Automatic sample concentration unit

Abstract

The present disclosure describes a sample concentration unit (100) and a sample concentration method, which can achieve rapid, accurate and reproducible analyte concentration in a sample (1, 1', 1") by evaporating the sample solvent. A specifically guided airflow cooperates with the vacuum generated in the sample concentration unit (100) to keep the sample (1, 1', 1") at boiling point throughout the evaporation process while reducing the risk of analyte loss and cross contamination. The fully automatic sample concentration unit (100) is designed to be integrated into an in vitro diagnostic analyzer.

Description

Technical Field

[0001] The present disclosure relates to an automated sample concentration unit and a method for automatically concentrating analytes in a sample for further analysis in an in vitro diagnostic analyzer, in particular by evaporating a sample solvent from the sample by applying a vacuum and a gas flow. Background Art

[0002] There is increasing interest in implementing mass spectrometry (MS) and more specifically liquid chromatography-mass spectrometry (LC / MS) in an in vitro diagnostic laboratory setting. Sample preparation plays a crucial role in LC / MS analysis. In some cases, it may be advantageous to exchange the sample solvent and / or concentrate the analytes present in the sample prior to further sample processing (e.g. subsequent resuspension) and / or further analysis, in particular prior to injection into a liquid chromatography column. Active sample solvent evaporation can be used for this purpose. Commercially available evaporation devices usually require observation and manual intervention and are designed for processing small amounts of samples in a low-throughput laboratory environment. However, when it comes to a fully automated environment and the processing of a large number of samples, such as in an in vitro diagnostic laboratory, commercially available evaporation devices are not suitable. In such an environment, any manual intervention will have a significant impact on labor costs and may further lead to inaccurate results due to the "human factor" in the process.

[0003] In order to achieve a fully automated LC / MS workflow for high-throughput in vitro diagnostic laboratories, it is also important to integrate and automate the sample preparation procedure as much as possible. Specifically, in the case of a random access approach, the operating conditions may need to be adjusted quickly for any given test. In a random access approach, samples are inserted into the analyzer in a random order and processed in this way, rather than processing samples in batches. Random access allows for higher throughput, high flexibility, and longer standby times. Therefore, any integrated sample preparation procedure and its underlying sample preparation unit need to meet the same requirements of rapid adaptation and flexibility.

[0004] Evaporation devices known in the prior art usually use an airflow (also referred to as a jet or purge) directed perpendicular to the sample surface to support the evaporation process. US4465554A discloses a device for evaporation, which applies a heated jet vertically to the sample surface. The jet thus allows the sample to enter the temperature range in which it begins to evaporate. US5897838A discloses an evaporation device that combines vacuum and purge to take away gaseous solvents. However, applying an airflow perpendicular to the sample surface causes the sample and therefore the target analyte to splash onto the side wall of the sample container or even the outside of the sample container, thereby losing the target analyte and causing the risk of cross contamination.

[0005] Other commercially available evaporation devices agitate the sample by vortexing, thereby increasing the exposed sample surface area to support sample solvent evaporation. Or they spin the sample in a rotary evaporator or centrifuge to remove the solvent and concentrate the target analyte. However, these devices (i.e., vortexers, rotary evaporators, and centrifugal evaporators) are large, complex, and require high-frequency maintenance, which makes them inconvenient to integrate into automated in vitro diagnostic systems. Summary of the invention

[0006] Against the foregoing background, embodiments of the present disclosure provide certain non-obvious advantages and advances over the prior art. In particular, it is recognized that there is a need for improved fully automated sample concentration units as part of an automated sample preparation procedure integrated in a high throughput in vitro diagnostic analyzer.

[0007] In particular, a sample concentration unit and a sample concentration method are disclosed, which enable fully automated, rapid, accurate, reliable and reproducible sample concentration as part of a sample preparation procedure in an in vitro diagnostic analyzer. The sample concentration unit and sample concentration method disclosed herein are particularly suitable for integration in an automated LC / MS in vitro diagnostic system, however, they can be implemented in any in vitro diagnostic system that can benefit from an automated sample concentration procedure.

[0008] Although the embodiments of the present disclosure are not limited to specific advantages or functions, it should be noted that the present disclosure allows for a sample concentration unit and a sample concentration method that achieves faster, more accurate and reproducible analyte concentrations in a sample by evaporating the sample solvent in a controlled manner. This is achieved by combining a specifically directed gas jet with a vacuum generated in the sample concentration unit and maintaining the sample at a boiling point via a feedback control process throughout the evaporation process.

[0009] Another advantage of the sample concentration unit and method disclosed herein is that it reduces the risk of analyte loss and cross-contamination by eliminating splashing of sample material onto the side walls or even the exterior of the sample holding container. Thus, this ensures higher sensitivity and more reliable analytical results.

[0010] Another advantage of the sample concentration unit and method disclosed herein is the compact design and fully automated implementation, thereby making it deployable in automated in vitro diagnostic analyzers. Its mechanical structure requires less maintenance, thus making it more reliable while extending its service life. In addition, it requires less space, which is an advantage when deployed in automated in vitro diagnostic analyzers. It further eliminates the "human factor" in the sample preparation procedure, thereby obtaining more reliable results.

[0011] Specifically, the sample concentration unit for concentrating the analyte in the sample by evaporating the sample solvent of the present disclosure includes: a sample receiving element having at least one sample receiving position, the at least one sample receiving position having an opening for receiving the sample or an open sample container for accommodating the sample; and a cover element, the cover element is used to seal the at least one sample receiving position. The cover element and the at least one sample receiving position and / or the sample container are designed to leave a cavity between the cover element and the upper sample surface. The sample concentration unit further includes: a cavity inlet, the cavity inlet is connected to the gas source via a gas channel and includes a gas flow guiding nozzle for guiding the gas flow into the cavity; and a cavity outlet, the cavity outlet is connected to a vacuum pump for generating a negative pressure in the cavity. The gas flow guiding nozzle is thus arranged so that the gas flow enters the cavity in a direction parallel to the sample surface section, thereby cooperating with the vacuum pump to transport the evaporated sample solvent out of the cavity through the cavity outlet. The sample concentration unit further includes a controller, the controller is configured to control the vacuum pump to automatically adjust the negative pressure in the cavity to keep the sample at a boiling point until a predetermined solvent evaporation level is reached.

[0012] The term "sample" as used herein refers to a biological material suspected of containing one or more analytes, the detection of which (qualitatively and / or quantitatively) may be associated with a medical condition. The physical properties (e.g., pH, color, turbidity, viscosity) of the sample can also be analyzed to detect certain medical conditions. It can come from any biological source, such as physiological fluids, including blood, saliva, sputum, lens fluid, cerebrospinal fluid (CSF), sweat, urine, emulsion, ascites, mucus, synovial fluid, peritoneal fluid, pleural fluid, amniotic fluid, tissue, bone marrow, feces, cells, etc. The sample can be pre-treated before use, such as preparing plasma from blood, diluting viscous fluids, cracking, etc. The processing method can involve filtering, centrifuging, distilling, concentrating, inactivating interfering components, and adding reagents. The sample can be used directly after being obtained from the source, or it can be pre-treated and / or sample preparation workflow to change the characteristics of the sample, such as after adding an internal standard, after diluting with another solution, or after mixing with a reagent, such as enabling one or more in vitro diagnostic tests. Therefore, the term "sample" as used herein is not necessarily used to refer to the original sample, it may also refer to a sample that has been processed (pipetting, diluting, mixing with reagents, enriching, purifying, amplifying, etc.). The term "sample" may further refer to a liquid containing a known level of an analyte and used to confirm the operability of a diagnostic device, such as a quality control and / or calibrator.

[0013] The term "analyte" as used herein refers to any substance or compound in a sample that an analytical method or test seeks to detect, such as a chemical element such as an ion, or a molecule such as a peptide, protein, RNA, DNA, fatty acid, carbohydrate, etc. Generally speaking, information about the presence, absence, and / or concentration of an analyte in a sample can indicate the health status of a patient and can therefore be used to arrive at a diagnosis, or can be used to determine and adjust a treatment regimen. Generally speaking, examples of target analytes in the context of the present disclosure are vitamin D, drugs of abuse, therapeutic drugs, hormones, and metabolites. However, this list is not exhaustive.

