EA043294B1 - DEVICE FOR BIOCHEMICAL ANALYSIS - Google Patents

Description

The present invention relates to a device for biochemical analysis.

Biochemical analysis is an analysis method used, among other things, in laboratory medicine, pharmacology, environmental biology, or molecular biology to qualitatively or quantitatively measure the presence, amount, or functional activity of a biochemical analyte in a sample.

Although biochemical assays are many and varied, the steps of analysis are typically (a) sample preparation and manipulation to selectively present the analyte to the detection system in a measurable form, (b) identify the analyte in the sample by a specific trait, (c) convert the presence or amount of the analyte to a detected signal; and (d) detecting the detected signal and determining an association of the detected signal with an interpretable feature, which may be quantitative or qualitative.

To carry out these steps, the analytical device typically contains means for sample preparation and means for detection (for example, a reader). An example of an immunoassay device is described in GB-A-2521885.

The present invention is intended to improve the performance of biochemical analysis by integrating sample preparation with a detection device. More specifically, the present invention relates to an apparatus in which a sample preparation apparatus is controlled by a detection apparatus through a series of linear and/or rotational drives to perform a biochemical analysis of a biological fluid sample.

Thus, in one aspect, the present invention relates to a device for biochemical analysis for analyzing a sample of a biological fluid, containing a device for detection, containing a housing;

a movable platform in the housing selectively movable to a plurality of positions;

a linear actuator mounted in a housing above the movable platform and driven along a linear axis;

a sample preparation device installed or installed on a movable platform in a housing, containing a collector;

a compartmented housing mounted on the manifold and capable of accommodating a biological fluid sample into an elongated fluid compartment, where the compartmented housing has a valve compartment, a tripod compartment, and an elongated air chamber sealed by an air plunger;

rack for elongated vessels installed in a rack compartment in a raised non-deployed position or in a non-raised deployed position, where each elongated vessel defines a fluid chamber sealed by a fluid plunger, where the elongated vessel rack can be moved from a raised non-deployed position to a non-raised deployed position a position for fluid connection of the elongated vessels to the manifold;

an antibody matrix positioned below the bottom of the manifold such that the manifold can selectively fluidly couple each elongated antibody matrix vessel; and a matrix valve having a closed position to isolate the elongated vessels from the antibody array and an open position to allow fluid connection of the elongated vessels to the antibody array via a manifold, where, if the elongate vessel rack is in a non-raised deployed position, the movable platform is moved sequentially to selected positions among the plurality of positions, where in the initial position among the plurality of positions, the linear actuator is essentially coaxial with respect to the elongated air chamber, while driving by the linear actuator results in pressure on the air plunger, which forces air out of the elongated air chamber enter the elongated fluid compartment and flush the biological fluid sample into the first fluid chamber of the first elongated vessel of the elongated vessel rack, containing the first diluent reagent, to obtain a diluted biological fluid sample, where in the first position among the plurality of positions, the linear actuator is , substantially coaxial with respect to the first fluid chamber of the first elongate vessel, whereby linear actuator actuation causes the fluid plunger of the first elongate vessel to be depressed, causing the diluted biological fluid sample to flow into the antibody matrix through the manifold, where in a second position, among a plurality of positions, the linear actuator is substantially coaxial with respect to the second fluid chamber of the second elongate vessel of the elongate vessel rack, wherein actuation by the linear actuator results in depression of the fluid plunger of the second elongated vessel, causing the flush reagent to enter the antibody matrix through the manifold, and wherein, at a third position among the plurality of positions, the linear actuator is substantially coaxial with respect to the third fluid chamber of the third elongated vessel from the elongated vessel rack, wherein the actuation movement by means of a linear actuator causes the fluid plunger of the third elongated vessel to be depressed, which forces the label reagent to flow into the antibody matrix through the manifold.

In a preferred embodiment, the movable platform is a rotary platform selectively rotated to a plurality of rotational positions. The linear axis of the linear actuator may be substantially parallel and spaced from the axis of rotation of the rotary platform.

In a preferred embodiment, the movable platform is an xy-platform selectively movable in a plurality of positions in the xy-plane. The linear axis of the linear actuator may be substantially parallel to the z-axis of the x-y platform.

Preferably, in a fourth position among the plurality of positions, the linear actuator is substantially coaxial with respect to the fourth fluid chamber of the fourth elongated vessel of the elongated vessel rack, whereby actuation by the linear actuator results in depression of the fluid plunger of the fourth elongated vessel , which causes additional wash reagent to flow into the antibody matrix through the manifold.

The biochemical analysis device of the invention preferably facilitates bedside diagnosis.

The matrix valve may be a fluid pressure valve that opens when a fluid pressure threshold is reached, or an umbrella valve. The umbrella valve may be located at or near the inlet of the antibody array.

Preferably, the matrix valve is an actuated matrix valve installed in the valve compartment. Typically, an actuated matrix valve includes a valve plug.

In a particularly preferred embodiment, if the elongate vessel stand is in a non-raised deployed position, the movable platform may further be moved to a valved position among a plurality of positions where, in the valved position, the linear actuator is substantially coaxial with respect to the valve compartment, with the actuation in the linear actuator movement allows the actuated matrix valve to be moved to an open position to effect fluid communication between the elongated vessels and the antibody array through the manifold.

The actuated matrix valve may include a valve spindle, a valve cap, and a valve plunger. The valve stem may be part of a manifold and comprise a substantially central channel with a trough that terminates substantially midway through the length of the central channel. The outlet channel may be substantially parallel to the central channel. The valve plug can seal the center passage above the trough. The valve plug may be reinforced so that it can be pushed down by the valve cover to the location of the trough.

