Suction head

Abstract

The present invention relates to a device for aspirating liquid from a microplate equipped with a filter. The device includes an aspiration head (1), a collection reservoir (3), and a microplate mount (4) that locks the microplate in place and seals the connection between the aspiration head (1) and the microplate. The microplate mount (4) has an opening (4o) facing the collection reservoir (3). The aspiration head (1) also includes an aspiration vent (5) at the collection reservoir (3). Mounting the microplate on the microplate mount (4) creates a continuous cavity between the microplate and the collection reservoir (3). By applying negative pressure to the aspiration vent (5), liquid in the microplate is aspirated through the filter and into the collection reservoir through the opening (4o) in the microplate mount (4). In this way, the present invention creates a device that allows for simple and reliable filtration of liquid from many wells of a microplate. This device additionally allows for the safe filtration of hazardous liquids.

Description

[Technical Field]

[0001] The present invention relates to an aspiration head for aspirating liquid from a microplate equipped with a filter. The invention further relates to a filtration system and a dispensing / filtration system comprising such an aspiration head. Furthermore, the invention relates to a method for the automated injection of liquid into and filtration of liquid from a microplate. [Background technology]

[0002] Synthetic peptides play an important role in the pharmaceutical (e.g., drug discovery) industry and in other fields of research, such as biology or biomedicine. These molecular chains can be synthesized step by step by using the method of solid-phase synthesis (SPPS), beginning with the first amino acid, for example, chemically linked to a resin bead. To prevent unwanted reactions, these amino acids are protected on their otherwise reactive, unbound ends. Only upon addition of another substance is the protection removed, and the amino acid on the bead can be reacted with another suitably activated amino acid. The result of such cycles is a longer chain of amino acids linked to the resin bead, where the ends of the chain are again chemically protected. Repeated cycles of deprotection and subsequent coupling must be performed until an amino acid chain of the desired length and sequence is produced.

[0003] Other chain-like molecules, such as deoxyribonucleic acid (DNA), can be produced in similar processes. For modern research, it is essential to automate these types of processes as much as possible, especially when many different such molecules are produced in parallel.

[0004] Automated dispensing units can significantly improve throughput in some of the above-mentioned steps by automatically dispensing the necessary liquids for synthesis into several reaction vessels, such as the wells of a microplate.

[0005] However, the production of peptides, for example, also usually requires additional steps, where unwanted liquids must be removed from the reaction vessel before the next step in the production can be taken. For example, one process is repeated washing during and after the above cycles to remove excess reagents from the reaction vessel. Another example is cleaving, where the peptide linked to the resin bead is released from it and also fully deprotected by the addition of a cocktail of agents, such as trifluoroacetic acid (TFA).

[0006] Several concepts exist for achieving automatic removal of liquid from reaction vessels: for example, commercially available dispensing and washing units are equipped with several aspiration needles that are moved into the vessels to suck out the liquid.

[0007] Here, the drawback is that the aspiration needle can become clogged and must be rinsed separately, preferably after each step. Also, the size of the reaction vessel poses geometric constraints for the maximum needle size (and vice versa), which means that only a spatially limited density of reaction vessels can be used with this type of device.

[0008] Another method for removing liquid from a reaction vessel in the context of automated peptide synthesis is described in Patent Document 1 (CEM Corporation). This document discloses an improved method for deprotection in solid-phase peptide synthesis. The proposed method involves reducing the atmospheric pressure in the reaction vessel by drawing a vacuum, thereby removing the liquid by evaporation. This can be combined with microwave heating of the liquid to further accelerate vacuum removal. This can allow peptide synthesis to be performed while avoiding two steps: washing and draining.

[0009] A drawback of this method is the complex equipment required to perform the disclosed steps. The evaporation process is plagued by condensation, and great care must be taken to ensure that any condensation does not interfere with other steps in the process, such as peptide synthesis. In addition, the process, like microwave heating, as mentioned in U.S. Pat. No. 5,629,499 (CEM Corporation), is temperature-dependent (meaning that additional equipment may be required), making the equipment expensive and complex. A third drawback is that cleavage, as in peptide synthesis, as described above, cannot be easily performed in this way (here the liquid itself is the subject of interest and therefore needs to be recaptured from the vapor).

[0010] Additionally, cleaving can be performed using substances that are harmful to humans, making any vaporization of this substance potentially dangerous, which further increases the complexity of the process as the protection of any personnel must be guaranteed. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] US Patent Application Publication No. 2019 / 0194246 Summary of the Invention [Problem to be solved by the invention]

[0012] The present invention aims to create a method and a device related to the technical field mentioned at the beginning, which method and device allow a simple and reliable filtration of liquid from many wells of a microplate. [Means for solving the problem]

[0013] The solution of the invention is defined by the features of claim 1. According to the invention, the aspiration head comprises a collection reservoir, a microplate mount and an aspiration vent in the collection reservoir.

[0014] The microplate mount serves to lock the microplate in place and seal the connection between the aspiration head and the microplate, and has an opening facing the collection reservoir. The collection reservoir, microplate mount, and aspiration vent are positioned such that mounting of the microplate on the microplate mount creates a continuous cavity between the microplate and the collection reservoir. By applying negative pressure to the aspiration vent, liquid in the microplate is drawn through the filter and through the opening in the microplate mount into the collection reservoir.

[0015] Such aspiration heads are devices that allow the filtration of liquids from many wells of a microplate. To describe the orientation of some devices or components, the terms: up, down, upper, lower, horizontally, etc. will be used below. The invention will typically be used in an environment with gravity, and these terms then refer in the usual way to the intended orientation relative to this force.

[0016] In the following, the term liquid refers to the liquid substance to be filtered from the microplate. Liquid is any type of substance that is liquid or viscous during use of the suction head. In most applications, any type of substance will be liquid at room temperature, but it can be said to be a cooled substance that is gaseous at room temperature or a heated substance that is solid at room temperature. Instead of or in addition to the substance temperature, the device of the present invention can be used in ambient conditions that are artificially created (e.g., by lowering or increasing the ambient temperature and / or by lowering or increasing the atmospheric pressure) to maintain the substance in a liquid state.

[0017] A microplate is a flat plate with multiple openings called wells that can be used as sample holders or test tubes for parallel chemical experiments and / or for preparing chemicals. A microplate typically contains 96 to 384 wells (with variations having fewer or more wells) and is usually rectangular in format. Hereinafter, the term "microplate" refers to a microplate in which a well is characterized by a through-hole that penetrates the base of the microplate (i.e., each well is characterized by a channel from the top side of the microplate to its bottom side). Microplates of this type are commercially available or can be generated in a laboratory environment by drilling holes into commercially available microplates that do not originally contain such holes. The preferred material for such microplates is polypropylene.

[0018] The filter can be of any material that is permeable to the liquid being used or its components (at least when the liquid exerts a minimum pressure on the material). This can be, for example, commercially available dew paper. It may be useful for some applications of the present invention for the filter medium to be of limited permeability only when the liquid exerts hydrostatic pressure that would result from the amount of liquid filling a microplate well.

[0019] In particular, a filter is contained within each of the wells (or designated subgroups of wells). Alternatively, in principle, a common filter for some or all of the wells may be attached to the backside of the microplate.