[0014] In order to separate and / or concentrate the target analyte in the sample before analysis (e.g., before injection into a liquid chromatography column), the sample can undergo an automated sample processing or sample preparation procedure, which may involve the use of a solvent. Therefore, the processed sample or sample component can be mixed with a sample solvent selected based on the solubility of the target analyte and its compatibility with downstream analytical methods (e.g., liquid chromatography, ionization techniques). The "sample solvent" used in the present disclosure may refer to any liquid having the property of dissolving compounds to form a solution, such as water, acetonitrile, methanol, ethanol, propanol, isopropanol, etc. The sample solvent may contain additives such as acetic acid, formic acid, ammonium hydroxide, ammonium formate, ammonium acetate, non-volatile salts, etc. In addition, the sample solvent may be a mixture of more than one solvent (e.g., water and methanol). However, the term "sample solvent" may also refer to the liquid solvent component of the original sample, in which the analyte is dissolved. For example, a blood sample naturally contains a certain amount of water (e.g., the water content of plasma is about 90%, and the water content of serum is>90%).

[0015] The term "sample container" is used herein to refer to a container comprising a body having an interior space and an opening defined by an edge, the interior space being suitable for receiving a liquid, through which the liquid can be introduced into the interior space. The sample container can be a sample collection tube, also referred to as a primary tube, for receiving a sample from a patient and transporting the sample contained therein to an analytical laboratory for in vitro diagnostic testing. The primary tube is usually closed by a tube cap. However, these lids can be automatically removed on many available in vitro diagnostic analyzers before further processing. Specifically, the term "sample container" refers to a secondary tube, which can be used to receive at least a portion of a sample from a primary tube. The sample container can also refer to a reaction vessel, for example, for reacting one or more samples with one or more reagents and / or allowing the liquid contained therein to be analyzed. The sample container can further include a plurality of receptacles to receive different samples or a plurality of aliquots from the same sample, such as a multi-well plate, to achieve higher throughput or multi-channel transmission.

[0016] "Unit" as used herein refers to a functional entity dedicated to performing a specific set of operations. Therefore, the unit is constructed in a way that best performs these operations. The function can be an analytical function, but it can also be a function before analysis or a function after analysis, or it can be an auxiliary function of any one of the functions before analysis, the analytical function or the function after analysis. It can operate autonomously as an independent device, in coordination with other units, or as a subunit of a more complex device. In the field of in vitro diagnosis, the unit can therefore be an independent in vitro diagnostic analyzer or in vitro diagnostic device, it can be connected to one or more in vitro diagnostic analyzers / equipment or work in coordination with one or more in vitro diagnostic analyzers / equipment, or it can be fully integrated into an in vitro diagnostic analyzer or in vitro diagnostic device. Examples of units are, for example, conveyors, clamps, centrifuges, pipetting units, incubation units, analysis (measurement) units, sample concentration units, result display units, etc. Therefore, a "sample concentration unit" is a functional entity designed to perform concentrated samples and thus concentrate the target analyte dissolved therein by, for example, evaporating the sample of a predetermined volume. "Concentration" in the context of the present disclosure refers to the process of bringing an analyte or compound dissolved in a solvent at a certain concentration to a higher concentration state, such as by removing the solvent.

[0017] According to the function of the unit, it may be necessary to place the sample or sample container for a period of time, such as when adding reagents, during incubation, during sample concentration, etc. Therefore, this functional unit includes a sample receiving element with one or more sample receiving positions. The sample receiving element may include a heat-conducting material, such as metal, or be designed to accommodate a heat-conducting material, such as water or oil, to achieve heat exchange between the sample receiving position and its surroundings. Or they may alternatively include a heat-insulating material to prevent heat exchange between the sample receiving position and its surroundings. The sample receiving position generally includes an opening (such as a groove, a hole, a channel, etc.) defined by an edge, into which the sample can be directly inserted or a container containing the sample can be placed. The sample receiving position is generally designed to stably accommodate the sample or sample container in a specific direction to avoid tilting and overflowing of the sample material, and to be able to interact potentially with other units (such as a pipetting unit or a clamp, etc.). If it is necessary to handle containers from different manufacturers or if it is necessary to compensate for manufacturing tolerances, the sample receiving position may include additional components whose characteristics allow for certain adjustments in size while maintaining the ability to stably accommodate the sample container, such as a coil spring, sponge rubber, StyrofoamTM insert, etc.

[0018] As used herein, "upper sample surface" refers to the sample surface area that is not in direct contact with any container wall or any wall of the opening of the sample receiving location, regardless of the orientation of the sample receiving location. However, the upper sample surface is in direct contact with the gas phase surrounding the sample container or sample receiving location. Depending on the surface tension of the sample, the upper sample surface can form a meniscus.

[0019] As used herein, an "in vitro diagnostic analyzer" refers to an automated analytical device configured to obtain analytical measurements from a sample. An in vitro diagnostic analyzer may have different configurations, depending on the needs and / or the desired laboratory workflow. It may be operated as a standalone instrument or in conjunction with one or more other in vitro diagnostic analyzers and / or in vitro diagnostic devices. As used herein, an "in vitro diagnostic device" is a broader term that further includes, in addition to an in vitro diagnostic analyzer, any pre-analytical or post-analytical device or combination thereof.

[0020] As used herein, "evaporation" refers to the phase change from liquid to vapor that occurs at the surface of a liquid. When the molecules on the surface of the liquid gain enough kinetic energy, they will change from the liquid phase to the gas phase. Therefore, they must overcome the intermolecular forces or surface tension of the liquid phase and the pressure exerted by the surrounding gas phase. The temperature at which the vapor pressure of a given liquid is equal to the pressure around the liquid is called the "boiling point". Therefore, the boiling point depends on the temperature of the liquid and the surrounding pressure of the gas phase. Any change in temperature and / or pressure will result in a change in the boiling point (boiling point curve). For example, reducing the surrounding gas pressure will reduce the boiling point of the liquid. The boiling point and boiling point curves are different between different liquids. The term "at boiling point" used in this disclosure refers to bringing the sample as close to the boiling point as possible while avoiding overheating. For example, the temperature of the sample may be slightly lower than the boiling point of the evaporation procedure to be performed. In addition, in a mixture of solvents with different evaporation characteristics, the boiling point may change over time. This happens when one solvent evaporates faster than other solvents, thereby changing the volume ratio from one solvent to another. In addition, when the solvent evaporates, the solutes in the sample become more concentrated, which affects the liquid phase intermolecular forces or surface tension, thereby affecting the boiling point. Depending on the type of solvent and the type of solute, the surface tension and boiling point may increase or decrease, directly affecting the amount of energy required to transform the molecules from the liquid phase to the gas phase. It is also known that the larger the surface between the liquid and its surroundings, the faster the evaporation proceeds when the evaporated gas is removed above the liquid surface. In addition, when the molecules evaporate, the average kinetic energy of the remaining molecules is lower, resulting in a decrease in the temperature of the liquid, a phenomenon known as evaporative cooling. All of these effects must be considered to accurately control the evaporation of a predetermined volume of a given liquid. The "evaporation of the sample solvent" used in this disclosure is not limited to the evaporation of the solvent that has been added to the sample before the evaporation procedure, but can also refer to the evaporation of the liquid component of the original sample. In fact, once the sample is mixed with the sample solvent, the liquid phase of the sample will be evenly mixed with the sample solvent, so it is impossible to distinguish between the liquid component of the original sample and the added sample solvent. For example, if a plasma sample with a water content of about 90% is mixed with the sample solvent water, then both the sample solvent and the liquid component of the original sample will evaporate during the evaporation process.

[0021] As used herein, "cover element" is an element for hermetically sealing at least one sample receiving position, i.e., it prevents gas or liquid exchange between the sample receiving position and the outside of the sample concentrating unit. Specifically, it prevents the uncontrolled exchange of gas or liquid, which means that the cover element may include an inlet and outlet for realizing controlled gas flow into the sample receiving position and flowing out therefrom. At the connection area with its corresponding part, the cover element may include additional materials with sealing features to improve sealing ability, such as rubber, PTFE, epoxy resin, etc. The cover element can be removed from the sample receiving position so that other units (such as pipetting units, container holders, etc.) can approach the sample receiving position. The sample receiving position can therefore be referred to as being in an open state, i.e., the cover element is removed from the sample receiving position, or in a closed state, i.e., the cover element seals the sample receiving position. Alternatively, the sample receiving position can be approached via a sample inlet channel and a sample outlet channel, so that the cover element can be fixed. In addition, the cover element can be temperature-controlled, so that the temperature of the cover element is adapted to the temperature of the evaporated sample solvent, thereby preventing its condensation. The cover element and the sample receiving location are designed to provide a hollow space between the cover element and an upper sample surface of the sample in the sample receiving location.

