Biological sample processing system and microfluidic cartridge for biological sample processing system

Abstract

The biological sample processing system includes an imaging unit (2) including a digital image processing system and at least one microscope including at least one lens (14), a sample processing station (3) including a handling platform (5) including a support (17) and a displacement mechanism for moving the support (17), and a sample processing unit (7) attached to the handling platform (5). The sample processing unit (7) includes a tissue slide holder (11) for mounting a tissue slide (34) on the tissue slide holder (11) together with a biological sample (36) fixed on the tissue slide (34), and a microfluidic cartridge holder (9) for mounting a microfluidic cartridge (4) on the microfluidic cartridge holder (9). The tissue slide holder (11) is coupled to the microfluidic cartridge holder (9) via a coupling (13) that, in an open position, allows the microfluidic cartridge and tissue support to be attached to and detached from the sample processing unit, and, in a closed position, allows the tissue support (34) to be in sealing contact with the microfluidic cartridge (4). The sample processing station comprises a plurality of said sample processing units mounted on a handling platform (5), the plurality of sample processing units being movable from positions that allow attachment or detachment of a tissue slide, a microfluidic cartridge, respectively, to a position where an observation window of the microfluidic cartridge holder (9) is positioned in registration with at least one lens of the microscope.

Description

Technical Field

[0001] The present invention relates to a biological sample processing system for analyzing a tissue sample fixed to a support using an imaging system including a microscope.

Background Art

[0002] Conventional supports for tissue sample analysis typically include a slide glass or a cover glass for fixing the tissue sample to the support, and the slide glass or the cover glass may be uncoated or coated such as a polylysine-coated slide or a gel-coated slide. The support, however, may be made of other materials.

[0003] Samples include whole tissue samples, surgical biopsies or needle biopsies of tissue types, blood samples or cytological smears. The tissue sample can be provided as tissue cut into thin sections and placed on a support, a tissue sample smeared on a support, or a tissue sample provided as a fluid dropped or otherwise placed on a support. The tissue sample can be, for example, a sample such as breast tissue, lung tissue, tonsil tissue, colon tissue, lymph node tissue, prostate tissue, intestinal tissue, liver tissue, kidney tissue. Samples for analysis can be, for example, tumor samples including biopsies from cancers such as breast cancer, lung cancer, prostate cancer, ovarian cancer, colon cancer, and melanoma. The present invention can also be applied to samples of microorganisms such as bacteria or samples of living tissues such as tissue cultures.

[0004] A common form of fixation of tissue samples for analysis is formalin-fixed paraffin-embedded (FFPE) samples.

[0005] Analysis of living tissue samples includes immunohistochemistry (IHC) and immunofluorescence.

[0006] IHC is a technique that requires the use of specific probe molecules, such as antibodies, to detect the presence of unique biomarkers (such as antigens) that may be expressed by cells in a tissue sample. IHC is widely used in both clinical and research settings to diagnose specific diseases, such as types of cancer, or to investigate the correlation between disease prognosis and the expression of new biomarkers. While the primary application area of ​​IHC is cancer diagnosis, it has other applications, including the detection of pathogens such as viruses, and supports the diagnosis of other diseases such as Alzheimer's disease.

[0007] Immunofluorescence is an alternative to classical immunohistochemistry, particularly for applications where it is desired to observe multiple molecular measurements in a single sample. However, it has some limitations, such as low multiplexity (i.e., the number of simultaneous molecular readings). The main limitation of immunofluorescence is interference between phosphor signals. The overlap of the emission spectra of the detected molecules reduces the specificity of each signal, thus limiting simultaneous readings to a maximum of 4-5 types. Another limitation stems from the fact that each molecular target requires primary antibodies derived from different species, which severely limits multiplexity. This can be overcome by using direct labeling of antibodies instead of sandwich assays, but this results in a much lower output signal due to lack of amplification, leading to decreased sensitivity.