[0020] When a higher pressure of ambient gas (usually air) exists above the microplate compared to the pressure below the microplate, the gas above the microplate exerts a force on the liquid in the microplate wells and pushes the liquid through the filter. According to the present invention, this pressure difference is created by establishing a negative pressure below the microplate, where the negative pressure refers to a pressure lower than the gas pressure surrounding the aspiration head when the microplate is mounted on the microplate mount. In most applications, this ambient pressure will be normal atmospheric pressure, but it could also be the pressure of an artificial ambient atmosphere, e.g., pure nitrogen gas.

[0021] The force generated due to a pressure difference, especially due to the presence of a negative pressure, is referred to below as suction. The microplate mount is an area of ​​the aspiration head that contains functional elements for locking a microplate in place above a collection container. The microplate mount of the present invention locks a microplate in place on the aspiration head so that the microplate cannot move freely relative to the aspiration head and / or collection container.

[0022] The microplate mount features openings facing the collection container so that air and liquid can pass through the majority (in particular all) of the microplate wells and into the collection container (unless these wells are blocked with respect to the respective substances by other means, e.g., by a filter).

[0023] Preferably, the opening is continuous, allowing for easy manufacturing and transmitting the negative pressure of the collection vessel to microplates with large numbers of wells, such as microplates with 1536 wells.

[0024] The microplate mount also creates a sufficiently sealed connection to maintain negative pressure within the collection reservoir and prevents airflow between the microplate and the collection reservoir other than through the microplate wells.

[0025] To this end, the microplate mount includes a contact surface that forms a continuous contact area with the microplate around the opening of the microplate mount when the microplate is placed on the microplate mount.

[0026] Preferably, the microplate mount may feature one or more surfaces that provide additional surface area for stabilizing the microplate against movement (e.g., horizontal or vertical movement) and ensuring correct placement of the microplate relative to the aspiration head. This may be achieved by an additional portion of the microplate mount that surrounds the microplate and is inserted into the microplate mount.

[0027] In addition, the microplate mount may also preferably feature a movable part that can exert a force on the microplate to strengthen the mutual contact within the contact area. This can be achieved, for example, by a clamping block connected to the aspiration head by a screw. Such a clamping block can overlap at least a portion of the microplate. When the screw is tightened, the clamping block is brought closer to the collection container, and the portion of the clamping block that overlaps the portion of the microplate presses the microplate against the contact surface of the microplate mount. Alternatively, the contact surface of the microplate mount that forms the contact area for the microplate can be of such quality that the microplate does not need to be additionally pressed into the collection container.

[0028] The aspiration vent is a channel that can transport gas and liquid from at least the continuous cavity between the collection reservoir and the loaded microplate to the outside of the aspiration head. By applying negative pressure to one side of the aspiration vent, air will flow through the aspiration vent and transmit the negative pressure to the other side of the vent. Thus, negative pressure applied to the outside of the aspiration head at the aspiration vent is transmitted into the collection reservoir of the aspiration head as air moves from the collection reservoir through the aspiration vent. The aspiration vent is also a channel through which liquid is removed from the collection reservoir. In a preferred embodiment of the invention, the collection reservoir has exactly one vent (aspiration vent) apart from the microplate mount. Alternatively, there can be several vents in the aspiration head, where at least one of them serves as a aspiration vent.

[0029] There are various means of generating negative pressure at the end of the suction vent. Many chemistry labs can already provide negative pressure through their standard installation. In other cases, a local vacuum pump can be used. Many different types of vacuum pumps are known and commercially available.

[0030] The negative pressure created by this external device and the device itself will be referred to herein as laboratory vacuum. The collection reservoir is a part of the aspiration head that at least partially (preferably completely) encloses a volume between the aspiration vent and the mounted microplate on the microplate mount. This volume is a continuous cavity that allows gas or liquid to travel from the microplate's accommodation provided by the microplate mount into the aspiration vent.

[0031] Negative pressure from the outside of the suction vent can be transmitted to the bottom of the microplate via the collection container, creating a suction force on most of the microplate wells and drawing liquid from the microplate into the aforementioned region. The collection container can also be equipped with, for example, multiple suction vents. To create negative pressure inside the collection container, negative pressure can be applied to all of them, or alternatively, negative pressure can be applied to one or some of them while the rest are blocked.

[0032] Preferably, the collection vessel has a cuboid shape and has a recess in its upper side, creating a closed volume that is open only to the top, the recess preferably having a horizontal geometry in its upper region (matching the horizontal geometry of the distribution of wells on the microplate).

[0033] Preferably, the collection vessel comprises a portion that includes or is made entirely from polyether ether ketone (PEEK), although other materials are possible, such as aluminum, ceramic or stainless steel.

[0034] The aspiration head with its microplate mount, suction vent, and collection reservoir creates a device that allows liquid to be aspirated from multiple wells in a microplate by mounting the microplate in the microplate mount and applying negative pressure to the suction vent. The collection reservoir will transmit negative pressure to the bottom side of the microplate, where suction will act on the liquid in the microplate wells. This suction will draw the liquid through the filters in the microplate wells and into the collection reservoir. This allows for simple and reliable filtration of liquid from multiple wells of a microplate. Depending on the application, either the remaining filtrate in the microplate can be further processed (e.g., for rinsing during SPPS as described above) or the liquid itself can be collected and used (e.g., after cleaving during SPPS as described above).

[0035] In a preferred embodiment of the present invention, the microplate mount includes a gasket (especially a polytetrafluoroethylene (PTFE) gasket), which ensures an airtight connection between the microplate and the aspiration head, apart from the microplate wells. Alternatively, microplates that themselves feature gaskets on their bottom side, or microplates with sufficiently flat surfaces that do not require a gasket to create an airtight connection, can be used. A gasket (especially a PTFE gasket) as part of the microplate mount has the advantage of lower requirements for the microplates used. PTFE has the advantage of high chemical stability.

[0036] Preferably, the inner surface of the collection canister is sloped, and the suction vent is located at the bottom of this slope within the collection canister. "Sloped" here generally means that at any point on the inner surface, there is a path to the lowest height carried by the inner surface without the need to climb at any point along this path. In a preferred embodiment, this is achieved by the inner surface having at least one flat surface that is sloped (with respect to the direction of gravity) compared to the horizontal. Alternatively, it can be any other shape that meets this requirement.

[0037] The bottom of the ramp refers to the area "where the interior surface of the collection container has its lowest height and can be a point, a curve, a surface, or any number of these." Being located at the bottom of the ramp means that the point that is part of the suction vent is equal to any of the above points, including the bottom of the ramp.

[0038] In a preferred embodiment of the present invention, the inner surface of the collection container has a form in which the sloped bottom is one continuous area and the suction vent is located in this area. This can be realized, for example, by a collection container formed by a body having a cuboid shape with a recess on its upper side, where the upper side is horizontal and forms an opening facing the microplate mount, four sides are vertical and form walls, and the lower side forms the bottom of the recess. The bottom can now be inclined to form a slope compared to the horizontal plane. In addition, the vertical wall adjacent to the sloped bottom can be at an angle other than 90° with its two other adjacent vertical sides. Thus, the minimum height of the recess is one corner of the cuboid, and the suction vent can be located here.

[0039] Alternatively, the inner surface of the collection container can have any other shape. The advantage of having a sloped inner surface is that liquid entering the collection container from above will flow down the slope and thereby collect in the intended area (where the suction vent is located). This allows for efficient suction of liquid from the suction head out of the collection container through the suction vent, thereby enabling subsequent use of the suction head.