[0022] This hollow space is referred to as "cavity" in the present disclosure. If the sample concentration unit is designed so that the cover element is flush with the edge of the sample receiving position or the edge of the sample container, the cavity can be limited to the hollow space between the sample surface and the edge of the sample receiving position or the hollow space between the sample surface and the edge of the sample container, respectively. Alternatively, if the cover element is designed accordingly, the cavity can extend above the edge of the sample receiving position. In the case of multiple sample receiving positions, the design can provide a cavity for each sample receiving position, respectively, or it can provide a single cavity shared by multiple sample receiving positions, or it can provide a combination of a single cavity and a shared cavity. The cover element combined with the sample receiving position is designed to provide a cavity structure that supports solvent evaporation. For example, the cavity structure can be funnel-shaped, wherein the tapered end transitions to the cavity outlet. The funnel-shaped cavity can thus taper in the vertical direction above the sample receiving position. Alternatively, the cavity structure can be bell-shaped or cylindrical or cuboid, or a combination thereof. In addition, the cavity can be temperature-controlled to adjust the temperature of the gas inside the cavity.

[0023] The "cavity inlet" mentioned in the present disclosure is an opening that enables gas to flow into the cavity in a controlled manner. The cavity inlet can be formed in a cover element, or it can be formed in a sample receiving element, or it can be partially formed by two elements. In this way, one end of the cavity inlet leads to the cavity, and the other end of the cavity inlet is connected to the "gas source" via a "gas channel" outside the cavity. The sample concentration unit may include an additional auxiliary cavity inlet so that gas can flow into the cavity at different positions. Thus, the "gas source" can provide a gas mixture, such as the air around the sample concentration unit, or it can provide a specific type of gas, such as nitrogen. Typically, the gas provided is inert to avoid any reaction with the sample or target analyte. The gas source can provide gas passively or actively. For example, in a passive setting, the gas is passively sucked into the cavity through the gas channel and the cavity inlet by the negative pressure generated by the vacuum pump inside the cavity. On the other hand, in an active setting, the gas source can be a gas container operably connected to a pump, wherein the pump actively transports the gas from the gas container through the gas channel to the cavity inlet. A "gas channel" in the context of the present disclosure may be a tubular element or other fluid structure that operably connects a gas source to an inlet of a cavity, wherein the gas channel is made of a material or reinforced by a material that is sufficiently stable to avoid collapse of the gas channel when a negative pressure is generated inside the cavity. The gas channel may further include a chamber for mixing gases from different gas sources or for temperature regulation of the gas inside the gas channel or for controlling the gas flow rate.

[0024] The sample concentration unit further includes a "gas flow guiding nozzle" installed at the transition point from the cavity entrance to the cavity. The gas flow guiding nozzle may have a cylindrical shape, that is, the cross-sectional area is the same over its entire length, wherein the cross-sectional area is equal to or less than the cross-sectional area of ​​the gas channel and the cavity entrance. For example, the cross-sectional area may have a width of 1 mm or less. Alternatively, the gas flow guiding nozzle may taper toward the cavity. The gas flow guiding nozzle can gather the gas flow so that the gas flow enters the cavity at a higher entry speed. The gas flow entry speed is ideally within the range of ensuring that the gas flows into the cavity without turbulence (laminar flow), and enables the incoming gas flow to advance through the opening of the sample receiving position until the edge is located at the farthest part from the gas flow guiding nozzle or beyond. In addition, the gas flow guiding nozzle can guide the incoming gas flow at a desired angle or direction. Specifically, the gas flow is guided into the cavity in a direction parallel to the sample surface tangent plane. The term "sample surface tangent plane" is used in the present disclosure because the sample surface is likely to form a concave meniscus in the sample receiving position or sample container. Therefore, the sample surface section refers to the plane close to the lowest point of the meniscus (or the highest point, in the case of a convex meniscus). However, the direction of the gas flow can change inside the cavity and deviate from the flow parallel to the sample surface section. This may occur due to the cavity design, for example, if the cavity outlet is positioned orthogonally relative to the cavity entrance, or due to obstacles inside the cavity causing turbulence. In addition, if the container protrudes from the sample receiving position, the air flow guiding nozzle can adjust the height of the incoming air flow to the same level as the edge of the sample receiving position or the edge of the sample container located at the sample receiving position. For example, the air flow guiding nozzle can be made of a flexible material to be able to adjust the height. The direction of the air flow parallel to the sample surface section and its controlled entry speed support the rapid removal of evaporated solvents while avoiding sample splashing, thereby reducing the risk of cross contamination and undesirable analyte loss. Therefore, two effects begin to play a role: the air flow moving through the opening of the sample receiving position at a predetermined speed and in a direction parallel to the sample surface section will be pulled together with its adjacent gas layer, thereby causing the movement of the gas layer in the sample receiving position, which causes the vortex gas movement above the sample surface. Secondly, it reduces the static pressure of the gas phase above the sample surface according to the Bernoulli principle, thereby improving the removal efficiency of the gas molecules evaporated from the sample surface. In addition, the gas flow effectively guides the evaporated sample solvent to the cavity outlet, thereby cooperating with the vacuum pump to effectively transport it to the outside of the sample concentration unit. "Cooperation" as used herein means that at least two subunits operate in a coordinated manner to produce an additional effect compared to if they operate separately. At least two subunits can thus operate simultaneously or in an alternating manner.The height alignment of the nozzle leveled at the height of the edge of the sample receiving position or the edge of the sample container is combined with a controlled entry speed so that the airflow is partially torn above the edge of the sample receiving position or the edge of the sample container, respectively, which is positioned closest to the airflow guiding nozzle. Specifically, the edge of the sample receiving position or the edge of the sample container represents an obstacle that causes turbulence in multiple parts of the laminar airflow. A portion of the airflow continues to flow through the opening in a direction parallel to the sample surface section, while another portion of the airflow is diverted by the edge and enters the sample receiving position, thereby supporting the generation of gas vortices above the sample surface, which further supports the evaporation of the sample solvent and the removal of the evaporated sample solvent from the sample surface. The airflow guiding nozzle can be radially guided (pointing to the central axis) relative to the vertical central axis of the sample receiving position, or it can be dispersedly guided to achieve a desired vortex shape in the cavity above the sample surface.

[0025] As used herein, "cavity outlet" refers to an opening that enables gas to flow out of the cavity in a controlled manner. The cavity outlet can be formed in a cover element, or it can be formed in an element comprising a sample receiving position, or it can be formed in part by two elements. Therefore, one end of the cavity outlet leads to the cavity, and the other end of the cavity outlet is operably connected to a vacuum pump. Thus, the size of the diameter of the cavity outlet is designed so that the gas flow rate is sufficient to generate a negative pressure inside the cavity.

[0026] "Vacuum pump" as used herein refers to a device configured to generate negative pressure (i.e., pressure lower than the ambient pressure) and remove gas molecules (possibly including gas molecules evaporated from the sample) from the cavity. Such devices are well known in the prior art and are widely used, so they will not be described in further detail. If the sample concentration unit includes multiple sample receiving positions and multiple cavities, each cavity can be operably connected to a separate vacuum pump to independently generate negative pressure in each cavity. Or one or more cavities can share an operably connected to the same vacuum pump. The vacuum pump can be operably connected to a condenser for capturing and then discarding evaporated sample solvent.

[0027] The degree of "negative pressure" generated by the vacuum pump in the cavity depends on the selected in vitro diagnostic test, the target analyte in the sample, and the sample solvent. The controller controls the vacuum pump to reduce the pressure inside the cavity to reduce the boiling point of the sample solvent. This allows the sample concentration unit to bring the sample solvent to the desired evaporation temperature faster and more energy efficiently. The vacuum pump is further controlled to continuously adjust the negative pressure in the cavity according to changing conditions (such as sample volume and / or sample temperature that changes during the evaporation process) to keep the sample solvent at its boiling point. The regulation of the negative pressure can follow a predetermined curve or it can be based on feedback control. Therefore, the negative pressure is maintained below atmospheric pressure. During the evaporation process, the pressure in the cavity is continuously adjusted according to a predetermined evaporation curve, which is based in particular on the boiling point curve of the solvent. The pressure is typically set to a value that is at most 5% higher than the target pressure to prevent overheating. In order to generate a negative pressure in the cavity, the vacuum pump must compensate for the gas flowing into the cavity through the cavity inlet. Therefore, the outflow of gas from the cavity needs to occur at a higher rate than the inflow of gas until the desired degree of negative pressure is reached.