[0008] Multi-cycle multiplexing is a technique that can overcome some of the limitations of classical multiplexing methods. This technique requires the elution of the target antibody or inactivation of the labeling molecule after each staining and imaging cycle. However, there are some drawbacks associated with conventional multi-cycle staining and imaging techniques for tissue sections. The first drawback is the very long turnaround time, which stems from long incubation and washing cycles (usually several hours), limiting processing capacity and potentially causing sample degradation over time. Furthermore, the repeated mounting / removal of imaging coverslips further degrades tissue integrity. Manual sample handling during the cycle also reduces reproducibility and reliability. Another consideration is the accuracy of the scan of the sample area being imaged and the entire slide. When the entire slide or a broad area of ​​interest is imaged with a high-magnification objective lens, overlay / stitching software solutions are used to acquire the image. Removing and reinserting the sample under the objective lens after each staining cycle can lead to alignment errors between images corresponding to different markers, reducing the accuracy of multiplex analysis. [Overview of the project] [Problems that the invention aims to solve]

[0009] The object of the present invention is to provide a biological sample processing system for imaging and analyzing tissue samples fixed to a support, the biological sample processing system being rapid and efficient, and enabling accurate imaging of tissue samples over a wide area.

[0010] It is advantageous to provide a general-purpose biological sample processing system that can be used or adapted for different applications.

[0011] It is advantageous to provide a biological sample processing system that can perform sequential multiplex processing of biological samples, generating rapid, accurate, and reliable results through reagent sequencing.

[0012] Another object of the present invention is to provide a microfluidic cartridge for a biological sample processing system for imaging and analyzing tissue samples immobilized on a support, the microfluidic cartridge enabling rapid, efficient, and accurate imaging of tissue samples over a wide area.

[0013] It is advantageous to provide a versatile microfluidic cartridge that can be used or adapted for different applications.

[0014] Providing a microfluidic cartridge that is compact, economical, and easy to install and replace is advantageous. [Means for solving the problem]

[0015] The object of the present invention is achieved by providing the biological sample processing system described in claim 1.

[0016] The object of the present invention is achieved by providing the microfluidic cartridge described in claim 10.

[0017] A biological sample processing system disclosed herein comprises: an imaging unit comprising: a digital image processing system and at least one microscope including at least one lens; a sample processing station comprising a handling platform comprising: a support and a displacement mechanism for moving the support; and a sample processing unit mounted on the handling platform. The sample processing unit comprises: a tissue slide holder for mounting tissue slides (34) on which a biological sample (36) is fixed, and a microfluidic cartridge holder for mounting a microfluidic cartridge on the microfluidic cartridge holder. The tissue slide holder is coupled to the microfluidic cartridge holder via a coupling, thereby enabling, in the open position, the microfluidic cartridge and the tissue support to be attached to and removed from the sample processing unit, and, in the closed position, the tissue support to be in seal contact with the microfluidic cartridge.

[0018] The sample processing station comprises a plurality of sample processing units mounted on a handling platform, the plurality of sample processing units being movable from a position that allows for the mounting or removal of tissue slides and microfluidic cartridges, respectively, to a position in which the observation window of the microfluidic cartridge holder is aligned with at least one of the microscope lenses.

[0019] In an advantageous embodiment, the microfluidic cartridge holder window includes a recess into which a lens is partially inserted at the imaging position.

[0020] In an advantageous embodiment, the sample processing station comprises at least three, preferably four or more, sample processing units.

[0021] In an advantageous embodiment, the handling platform comprises a rotational displacement mechanism for rotating the support between a plurality of positions.

[0022] In an advantageous embodiment, each of the sample processing units is coupled to at least one reagent supply tube and at least one reagent outflow tube.

[0023] In an advantageous embodiment, each of the sample processing units comprises a clamping mechanism including a locking mechanism and a pressure actuator configured to apply pressure to the tissue support against the microfluidic cartridge in the closed position, the clamping mechanism comprising a compression gas piston.

[0024] In an advantageous embodiment, each of the sample processing units comprises a temperature control system including a cooling / heating system coupled to a tissue slide holder.

[0025] In an advantageous embodiment, the microfluidic cartridge holder and the tissue holder are pivotally coupled together via a hinge joint.

[0026] In an advantageous embodiment, the microfluidic cartridge holder is in the form of a movable lid and the tissue slide holder is in the form of a base statically fixed to the support of the handling platform.

[0027] In an advantageous embodiment, the observation window of the microfluidic cartridge holder comprises a chamfered recess.