[0040] In a preferred embodiment of the present invention, the suction vent includes a check valve to prevent liquid from leaking from the suction head when the check valve is in the closed position. The check valve is a valve that includes a mechanism that closes the check valve when a specific force is not acting on it. This embodiment allows the suction head to be used reliably even in installations where the suction head is temporarily disconnected from the laboratory vacuum. The check valve in the suction vent then closes the suction vent, thereby preventing any unwanted leakage. This has the following advantage: the suction head can also be used with liquids that need to be handled with care because they may damage other equipment or even be harmful to humans. Alternatively, the suction vent can be dispensed with without a check valve, for example, if the liquid is not a danger to both equipment and humans and leakage is acceptable. Also, in some embodiments where the suction head is permanently connected to the laboratory vacuum, the check valve may be omitted.

[0041] In a preferred embodiment, the check valve opens when a biasing force from outside the suction head is applied to a spring-loaded body inside the check valve. Such a biasing force may be provided by a connector unit, further described below. Such a check valve may be easily opened from the outside to allow connection between the suction head and laboratory vacuum, and automatically closes when the connection is broken.

[0042] The advantage of this type of check valve is that it closes the suction vent of the collection container, thereby stopping any liquid from flowing through the suction vent in an unwanted manner when the connection to the outer part of the suction head is closed. Only when a pushing force is applied will the check valve open and allow gas or liquid to pass through the suction vent.

[0043] In another preferred embodiment, the check valve may include a spring-loaded body that opens only when a strong enough force from inside the collection canister pushes against the body, where the check valve will open when negative pressure is applied to the outer end of the suction vent, but will block the suction vent in the absence of any such negative pressure (i.e., the spring force pushes against any hydrostatic pressure of the liquid in the collection canister).

[0044] In yet another alternative embodiment, the check valve includes an electromagnet, which allows the check valve to be opened and closed electrically by energizing or turning off the electromagnet. Alternatively, check valves can also be used where an external electromagnet exerting a force on the check valve opens and closes the check valve. A further alternative is a check valve that opens and closes by other electrical means (such as an electric motor), pneumatic or hydraulic means.

[0045] Preferably, the check valve comprises parts made from one of the following materials: stainless steel 1.4401 (grade 316) or stainless steel 1.4404 (grade 316L). Alternatively, the check valve can also be produced from other materials, such as aluminum or alloys containing titanium or tantalum. Particularly preferred embodiments of the check valve comprise parts made from sapphire and / or parts made from ruby.

[0046] Preferably, the check valve in any of the described embodiments includes a ball whose position within the check valve opens and closes the valve. Preferably, the aspiration head has a contact geometry (matching the receiving geometry of its own microplate mount) on its outer surface opposite the microplate mount. This allows the aspiration head to be placed into a type of mount that also locks the microplate in place (especially in a pipetting system). The contact geometry is one or several outer surfaces that contact such a mount when the aspiration head is placed into the mount. The receiving geometry here refers to the set of surfaces on the microplate mount that form a contact area when a microplate is inserted into the microplate mount. This also does not necessarily include additional contact areas that are only created when the microplate is locked in place (e.g., by tightening a spring or closing some type of clamp) after its insertion into the microplate mount.

[0047] If the aspiration head features a geometry that matches this receptacle geometry, it can be placed into such a microplate mount. And since the microplate mount of the aspiration head itself has the receptacle geometry of one or several types of microplates, the aspiration head will fit into a series of microplate mounts designed for this type of microplate. Thus, the aspiration head constitutes an adapter that provides the same receptacle as the element to which it is attached, and the same microplate can be used with this element selectively with or without the adapter.

[0048] Preferably, the contact geometry on the aspiration head is arranged such that a microplate mounted on the microplate mount of the aspiration head inserted into the external mount is only moved vertically compared to the case where the microplate is placed directly into the external mount without the aspiration head therebetween.

[0049] In a preferred embodiment of the present invention, the maximum height of the aspiration head is less than 30% of its maximum width. The maximum height refers to the maximum dimension of the aspiration head along a vertical line, while the maximum width is its maximum dimension along a horizontal line. The advantage of a height less than 30% of the maximum width is that the aspiration head produces a body that is relatively flat and therefore suitable for applications where the height of the aspiration head is important. This is the case, for example, when the aspiration head is inserted into laboratory equipment that was not originally designed with the aspiration head in mind, thus imposing constraints on the possible aspiration head, especially when the top of the microplate still needs to be accessible by such equipment. Alternatively, the aspiration head can have any other relative dimensions, which has the disadvantage that it may not be easily integrated into existing equipment.

[0050] A preferred embodiment of the present invention is a filtration system comprising an aspiration head as described above together with a vacuum unit connectable to the aspiration vent of the aspiration head and including a vacuum connection connectable to a vacuum source, which can be any external laboratory vacuum such as a local vacuum pump or a stationary vacuum system.

[0051] The vacuum unit interfaces between the laboratory vacuum and the suction head. The vacuum unit is connectable to the suction vent of the suction head, and when the connection is open between the suction head and the vacuum connection, the vacuum unit transfers negative pressure from the laboratory vacuum to the suction vent of the suction head.

[0052] Alternatively, the suction head itself may contain a vacuum pump with no further connection required, or the suction head may be connected to a laboratory vacuum without the vacuum unit, but in this case the laboratory vacuum and the suction head must be compatible.

[0053] In a preferred embodiment of the filtration system, the vacuum unit includes a vacuum valve connectable to the suction vent and having an open configuration and a closed configuration, the open configuration opening the connection to the suction head and the closed configuration closing the connection.

[0054] When the vacuum unit is connected to the suction head and the laboratory vacuum and the vacuum valve is opened, the vacuum unit transmits negative pressure from the laboratory vacuum to the suction head. Preferably, the vacuum valve is a two-port valve that can be opened and closed electrically, and in a particularly preferred embodiment, can be opened and closed by an external signal, which can be either an analog signal or a digital signal. Alternatively, the vacuum valve can also be a manual valve. Also alternatively, the vacuum unit can be designed without a vacuum valve. In this case, to switch off the negative pressure at the suction head, either the connection to the suction head is broken or the laboratory vacuum is turned off.

[0055] Preferably, the suction head is movable independently of the vacuum unit within a range, and this range includes at least one contact position of the suction head, at which position the filtration system has a configuration in which the vacuum unit is connected to the suction head.

[0056] "Connected" defines that "the vacuum unit establishes negative pressure in the aspiration head with a loaded microplate" when negative pressure exists at the vacuum connection of the vacuum unit and (if present) the vacuum valve of the vacuum unit is opened. In contrast, "disconnected" or "detached" defines that "the vacuum unit does not establish negative pressure in the aspiration head with a loaded microplate" even when negative pressure exists at the vacuum connection and the vacuum valve is opened.

[0057] In the filtration system described above, the aspiration head with a loaded microplate can be moved to use the microplate in processes other than filtration, such as dispensing liquid into the microplate. However, for this filtration to occur, the aspiration head must be (at least temporarily) connected to a vacuum unit. Therefore, the range of movement must include at least one contact position of the aspiration head with the vacuum unit that allows such connection. When the aspiration head with a loaded microplate is used in other processes, either the aspiration head is permanently connected to the vacuum unit, for example, by a flexible tube that allows a range of movement, or the filtration system is only temporarily connected and then disconnected again. The filtration system can be designed, for example, so that when the aspiration head is in the contact position, the aspiration vent and part of the vacuum unit have a contact area that establishes a connection between the aspiration head and the vacuum valve. When the vacuum valve is now opened, negative pressure from the laboratory vacuum establishes negative pressure within the aspiration head and possibly strengthens the connection.