[0028] As used herein, a "controller" is a programmable logic controller or processor running a computer-readable program that is provided with instructions for performing operations in accordance with an operation plan. The term may refer to a central processing unit, a microprocessor, a microcontroller, a reduced instruction set circuit (RISC), an application specific integrated circuit (ASIC), a logic circuit, and any other circuit or processor capable of performing the functions / methods described herein. Regardless of the type of processor, it is configured to perform one or more of the methods described herein.

[0029] The controller may be integrated into the in vitro diagnostic device, may be integrated into a unit or subunit of the in vitro diagnostic device, or may be an independent logical entity that communicates with the in vitro diagnostic device or its units or subunits via a direct connection, either wired or wireless, or indirectly via a communication network (e.g., a wide area network, such as the Internet or a local area network or intranet of a health care provider) via a network interface device, either wired or wirelessly. In some embodiments, the controller may be integrated with the data management unit, for example, implemented on a computing device (such as a desktop computer, laptop computer, smart phone, tablet computer, PDA, etc.), the controller may be composed of a server computer, and / or distributed / shared across / among multiple in vitro diagnostic devices. In addition, the system may include a communication interface, such as a wireless, wireless, infrared, cellular, Bluetooth, etc., to communicate with the in vitro diagnostic device or its units or subunits. ) or a remote PC / server or a cloud-based system to communicate with the remote device, server and cloud-based elements. The processor can also be configured to control the in vitro diagnostic device so that the workflow and workflow steps are performed by the in vitro diagnostic device. Specifically, the controller is configured to control the vacuum pump to automatically adjust the negative pressure in the cavity to keep the sample at the boiling point until a predetermined solvent evaporation level is reached.

[0030] As used herein, "predetermined solvent evaporation level" refers to the volume of sample solvent that needs to be evaporated to reach the desired amount of analyte concentration in the remaining sample and make the sample processable for subsequent analytical procedures. The evaporation volume is determined by the manufacturer in the context of analytical development activities and depends on the target analyte, its solubility in the sample solvent, the sensitivity of the subsequent analytical procedure, and possible time constraints caused by a given time scheme on the in vitro diagnostic device. The solvent can be evaporated to dryness or partially evaporated. In-house experiments have shown that partial evaporation to 20% of the initial sample volume results in up to five times more analytes transferred to subsequent analytical procedures than unevaporated samples, resulting in up to five times more signal increases. It has been further shown that partial evaporation provides higher analyte yields and higher signal gain, and has better reproducibility than evaporation to dryness.

[0031] According to one embodiment, the sample concentration unit includes a pressure gauge for measuring and monitoring the negative pressure generated by the vacuum pump in the cavity, wherein the controller is configured to control the vacuum pump in response to the pressure measured by the pressure gauge to automatically adjust the negative pressure in the cavity. In other words, the pressure gauge is capable of feedback control and adjustment of the negative pressure inside the cavity. The pressure gauge can be a mechanical pressure gauge, such as a Bourdon tube pressure gauge, a diaphragm pressure gauge, or an electronic pressure gauge, such as a piezoresistive or capacitive pressure gauge. The pressure gauge can be installed inside the cavity or at the connection between the cavity outlet and the vacuum pump, or it can be part of the vacuum pump. Specifically, the pressure gauge transmits pressure records to the controller at predetermined time intervals to ensure monitoring of the pressure state inside the cavity and enable the controller to control the vacuum pump accordingly.

[0032] According to a further embodiment, the sample concentration unit includes a gas temperature regulating element connected to the gas channel. Any principle for regulating the temperature of the gas that can accurately and controllably regulate the temperature of the gas can be used. The gas temperature regulating element can be installed at any position between the gas source and the cavity entrance. Typically, the gas temperature regulating element is in direct contact with the gas channel, it can completely surround the gas channel, or it can be integrated into the gas channel. The gas temperature regulating element can include a material with high thermal conductivity. For example, it can include a liquid heat exchanger or a metal resistance heating element, such as a heating wire or a heating coil, or it can include a thermoelectric heating element, such as a Peltier element.

[0033] The greater the temperature difference between the interior of the cavity and the gas flow entering the cavity, the greater the effect of hindering evaporation, for example by cooling, and the greater the possibility of inhomogeneous mixing of the gas phase. As a result, uncontrolled turbulence may occur inside the cavity, which reduces the efficiency of the sample solvent evaporation process. The gas temperature is regulated within a range of + / -10°C of the temperature inside the cavity. In particular, the gas temperature in the gas channel is controlled within a range of 0 to +10°C of the boiling temperature of the present sample to prevent cooling of the sample while preventing overheating. The equilibration of the gas temperature in the gas channel with the gas temperature in the cavity before mixing further prevents the occurrence of uncontrolled turbulence.

[0034] The controller is configured to control the gas temperature regulating element to automatically regulate the gas temperature. The temperature regulation may follow a fixed operating curve or it may be feedback controlled. For example, in a fixed operating curve, the gas temperature regulating element may be switched to a heating state within a predetermined amount of time and then switched to a non-heating state within a predetermined amount of time, wherein these steps may be repeated 1 to n times, depending on the selected operating mode. Switching the gas temperature regulating element to a heating state or a non-heating state is therefore performed independently of the actual airflow temperature in the gas channel or the gas temperature in the cavity. Alternatively, in feedback controlled temperature regulation, the actual airflow temperature is monitored, and when above or below a predetermined temperature range, the gas temperature regulating element will be switched to a heating state or a non-heating state, respectively, to bring the airflow temperature back within a predetermined temperature range. In this case, the gas temperature regulating element includes a thermometer for monitoring the airflow temperature.

[0035] According to one embodiment, the sample concentration unit includes a gas volume regulating valve, wherein the controller is configured to control the gas volume regulating valve to automatically adjust the volume of gas entering the cavity. The "gas volume regulating valve" used herein can be integrated into the gas channel or it can be part of the gas source. Typically, the gas volume regulating valve adjusts the volume of gas flowing through the gas channel into the cavity within a given time period by closing, opening or partially blocking the gas channel. The volume of gas entering the cavity directly affects the generation of a jet flow by the airflow guiding nozzle and the generation of negative pressure inside the cavity. Therefore, the controller cooperates with the airflow guiding nozzle and the vacuum pump to control the gas volume regulating valve.

[0036] According to one embodiment, the sample concentration unit includes at least one sample temperature adjustment element, wherein the controller is configured to control the sample temperature adjustment element to automatically adjust the sample temperature. Generally speaking, a "sample temperature adjustment element" directly or indirectly transfers heat to or from a sample in a sample receiving position. It can be in direct contact with a sample or a sample container for optimal heat exchange, or it can transfer heat to the sample receiving position via a sample receiving element or via a gas (e.g., a temperature-regulated air flow) around the sample. Temperature regulation can follow a fixed operating curve and / or it can be feedback controlled. For example, in a fixed operating curve, the sample temperature adjustment element can be switched to a heating state within a predetermined amount of time, and then switched to a non-heating state within a predetermined amount of time, wherein, if necessary, these steps can be repeated 1 to n times, regardless of the actual sample temperature. Alternatively, the actual sample temperature or the temperature of the sample receiving element can be monitored to achieve more adequate and real-time temperature regulation, such as using an infrared thermometer. The operating curve is based on the sample solvent and the sample volume, and is designed to keep the sample temperature at a boiling temperature during the evaporation process. The sample temperature adjustment element may comprise, for example, a metal resistive heating element, such as a heating wire or a heating coil, or it may comprise a thermoelectric heating element, such as a Peltier element, or it may comprise a thick film heater, or it may comprise a laser heater. The sample temperature adjustment element may be operably coupled to the sample receiving element and / or the sample receiving position and / or the cover element.

[0037] According to one embodiment, the diameter of the airflow guide nozzle can be automatically adjusted or can be automatically interchanged with another airflow guide nozzle having a different diameter. As previously mentioned, the operating conditions of the in vitro diagnostic device must be quickly adjusted according to the selected in vitro diagnostic test, especially when following the random access method. Since the diameter of the airflow guide nozzle affects the characteristics of the airflow entering the cavity (speed, laminar flow and turbulence, etc.), the airflow guide nozzle is configured so that its diameter can be adjusted according to the selected in vitro diagnostic test. In the case of a conical airflow guide nozzle, the diameter referred to herein is the diameter of the orifice facing the cavity. According to mechanisms known to those skilled in the art, adjusting the diameter of the airflow guide nozzle refers to mechanically reducing or expanding the cross-sectional area of ​​the nozzle itself. Or it refers to replacing the airflow guide nozzle with another airflow guide nozzle with a different diameter. For example, a plurality of airflow guide nozzles (each with a different diameter) can be mounted on a cylindrical rotating device. According to the selected in vitro diagnostic test, the cylindrical rotating device moves to a position so that the appropriate airflow guide nozzle is located at the transition point between the cavity entrance and the cavity.

