodily fluids onto the application sides (118) of the subsequent slides (112).

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