The valve cover may include a lip-type seal that seals the valve spindle around the circumference and a pusher that moves the valve plunger. If the matrix valve is closed, the valve cover and valve plug may be in the raised position if the center passage is blocked. The actuated matrix valve is open if the linear actuator moves the valve cover, which moves the valve plug into the center port. This allows fluid connection with the outlet port. The outlet port is used to fluidly connect the collector to the antibody matrix.

Preferably, the antibody array is sealed under the bottom of the collector. The antibody array can be sealed to the manifold mechanically (eg, with a luer-type connector or flare) or by bonding (eg, laser welding or adhesive bonding).

Preferably, the antibody matrix includes one or more channels defining a continuous fluid path between the matrix inlet and the matrix outlet, where the antibodies are attached to the walls and/or bottom of the channel. The matrix cover can be installed on the base of the antibody array (for example, by means of fasteners or a connection such as laser welding or adhesive bonding) to seal the channel and prevent leakage.

In a preferred embodiment, protrusions (eg, ribs or pins) are provided on the walls or bottom of the channel. They are designed to increase the surface area exposed to the biological fluid sample. It is particularly preferred to space the protrusions apart (eg randomly or non-randomly). By placing the protrusions at a distance, it is possible to disrupt the fluid flow to stimulate the interaction between the analyte (for example,

- 2 043294 target pathogen) in a biological fluid sample and antibodies on the walls or bottom of the fluid channel.

The fluid channel may have a constant cross section. The fluid channel may have a rectangular or oval cross section.

The fluid path may be tortuous. Preferably the fluid path is a helical or zigzag fluid path.

Preferably, liquid is diverted through the die outlet to a waste chamber in the manifold (eg, in a peripheral region of the manifold). A hydrophobic frit or vent can be included in the top of the waste chamber to relieve air pressure.

The antibody matrix may contain a control zone on which the ligand is immobilized to capture the probe, and the first main surface on which two or more test zones are defined, where the first test zone contains the first pathogen-specific antibody immobilized thereon, adapted to bind to the first target to be captured. on the first pathogen or marker, where the second test zone contains a second pathogen-specific antibody immobilized thereon, adapted to bind to a second captured target on the second pathogen or marker.

The casing may have a partial cover. For example, the lid may have an arcuate opening. The stand for elongated vessels can be inserted through the arcuate opening. The extended air chamber and valve compartment can be accessed through openings in the cover.

The casing can be movably mounted on the collector (for example, the outer part of the collector).

Preferably, the manifold includes a fluid circuit that can fluidly connect each of the elongated antibody array vessels.

Preferably, the elongated vessel stand comprises a plurality of substantially cylindrical vessels spaced apart and connected at their thinner portions by a ring. Typically, an elongated vessel stand comprises four elongated vessels defining a first chamber, a second chamber, a third chamber, and a fourth chamber, respectively. The ring may be an arcuate or box-shaped ring.

In the raised, non-deployed position, the elongated vessel rack is placed in the rack compartment and each elongated vessel is aligned and spaced from a bell or needle protruding from the bottom of the manifold. The elongated vessel stand may be lowered to a non-raised deployed position such that a bell or needle penetrates the lower end of the elongated vessel.

In the non-raised deployed position, the elongated vessel stand is held vertically by the shroud. The Elongated Vessel Rack can be held vertically with a clamp attached to the outer surface of the Elongated Vessel Rack. Alternatively, the elongate vessel rack may be held vertically by locking to the manifold.

Each elongated vessel can be equipped with a stopper, syringe tip or a fragile element (eg foil or film) at the lower end.

Preferably, each elongated vessel is equipped with a stopper at the lower end. When the elongate vessel rack is moved to the non-raised deployed position, the bell displaces the plug, opening a fluid path between the elongate vessel and the manifold (eg, fluid circuits). The plug can be forced into the lower part of the elongated vessel. It is possible to make a feature (eg, a groove or barbs) on the top surface of the bell to prevent blocking the fluid path between the elongate vessel and the manifold (eg, fluid circuits) with a plug.

The biological fluid sample may be placed in the fluid compartment of the vacutainer. The vacutainer can be inserted into the sample preparation device through the vacutainer opening in the housing (eg the lid).

Alternatively, a sample vessel having a lid may be sealed to a manifold to form a fluid compartment. The user may place a sample of the biological fluid into the sample container.

In a preferred embodiment, the collector contains the first and second hollow needle protruding from its bottom. The first and second needles may substantially coincide with the major axis (eg, z-axis or rotational axis) of the sample preparation device. The first and second needles can be adapted to pierce a vacutainer (eg, a diaphragm of the vacutainer). The first needle may be in fluid communication with the first chamber. The second needle may be in fluid communication with the air chamber. The second needle may be positioned at a different height relative to the first needle to prevent bypassing air from the air chamber directly into the first needle.

In an alternative preferred embodiment, a first fluid port and a second fluid port are included in the manifold (eg, fluid circuit). The first and second fluid ports can be positioned at different heights to prevent air from the air chamber from moving directly between them.

If the linear actuator causes the air plunger to be depressed, the air from the air chamber

- 3 043294 can penetrate into the fluid compartment through the second needle and wash the sample of biological fluid into the first chamber through the first needle and the channel into the socket. The air plunger may be non-retractable. For example, the air plunger may be connected to a retainer securing the air plunger at the bottom of the plunger stroke. Alternatively, a one-way valve, such as a duckbill valve, pilot dome valve, or similar valve, may be included in the air chamber to prevent fluid from flowing back into the air chamber.

The fluid plunger in the first chamber may initially be positioned substantially in the middle of the plunger stroke. The first chamber may include a height stop to stop the fluid plunger at the top of the plunger stroke. This prevents the fluid plunger from exiting the first chamber.