[0028] This specification also discloses a microfluidic cartridge for a biological sample processing system, the microfluidic cartridge comprising a substrate, a fluid flow network formed within the substrate, a seal attached to the substrate, a cavity of a reaction chamber formed within the substrate, and an observation window, the microfluidic cartridge being installed in contact with a tissue support and configured to cover the cavity and constitute the side of the reaction chamber, so that the reaction chamber is formed between the tissue support and the microfluidic cartridge. The fluid flow network comprises an inlet, an inlet channel network, and a plurality of chamber inlet holes. The fluid flow network further comprises an outlet, an outlet channel network, and a plurality of chamber outlet holes. The chamber inlet holes and chamber outlet holes are located on both sides of the cavity of the reaction chamber for the flow of reagents passing through the reaction chamber. The seal surrounds the cavity of the reaction chamber and the chamber inlet holes and chamber outlet holes.

[0029] The observation window is provided with a transparent cover that is less than 1 mm thick and has its outer surface within a recess formed in the substrate of the observation window with respect to the outer surface of the substrate, and the observation window is configured so that a microscope lens can be partially inserted into the recess of the observation window.

[0030] In an advantageous embodiment, the transparent cover is made of glass or sapphire.

[0031] In an advantageous embodiment, the transparent cover has a thickness of less than 0.5 mm, preferably less than 0.3 mm.

[0032] In an advantageous embodiment, the cartridge further comprises a spacer element that defines the height of the reaction chamber when the tissue support is installed and pressed against the reaction chamber.

[0033] The spacer elements may be in the form of continuous or partially continuous projections, or preferably, spaced-out discrete projections.

[0034] In an advantageous embodiment, the spacer element is positioned outside the seal relative to the reaction chamber.

[0035] In an advantageous embodiment, the seal is attached to a groove in the substrate.

[0036] Further objectives and advantageous features of the present invention will become apparent from the claims, detailed description and accompanying drawings. [Brief explanation of the drawing]

[0037] [Figure 1] This is a schematic perspective view of a biological sample processing system according to an embodiment of the present invention. [Figure 2] This is a schematic perspective view of the main components of the sample processing station of a biological sample processing system according to an embodiment of the present invention. [Figure 3a] This is a perspective view of the sample processing unit of a sample processing station according to an embodiment of the present invention, in the open position. [Figure 3b] This is a perspective view of the sample processing unit of a sample processing station according to an embodiment of the present invention, in the closed position. [Figure 3c] This is a cross-sectional perspective view of the sample processing unit of a sample processing station according to an embodiment of the present invention, in the closed position. [Figure 4a] This is a top-side perspective view of a microfluidic cartridge of a biological sample processing system according to an embodiment of the present invention. [Figure 4b] This is a perspective view of the bottom side of the microfluidic cartridge of a biological sample processing system according to an embodiment of the present invention. [Figure 5] This is a schematic enlarged cross-sectional view of a microfluidic cartridge attached to a sample slide in a biological sample processing system according to an embodiment of the present invention. [Modes for carrying out the invention]

[0038] Referring to the drawing, An embodiment of the present invention comprises an imaging unit 2, a sample processing station 3, and a plurality of microfluidic cartridges 4 attached to the sample processing station 3. The biological sample processing system 1 is for analyzing a biological tissue sample 36 that can be fixed to a support 34.

[0039] The support 34 may take the form of a conventional microscope slide, for example, made of glass and having typical dimensions of a surface area of ​​3 cm × 2 cm and a thickness of about 1 mm. Such microscope slides are widely used to fix tissue samples for placement under the microscope objective lens for analysis of the sample by a manual or automated imaging system. However, other supports, whether conventional or not, may also be used to fix tissue samples for analysis in an imaging system according to embodiments of the present invention. Preferably, the support is transparent to allow a light source to be placed beneath the sample, but within the scope of the present invention, the support may be opaque and the light for imaging may be provided from the observation side of the sample.

[0040] Various tissue samples can be analyzed, examples of which are given in the background art of this specification above.

[0041] Applications that benefit from the advantageous features of the present invention include the analysis of tissue samples from biopsies that are taken immediately before analysis and require rapid analysis of the tissue. This may occur, for example, during a biopsy for potential cancer. In particular, applications where rapid result generation is highly advantageous are to confirm that all tissue containing cancer cells has been completely removed during the surgical removal of cancerous tissue. Thus, analysis can be performed during surgery and before the completion of the surgery. The present invention enables tissue sample processing to be carried out in less than one hour, preferably less than 45 minutes, and in some cases less than 30 minutes.