[0038] In another embodiment, the sample concentration unit comprises a plurality of sample receiving positions and a corresponding airflow guiding nozzle for each of the sample receiving positions, wherein each airflow guiding nozzle has a different diameter. The airflow guiding nozzles are arranged so that they do not interfere with each other, i.e., they can be partially or completely separated from each other by means of a separation member arranged between the sample receiving positions. Depending on the selected in vitro diagnostic test, the sample is placed in the sample receiving position assigned to the airflow guiding nozzle having the appropriate diameter.

[0039] According to one embodiment, the controller is configured to adjust the negative pressure and / or gas temperature and / or gas volume and / or sample temperature and / or gas flow according to a predetermined evaporation curve based on the type of analyte in the sample and / or the type of solvent and / or the initial sample volume and / or the predetermined sample solvent evaporation level to take into account the changes in sample volume and concentration during the solvent evaporation process. The "evaporation curve" used herein is predetermined during the manufacturer's development process. Therefore, the evaporation curve includes instructions on how the controller cooperates with the operation of the above-mentioned functional subunits to make the sample reach its boiling point in a fast and reliable manner, to keep the sample at its boiling point until the predetermined solvent evaporation level is reached, while preventing possible overheating or boiling of the sample, and to gradually reduce the functional subunits after the evaporation process is completed. The above parameters can be monitored to provide real-time status information to the controller, thereby achieving rapid adjustment. In addition, the sample volume can be monitored during the evaporation process, for example, by means of an optical liquid level detector, so that the controller can adjust the operation of the subunits in real time in response to the available sample volume.

[0040] According to one embodiment, the cover element can be automatically removed from the sample receiving position to automatically insert the sample and / or sample container into the sample receiving position or remove the sample and / or sample container from the sample receiving position. There are multiple options for transporting the sample from one interaction position to another interaction position on the in vitro diagnostic device, and the interaction position is such as a mixing position, a handover position, an incubation position, a vortex position, a measurement position, etc. Usually, the sample is sucked by a pipette and moved (in the pipette) to the next interaction position, and then the sample is distributed at this position. In such a setting, the pipette needs to be able to approach the interaction position to absorb or distribute the sample material. In this sample concentration unit, the cover element can automatically move away from the sample receiving position to allow the pipette to approach the sample receiving position. The cover element can move in a translational or rotational manner, wherein the rotational movement can refer to a horizontal rotation around, for example, a bolt, or refers to the rotation of a hinge so that the cover element is flipped away from the sample receiving position.

[0041] According to one embodiment, the cavity outlet is arranged opposite to the airflow guiding nozzle, or is arranged in a cover element above the sample or sample container at an angle of about 90° relative to the airflow guiding nozzle. Specifically, the cavity outlet is arranged at a height approximately the same as the airflow guiding nozzle relative to the sample surface. The arrangement of the cavity outlet opposite to the airflow guiding nozzle ensures that the airflow entering the cavity through the airflow guiding nozzle flows at least partially toward the cavity outlet above the sample surface, thereby cooperating with the vacuum pump to remove the evaporated sample solvent from above the sample surface according to the above effect. Alternatively, the cavity outlet is arranged at an angle of about 90° relative to the airflow guiding nozzle, wherein the cavity outlet does not have to be arranged in the center above the sample receiving position or the sample container. If the sample concentration unit includes two or more sample receiving positions, the arrangement can generate a vortex above the sample surface, which supports the removal of the evaporated solvent and prevents sample residue.

[0042] Also described herein is an automated method for concentrating an analyte in a sample by evaporating a sample solvent. The method comprises: placing at least one sample or an open sample container containing the sample in at least one sample receiving position of a sample receiving element; sealing the at least one sample receiving position by a cover element, wherein the cover element and the at least one sample receiving position and / or the sample container are designed to leave a cavity between the cover element and an upper sample surface; generating a negative pressure in the cavity by a vacuum pump connected to an outlet of the cavity; introducing a gas flow into the cavity through a cavity inlet connected to a gas source via a gas channel, the cavity inlet comprising a gas flow guiding nozzle, wherein the gas flow guiding nozzle is arranged so that the generated gas flow is guided into the cavity in a direction parallel to a tangent plane of the sample surface, thereby cooperating with the vacuum pump to transport the evaporated sample solvent out of the cavity through the cavity outlet; and controlling the sample concentration unit to maintain the sample at a boiling point until a predetermined solvent evaporation level is reached.

[0043] According to one embodiment, the method comprises automatically regulating the negative pressure in the cavity by controlling a vacuum pump in response to the pressure measured by the pressure gauge.

[0044] According to one embodiment, the method includes regulating the gas temperature by controlling a gas temperature regulating element coupled to the gas channel.

[0045] According to one embodiment, the method comprises regulating the gas volume by controlling a gas volume regulating valve.

[0046] According to one embodiment, the method comprises controlling at least one sample temperature adjustment element to adjust the temperature of the sample in the sample receiving location.

[0047] According to one embodiment, the method includes adjusting the negative pressure and / or gas temperature and / or gas volume and / or sample temperature and / or gas flow based on the type of analyte in the sample and / or the type of solvent and / or the initial sample concentration to account for changes in sample volume and concentration during solvent evaporation.

[0048] Other and further objects, features and advantages will appear from the following description of exemplary embodiments in conjunction with the accompanying drawings and the appended claims.It should be noted that the scope of the claims is defined by the references therein rather than by the specific discussion of the features and advantages set forth in this specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 The sample concentration unit is schematically shown in a transverse cross-sectional view.

[0050] Figure 2 A sample concentration unit including additional elements according to a further embodiment is schematically shown in a transverse cross-sectional view.

[0051] Figure 3 Schematically shows Figure 1 A variation of the embodiment of FIG.

[0052] Figure 4 A sample concentrating unit comprising a plurality of sample receiving locations is schematically shown in a top cross-sectional view.

[0053] FIG5 is a top cross-sectional view ( Figure 5a ) and transverse cross-section ( Figure 5b ) schematically shows more details of the sample concentration unit.

[0054] The skilled person will appreciate that the elements in the drawings are shown for simplicity and clarity and are not necessarily drawn to scale. For example, the size of some elements in the drawings may be magnified relative to other elements to help enhance understanding of the embodiments of the present disclosure. DETAILED DESCRIPTION

[0055] Figure 1 An example of a sample concentration unit 100 is schematically shown. The sample concentration unit 100 includes a sample receiving element 10 having a sample receiving position 11 having an opening 12 defined by an edge for receiving a sample 1 or an open sample container 13 containing the sample 1. The sample container 13 includes a body having an inner space and an opening 14 defined by an edge. The sample 1 in the sample receiving position 11 may have been mixed with a sample solvent in a previous sample preparation step, or the sample solvent may have been added to the sample 1 in the sample receiving position 11. In any case, as Figure 1The sample 1 depicted in the embodiment in FIG. 1 contains a sample solvent and has an initial upper sample surface 2 before the evaporation process. The sample surface tangent plane 3 is indicated by a dotted line.

[0056] The sample concentration unit 100 further comprises a cover element 20. Figure 1 1 , the cover element 20 is in a position in which it hermetically seals the sample receiving position 11, i.e., in a closed state, thereby preventing the gas from the sample receiving position 11 from being uncontrolledly exchanged with the exterior of the sample concentration unit 100. The cover element 20, the sample receiving element 10, the sample receiving position 11, and the sample container 13 are designed to create a cavity 30 between the cover element 20 and the upper sample surface 2 when sealed. The sample concentration unit 100 further includes a cavity outlet 32 ​​formed in the cover element 20 and connected to the vacuum pump 50. The type of vacuum pump 50 is selected based on its effectiveness in reliably and reproducibly generating a negative pressure in the cavity 30.

[0057] During the evaporation process, the pressure inside the cavity 30 is reduced to the vapor pressure of the current sample 1 at a given temperature, i.e., room temperature, thereby correspondingly reducing the boiling point of the sample 1. For example, assuming that the sample is 100% methanol, the pressure will be reduced to about 16.9 kPa to reach the vapor pressure of methanol at room temperature (assuming 25° C.). In another example, assuming that the sample is 100% water, the pressure will be reduced to about 3.17 kPa to reach the vapor pressure of water at room temperature. When the pressure reaches the vapor pressure of the sample 1, the sample 1 is at its boiling point.