The fluid plunger in each of the second, third and fourth chambers may initially be positioned substantially at the top of the plunger stroke. Each of the second, third, and fourth chambers may include an internal latch to stop the fluid plunger at the top of the plunger stroke. This prevents the body fluid sample from entering the second, third and fourth chambers.

Each of the first, second, third, and fourth chambers may include an internal latch that locks the fluid plunger at the bottom of the plunger stroke. This prevents the plunger from retracting.

The detection device can be equipped with a power cable and connectors (for example, USB connectors) for connecting to peripherals. Peripherals may include a barcode scanner, printer, and LAN. The detection device may include optical or proximity sensors to confirm the presence of the sample preparation device and an external touch screen serving as a user interface.

The detection device may include a door to close the housing.

The detection device may include a drive that moves the movable platform.

In a preferred embodiment, the air chamber, valve compartment, and first, second, third, and fourth chambers define a pitch circle with a substantially common diameter. If the sample preparation device is mounted on a rotary platform, the pitch circle is intersected by the linear axis of the linear actuator such that, when the sample preparation device rotates, the air plunger, valve plunger, and fluid plunger of each of the first, second, third, and fourth chambers substantially , aligned under the linear actuator.

In a preferred embodiment, the air chamber, valve compartment, and first, second, third, and fourth chambers define a rectangular matrix. If the sample preparation device is mounted on an x-y platform, the rectangular matrix is traversed by the linear axis of the linear actuator so that when the sample preparation device moves, the air plunger, valve plunger, and fluid plunger of each of the first, second, third, and fourth chambers are essentially aligned under the linear actuator.

The linear actuator and movable platform may include position sensors to coordinate actuation of the fluid plungers, air plungers, or valve plunger at each of a plurality of positions.

Typically, the optical module is located at the base of the detection device. The optical module may be a fluorescent imaging device, or a thermal imager, or a laser that allows visualization of the bottom surface of the antibody array. The optical module can be adapted to visualize magnetic marks.

The analyte may be a cellular analyte (such as a microorganism, bacteria, fungus, or virus), a single-celled protozoan, eukaryotic cells of human or non-human origin (eg, human cancer cells), or organic or inorganic molecules.

Antibodies can be adapted to selectively bind to a target molecule in an analyte. The antibodies may be immunoglobulins, affimers or aptamers.

In a further aspect, the present invention relates to a sample preparation apparatus as defined above.

In another additional aspect, the present invention relates to a device for detection, as defined above.

The present invention will now be described in a non-limiting sense with reference to the accompanying figures, in which FIG. 1 shows an embodiment of a biochemical assay device according to the invention;

in fig. 2a and 2c show the sample preparation apparatus of the embodiment shown in FIG. 1 disassembled and assembled, respectively;

in fig. 2b-1 and 2b-2 are cross-sectional views of the sample preparation apparatus shown in FIG. 2s before and after deploying the vessel rack, respectively, and before placing the vakutei in it

- 4 043294 nera;

in fig. 3a shows a cross section of the sample preparation device shown in FIG. 2s after placing the vacutainer in it;

in fig. 3b shows a cross-sectional view of an alternative embodiment of a sample preparation apparatus;

in fig. 4a and 4b show an under-bottom view of the collector of the sample preparation apparatus shown in FIG. 3a and 3b, respectively;

in fig. 4c shows the antibody array of the sample preparation device shown in FIG. 2c, dismantled from under the bottom of the collector;

in fig. 5a and 5b show a cross-section of the valve of the sample preparation device shown in FIG. 2c, in the closed (non-activated) and open (activated) positions, respectively;

in fig. 6a and 6b show an embodiment of the biochemical analysis device before and after closing the door of the detection device;

in fig. 6c and 6d show a cross section of an embodiment of a biochemical assay device;

in fig. 7a-c show various embodiments of the sample preparation apparatus;

in fig. 8 schematically shows a test carried out using a biochemical assay device according to the invention;

in fig. 9 is a cross-sectional view of an alternative embodiment of the biochemical assay device of the invention;

in fig. 10 shows the sample preparation apparatus of the embodiment shown in FIG. 9, disassembled; and in FIG. 11 shows the antibody array of the sample preparation device shown in FIG. 10.

In FIG. 1 shows an embodiment of a biochemical assay device according to the invention, typically comprising a detection device (1) and a sample preparation device (2), controlled by the detection device (1) through a series of linear and rotational drives, to carry out biochemical analysis of a biological fluid sample.

The sample preparation device (2) is disposable and ready to use, containing liquid reagents (for example, functionalized elements, buffers and labels) necessary for performing a biochemical analysis of a biological fluid sample. In FIG. 2a shows that the sample preparation device (2) comprises a casing (7) and a vessel rack (3) fixed vertically in the casing compartment (7).

The support for vessels (3) contains four essentially cylindrical vessels (3a) located at a distance from each other and connected in their thinned parts by an arcuate ring (333). Each vessel (3a) is equipped with a stopper (4) at its lower end and a fluid plunger (5) at its head end. As shown in FIG. 2c, four vessels (3a) define, respectively, a first chamber (19) for the dilution buffer, a second chamber (21) for the first wash buffer, a third chamber (22) for the label, and a fourth chamber (23) for the second wash buffer. The vessel stand (3) is inserted through the appropriately shaped arcuate hole (113) in the cover (77) of the casing (7).