[0058] The independence of the aspiration head has the advantage that the system allows for easy integration of the aspiration head in workflows that require movement of microplates. Alternatively, the vacuum unit can be permanently fixed to the aspiration head in a way that does not allow any relative movement of the two parts. This has the advantage that the vacuum unit needs to be moved together with the aspiration head or the process needs to be adapted to a fixed microplate.

[0059] In a preferred embodiment of the present invention, the filtration system has a vacuum unit including a connector unit, while the suction head is placed in a contact position with the vacuum unit, the connector unit has a connection configuration in which it is connected to a suction vent of the suction head and a non-connection configuration in which it is not connected to the suction head, and the connector unit is switchable from the connection configuration to the non-connection configuration (and vice versa).

[0060] The connected configuration defines a configuration in which the vacuum unit is connected to the suction head, while the disconnected configuration defines that the suction head and the vacuum unit are disconnected. The ability to switch indicates that the connector unit can reproducibly establish and break the connection between the suction head and the vacuum unit either electrically or by mechanical manipulation by a laboratory technician.

[0061] Such a connector unit is part of the vacuum unit and can therefore be connected to the vacuum valve of the vacuum unit if the vacuum unit has such a valve, or to the laboratory vacuum itself. Such a connector unit can be connected to and disconnected from the suction head as long as the suction head is in a specific contact position relative to the vacuum unit. The connector unit can be connected to the suction head, for example, by moving a part of it into the suction vent of the suction head or by moving a part of it in the opposite direction of the suction head at the location of the suction vent. Alternatively, the contact position of the suction head can already be selected in such a way that the suction vent touches the connector unit, and the connector unit opens or closes an internal valve to establish connection of the suction head to the vacuum unit. Alternatively, the vacuum unit can be designed without a connector unit (e.g., by using a flexible tube that permanently connects the vacuum unit and the suction head).

[0062] In the case where the filtration system is temporarily disconnected, the connection can be established either by electrical signals or by manipulation by a laboratory technician, and is preferably easy and fast to do. A laboratory technician here refers to any person who uses any of the described systems or devices.

[0063] Preferably, the connector unit as described above can be switched from a disconnected configuration to a connected configuration by being moved toward or away from the suction head (or vice versa). A movably mounted connector unit can establish a connection to the suction head by being moved toward the suction head and to a position where the connector unit is in direct contact with some portion of the suction head (and thus connected to the suction head). To disconnect the vacuum unit from the suction head, the connector unit is moved away from the suction head. In a preferred embodiment of the filtration system, this type of connector unit is combined with a check valve as described above. By moving into a predetermined position, the connector unit can not only establish a connection between the vacuum unit and the suction head but also open the check valve (e.g., by applying a biasing force to a spring-loaded body in the check valve or by negative pressure force). Alternatively, the connector unit can also make electrical contact with a suitable check valve to open it, or the connector unit can include an electromagnet that exerts a force on the check valve to open it.

[0064] Conversely, when the connector unit is moved away from the suction head, the check valve closes and the connection is broken. The movement itself can be caused by a pneumatic or hydraulic cylinder connected to the connector unit in the vacuum unit or to a stepper motor in the vacuum unit. In alternative embodiments, the connector unit can also be fixed relative to the vacuum unit and the connection established in another way (for example by the pull of an electromagnet).

[0065] Another preferred embodiment of the present invention is a dispensing / filtration system comprising a filtration system as described above and a dispensing unit for automatic dispensing of liquid into a microplate (including a movable carrier for the microplate (on which the suction head is mounted)).

[0066] A dispensing unit is a device that automatically dispenses various liquids into defined wells of a microplate in a predetermined volume and sequence. These units are commercially available and used in many laboratories for various applications, such as high-throughput screening (HTS) or biochemical analysis. An example of such a device is the CERTUS FLEX dispensing system manufactured by Fritz Gyger AG. It features a dispensing head with several valves for various substances, which can move along multiple directions (one horizontally and one vertically). The dispensing head is placed on a movable microplate carrier with a receiving geometry for receiving the microplate. The movable carrier can move along a horizontal direction perpendicular to the horizontal direction of movement of the dispensing head. This allows the dispensing unit to place any valve of its dispensing head over any well of a microplate on the movable carrier. Both the dispensing head and the microplate carrier are moved by electric motors within the dispensing unit. Precise control of these motors and possibly one or several valves enables the dispensing unit to automatically dispense liquids into the microplate.

[0067] In a preferred embodiment of the present invention, the aspiration head from the filtration system as described above is mounted on a carrier, which means that the aspiration head is placed on the carrier in such a way that a microplate attached to the microplate mount of the aspiration head is still accessible for automatic dispensing by the dispensing unit.

[0068] For this purpose, the aspiration head may be placed on a part of the carrier intended to be in contact with the microplate, or the aspiration head may be placed on the carrier in a way that it contacts other areas of the carrier rather than the way the microplate does. The aspiration head may also be additionally fixed to the carrier.

[0069] Preferably, the dispensing / filtration system includes a control unit that can control the automated dispensing of liquid into the microplate and the movement of the carrier, as well as open and close the vacuum valve. Such a control unit can control all relevant parts (e.g., motors, valves, and sensors) within the dispensing unit to perform the automated dispensing. The control unit can also control the movement of the carrier (which would normally already be necessary for automated dispensing). In addition, the control unit controls the opening and closing of the vacuum valve within the vacuum unit. This allows for centralized control of the dispensing / filtration functions of the dispensing / filtration system and therefore allows for the coordination and programming of processes involving both filtration and dispensing steps.

[0070] To control the filtration process (e.g., after the dispensing process), the control unit opens and closes the vacuum valve of the vacuum unit, while the laboratory vacuum does not need to be operated. If necessary, the control unit can also move the carrier into contact with the vacuum unit.

[0071] Alternatively, the dispensing unit and filtration system may be controlled by independent controllers, but this makes it more difficult to automate processes that involve both filtration and dispensing. In a preferred embodiment of the dispensing / filtration system, the control system also controls the switching of the connector unit between the connected and disconnected configurations. In this embodiment of the invention, the dispensing / filtration system includes a connector unit in a vacuum unit. The control unit also controls the connector unit to allow full automation of the process, including the dispensing and filtration steps. Preferably, the vacuum unit is located within the range of movement of the carrier but outside the area where dispensing takes place. The following procedure can serve as an example of a control sequence for the control unit. This is, of course, not exhaustive or exclusive of the possible sequences that can be realized by the control unit of such a system: Starting with the filtration step (e.g., after a dispensing step), the control unit moves the carrier into contact with the vacuum unit. The control unit then switches the connector unit from the disconnected configuration to the connected configuration. Here, for example, the connector unit moves toward and away from the check valve in the suction vent of the aspiration head, opening this valve with its pressing force. The control unit then also opens the vacuum valve, and negative pressure from the laboratory vacuum is transmitted into the aspiration head. Now, liquid is first aspirated from the microplate wells into the aspiration head and then continuously aspirated through the aspiration vent into the waste container of the laboratory vacuum. To stop the filtration, either the vacuum valve is closed or the connector unit is switched to the disconnected configuration. Once both steps are taken, the carrier can again leave the contact position (e.g., under the dispenser head for a new dispensing operation). This allows many dispensing and filtration steps to be performed automatically without the need for intervention by a laboratory technician and also helps protect anyone from harm due to the hazardous materials involved.