[0042] However, the bioprocessing systems according to embodiments of the present invention may be used in other applications that do not require such rapid output of results but benefit from rapid, reliable, and efficient analysis of tissue samples. One highly desirable advantage is reducing the amount of tissue required for analysis in order to ensure that the biopsy process is as minimally invasive as possible.

[0043] The imaging unit 2 comprises one or more microscopes, each having at least one lens 14, and an image processing system (internal details of which are not explicitly shown) comprising an image capture sensor and associated electronic circuitry and software for capturing and processing images observed through the microscope lenses. The imaging system for capturing, processing and storing images is well known in itself and does not need to be described further herein.

[0044] The biological sample processing system may further include a reagent storage and delivery module (not shown) for supplying reagents, buffers, and washing solutions to the sample processing station, in particular for the flow of the microfluidic cartridge 4 through the reaction chamber 29 for the analysis of the sample.

[0045] The sample processing station 3 comprises a handling platform 5 and a plurality of sample processing units 7 mounted on a support 17 of the handling platform 5. The handling platform 5 further comprises a displacement mechanism (not shown) for moving the sample processing units 7 on the support 17 and / or on the support in order to move the sample processing units 7 from a position below the microscope lens 14 to at least the loading and unloading positions of tissue slides 34 from the sample processing units 7.

[0046] In an embodiment, the displacement mechanism may include, for example, a rotational coupling positioned below the support 17 for the rotation of the support around a central axis. In the illustrated embodiment, a plurality (four shown here) of sample processing units 7 are rotated around a central axis A between a loading position, an observation position, and other arbitrary positions (e.g., a standby position).

[0047] In another embodiment (not shown), the sample processing station may comprise, for example, only two sample processing units mounted on a slide of a displacement mechanism for translation between an observation position and a loading position.

[0048] However, various combinations of the rotation axis and / or translation axis of the displacement can be implemented in the displacement mechanism within the scope of the present invention.

[0049] Each sample processing unit 7 comprises a microfluidic cartridge holder 9, a tissue holder 11, and a coupling portion 13 between the microfluidic cartridge holder 9 and the tissue holder 11 that allows the cartridge holder 9 to move relative to the tissue slide holder 11 for mounting and removing tissue slides 34. In the illustrated embodiment, the microfluidic cartridge holder is provided in the form of a lid that is rotatably coupled to a base portion forming the tissue slide holder 11 via a hinge that forms the coupling portion 13.

[0050] However, within the scope of the present invention, it is also conceivable that the device may have a microfluidic cartridge holder as a base and a tissue slide holder as a lid movably attached to the base. This configuration can be used, for example, in combination with inverted microscopy.

[0051] The base unit is permanently attached to the handling platform 5 of the sample processing station 3.

[0052] The joint 13 may be provided in other forms as an alternative to the pivot hinge, for example, by a link arm or slide that allows the microfluidic cartridge holder to detach from the base that holds the tissue slide holder 11 in translational motion or a combined translational and rotational motion. However, the joint 13 in the form of a pivot hinge is simple and robust and corresponds to a preferred embodiment.

[0053] The microfluidic cartridge holder 9 advantageously includes an observation window 19 with a recess 43 such that a microscope lens can be positioned very close to the observation window 12 of the microfluidic cartridge, and the recess 43 is configured to receive the microscope lens 14 at least partially within the recess 43. Thus, lenses with a very large numerical aperture can be used to improve the quality of image capture of the sample during observation.

[0054] The sample processing unit 7 further advantageously includes a clamping mechanism 15, which includes a locking mechanism 16 and a pressure actuator 18. The pressure actuator 18 may comprise a compressed fluid-driven piston, such as a compressed air piston 37, which applies pressure to the tissue slide 34 relative to the microfluidic cartridge 4. This pressure ensures that the seal 10, positioned between the substrate 6 of the microfluidic cartridge 4 and the tissue slide 34, is hermetically closed to withstand the pressure inside the reaction chamber 29 during the injection of reagents and other fluids into the reaction chamber. The pressure applied by the pressure actuator ensures that the maximum pressure reached inside the reaction chamber does not cause leakage to the seal 10.

[0055] The locking mechanism 16 may take the form of one or more locking pins, for example, inserted into corresponding holes in the locking flange or tab of the other side of the lid or base portion. However, within the scope of the present invention, the locking mechanism may have other configurations, such as a pivotable arm having a catch shoulder that engages with a corresponding catch shoulder of the other side of the lid or base portion.