The casing (7) is movably mounted on the outer part of the collector (6). The manifold (6) contains a fluid circulation circuit (32) that can be used to fluidly connect the first, second, third and fourth chambers (19, 21, 22 and 23) to the antibody matrix (27) sealed under the bottom of the manifold. (6). The fluid circulation circuit (32) is sealed against the chambers (19, 21, 22 and 23) of the vessels (3a) until transport to the place of use, where it is selectively subjected to fluid connection with each vessel (3a), as described in the present description below. The casing (7) additionally defines an air chamber (17) and a valve compartment (24) for the matrix valve (26). The air chamber (17) and the valve compartment (24) are accessible, respectively, through openings (17a, 24a) in the cover (77) of the housing (7). The air chamber (17) is sealed by an air plunger (18).

The matrix inlet (28) in the antibody matrix (27) is generally isolated from the fluid circuit (32) by a matrix valve (26) above the matrix inlet (28) (see Figs. 4a and 4c). The antibody matrix (27) contains a spiral channel (90) that creates a continuous fluid path between the matrix inlet (28) and the matrix outlet (29), from where the liquid is discharged into the waste chamber (30) in the peripheral region of the collector (6). Antibodies are attached to the walls of the channel (90). The ribs (31) at the bottom of the channel (90) are designed to increase the surface area exposed to the liquid and disrupt the flow of the liquid to stimulate the interaction of analytes (eg, pathogens) with antibodies attached to the walls. The antibody array (27) is sealed to the manifold (6) by mechanical means such as luer-type connectors or flares, or by laser welding or adhesive bonding. The matrix cover (191) is installed on the base of the antibody array (27) by laser welding or adhesive bonding to seal the channel (90) and prevent leakage. Path length and transverse area

- 5 043294 channel section (90) is minimized to reduce dead volumes.

In FIG. 2b-1 shows a cross section of the sample preparation device (2) with the vessel rack (3) inserted through the appropriately shaped hole (113) in the lid (77) in the raised (non-deployed) position before deployment. In this raised (non-deployed) position, the vessel rack (3) is installed in the rack compartment of the housing (7) and each vessel (3a) is aligned and positioned at a distance from the socket (8) protruding from the bottom of the manifold (6). At the point of use, the vessel stand (3) is lowered to the unraised (unfolded) position in such a way that the socket (8) penetrates into the lower end of the vessel (3a) (see Fig. 2b-2). In the non-raised (unfolded) position, the vessel rack (3) is fixed with the help of a casing (7). The bell (8) displaces the plug (4), opening a fluid path between the vessel (3a) and the fluid circuit (32). The plug (4) is forced into the bottom of the vessel (3a). The groove on the top surface of the bell (8) is designed to prevent the plug (4) from blocking the fluid path between the vessel (3a) and the fluid circuit (32).

In FIG. 3a shows a cross section of the sample preparation device (2) shown in FIG. 2c, in a sealed state after placing a standard vacutainer (12) into it. The vacutainer (12) containing the biological fluid sample is placed into the sample preparation device (2) through the vacutainer opening (12a) in the lid (77). The collector (6) contains the first and second hollow needles (10, 11) protruding from the bottom and essentially coinciding with the main axis of rotation of the device for sample preparation (2). The first and second needles (10, 11) are adapted to pierce the diaphragm of the vacutainer (12). The first needle (10) is in fluid communication with the first chamber (19). The second needle (11) is in fluid communication with the air chamber (17). The second needle (11) is positioned at a different height relative to the first needle (10) to prevent air bypassing from the air chamber (17) directly into the first needle (10).

In FIG. 3b shows a cross section of an alternative embodiment of the sample preparation device (2a). In this embodiment, the fluid circuit (32) includes a pair of fluid ports (14) instead of needles. The fluid holes (14) are positioned at a different height to prevent air from the air chamber (17) from entering directly between them. The sample container (15) containing the lid (16) is sealed to the manifold (6) and the user can place a biological fluid sample into it.

When the air plunger (18) is driven (as described herein below), the air from the air chamber (17) is forced into the vacutainer (12) through the second needle (11) (or into the sample vessel (15) through one of the holes (14) for fluid in an alternative embodiment) and flushes the biological fluid sample into the first chamber (19) containing the dilution buffer through the first needle (10) and the narrow bore in the bell (8). The air plunger (18) is connected to a retainer (20) that secures the air plunger (18) at the bottom of the plunger stroke so that it is pulled out by fluid pressure.

In the first chamber (19), the fluid plunger (5) is initially in the middle of the plunger stroke and moves to increase the volume to accommodate the dilution buffer and the biological fluid sample. The action of the biological fluid sample entering the first chamber (19) through the narrow channel in the bell (8) and expanding the volume in the first chamber (19) causes efficient mixing of the biological fluid sample and the dilution buffer. The height stop (66) prevents the fluid plunger (5) from penetrating into the first chamber (19). The biological fluid sample cannot enter the second, third and fourth chambers (21, 22 and 23) due to the internal lock (33) preventing the respective fluid plungers (5) from moving beyond the full stroke of the plunger.

The valve compartment (24) in the housing (7) contains the matrix valve (26) shown in FIG. 5a and 5b in the closed and open states, respectively. Matrix valve (26) contains valve stem (50), valve cover (51) and valve plunger (52). The valve stem (50) is part of the manifold (6) and contains a central channel (53) with a groove (54) terminating at the middle of the length of the central channel (53). The outlet channel (55) is parallel to the central channel (53). The valve plug (52) seals in the central passage (53) above the trough (54) and is reinforced so that it can be pushed by the valve cover (51) down to the location of the trough (54). The valve cover (51) includes a lip seal (56) sealing the valve stem (50) around the circumference, and a plunger (57) driving the valve plunger (52). When the matrix valve (26) is closed (see Fig. 5a), the valve cap (51) and valve plug (52) are in the raised position when the central port (53) is blocked and no liquid can flow into the outlet port (55) . The matrix valve (26) is opened by actuating the valve cap (51) (as described herein below) forcing the valve plunger (52) into the center port (53) and allowing fluid connection to the outlet port (55). The outlet channel (55) is used to fluidly connect the fluid circulation circuit (32) to the inlet of the matrix (28).