[0058] The sample concentration unit 100 further comprises a cavity inlet 31 connected to a gas source 40 via a gas channel 41. The cavity inlet 31 comprises a gas flow guiding nozzle 33a for guiding a gas flow into the cavity. Figure 1 The air flow guide nozzle 33a shown has a conical shape to focus the air flow, thereby increasing the speed of the air flow entering the cavity 30, and is oriented in a direction parallel to the sample surface section 3 (by Figure 1 The solid right-pointing arrow in the figure directs the incoming airflow. Figure 1 In an embodiment not shown, the airflow guide nozzle 33a is adjustable in the z direction. During the evaporation process, the parallel airflow effectively moves the evaporated molecules from the opening 14 of the sample container 13 to the cavity outlet 32, thereby cooperating with the vacuum pump 50. In addition, the airflow is partially torn above the edge of the opening 14 of the sample container 13. This causes part of the airflow to enter the sample container 13, thereby generating a vortex above the sample surface 2, which is caused by Figure 1 The vortex further increases the removal rate of the evaporated sample solvent from the upper sample surface 2 and out of the sample container 13 (indicated by Figure 1 The evaporated gas molecules are transported out of the cavity 30 through the cavity outlet 32.

[0059] The sample concentration unit 100 further includes a controller 60 configured to control the vacuum pump 50 to automatically adjust the negative pressure in the cavity 30 to keep the sample 1 at the boiling point until a predetermined solvent evaporation level is reached. Figure 1 , is represented as the difference between the initial upper sample surface 2 before the evaporation process and the final upper sample surface 4 after the evaporation process. The negative pressure inside the cavity 30 needs to be constantly adjusted during the evaporation process to keep the sample 1 at the boiling point. This is especially true in the case where the sample solvent is a binary mixture (e.g., methanol and water), where one component evaporates faster than the other, thereby shifting the concentration from one component to the other and thus changing the vapor pressure of the sample 1 during the evaporation process. Other factors that have an impact on the evaporation conditions during the evaporation process and therefore require adjustment of the negative pressure in the cavity 30 are: the volume change of the sample 1 during the evaporation process, i.e., from the initial upper sample surface 2 to the final upper sample surface 4; the temperature change of the sample 1 caused by evaporative cooling by removing the gas phase above the upper sample surfaces 2 and 4; and the change in the concentration of the analyte or other compound in the sample 1, thereby affecting the intermolecular forces and surface tension in the sample 1. Prior to the evaporation process, the controller 60 is provided with information about the sample 1 intended for the evaporation process, such as sample type, initial sample volume, type and volume of sample solvent added, target analyte, expected level of solvent evaporation, possible presence of other additives or reagents, etc. Based on these parameters, the controller 60 selects an evaporation profile and controls the vacuum pump 50 to adjust the negative pressure in the cavity 30 accordingly. The controller 60 further controls the gas source 40 in coordination with the operation of the vacuum pump 50 to provide gas into the cavity 30. In an experimental setup without a pressure gauge, water was partially evaporated to 20% of the initial volume in ˜3.5 minutes and evaporated to dryness in ˜9 minutes.

[0060] Figure 2 An example of a sample concentration unit 100 according to a further embodiment of the present disclosure is schematically shown. The sample concentration unit 100 includes a pressure gauge 51 coupled to the operative connection between the cavity outlet 32 ​​and the vacuum pump 50 to measure and monitor the negative pressure generated by the vacuum pump 50. The pressure gauge 51 may alternatively be installed in the cavity 20 or as part of the vacuum pump 50 instead of being coupled to the connection between the cavity outlet 32 ​​and the vacuum pump 50. The pressure gauge 51 provides continuous information about the pressure state to the controller 60, which compares the information with an evaporation curve specifically selected for a given sample 1. The controller 60 is configured to control the vacuum pump 50 in response to the pressure measured by the pressure gauge 51 to automatically adjust the negative pressure in the cavity 20 to be consistent with a predetermined evaporation curve.

[0061] like Figure 2The sample concentration unit 100 shown further includes a gas temperature adjustment element 42 coupled to the gas channel 41. The gas temperature adjustment element 42 includes an element for supplying heat to or removing heat from the gas flow 42a and a thermometer 42b for monitoring the actual temperature of the gas flow. The controller 60 is configured to control the gas temperature adjustment element 42 to automatically adjust the gas temperature so that it enters the desired temperature range. If the temperature in the cavity 30 is monitored and fed back to the controller 60 (not in Figure 2 ), the temperature regulation of the gas flow to the desired temperature range will be more precise. The sample concentration unit 100 further includes a gas volume regulating valve 43 connected to the gas channel 41. The controller 60 is configured to control the gas volume regulating valve 43 to automatically adjust the volume of gas entering the cavity 30. Sample solvents with higher boiling points require higher gas flow rates than sample solvents with lower boiling points to achieve rapid evaporation. For example, in indoor experiments, a sample with an initial volume of 100 microliters was concentrated to 20 microliters using a gas flow rate of ~9.8 l / min. The controller 60 thus coordinates the operation of the gas volume regulating valve 43 with the operation of the vacuum pump 50 so that a negative pressure can be generated inside the cavity 30, while allowing a gas flow sufficient to remove the evaporated sample solvent from the upper sample surface 2 to flow into the cavity 30. With Figure 1 Compared to the illustrated embodiment, in the case where a pump connected to the gas source 40 provides gas into the cavity 30, the gas volume regulating valve 43 allows for more precise regulation of the gas volume and thus allows for faster adaptation to changing conditions inside the sample concentration unit 100. In further embodiments not shown in the present disclosure, the sample concentration unit 100 may include the gas temperature regulating element 42 without the gas volume regulating element 43, or it may include the gas volume regulating element 43 without the gas temperature regulating element 42.

[0062] like Figure 2The sample concentration unit 100 shown further includes a sample temperature regulating element 15 operably connected to the sample receiving element 10 and an auxiliary temperature regulating element 16 operably connected to the cover element 20. The sample temperature regulating element 15 and the auxiliary temperature regulating element 16 include elements (15a, 16a) for supplying or removing heat, such as Peltier elements, and thermometers (15b, 16b) for monitoring the temperature of the sample receiving element 10 and the cover element 20, respectively. The sample temperature regulating element 15 indirectly supplies heat to the sample 1 or removes heat from the sample through the sample receiving element 10 made of a thermally conductive material (such as metal). On the other hand, the auxiliary temperature regulating element 16 supplies heat to the cover element 20 to indirectly provide heat to the sample 1 via the gas phase in the cavity 30 and prevent the gas phase from condensing on the cover element 20. Once the evaporation program starts, the controller 60 is provided with information about the sample 1, such as the sample type, the initial sample volume, the type and volume of the sample solvent added, the target analyte, the expected solvent evaporation level, the possible presence of other additives or reagents, etc. Based on these parameters, the controller 60 selects a suitable evaporation curve, and controls the sample temperature adjustment element 15 to provide heat to the sample 1 via the sample receiving element 10 according to the evaporation curve, and controls the auxiliary temperature adjustment element 16 to provide heat to the cover element 20 in cooperation with the vacuum pump 50 to generate a negative pressure in the cavity 30. By generating a negative pressure inside the cavity 30 and heating the sample 1 in a controlled manner at the same time, the boiling point of the sample 1 will be reached faster. Once a predetermined solvent evaporation level is reached, the controller 60 controls the temperature adjustment elements 15, 16, 42 to stop supplying heat to the sample receiving element or the cover element or the gas channel, respectively, or alternatively actively cools the sample receiving element or the cover element or the gas channel, respectively, by removing heat from the sample receiving element or the cover element or the gas channel. In addition, the controller 60 controls the vacuum pump 50 to stop generating a negative pressure inside the cavity 30 to stop the evaporation process.

[0063] like Figure 2 The cavity inlet 31 of the sample concentration unit 100 shown includes an airflow guide nozzle 33b for guiding the airflow into the cavity. The airflow guide nozzle 33b has a cylindrical shape, wherein its cross-sectional area is smaller than the cross-sectional area of ​​the gas channel 41, so as to concentrate and increase the speed of the airflow entering the cavity 30. The airflow guide nozzle 33b is fixedly mounted in the cover element 20 at a position where the airflow enters the cavity 30 in a direction parallel to the sample surface section 3 and at the level of the edge 14 of the sample container 13 (indicated by the solid arrow). Figure 2 The cavity 30 in the embodiment has a tapered shape in a horizontal direction toward the cavity outlet 32 ​​to support guiding the gas phase toward the cavity outlet 32 ​​when it is removed from the cavity 30 .