[0056] The movable parts of the microfluidic cartridge holder or tissue slide holder may be manually operated or may include an electrically operated mechanism (not shown), and similarly, the locking mechanism may be manually operated or may include an electrically operated system for automatic opening and closing of the movable and fixed parts.

[0057] The sample processing unit 7 further comprises a reagent fluid flow system for guiding the flow of reagents and other fluids from an external reagent source to the microfluidic cartridge 4. Accordingly, the reagent fluid flow system comprises an inlet coupling for reagent conduits such as reagent tubes for the inflow and outflow of reagents, and an interface surrounded by sealing elements that coupled to a fluid flow network 8 on the microfluidic cartridge 4.

[0058] The clamping mechanism 15 may function to press the microfluidic cartridge against the tissue slide holder 11 when the tissue slide 34 is pressed against the microfluidic cartridge 4, thereby ensuring a tight seal at the interface between the inlet and outlet of the microfluidic cartridge and the corresponding outlet and inlet of the reagent fluid flow system within the microfluidic cartridge holder 9.

[0059] The sample processing unit may further comprise a temperature control system 24 for cooling and / or heating the tissue slides 34, taking into consideration heating or cooling the reagents in the reaction chamber 29 during tissue sample processing, particularly for the purpose of multiplex analysis. The temperature control system 24 may advantageously comprise a Peltier chip 31 positioned within or below the base portion forming the tissue slide holder 11. In a modified example, the temperature control system may further comprise heating and / or cooling elements positioned to heat and / or cool the reagent fluid flow system within the sample processing unit, particularly for preheating or precooling the reagents entering the reaction chamber 29.

[0060] A microfluidic cartridge according to an embodiment of the present invention comprises a substrate 6, a fluid flow network 8 formed within the substrate 6, a seal 10, and an observation window 12. The fluid flow network 8 comprises an inlet 26 for coupling with a reagent fluid flow system in the base of a sample processing unit 7, an outlet 32 ​​for discharging reagents from a reaction chamber 29, and an inlet channel network 27 and an outlet channel network 31 connected to a chamber inlet hole 28 and a chamber outlet hole 30, respectively. The fluid flow network is configured to provide a substantially uniform flow of reagents passing through the reaction chamber 29, intended to ensure substantial advection transport of reagents to a biological sample 36 fixed on a tissue support 34.

[0061] The seal 10 is attached to the chamber inlet hole 28 and the chamber outlet hole 30, as well as to the grooves in the substrate 6 surrounding the reaction chamber 29. The reaction chamber 29 is formed between the tissue support 34 and the observation window 12, which is surrounded by the seal 10 sandwiched between the substrate 6 and the tissue support 34.

[0062] Advantageously, the microfluidic cartridge 4 may further comprise a spacer element 40, for example, preferably in the form of a continuous rim or a plurality of discrete protrusions, positioned outside the seal 10. The spacer element ensures that the height of the reaction chamber 29 is maintained at a defined predetermined height, independent of the compressive force applied to the seal 10 by the pressure actuator 18. The forces of the pressure actuator and clamping mechanism 15 are adjusted to be sufficient to compress the seal 10 until the spacer element 40 contacts the tissue support 34, thereby preventing excessive pressure from further compressing the seal or altering the height of the reaction chamber due to the rigid spacer element. The spacer element also advantageously ensures that the observation window 12 remains parallel to the tissue support 34 and does not tilt relative to the tissue support 34.

[0063] The observation window 12 comprises a transparent cover 33 having a thickness of less than 1 mm, preferably less than 0.5 mm, for example about 0.2 mm (e.g., 0.17 mm). The transparent cover 33 may be advantageously made of glass or sapphire. The transparent cover 33 may be formed separately from the substrate 6 and assembled with the substrate 6 by adhesive bonding, welding, or overmolding with the material of the substrate 6. The observation window 12 comprises a recess relating to the outer surface of the substrate 6, which, as described later, allows a microscope lens to be partially inserted into the observation window recess so as to be very close to the surface of the transparent cover 33 and the tissue sample beneath the transparent cover 33.

[0064] The substrate 6 may be advantageously formed from a molded polymer, such as an injection-molded polymer, which may be transparent or opaque, such as COP, COC, PC, PSU, and PEEK.