When the matrix valve (26) is open, the fluid circuit (32) in the manifold (6) can selectively connect the chambers (19, 21, 22 and 23) to the antibody matrix (27) (see FIGS. 4a-4c). sleep

The fluid plunger (5) in the first chamber (19) is driven at a controlled rate (as described below) and the diluted sample is evacuated into the fluid circuit (32). The diluted sample is then fed through the matrix valve (26) through the matrix inlet (28) into the antibody matrix (27). Fluid leaves the antibody array (27) through the matrix outlet (29) and is discharged into the waste chamber (30). When the fluid plunger (5) in the first chamber (19) reaches the bottom of the plunger stroke, the internal retainer (34) secures the fluid plunger (5) in place so that it cannot be pulled out by fluid pressure.

The fluid plunger (5) in the second chamber (21) is then driven at a controlled rate (as described herein below) to pass the first wash buffer over the antibody array (27) into the waste chamber (30). The fluid plunger (5) in the second chamber (21) is secured at the bottom of the plunger stroke with an internal retainer (34). The fluid plunger (5) in the third chamber (22) is then driven at a controlled rate (as described herein below) to pass the label over the antibody array (27) into the waste chamber (30). The fluid plunger (5) in the third chamber (22) is secured at the bottom of the plunger stroke with an internal retainer (34). The fluid plunger (5) in the fourth chamber (23) is then driven at a controlled rate (as described herein below) to pass the second wash buffer over the antibody array (27) into the waste chamber (30). The fluid plunger (5) for the fourth chamber (23) is secured at the bottom of the plunger stroke with an internal retainer (34).

The detection device (1) is equipped with a power cable and connectors (for example, USB connectors) for connection with the peripherals necessary for the operation of the device (for example, a barcode scanner, a printer and a local network). The LED indicator (660) on the front of the detection device (1) displays a color indication of the device status, such as ready for operation (green), busy (yellow), test completed (blue), error (red) or off (no light) . The detection device (1) includes optical sensors, proximity sensors or other sensors to confirm the presence of the sample preparation device (2). The barcode on the outer surface of the detection device (1) is read using the barcode scanner in the detection device (1) to confirm the shelf life and test type. The detection device (1) includes an external touch screen (60) serving as a user interface during setup and displaying prompt instructions, error messages and test results.

As shown in FIG. 6a, the detection device (1) includes a housing (67) containing a sample preparation device (2) with an extended vessel rack (3) and a lowered vacutainer (12). The door (61) closes the housing (67) during the test (see Fig. 6b) to prevent the user from interfering with the sample preparation device (2) and to protect the optics from ambient light.

The detection device (1) includes a rotary actuator (62) driving a rotary platform (63) mechanically connected to the sample preparation device (2) located in the housing (67) (see Figs. 6c and 6d). The rotary actuator (62) rotates the rotary platform (63) and the sample preparation device (2) to predetermined rotational positions to enable the successive driving steps described above of the air plunger (18), the valve plunger (52), and each plunger. (5) for fluid. In this regard, the air chamber (17), the valve compartment (24) and the first, second, third and fourth chambers (19, 21, 22 and 23) define a starting circle with a common diameter in such a way that when the sample preparation device (2) rotates ) the air plunger (18), valve plunger (52) and fluid plunger (5) of each of the first, second, third and fourth chambers (19, 21, 22 and 23) are aligned under the linear actuator (64). The linear actuator (64) and rotary platform (63) include position sensors allowing them to function together to drive the fluid plungers (5), air plunger (18), or valve plunger (52) in each of predetermined rotational positions.

At the base of the detection device (1) is an optical module (65), which is a fluorescent optical system that allows visualization of the lower surface of the antibody matrix (27). The components of the optical module (65) are mounted on the linear platform (66) in such a way that the entire area of the antibody array (27) can be visualized by rotating the sample preparation device (2).

In FIG. 7a-c show alternative embodiments of the sample preparation device (2) differing in height to allow sample volumes to be reduced without affecting operations. Fig. 7a corresponds to FIG. 3c, and a vacutainer (12) is used on it to test (for example) 10 ml of whole blood. In FIG. 7b shows a small volume sample preparation device (2a) suitable for testing (eg) 0.5 ml of neonatal blood or 0.1 ml of cerebrospinal fluid. In FIG. 7c shows a large volume sample preparation device (2b) suitable for testing (eg) 10 ml of urine.

In FIG. 8 shows schematically the steps involved in performing a biochemical analysis of a biological fluid sample in the biochemical analysis device of the invention. Liquid reagents and the required volumes are given in table. 1. The duration of the test is usually in the range from 3 minutes to 6 hours.

Table 1

Liquid Reagent Expected minimum volume Expected maximum volume dilution buffer 0.1 ml 20 ml Wash Buffer #1 0.1 ml 20 ml Label 0.1 ml 20 ml Wash Buffer #2 0.1 ml 20 ml Biological sample 0.1 ml 20 ml liquids

In FIG. 9 is a cross-sectional view of an alternative embodiment of the biochemical assay device of the invention, typically designated by reference number (90). The device for biochemical analysis (90) contains a device for detection (91), including a housing in which the device for sample preparation (99) is located. The door (94) covers the housing during the test to prevent the user from interfering with the sample preparation device (99) and to protect the optics from ambient light. The sample preparation device (99) is controlled by the detection device (91) through a series of linear drives to perform a biochemical analysis of the biological fluid sample.