[0072] The present invention also relates to a method for automated injection of liquids into and filtration from a microplate, said method comprising the steps of: - providing a dispensing unit having a movable carrier; - providing a suction head, the suction head comprising: - collection containers, - a microplate mount for locking the microplate in place and sealing the connection between the aspiration head and the microplate, the microplate mount having an opening facing towards the collection vessel; and - providing a suction head, including a suction vent in the collection container; - providing a filter-equipped microplate; - mounting the filter-equipped microplate onto an aspiration head to create a continuous cavity between the microplate and the collection vessel; - placing the suction head on the movable carrier of the dispensing unit; - dispensing liquid into a number of wells in the microplate using a dispensing unit; - Applying negative pressure to the aspiration vent of the aspiration head to filter the liquid from the microplate into a collection vessel.

[0073] The mounting of the microplate onto the aspiration head and the installation of the aspiration head onto the movable carrier can be performed manually by a laboratory technician or with the aid of another device, such as a handling system, that can hold and position the microplate or the aspiration head, respectively. There are various ways of installing the aspiration head onto the movable carrier as described above. Preferably, the aspiration head includes a geometric shape that allows it to be inserted in the same way as the microplate is inserted into the movable carrier. However, it is also possible that the aspiration head is installed onto the movable carrier in a different way.

[0074] One application of the method of the present invention is peptide synthesis, where different liquids need to be added to reaction vessels at different times during synthesis. The dispensing unit can do this automatically and, depending on programming, can also vary the material in individual wells of a microplate. The number of wells can be any number between one and the number of wells available on the microplate.

[0075] By using an aspiration head as described above, the removal of liquid from the microplate can be done automatically without manual handling of the liquid by a laboratory technician and even without removing the microplate from the dispensing unit, which also allows for the introduction of hazardous substances (e.g., emitting toxic vapors) into a process that does not pose any risk to humans.

[0076] In a preferred embodiment of the method, a dispensing / filtration system as described above is used, which includes a vacuum unit with a connector unit. The following steps may then advantageously be included in the process: - moving a movable carrier having a suction head from a dispensing position into a contact position with a vacuum unit; - switching the connector unit from a disconnected configuration to a connected configuration; - switching the connector unit from a connected configuration to a disconnected configuration after filtering the liquid from the microplate.

[0077] According to a first of these steps, the carrier carrying the aspiration head and the microplate is moved to a position suitable for the vacuum unit to connect to the aspiration head. The vacuum unit, including the connector unit, needs to be connected to the aspiration head via the connector unit. For this purpose, the connector unit is switched to a connected configuration, allowing the vacuum unit to apply negative pressure to the aspiration vent of the aspiration head. Switching from the connected configuration to the disconnected configuration releases the aspiration head and allows the carrier to move to a position where, for example, a dispensing unit can dispense another liquid into the microplate. The carrier can also be moved to the withdrawn position if either the aspiration head with the loaded microplate is withdrawn from the dispensing / filtration system or if only the microplate is withdrawn from the dispensing / filtration system (manually or by a handling device).

[0078] Other advantageous embodiments and combinations of some features arise from the following detailed description and from the claims as a whole. The accompanying drawings used to explain the embodiments show the following figures: [Brief explanation of the drawings]

[0079] [Figure 1] 1 is an embodiment of a suction head according to the invention in isometric projection; [Figure 2] FIG. 1 is a direct top view of the suction head. [Figure 3] FIG. 1 is a direct side view of the suction head. [Figure 4] FIG. 1 is an isometric view of an aspiration head with a mounted microplate. [Figure 5] FIG. 10 is a direct top view of the aspiration head with the loaded microplate. [Figure 6] FIG. 10 is a direct side view of the aspiration head with the loaded microplate. [Figure 7] FIG. 1 is a cross-sectional view of an aspiration head with a loaded microplate. [Figure 8A] 1 is a cross-sectional view of a check valve of a suction head according to a first embodiment of the present invention; [Figure 8B] 2 is a cross-sectional view of a check valve of a suction head according to a second embodiment of the present invention; [Figure 9A] 1 is a first embodiment of a filtration system according to the invention in a disconnected configuration as a cross-section. [Figure 9B] 1 is a first embodiment of a filtration system according to the invention in a connected configuration as a cross-section. [Figure 10A] 2 is a second embodiment of a filtration system according to the invention in a disconnected configuration as a cross-sectional view. [Figure 10B] 2 shows a second embodiment of a filtration system according to the invention in a connected configuration as a cross-section. [Figure 11] 1 is a first embodiment of a filtration system as an isometric projection. [Figure 12] 1 is a schematic isometric view of one embodiment of a dispensing / filtration system according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0080] In the accompanying drawings, like parts are given like reference numerals. Figures 1-3 show the suction head 1 in an isometric projection (Figure 1), a direct top view (Figure 2) and a direct side view (Figure 3). With respect to the isometric projection of Figure 1, the height of the object is shown as upright on the screen, i.e., any edges of the object that would be upright if the object were placed on a flat surface are shown as upright on the screen.

[0081] The aspiration head 1 includes a collection reservoir 3 and a microplate mount 4 (shown in FIG. 4) for locking the microplate 2 in place, the microplate mount 4 and collection reservoir 3 being integral parts of the aspiration head 1. The aspiration head 1 further includes an aspiration vent 5 and a check valve 6.

[0082] The collection container 3 of the suction head 1 has a body 3a with an externally elongated cuboid shape: two parallel sides are longer than the other two. The height of the body 3a of the collection container 3 is approximately 10% of the length of its longest side. The long sides are approximately 1.5 times longer than the short sides. On its upper side, the body 3a of the collection container 3 has a cuboid recess that creates a basin with a lower side 3s, four upright side walls, and an upper opening 4o. The peripheral wall thickness of this basin is approximately 10% of the length of the short sides of the collection container 3. The lower side 3s of the basin is inclined compared to the horizontal plane (see also Figure 7). The depth of the basin is at least approximately 50% of the height of the upper body 3a at the upper side of the incline and approximately 90% at its deepest point.

[0083] Additionally, the inner surface 3w of the wall facing the bottom of this slope is angled, i.e., at an angle of approximately 95° to 85° relative to the adjacent inner wall. The slope of the inner surface 3s and the inner surface 3w create an area near the corner of the collection container 3 where the basin has its maximum depth. This is where the suction vent 5 along with the check valve 6 are located.

[0084] The suction vent 5 is a channel that penetrates the outer wall of the collection basin 3, leading from the tray to the outer wall of the suction head 1. Its outer opening is circular with a diameter approximately 40% of the height of the collection basin 3. Within the suction vent 5 and extending outward from the collection basin 3 is a check valve 6. A more detailed view of the suction vent 5 and check valve 6 is provided in Figures 8 and 9.

[0085] The upper surface of the upper body 3 a of the collection container 3 is also the base of a part of the microplate mount 4 . The microplate mount 4 contains various elements for locking the microplate 2 in place (see FIG. 4). The microplate mount 4 also serves to seal the connection between the microplate 2 and the collection container 3.