[0064] In the example of the evaporation procedure of sample 1, which is a serum sample mixed with a sample solvent (a mixture of 80% methanol and 20% water), the controller 60 controls the vacuum pump 50 to generate a negative pressure of about 29.7 kPa, and simultaneously controls the sample temperature adjustment element 15 to heat the sample to about 39.5° C. to reach the boiling point of the sample, at which mainly organic compounds will evaporate. During the evaporation process, these conditions will be adjusted according to the reduction of the methanol fraction in the mixture.

[0065] Figure 3 An example of a sample concentration unit 100 according to a further embodiment of the present disclosure is schematically shown. In this example, the cover element 20 is positioned in a closed state, i.e. it hermetically seals the sample receiving position 11, thereby forming a cavity 30 between the upper sample surface 2 and the cover element 20. The cavity outlet 32 ​​is formed in the cover element 20 above the sample receiving position 11 at an angle of 90° relative to the air flow guiding nozzle 33c. The cavity inlet 31 and the air flow guiding nozzle 33c are formed in the sample receiving element 10. The air flow guiding nozzle 33c includes sheet metal segments fixed to a rotatable ring, and when the ring rotates, the sheet metal segments can move relative to each other, so that the air flow guiding nozzle 33c can automatically adjust its diameter. The adjustment of the diameter of the air flow guiding nozzle 33c is controlled by the controller 60 and depends on the selected evaporation curve. During the evaporation process, the airflow enters the cavity 30 in a direction parallel to the sample surface cut plane 3 until it reaches the edge 14 of the sample container 13, where the airflow is partially torn above the edge 14, causing part of the airflow to enter the sample container 13, thereby generating a vortex above the sample surface 2 (caused by Figure 3 The airflow continues to travel in a direction parallel to the sample surface tangent plane 3 and then turns to the direction of the cavity outlet 32 ​​located above the sample receiving position 11 (indicated by the dashed arrow in the figure). Figure 3 Likewise, the vortex generated above the upper sample surface 2 further increases the removal rate of evaporated sample solvent (indicated by the solid arrows in Figure 3 The evaporated sample solvent is transported out of the cavity 30 through the cavity outlet 32 ​​by the air flow and the vacuum pump 50 .

[0066] Figure 4An example of a sample concentration unit 100 is schematically shown in a top cross-sectional view. The sample concentration unit 100 includes four sample receiving positions (10', 10", 10"', 10""). The sample concentration unit 100 includes a cover element 20 that hermetically seals the sample receiving positions (11', 11", 11"', 11""). The cross-sectional view shows four cavities (30', 30", 30"', 30""). Four cavity outlets (32', 32", 32"', 32"") corresponding to each sample receiving position (11', 11", 11"', 11"") are formed in the cover element 20 and are operably connected to a vacuum pump (50', 50", 50"', 50""). In addition, four cavity inlets (31', 31", 31"', 31"") corresponding to each sample receiving position (11', 11", 11"', 11"") are formed in the cover element 20, and each cavity inlet (31', 31", 31"', 31"") includes an airflow guiding nozzle (33', 33", 33"', 33""). The airflow guiding nozzles 33', 33", 33"' have a fixed diameter, wherein the diameters of the airflow guiding nozzles 33' and 33" are the same, but different from the diameter of the airflow guiding nozzle 33"'. The airflow guiding nozzle 33"" has an adjustable diameter. The airflow guiding nozzles (33', 33", 33"', 33"") are radially oriented (pointing to the center axis) relative to the vertical center axis of the sample receiving position (11', 11", 11"', 11""). Prior to the evaporation process, the controller 60 is provided with information about the sample (1', 1") intended for evaporation, and the controller 60 selects a suitable predetermined evaporation curve based on the information. The controller 60 controls the placement of the sample (1', 1") into one of the sample receiving positions (11', 11", 11"', 11"") according to the evaporation curve.

[0067] For example, the controller 60 receives an instruction to perform a diagnostic test on a sample 1' to detect a target analyte that does not require the addition of a sample solvent for extraction. Nevertheless, the test application requires evaporation of a certain volume of a liquid component of the sample 1', such as water, to concentrate the target analyte. The corresponding evaporation curve determines the conditions under which evaporation needs to occur. Therefore, the controller 60 controls the container 13' containing the sample 1' to be placed in the sample receiving position 11', because the sample receiving position 11' and its corresponding cavity inlet 31', the diameter of the airflow guiding nozzle 33' and the vacuum pump 50' have been adjusted for this type of evaporation curve. Once the sample container 13' has been placed in the sample receiving position 11', the controller 60 controls the corresponding subunit to start the evaporation program according to the evaporation curve. Specifically, the vacuum pump 50' cooperates with the airflow guiding nozzle 33' that introduces the airflow into the cavity 30' to generate a negative pressure in the cavity 30' (caused by Figure 4), which supports the removal of the evaporated liquid component of sample 1' as previously described.

[0068] In another example, the controller 60 receives an instruction to perform a diagnostic test to detect a target analyte, such as testosterone, in a sample 1″ that requires the addition of a certain volume of sample solvent (e.g., a mixture of methanol and water in a ratio of 80% to 20%). The test application for testosterone requires evaporation of a certain volume of sample solvent to concentrate the target analyte prior to liquid chromatography. The corresponding evaporation curve of testosterone determines the evaporation conditions. Based on the evaporation curve, the controller 60 controls the container 13″ containing the sample 1″ to be placed in the sample receiving position 11″″ and controls the corresponding airflow guiding nozzle 33″″ to adjust its diameter accordingly. In order to maximize throughput, the controller 60 aims to use as many sample receiving positions (11', 11", 11"', 11"") as possible during the evaporation cycle.

[0069] Figure 5a A sample concentration unit 100 according to a further embodiment is schematically shown in a top cross-sectional view. Figure 5b The same sample concentration unit 100 is schematically shown in a transverse cross-sectional view. Figure 4 The example in FIG. 1 is different from that in FIG. 1 and FIG. 2 is different from that in FIG. 1 and FIG. 3 is different from that in FIG. 1 and FIG. 4 ... Figure 5a The dispersed arrangement causes a spiral vortex, when a portion of the airflow is torn off above the edge 14 of the sample container 13 and enters the sample container 13 (indicated by the solid right arrow in the figure). Figure 5a and 5b When the sample 1 is heated to 100°, the spiral vortex is generated above the upper sample surface 2 of the sample 1, which supports the removal of the evaporated sample solvent (indicated by the dashed arrow in FIG. Figure 5b Indicated by the dotted arrow in the figure).

[0070] In the foregoing description, the apparatus and method according to various embodiments are described in detail. The apparatus and method can be embodied in many different forms and should not be construed as being limited to the embodiments set forth and illustrated herein. Therefore, it should be understood that the apparatus and method are not limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, these terms are used only in a general and descriptive sense, not for the purpose of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present disclosure belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present method, preferred methods and materials are described herein.

[0071] In addition, referring to an element by the indefinite article "a / an" does not exclude the possibility of the presence of more than one element, unless the context clearly requires that there is one and only one element. Therefore, the indefinite article "a / an" usually means "at least one". Similarly, the terms "have", "comprise" or "include" or any arbitrary grammatical changes thereof are used in a non-exclusive manner. Therefore, these terms can refer to the situation where there are no other features in the entity described in this context except the features introduced by these terms, or the situation where one or more other features are present. For example, expressions such as "A has B", "A contains B" and "A includes B" can refer to the situation where there are no other elements in A except B (i.e., A is only and exclusively composed of B), or the situation where there are one or more other elements in A except B, such as element C, element C and D or even other elements.

[0072] Furthermore, references throughout this specification to "one embodiment," "an embodiment," "an example," or "an instance" mean that a particular feature, structure, or characteristic associated with an embodiment or instance is included in at least one embodiment. Therefore, the phrases "in one embodiment," "in an embodiment," "an example," or "an instance" appearing in various places throughout this specification are not necessarily all referring to the same embodiment or instance.

[0073] Furthermore, the particular features, structures or characteristics may be combined in any suitable combinations and / or sub-combinations in one or more embodiments or examples, particularly but not limited to various forms and locations of airflow directing nozzles.