Sample preparation device (99) according to the embodiment shown in FIG. 9 is shown exploded in FIG. 10. The sample preparation device (99) is disposable and ready to use, containing liquid reagents (eg, functionalized elements, buffers, and labels) necessary to perform a biochemical analysis of a biological fluid sample. The sample preparation device (99) includes a casing (101) and a holder for vessels (103), which is vertically fixed in the tripod compartment of the casing (101).

The vessel holder (103) acts as a box ring for four spaced, substantially cylindrical syringe vessels (104), together forming a vessel rack. Each syringe barrel (104) is installed in the vessel holder (103) by means of an adhesive or mechanical connection (eg, threaded, push-in or snap-on connection). Each syringe barrel (104) is equipped with a syringe tip (164) at its lower end and a non-return plunger (105) at its head end. The four syringe barrels (104) define, respectively, a first chamber for the dilution buffer, a second chamber for the first wash buffer, a third chamber for the mark, and a fourth chamber for the second wash buffer.

The casing (101) is connected to the collector (117) through its base (107). The manifold (117) contains a fluid circuit that can fluidly connect the first, second, third, and fourth chambers to the antibody matrix (127) (see FIG. 11) sealed below the bottom of the manifold (117). The fluid circulation circuit is sealed from the chambers of the syringe barrels (104) prior to transport to the point of use, where it is selectively subjected to fluid communication with each syringe barrel (104). The housing (101) further defines an air chamber (221) sealed by an air plunger (222) and a valve compartment for the matrix valve. The air chamber (221) and the valve compartment are respectively accessible through openings in the casing cover (101). The air chamber (221) is installed on the base (107) by adhesive bonding or laser welding.

The matrix inlet (280) in the antibody matrix (127) is typically isolated from the fluid circuit by a matrix valve above the matrix inlet (280). The antibody matrix (127) contains a zigzag channel (240) that creates a continuous fluid path between the matrix inlet (280) and the matrix outlet (290), from where the liquid is discharged into the waste chamber (150) in the peripheral region of the collector (117). Antibodies are attached to the walls of the channel (240). The matrix cover (191) is placed on the base of the antibody matrix (127).

The detection device (91) includes a movable platform (98) mechanically connected to the sample preparation device (99) located in the housing. The movable platform (98) and the sample preparation device (99) are moved to predetermined positions in the x-y plane, which allows successive stages of driving the air plunger (222), the valve plunger (147) and each non-return plunger (105). As the sample preparation device (99) moves, the air plunger (222), valve plunger (147), and non-return plunger (105) of each of the first, second, third, and fourth chambers are aligned under the linear actuator (911) on the actuator frame (910). Linear actuator (911) and movable platform (98) include encoders allowing them to function together to drive non-return plungers (105), air plunger (222)

- 8 043294 or the valve plug (147) to each of the predetermined positions in the xy plane.

At the point of use, the vessel stand is lowered to the non-raised (deployed) position and the successive driving steps performed at predetermined positions in the xy-plane are similar to those described herein above for the embodiment of FIG. 1. In the non-raised (unfolded) position, the vessel rack is secured using the cover (101).

A needle (300) pierces the tip of the syringe (164) to open a fluid path between the syringe barrel (104) and the fluid circuit in the manifold (117). A standard vacutainer (212) is placed in the sample preparation device (99). The vacutainer (212) containing the biological fluid sample is placed into the sample preparation device (99) through the vacutainer opening (202). The manifold (117) contains a latch for the vacutainer (187) to prevent the user from connecting the vacutainer (212) directly to the fluid circuit in the manifold (117) and a pair of needles (167) piercing the diaphragm of the vacutainer (212). The first of the pair of needles (167) is in fluid communication with the air chamber (221), and the second of the pair of needles (167) is in fluid communication with the first chamber containing the dilution buffer. When the air plunger (222) is actuated, air from the air chamber (221) enters the vacutainer (212) through the second of the pair of needles (167) and flushes the body fluid sample into the first chamber containing the dilution buffer through the first of the pair of needles. (167).

The matrix valve is opened by offset driving of the valve plug (147). When the matrix valve is opened, the fluid circuit in the manifold (117) can selectively connect the chambers to the antibody matrix (127). First, the non-return plunger (105) in the first chamber is driven at a controlled rate and the diluted sample is evacuated into the fluid circuit. The diluted sample is then fed through the matrix valve through the matrix inlet (280) into the antibody matrix (127). Fluid leaves the antibody array (127) through the matrix outlet (290) and into the waste chamber (150).

The non-return plunger (105) in the second chamber is then driven at a controlled rate to pass the first wash buffer over the antibody matrix (127) into the waste chamber (150). The non-return plunger (105) in the third chamber is then driven at a controlled rate to pass the label over the antibody matrix (127) into the waste chamber (150). The non-return plunger (105) in the fourth chamber is then driven at a controlled rate to pass the second wash buffer over the antibody array (127) into the waste chamber (150). A PTFE frit (106) is included in the top of the waste chamber (150) to relieve air pressure.

At the base of the detection device (91) there is an optical module (97), which is a fluorescent optical system, with which the lower surface of the antibody matrix (127) is visualized. The optical module (97) is switched on using an external switch (95) and the functionality is provided by the printer (93), scanner (92) and screen (999). The detection device (91) is further provided with a handle (96) for portability.