[0065] Given that the reaction chamber height is in the range of 0.05 mm to 0.5 mm, the thin transparent cover 33 and the recess of the observation window 12 can be positioned so that the observation surface 41 of the microscope lens 14 is at a distance of less than 1 mm, particularly less than 0.5 mm, from the reaction chamber 29, so that the distance from the tissue sample to the microscope lens is typically less than 1 mm. The height of the spacer element is advantageously in the range of 0.05 mm to 0.3 mm, preferably in the range of 0.05 mm to 0.2 mm, in order to have optimal flow of reagents through the reaction chamber and advection transport of reagents to the tissue support.

[0066] Therefore, a wide surface area of ​​the tissue sample, for example 80 mm, can be imaged through a series of imaging steps. 2 From 120mm 2 The range is typically 80mm. 2 From 100mm 2 To capture the range, a microscope lens with a high numerical aperture may be used, such as 50mm. 2This enables good image capture and analysis of tissue sample sections exceeding a certain size. Advantageously, a very thin, transparent cover, which can be made of materials such as glass, reduces artifacts and aberrations in the image captured by the microscope lens 14 for high-performance sample analysis.

[0067] Multiple sample processing units mounted on the handling platform advantageously allow for simultaneous image capture and analysis of other samples positioned under the microscope while processing tissue samples with reagents, particularly during multiplex analysis, thereby increasing the speed of sample analysis.

[0068] For example, each of the multiple sample processing units 7 may be at a different stage of the multiplex process, in other words, have different reagents, and the sample processing units are advanced sequentially to the lens of the imaging unit. Also, loading and unloading of tissue samples 36 may be performed on one sample processing unit 7, while other sample processing units 7 are being analyzed by the imaging unit 2 or are injecting reagents into the reaction chamber for later analysis.

[0069] Multiple sample processing units are provided on a common handling platform 5, preferably comprising three or more sample processing units, and preferably four or more sample processing units.

[0070] It should be noted that, for the analysis of biopsy tissue samples, tissue samples from the same patient may be distributed onto multiple tissue slides located in various corresponding sample processing units 7, so that various different reagents and analyses can be performed on the tissue samples simultaneously. Alternatively, the same reagents and analyses may be performed to provide multiple test results that can be compared to enhance the reliability of the diagnosis. Alternatively, multiple sample stations may also be used to analyze different tissue samples from the same patient or different patients.

[0071] List of reference codes used Biological sample processing system 1 Imaging Unit 2 microscope Lens 14 Observation surface 41 Image processing system Sample processing station 3 Handling Platform 5 Support 17 Displacement mechanism (not shown) Sample processing unit 7 Microfluidic cartridge holder 9 (lid) Observation window 19 Chamfered recess 43 Organization-side holder 11 Base Joint 13 Hinge Clamping mechanism 15 Locking mechanism 16 Lock pin Pressure actuator 18 piston Compressed air piston Reagent fluid flow system Inflow conduit 20 Outflow conduit 22 Temperature control system 24 Cooling / heating system Peltier chip 41 Temperature sensor (not shown) Microfluidic cartridge 4 Circuit board 6 Fluid flow network 8 Cartridge inlet 26 Inflow channels 27 Chamber inlet hole 28 Reaction chamber 29 Chamber outlet hole 30 Leakage Channel 31 Cartridge outlet section 32 10 stickers Observation window 12 Transparent cover 33 glass layer Spacer element 40 tissue support 34 Tissue sample 36 External reagent source Reagent tubes Thickness of the transparent cover: T