Claims

1. A sample concentrating unit (100) for concentrating an analyte in a sample (1, 1', 1") by evaporating a sample solvent, the sample concentrating unit comprising A sample receiving element (10) having at least one sample receiving location (11, 11', 11", 11"', 11""), the at least one sample receiving location having an opening (12) defined by an edge for receiving a sample (1, 1', 1") or an open sample container (13, 13', 13") containing a sample (1, 1', 1"), wherein the open sample container comprises a body having an interior space and an opening (14) defined by an edge, the interior space being suitable for receiving a liquid, Liquid can be introduced into the inner space through the opening (14); a cover element (20) for sealing the at least one sample receiving position (11, 11', 11", 11"', 11""), wherein the cover element (20) and the at least one sample receiving position (11, 11', 11", 11"', 11"") and / or the sample container (13, 13', 13") are designed to leave a cavity (30, 30', 30", 30"', 30"") between the cover element (20) and the upper sample surface (2); The sample concentration unit (100) further comprises a cavity inlet (31, 31', 31", 31"', 31"") connected to a gas source (40) via a gas passage (41) and comprising a gas flow guiding nozzle (33a, 33b, 33c, 33', 33", 33"', 33"") for guiding a gas flow into the cavity (30, 30', 30", 30"', 30""); a cavity outlet (32, 32', 32", 32"', 32"") connected to a vacuum pump (50, 50', 50", 50"', 50"") for generating negative pressure in the cavity (30, 30', 30", 30"', 30""); wherein the air flow guiding nozzles (33a, 33b, 33c, 33', 33", 33"', 33"") are arranged so that the air flow enters the cavity (30, 30', 30", 30"', 30"") at the same level as the edge of the sample receiving position (11, 11', 11", 11"', 11"") or the edge of the sample container (13, 13', 13") and in a direction parallel to the sample surface cut plane (3), thereby cooperating with the vacuum pump (50, 50', 50", 50"', 50"") to transport the evaporated sample solvent out of the cavity (30, 30', 30", 30"', 30"") through the cavity outlet (32, 32', 32", 32"', 32""), and A controller (60) is configured to control the vacuum pump (50, 50', 50", 50"', 50"") to automatically adjust the negative pressure in the cavity (30, 30', 30", 30"', 30"") to maintain the sample (1, 1', 1") at a boiling point until a predetermined sample solvent evaporation level is reached.

2. The sample concentration unit (100) according to claim 1 further comprises a pressure gauge (51) for measuring and monitoring the negative pressure generated by the vacuum pump (50) in the cavity (30), wherein the controller (60) is configured to control the vacuum pump (50) in response to the pressure measured by the pressure gauge (51) to automatically adjust the negative pressure in the cavity (30).

3. The sample concentration unit (100) according to claim 1 or 2 further comprises a gas temperature regulating element (42) connected to the gas channel (41), wherein the controller (60) is configured to control the gas temperature regulating element (42) to automatically adjust the gas temperature, and / or comprises a gas volume regulating valve (43), wherein the controller (60) is configured to control the gas volume regulating valve (43) to automatically adjust the volume of gas entering the cavity (30).

4. The sample concentration unit (100) according to any one of the preceding claims, further comprising at least one sample temperature adjustment element (15), wherein the controller (60) is configured to control the sample temperature adjustment element (15) to automatically adjust the sample temperature in the sample receiving position (11).

5. A sample concentration unit (100) according to any one of the preceding claims, wherein the diameter of the airflow guiding nozzle (33c, 33"") can be automatically adjusted or can be interchanged with another airflow guiding nozzle (33a, 33b, 33', 33", 33"') having a different diameter.

6. A sample concentration unit (100) according to any one of claims 1 to 4, comprising a plurality of sample receiving positions (11, 11', 11", 11"', 11"") and a corresponding air flow guiding nozzle (33', 33", 33"', 33"") for each of the sample receiving positions (11, 11', 11", 11"', 11""), wherein each air flow guiding nozzle (33', 33", 33"', 33"") has a different diameter.

7. A sample concentration unit (100) according to any of the preceding claims, wherein the controller (60) is configured to adjust the negative pressure and / or the gas temperature and / or the gas volume and / or the sample temperature and / or the gas flow according to a predetermined evaporation curve based on the type of analyte in the sample (1, 1′, 1″) and / or the type of solvent and / or the initial sample volume and / or the predetermined sample solvent evaporation level to take into account changes in sample volume and concentration during solvent evaporation.

8. A sample concentration unit (100) according to any of the preceding claims, wherein the cover element (20) is capable of being automatically removed from the sample receiving position (11, 11', 11", 11"', 11"") to automatically insert the sample (1, 1', 1") and / or the sample container (13, 13', 13") into the sample receiving position (11, 11', 11", 11"', 11"") or remove the sample (1, 1', 1") and / or the sample container (13, 13', 13") from the sample receiving position (11, 11', 11", 11"', 11"").

9. A sample concentration unit (100) according to any of the preceding claims, wherein the cavity outlet (32, 32', 32", 32"', 32"") is arranged opposite to the air flow guiding nozzle (33a, 33b, 33', 33", 33"', 33"") or is arranged in the cover element (20) above the sample receiving position (11) at an angle of approximately 90° relative to the air flow guiding nozzle (33c).

10. An automated method for concentrating an analyte in a sample (1, 1', 1") by evaporating a sample solvent, the method comprising Placing at least one sample (1, 1', 1") or an open sample container (13, 13', 13") containing the sample (1, 1', 1") at at least one sample receiving position (11, 11', 11", 11"', 11"") of the sample receiving element (10), wherein the sample receiving position (11, 11', 11", 11"', 11"") has an opening (12) defined by an edge for receiving the sample (1, 1', 1") or for receiving the open sample container (13, 13', 13"), and wherein the open sample container comprises a body having an inner space and an opening (14) defined by an edge, the inner space being suitable for receiving a liquid, and the liquid can be introduced into the inner space through the opening (14); The at least one sample receiving position (11, 11', 11", 11"', 11"") is sealed by means of a cover element (20), wherein the cover element (20) and the at least one sample receiving position (11, 11', 11", 11"', 11"") and / or the sample container (13, 13', 13") are designed to leave a cavity (30, 30', 30", 30"', 30"") between the cover element (20) and the upper sample surface (2); generating a negative pressure in the cavity (30, 30', 30", 30"', 30"") by means of a vacuum pump (50, 50', 50", 50"', 50"") connected to an outlet (32, 32', 32", 32"', 32""); A gas flow is introduced into the cavity (30, 30', 30", 30"', 30"") through a cavity inlet (31, 31', 31", 31"', 31"") connected to a gas source (40) via a gas channel (41), the cavity inlet (31, 31', 31", 31"', 31"") comprising a gas flow guiding nozzle (33a, 33b, 33c, 33', 33", 33"', 33""), wherein the gas flow guiding nozzle (33a, 33b, 33c, 33', 33", 33"', 33"") is arranged so that the generated gas flow is in contact with the sample The edge of the receiving position (11, 11', 11", 11"', 11"") or the edge of the sample container (13, 13', 13") is guided into the cavity (30, 30', 30", 30"', 30"") at the same level and in a direction parallel to the sample surface cut plane (3), so as to cooperate with the vacuum pump (50, 50', 50", 50"', 50"") to transport the evaporated sample solvent out of the cavity (30, 30', 30", 30"', 30"") through the cavity outlet (32, 32', 32", 32"', 32""); The sample concentration unit (100) is controlled to maintain the sample (1, 1', 1") at a boiling point until a predetermined solvent evaporation level is reached.

11. The method of claim 10, further comprising automatically adjusting the negative pressure in the cavity (30, 30', 30", 30'", 30") by controlling the vacuum pump (50, 50', 50", 50") in response to a pressure measured by a pressure gauge (51).

12. The method according to any one of claims 10 or 11, further comprising regulating the gas temperature by controlling a gas temperature regulating element (42) coupled to the gas channel (41).

13. The method according to any one of claims 10 to 12, further comprising regulating the gas volume by controlling a gas volume regulating valve (43).

14. The method according to any one of claims 10 to 13, further comprising controlling at least one sample temperature adjustment element (15) to adjust the temperature of the sample (1, 1', 1") in the sample receiving location (11).

15. The method according to any one of claims 10 to 14 further comprises adjusting the negative pressure and / or the gas temperature and / or the gas volume and / or the sample temperature and / or the gas flow according to a predetermined evaporation curve based on the type of analyte in the sample (1, 1′, 1″) and / or the type of solvent and / or the initial sample volume and / or the predetermined sample solvent evaporation level to take into account changes in sample volume and concentration during solvent evaporation.

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