Claims (34)

1. A device for biochemical analysis of a sample of a biological fluid, containing a device for detection, containing a body; a movable platform in the housing selectively movable to a plurality of positions; a linear actuator mounted in a housing above the movable platform and driven along a linear axis; a sample preparation device installed or configured to be installed on a movable platform in a housing, containing a collector; a compartmented housing mounted on a manifold and capable of accommodating a biological fluid sample in an elongated fluid compartment, the compartmented housing having a valve compartment, a tripod compartment, and an elongated air chamber sealed by an air plunger; rack for elongated vessels installed in a rack compartment in a raised non-deployed position or in a non-raised deployed position, where each elongated vessel defines a fluid chamber sealed by a fluid plunger, where the rack for elongated vessels is movable from a raised non-deployed position to a non-raised deployed position for fluid connection of the elongated vessels to the manifold; an antibody matrix positioned below the bottom of the manifold such that the manifold is configured to fluidly selectively couple each elongated antibody matrix vessel; and a matrix valve having a closed position to isolate elongated vessels - 9 043294 from the antibody array, and an open position allowing fluid connection of the elongated vessels with the antibody matrix through the manifold, where when the stand for the elongated vessels is in a non-raised deployed position, the movable platform is movable sequentially to selected positions among a plurality of positions, where in the initial position, among a plurality of positions, the linear actuator is substantially coaxial with respect to the elongated air chamber, wherein actuation by the linear actuator results in pressure on the air plunger, which causes air from the elongated air chamber to flow into the elongated fluid chamber, and flush the biological fluid sample into the first fluid chamber of the first elongated vessel of the elongated vessel rack, containing the first diluent reagent, to obtain a dilute biological fluid sample, where in the first position among the plurality of positions, the linear actuator is essentially coaxial with respect to the first fluid chamber of the first elongated vessel, whereby actuation by the linear actuator causes the fluid plunger of the first elongated vessel to be depressed, causing the diluted biological fluid sample to flow into the antibody matrix through the manifold, where in the second position among the plurality of positions, the linear actuator is substantially coaxial with respect to the second fluid chamber of the second elongated vessel from the elongated vessel rack, whereby linear actuator actuation presses the fluid plunger of the second elongated vessel, causing the flush reagent to flow into the antibody matrix through the manifold, and where in a third position, among a plurality of positions, the linear actuator is substantially coaxial with respect to the third fluid chamber of the third elongate vessel of the elongate vessel rack, the linear actuator being driven to depress the plunger to fluid medium of the third elongated vessel, which causes the reagent label to flow into the antibody matrix through the manifold. 2. The chemistry analysis apparatus of claim 1, wherein the movable platform is a rotary platform selectively rotated into a plurality of rotational positions. 3. The biochemical analysis apparatus of claim 1, wherein the movable platform is an x-platform selectively movable in a plurality of positions in the x-y plane. 4. The biochemical assay apparatus according to any one of the preceding claims, wherein at a fourth position among the plurality of positions, the linear actuator is substantially coaxial with respect to the fourth fluid chamber of the fourth elongate vessel of the elongate vessel rack, being driven by the linear the actuator causes the fluid plunger of the fourth elongated vessel to be depressed, which causes additional flush reagent to flow into the antibody matrix through the manifold. 5. The biochemical analysis device according to any one of the preceding claims, wherein the matrix valve is an actuated matrix valve installed in the valve compartment. 6. The device for biochemical analysis of a sample of biological fluid according to claim 5, where when the rack for elongated vessels is in a non-raised deployed position, the movable platform is additionally configured to move to a valve position among a plurality of positions, where in the valve position the linear actuator is essentially coaxial with respect to the valve compartment, while driving by means of a linear actuator allows you to move the driven matrix valve to the open position for fluid connection of the elongated vessels and the antibody matrix through the manifold. 7. A biochemical assay device according to any one of the preceding claims, wherein the antibody array is sealed under the bottom of the collector. 8. The biochemical assay device according to any one of the preceding claims, wherein the antibody array includes one or more channels providing a continuous fluid path between the matrix inlet and the matrix outlet, where the antibodies are attached to the walls or bottom of the channel. 9. A device for biochemical analysis according to any one of the preceding claims, where there are protrusions on the walls or bottom of the channel, where the protrusions are located at a distance from each other. 10. A device for biochemical analysis according to claim 8 or 9, where the fluid path is a spiral or zigzag fluid path. 11. A biochemical assay device according to any one of claims 8-10, wherein the fluid is diverted through the outlet of the matrix to a waste chamber in the manifold. 12. The biochemical assay apparatus of any one of the preceding claims, wherein the manifold comprises a fluid circuit configured to fluidly connect each elongated antibody matrix vessel. 13. A device for biochemical analysis according to any one of the preceding claims, where the stand - 10 043294 for elongated vessels contains a plurality of essentially cylindrical vessels located at a distance from each other and connected in their thinned parts by means of a ring. 14. The chemistry analysis apparatus of any one of the preceding claims, wherein in the raised, non-deployed position, the elongate vessel rack is placed in the rack compartment and each elongate vessel is aligned and spaced from a bell or needle protruding from the bottom of the manifold, the elongate vessel rack being lowered in a non-raised deployed position so that a bell or needle penetrates the lower end of the elongated vessel. 15. An apparatus for biochemical analysis according to any one of the preceding claims, wherein the collector comprises a first and a second cannula protruding from the bottom. 16. The device for biochemical analysis according to claim 2, where the air chamber, the valve compartment and the first, second, third and fourth chambers define a starting circle, essentially with a common diameter, where when installing the sample preparation devices on a rotary platform, the starting circle is crossed by a linear axis of the linear actuator such that, as the sample preparation device is rotated, the air plunger, valve plunger, and fluid plunger of each of the first, second, third, and fourth chambers are substantially aligned under the linear actuator. 