[0086] The components of the microplate mount 4 are an opening 4o, corners 4e1-4e4, clamps 4s1-4s4, and a PTFE (polytetrafluoroethylene) gasket 4c. The PTFE gasket 4c is a support for the microplate 2 that is placed in the microplate mount 4. The PTFE gasket 4c forms a rectangular closed curve and completely surrounds the opening 4o on the upper side of the collection container 3 (see Figures 1 or 2). Its thickness is about 1 / 3 of the wall thickness of the collection container 3, except for the wall at the inner surface 3w (which is partially thicker due to the slope of the inner surface 3w).

[0087] The PTFE gasket 4c is placed in a groove in the upper surface of the wall surrounding the basin of the collection container 3 so that in a stress-free position its upper surface projects slightly above the upper surface of the collection container 3 (see Figure 7).

[0088] There are four corners 4e1-4e4. Each of the corners 4e1-4e4 has the shape of two cuboids angled at right angles to each other. The length of each cuboid section is approximately 10% of the length of the short side of the collection bin 3. Each corner 4e1-4e4 has a maximum height that is approximately 70% of the height of the collection bin 3.

[0089] Corners 4e1-4e4 are attached to the wall of the tray of collection container 3 (directly on each one of the four corners of collection container 3) and are flush with the outer wall. The thickness of the corners is approximately 50% of the wall thickness of the tray of collection container 3. The inner surfaces of corners 4e1-4e4 overlap PTFE gasket 4c slightly, leaving enough space for a microplate 2 to be placed on gasket 4c. Corners 4e2 and 4e3 have a reduced height (approximately 50% of their maximum height) in their cuboidal portions that rest on the shorter faces of collection container 3 that house suction vent 5.

[0090] The microplate mount 4 further includes four clamps 4s1-4s4 (which clamp onto the upper surface of the collection container 3) along its long sides that are flush with its side walls. Each clamp 4s1-4s4 has a cuboid shape with a rectangular footprint. The long side wall of each clamp 4s1-4s4 is approximately 1 / 5 the length of the long side wall of the collection container 3. The long side walls of clamps 4s1-4s4 are also aligned with the long side wall of the collection container 3. The length of the short side walls of clamps 4s1-4s4 is such that they are flush with the outer wall of the collection container 3 on one side and almost completely overlap the PTFE gasket 4c on the other side. The height of clamps 4s1-4s4 is approximately 40% of the height of the upper body 3a of the collection container 3.

[0091] On the underside of the clamps 4s1-4s4, at the edge facing towards the opening 4o, the clamps 4s1-4s4 have a slight depression, which creates a contact area on the clamps 4s1-4s4 that not only contacts the microplate 2 attached to the suction head 1 from above (FIG. 4), but also additionally fixes the microplate 2 from the side against horizontal movements.

[0092] There are two clamps 4s1-4s4 on one side of the tray. Each clamp 4s1-4s4 is secured to the top surface of the collection container 3 by a screw with a head that rests on the top side of the clamp. The head of the screw is centered along the long side of the clamp. Each screw is centered with respect to the wall thickness of the collection container 3 tray. Additionally, for each clamp 4s1-4s4, two guide rods are secured to the top surface of the collection container 3 and enter two holes in the clamp 4s1-4s4, located on either side of the screw along the clamp's longitudinal axis. The guide rods prevent rotation of each clamp 4s1-4s4 around the screw. A retaining ring is clamped on the respective screw between each clamp 4s1-4s4 and the top surface of the collection container 3. The retaining ring is received in a groove on the underside of each clamp 4s1-4s4. Thus, not only do the screws press down onto the clamps 4s1-4s4, but each clamp 4s1-4s4 can be held by its respective screw and retaining ring so that its underside does not contact the upper side of the collection container 3 (see FIG. 3). The height of the clamps 4s1-4s4 can be adjusted by turning or tightening the screws. The screws themselves, and therefore the clamps 4s1-4s4, are constrainedly fixed to the collection container 3.

[0093] Below the upper body 3a of the collection container 3 is the contact portion 3b (see FIG. 3), which is part of the same body; that is, the upper body 3a and the contact portion 3b are made of a single material, in this case polyetheretherketone (PEEK). The contact portion 3b of the collection container 3 is a cuboid protruding from the lower surface of the upper body 3a of the collection container 3. The height of the contact portion 3b is approximately 30% of the height of the upper body 3a of the collection container 3. The bottom surface of the contact portion 3b is selected so that the lower edge of the contact portion 3b is aligned with the edge of the PTFE gasket 4c in the plan view of the suction head. In this way, the lower edge of the contact portion 3b of the collection container 3 matches the lower edge of the microplate 2 in the microplate mount 4 at their positions in the horizontal plane (see FIG. 7). The contact portion 3b therefore has a contact geometry that matches the receiving geometry of the microplate mount 4. The contacts 3b allow the aspiration head 1 to be placed into a mount of a type that locks the microplate 2 in place, particularly in a dispensing system (see Figure 12).

[0094] Figures 4, 5, 6 and 7 show the aspiration head 1 with a microplate 2 mounted on a microplate mount 4. Figure 4 shows the same isometric projection as Figure 1, Figure 5 shows a direct top view, Figure 6 shows a direct side view, and Figure 7 shows a cross section along a vertical plane containing line A shown in Figure 5.

[0095] The microplate 2 has an upper body 2a whose shape is primarily a cuboid with a rectangular footprint. Its height is approximately 10% of the length of its long sides. The long sides of the cuboid shape are approximately 1.5 times longer than the short sides. Below the upper body 2a, the microplate 2 also has a base 2b with an outer cuboid shape, extending from the horizontally outer side of the upper body 2a in all four directions by approximately 2% of the length of the short sides of the upper body 2a. The long sides of the base 2b have a length of approximately 128 mm, while the short sides have a length of approximately 85 mm. The overall height of the microplate 2 is approximately 14 mm.

[0096] The height of the base 2 b is about 20% of the height of the upper body 2 a of the microplate 2 . One of the outer edges of the upper body 2a is cut along its height, creating a surface that is at a 45° angle to the adjacent sidewall of the upper body 2a, which helps to orient the microplate 2 correctly.

[0097] The microplate 2 includes 384 wells 2w arranged in a rectangular matrix with 24 rows and 16 columns of wells 2w. The wells 2w are rectangular holes that are open on the upper surface of the upper body 2a of the microplate 2 and are separated by walls. The upper surfaces of the walls and the area of ​​the microplate 2 outside the area of ​​the wells 2w form a flat upper surface. The microplate 2 is made of polystyrene, but can also be manufactured from polycarbonate or other materials. There are microplates with different numbers of wells 2w; the microplate 2 shown is merely one example. Other microplates 2 can include, for example, 1536 wells with correspondingly smaller dimensions.

[0098] The microplate 2 is mounted onto the microplate mount 4. The bottom surface of the microplate 2 (its outer lower edge) is in contact exclusively with the PTFE gasket 4c. The corners 4e1-4e4 of the microplate mount 4 ensure that the microplate 2 is correctly positioned on the collection container 3 by preventing the microplate 2 from horizontal movement. The clamps 4s1-4s4 reach above the base 2b of the microplate 2 and prevent the microplate 2 from being able to move upward from the microplate mount. In addition, the clamps 4s1-4s4 exert a downward force on the base 2b of the microplate 2 to press the microplate 2 into the PTFE gasket 4c. Screws can be used to adjust the force exerted on the microplate 2 by each of the clamps 4s1-4s4.