Claims

1. An imaging unit (2) comprising a digital image processing system and at least one microscope including at least one lens (14), A sample processing station (3) includes a handling platform (5) which includes a support (17) and a displacement mechanism for moving the support (17), A sample processing unit (7) is attached to the handling platform (5), A biological sample processing system comprising, The sample processing unit (7) comprises a tissue holder (11), which is configured such that a tissue support (34) on which a biological sample (36) is fixed is mounted on the tissue holder (11), and a microfluidic cartridge holder (9), which is configured such that a microfluidic cartridge (4) is mounted on the microfluidic cartridge holder (9). The tissue holder (11) is connected to the microfluidic cartridge holder (9) via a coupling portion (13), thereby enabling the microfluidic cartridge and the tissue support (34) to be attached to and removed from the sample processing unit in the open position, and enabling the tissue support (34) to be in sealed contact with the microfluidic cartridge (4) in the closed position. The sample processing station comprises a plurality of sample processing units mounted on the handling platform (5), each of the plurality of sample processing units being movable by moving the support (17) by the displacement mechanism, from a position that allows for the attachment or removal of the tissue support (34) and the microfluidic cartridge, to a position in which the observation window (19) of the microfluidic cartridge holder (9) is aligned with the lens of at least one of the microscopes. The microfluidic cartridge holder (9) comprises an inlet and an outlet, Each of the microfluidic cartridge holders (9) is connected to at least one reagent supply tube via the inlet and to at least one reagent outlet tube via the outlet, so that when the microfluidic cartridge is mounted in the closed position to guide the flow of the reagent to the microfluidic cartridge, the inlet and outlet of the microfluidic cartridge holder are aligned with the inlet and outlet of the microfluidic cartridge. A biological sample processing system characterized by the following features.

2. The biological sample processing system according to claim 1, wherein the observation window (19) of the microfluidic cartridge holder is provided with a recess (43), and the lens (14) is partially inserted into the recess (43) at the imaging position.

3. The biological sample processing system according to claim 1 or 2, wherein the sample processing station (3) comprises at least three sample processing units (7).

4. The biological sample processing system according to any one of claims 1 to 3, wherein the handling platform (5) includes a rotational displacement mechanism for rotating the support (17) between multiple positions.

5. A biological sample processing system according to any one of claims 1 to 4, wherein each of the sample processing units comprises a clamping mechanism (15) including a locking mechanism (16) and a pressure actuator (18) configured to apply pressure to the tissue support (34) relative to the microfluidic cartridge (4) in the closed position, and the clamping mechanism comprises a compressed gas piston.

6. The biological sample processing system according to any one of claims 1 to 5, wherein each of the sample processing units comprises a temperature control system including a cooling / heating system coupled to the tissue holder (11).

7. The biological sample processing system according to any one of claims 1 to 6, wherein the microfluidic cartridge holder (9) and the tissue holder (11) are pivotably connected together via a hinge joint (13).

8. The biological sample processing system according to any one of claims 1 to 7, wherein the microfluidic cartridge holder is in the form of a movable lid, and the tissue holder (11) is in the form of a base statically fixed to the support (17) of the handling platform (5).

9. Circuit board (6) and A fluid flow network (8) formed within the substrate (6), The seal (10) attached to the aforementioned substrate, The cavity (29a) of the reaction chamber (29) formed within the substrate, Observation window (12), A microfluidic cartridge for a biological sample processing system (1) comprising, The microfluidic cartridge is positioned in contact with the tissue support (34), covering the cavity and forming the side of the reaction chamber (29). Therefore, the reaction chamber is formed between the tissue support and the microfluidic cartridge. The fluid flow network comprises an inlet (26) connected to the reagent fluid flow system of the biological sample processing system (1), an inlet channel network (27), and a plurality of chamber inlet holes (28). The fluid flow network further comprises an outlet section (32) for discharging reagents from the reaction chamber (29), an outlet channel network (31), and a plurality of chamber outlet holes (30). The chamber inlet and the chamber outlet are located on both sides of the cavity of the reaction chamber to allow the flow of reagents through the reaction chamber. The seal (10) surrounds the cavity of the reaction chamber (29), the chamber inlet hole (28), and the chamber outlet hole (30). The observation window (12) is provided with a transparent cover that is less than 1 mm thick and has its outer surface within a recess formed in the substrate (6) of the observation window (12) with respect to the outer surface of the substrate (6), and the observation window (12) is configured such that a microscope lens (14) can be partially inserted into the recess of the observation window. The system further includes a rigid spacer element (40) that defines the height of the reaction chamber (29) when the tissue support (34) is installed and pressed against the reaction chamber (29). Microfluidic cartridge.

10. The microfluidic cartridge according to claim 9, wherein the transparent cover (33) is made of glass or sapphire.

11. The microfluidic cartridge according to claim 10, wherein the transparent cover has a thickness of less than 0.5 mm.

12. The microfluidic cartridge according to claim 11, wherein the rigid spacer element (40) is positioned outside the seal (10) relative to the reaction chamber (29).

13. A biological sample processing system (1) according to any one of claims 1 to 8, further comprising a microfluidic cartridge according to any one of claims 10 to 12.

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