17. The device for biochemical analysis according to claim 3, where the air chamber, the valve compartment and the first, second, third and fourth chambers define a rectangular matrix, where when installing the device for sample preparation on the x-y platform, the linear axis of the linear actuator intersects the rectangular matrix such such that, as the sample preparation device moves, the air plunger, valve plunger, and fluid plunger of each of the first, second, third, and fourth chambers are substantially aligned under the linear actuator. 18. The biochemical assay device according to any one of the preceding claims, wherein the antibody array comprises a control zone on which a ligand is immobilized to capture the probe, and a first major surface on which two or more test zones are defined, where the first test zone has the first test zone immobilized thereon. a pathogen-specific antibody adapted to bind to a first capture target on the first pathogen or marker, wherein the second test area has a second pathogen-specific antibody immobilized thereon adapted to bind to the second capture target on the second pathogen or marker. 19. A device for sample preparation, for use with a device for biochemical analysis according to claims 1 to 18, containing a collector; a compartmented housing mounted on a manifold and capable of accommodating a biological fluid sample in an elongated fluid compartment, the compartmented housing having a valve compartment, a tripod compartment, and an elongated air chamber sealed by an air plunger; rack for elongated vessels installed in a rack compartment in a raised non-deployed position or in a non-raised deployed position, where each elongated vessel defines a fluid chamber sealed by a fluid plunger, where the rack for elongated vessels is movable from a raised non-deployed position to a non-raised deployed position for fluid connection of the elongated vessels to the manifold; a matrix valve having a closed position and an open position, the elongated vessel rack comprising a first elongated vessel defining a first fluid chamber containing a first diluent; a second elongated vessel defining a second fluid chamber containing a flushing agent; a third elongated vessel defining a third fluid chamber containing the reagent label. 20. The sample preparation apparatus of claim 19, wherein the elongated vessel rack comprises a fourth elongated vessel defining a fourth fluid chamber containing an additional flush reagent. 21. The sample preparation apparatus according to claim 19 or 20, wherein the matrix valve is an actuated matrix valve installed in the valve compartment, and when the elongate vessel rack is in a non-raised deployed position, the actuated matrix valve is movable to an open position, or wherein the matrix valve may be a fluid pressure valve that opens at a fluid pressure threshold or an umbrella valve. 22. A sample preparation apparatus according to any one of claims 19-21, wherein the manifold comprises a fluid circulation circuit configured to fluidly connect each elongate vessel with an antibody matrix and/or wherein the elongate vessel rack comprises a plurality of substantially , cylindrical vessels located at a distance from each other and connected in their thinned parts with a ring. - 11 043294 23. A sample preparation apparatus according to any one of claims 19 to 22, wherein, in the raised, non-deployed position, the elongated vessel rack is placed in the rack compartment and each elongated vessel is aligned and spaced from a bell or needle protruding from the bottom of the manifold, the rack for elongated vessels are lowered to the unraveled deployed position in such a way that a bell or needle penetrates into the lower end of the elongated vessel / 24. The sample preparation apparatus of claim 23, wherein the first needle or flare is in fluid communication with the first chamber and the second needle or flare is in fluid communication with the air chamber and the second needle or flare is at a different height. relative to the first needle or bell to prevent bypassing air from the air chamber directly into the first needle or bell. 25. The sample preparation apparatus of claim 20, wherein the air chamber, valve compartment, and first, second, third, and fourth chambers form a pitch circle with a substantially common diameter, or wherein the air chamber, valve compartment, and first, second, third and the fourth chamber form a rectangular array. 26. The sample preparation apparatus according to any one of claims 20 to 25, wherein the fluid plunger in each of the second, third, and fourth chambers is initially located substantially at the top of the plunger stroke; wherein each of the second, third, and fourth chambers includes an internal latch to stop the fluid plunger at the top of the plunger stroke to prevent the body fluid sample from entering the second, third, and fourth chambers, and wherein each of the first, second, third, and fourth chambers includes an internal retainer that secures the fluid plunger at the bottom of the plunger stroke to prevent plunger retraction. 27. Device for detection for use with a device for biochemical analysis according to claims 1 to 18, containing a housing; a movable platform in the housing selectively movable to a plurality of positions; linear drive installed in the housing above the movable platform and driven along the linear axis; where in the initial position from a plurality of positions, the linear actuator is configured to be driven to press the air plunger in the sample preparation device, while in the first, second and third positions from the plurality of positions, the linear actuator is configured to be driven to press the plunger to fluid in the device for sample preparation. 28. The detection apparatus of claim 27, wherein the movable platform is a rotary platform selectively rotated to a plurality of rotational positions, or wherein the movable platform is an xy-platform selectively movable to a plurality of positions in an xy-plane. 29. The detection device according to claim 27 or 28, wherein at a fourth position among the plurality of positions, the linear actuator is operable to depress the fluid plunger in the sample preparation device. 30. A device for detection according to any one of claims 27-29, in which the device for detection is equipped with a power electric cable and connectors for connecting to peripherals, and wherein the peripheral includes a barcode scanner, a printer and/or a local area network, and/or wherein the detection device includes optical or proximity sensors to confirm the presence of the sample preparation device and an external touch screen serving as a user interface. 31. An antibody array for use with the chemistry assay device of claims 1 to 18, comprising one or more channels providing a continuous fluid path between the matrix inlet and the matrix outlet, wherein the antibodies are attached to the walls or bottom of the channel, and on the walls or bottom of the channel there are protrusions located at a distance from each other. 32. The antibody array of claim 31, wherein the fluid path is a helical or zigzag fluid path. 33. An antibody array according to claim 31 or 32, comprising a control zone on which a ligand is immobilized to capture the probe, and a first main surface on which two or more test zones are defined, where the first test zone contains the first pathogen-specific antibody immobilized thereon adapted to bind to a first capture target on a first pathogen or marker, wherein the second test area contains a second pathogen-specific antibody immobilized thereon adapted to bind to a second capture target on the second pathogen or marker. 34. An antibody array according to any one of claims 31-33, wherein fluid is removed from the matrix outlet and/or where the matrix lid is placed on the base of the antibody array to seal the channel and prevent leakage.