[0099] To remove the microplate 2 from the microplate mount 4, the clamps 4s1-4s4 can be lifted until they no longer contact the microplate 2. The microplate 2 can then be lifted slightly and slid horizontally over the undersides of the corners 4e2 and 4e3 and under the clamps 4s1-4s4 from the aspiration head 1. To mount the microplate 2 onto the microplate mount 4, these steps are followed in reverse.

[0100] In Figure 7, the profile of the microplate 2 is shown in more detail, along with its internal structure. The underside of the base 2b of the microplate 2 is in contact only with the PTFE gasket 4c of the microplate mount 4. On the lower end of the wells 2w, the wells 2w have a nozzle 2o with a diameter smaller than the upper opening of the well 2w. Above this nozzle 2o, each well 2w is equipped with a filter 2f. The nozzle 2o of the well 2w reaches the opening 4o of the microplate mount 4. The microplate 2 and the collection container 3 form a continuous cavity 3c. The cavity 3c is only connected to the outside of the suction head 1 via the suction vent 5 and via the nozzle 2o.

[0101] When negative pressure is applied to the outer end of the suction vent 5, the outer end will transmit this negative pressure into the cavity 3c. The negative pressure then acts on the nozzle 2o of the microplate 2. The liquid on the filter 2f is sucked through the filter and into the cavity 3c. Inside the cavity, the liquid is guided towards the suction vent 5. Then, the liquid is also sucked from the collection container 3 through the suction vent 5.

[0102] Figures 8A and 8B show cross-sectional views of two possible embodiments of valves located within the suction vents: Figure 8A shows check valve 6 located within suction vent 5, and Figure 8B shows check valve 106 located within suction vent 105.

[0103] The check valve 6 according to the first embodiment is composed of a sleeve 6d, a spring holder 6b, a spring 6a and a ball 6c. The ball 6c and the spring 6a are placed in the spring holder 6b, which is also held in the sleeve 6d.

[0104] The outer sleeve 6d of the check valve 6 has a cylindrically symmetrical shape, the axis of symmetry of which is the same as the axis of symmetry of the suction vent 5. For about 80% of its length, the outer sleeve 6d of the check valve 6 has the shape of a tube with a constant radius and a constant wall thickness along the axis of symmetry. Only on the outer end of the outer sleeve 6d of the suction vent 5 does the outer sleeve 6d of the check valve 6 have a conical taper.

[0105] The spring holder 6b is placed within the sleeve 6d. The spring holder 6b also has a cylindrically symmetrical outer profile, whose outer diameter matches the inner diameter of the sleeve 6d. The spring 6a is fixed within the spring holder 6b, and its spring force pushes it along the axis of symmetry of the sleeve 6d and toward the collection container 3. The free end of the spring 6a reaches into a chamber within the spring holder 6b. Within this chamber, the ball 6c can take several positions. Without an external force, the ball 6c is pressed by the spring 6a against a valve seat surrounding the opening toward the collection container 3. This causes the ball 6c to seal a possible passage for gas or liquid to cross the check valve 6. When an external force pushes the ball 6c into the chamber within the spring holder 6b away from the valve seat, the valve seat is opened for liquid or gas to enter the chamber and to cross further toward the outer end of the check valve 6.

[0106] Only a pushing force on the ball 6c coming from inside the collection reservoir 3 (e.g., a sufficiently strong pressure from the gas or liquid in the collection reservoir 3) can open the check valve 6. The strength of the spring 6a is selected so that the hydrostatic pressure of the liquid coming from the microplate 2 is not sufficient to open the check valve, even when the cavity 3c in the collection reservoir 3 is filled with this liquid. Only the application of negative pressure outside the suction vent 5 and the check valve 6 can create a pressure difference that generates a sufficiently strong pushing force on the ball 6c to open the check valve 6 by compressing the spring 6a.

[0107] The check valve 106 according to the second embodiment has a sleeve 106d that is identical to the sleeve 6d of the check valve 6. The shape of the spring holder 106b and the arrangement of the spring 106a and ball 106c within the spring holder 106b are also identical to those of the spring holder 6b. However, the spring holder 106b is positioned in the sleeve 106d in such a way that the force of the spring 106a acts along the axis of symmetry of the sleeve 106d and away from the collection container 3. Similar to the check valve 6, the check valve 106 opens when the ball is pressed against the spring 106a with a force stronger than the force of the spring 106a (and any other force, for example in the same direction as the hydrostatic pressure inside the collection container 3). However, in this case, the check valve 106 opens when a pushing force from outside the collection container acts on the check valve 106. In this way, even when gas or liquid inside the collection container 3 exerts high pressure on the check valve 106, the check valve 106 remains closed, and only a pushing force applied from outside the suction head 101 to the spring-loaded body, ball 106c, opens the check valve 106.

[0108] 9A and 9B show cross-sectional views of a portion of an aspiration head 1 having a mounted microplate 2 along with a portion of a vacuum unit 7 forming a filtration system 10 in two configurations a10 (FIG. 9A) and b10 (FIG. 9B). The filtration system 10 includes the aspiration head 1 and a vacuum unit 7 connectable to an aspiration vent 5 of the aspiration head 1, where the vacuum unit 7 includes a vacuum connection 7v connectable to a laboratory vacuum or vacuum valve 8 (FIG. 11).

[0109] The suction head 1 is movable independently of the vacuum unit 7 within a range, which includes at least one contact position of the suction head 1, where the filtration system 10 has a configuration in which the vacuum unit 7 is connected to the suction head 1 (here, the connection is shown as configuration b10).

[0110] The vacuum connection 7v includes an internal channel that faces toward the suction head 1 at its contact position and faces upward on the other end. The end of the channel of the vacuum connection 7v that faces toward the suction head 1 is connected to the connector unit 7c. The connector unit 7c can be selectively connected to the suction vent 5. In the connection configuration b10 of the filtration system 10, the connector unit 7c is connected to the suction vent 5 of the suction head 1 (FIG. 9B). In the non-connection configuration a10, the connector unit 7c is not connected to the suction head 1.

[0111] The connector unit 7c has a generally cylindrically symmetrical shape with a constant outer diameter and an axis of symmetry that is parallel to the axis of symmetry of the check valve 6 when the suction head 1 is placed in the contact position. The connector unit 7c features a central channel with a constant circular cross-section along most of its length. In its section adjacent its outer end, the inner diameter of the channel increases to match the geometry of the components to be connected. On its end facing the suction head 1, the channel of the connector unit 7c has an inner diameter that widens toward the end of the connector unit 7c. In this way, the connector unit 7c forms a contact geometry that matches the taper of the check valve 6. In addition, the connector unit 7c includes a gasket for sealing the connection to the check valve 6.

[0112] On its other end, the channel of the connector unit 7c has an inner diameter equal to the outer diameter of the vacuum connection 7v that is connected to this end. The connector unit 7c, including the vacuum connection 7v attached to and supported thereby, can be moved together in the direction of the suction head 1. For this purpose, the connector unit 7c is fixed to a holding plate 7t with a rectangular cross section, which is itself connected to a pneumatic cylinder 7r with a piston 7p.

[0113] In the configuration a10 of the filtration system 10 shown in FIG. 9A, the connector unit 7c is not extended toward the suction head 1. When the cylinder 7r is pressurized, the piston 7p moves the retaining plate 7t, and therewith, the connector unit 7c having the vacuum connection 7v toward the suction head. Thus, the piston 7p switches the connector unit 7c to the connection configuration b10 (shown in FIG. 9B). In the configuration b10 of the filtration system 10, the connector unit 7c is moved onto the check valve 6. If negative pressure is applied to the vacuum connection 7v, the negative pressure will be directly transmitted to the check valve 6. By the mechanism described above, the check valve then also opens to allow gas and liquid to pass from the suction head 1 into the vacuum unit 7.

[0114] 10A and 10B show filtration system 110 (an alternative embodiment of filtration system 10) again in cross section and in two configurations a110 and b110. The overall arrangement is very similar to the filtration system 10 according to the embodiment described in connection with Figure 9. However, in this case, the suction head 101 features a check valve 106 that will not open unless a pushing force is applied to the check valve 106 from outside the suction head 101. To apply this pushing force to the check valve 106, the vacuum unit 107 features a connector unit 107c that includes an opening pin 107cp. Again, the connector unit 107c is fixed to a retaining plate 107t with a rectangular cross section. The retaining plate 107t is itself connected to a pneumatic cylinder 107r with a piston 107p.

[0115] The opening pin 107cp is fixed to the connector unit 107c in its channel in such a way that liquid and gas can still pass from the suction vent 105 to the vacuum connection 107v. The opening pin 107cp has a body that is cylindrically symmetric with its axis of symmetry lying on the axis of symmetry of the channel of the connector unit 107c. In the disconnected configuration a110 of the filtration system 110, the connector unit 107c is positioned at a certain distance from the check valve 106, and the check valve 106 is closed due to the absence of an external pressure. In the configuration b110, the connector unit 107c is moved toward the suction head 101. Here, the opening pin 107cp enters the check valve 106 and presses against the ball 106c. In this way, the check valve 106 is opened by the connector unit 107c. Now, if negative pressure is applied to the vacuum connection 107v, this negative pressure is transmitted to the cavity 3c (FIG. 7) in the suction head 101.

[0116] Figure 11 shows the filtration system 10 as an isometric projection from above. On the left side of the image, the suction head 1 with the suction vent 5 and check valve 6 is connected to the connector unit 7c of the vacuum unit 7 (configuration b10 of Figure 9). In addition to the components shown in detail in Figure 9, the vacuum unit 7 also includes a vacuum valve 8 connected to the vacuum connection 7v via a piping connection t1 between the vacuum connection 7v and the connector 8v1. This piping connection t1 needs to be selected with a length that allows the connector unit 7c and the vacuum connection 7v to assume both the disconnected configuration a10 and the connected configuration b10 (both of Figure 9).

[0117] The vacuum valve 8 is connectable to laboratory vacuum via connector 8v2. The vacuum valve 8 has an open and a closed configuration, where the open configuration opens the connection to the suction head 1 and the closed configuration closes the connection.

[0118] To this end, vacuum valve 8 may internally open and close the connection between connector 8v1 and connector 8v2. Vacuum unit 7 also includes pressure valve 9 having connector 9c. Connector 9c of pressure valve 9 is connected to pneumatic cylinder 7r via piping connection t2. Pressure valve 9 is connectable to a compressor via connector 9pr and is responsive to electrical signals to open and close to extend or retract piston 7p into or from cylinder 7r.

[0119] All parts of the vacuum unit 7 (such as the vacuum valve 8, the pressure valve 9, the vacuum connection 7v and the connector unit 7c) are supported by a rectangular plate 10b which serves as a common base. On the plate 10b close to the suction head 1, the holding rod extends vertically upwards supporting a holding piece 7s which includes a pneumatic cylinder 7r and two boreholes in the guide rod.

[0120] From the retaining piece 7s, a piston 7p and two guide rods 7h in boreholes extend horizontally outwards towards the suction head 1. On their ends, these guide rods and pistons 7p are fixed to a retaining plate 7t which supports a connector unit 7c with vacuum connections 7v.

[0121] FIG. 12 is an isometric, schematic top view of a dispensing / filtration system 12 including a filtration system 7 and a dispensing unit 11 for automated dispensing of liquids into a microplate 2. The dispensing unit 11 is a CERTUS FLEX dispensing unit commercially available from Fritz Gyger AG. The dispensing unit 11 is a device that automatically dispenses selected liquids into individual wells of a microplate 2. The dispensing unit 11 includes a movable carrier 11c for the microplate 2. The dispensing unit 11 further includes a dispensing head 11d having several valves that allow for dispensing small amounts of liquid. The dispensing head 11d has several channels that allow for dispensing two or more liquids during the same workflow (i.e., without operating the dispensing unit 11). The dispensing head 11d can move along a horizontal axis 11dr parallel to the short side of the microplate 2. This allows the dispensing head 11d to position any of its several valves over any one of the wells in a row of wells. The dispensing head 11d in this embodiment is also capable of changing its height to accommodate different configurations and types of microplates 2.

[0122] Carrier 11c has a contact geometry that allows microplate 2 to be inserted into carrier 11c. Carrier 11c is movable along a horizontal axis 11cr that is perpendicular to axis 11dr and thus to the direction of movement of dispense head 11dr. In this manner, carrier 11c can be moved and positioned under dispense head 11d so that dispense head 11d can dispense liquid into any row of wells. By combining positioning along axis 11dr and axis 11c, dispense head 11d can dispense any of the liquid from its valve into any of the wells of microplate 2.

[0123] In the configuration shown in Fig. 12, the suction head 1 of the filtration system 10 is mounted on a carrier 11c. For this purpose, the suction head 1 is inserted into the carrier 11c of the dispensing unit 11 together with the contact portion 3b of the collection container 3 so that the body 3a of the collection container 3 is located directly on the carrier 11c (Fig. 2). The microplate 2 is mounted on the microplate mount 4 of the suction head 1, and due to the geometric shape of the contact portion 3b, the microplate 2 is still correctly positioned for the programmed dispensing of liquid by the dispensing unit 11. Due to the maximum height of the suction head 1 being less than 30% of its maximum length, the carrier 11c is still freely movable within its range of movement along the axis 11cr (without any interference with the dispensing head 11d), at least as long as the dispensing head 11d is located within the upper section of its vertical range.

[0124] The vacuum unit 7 is installed next to the dispensing unit 11 with its plate 10b fixed to the bottom of the dispensing unit 11. The vacuum unit 7 is connected to the waste container 14 via the connector 8v2 of the vacuum valve 8 (FIG. 10), and a laboratory vacuum 15 is connected to the waste container 14. The vacuum unit 7 is positioned so that the contact position of the suction head 1 is at the height of the movable carrier 11c and within the range of movement of the carrier 11c. In this way, the carrier 11c can bring the suction head 1 into contact with the vacuum unit 7.

[0125] In the context of the embodiment shown, the contact position and the position where the dispensing head 11d is required to dispense liquid into the microplate 2 are not the same position, and in order for filtration to occur the carrier 11c has to move into the contact position and away from the dispensing head 11d. However, there are possible embodiments of the invention in which this is not the case: for example if the vacuum connection 7v of the vacuum unit 7 is permanently connected to the suction head via flexible tubing.

[0126] The dispensing functions of the dispensing unit, including the movement of the dispensing head 11d and the control of the valves and movable carrier 11c, can be controlled by a control unit 13. The control unit 13 also controls the opening and closing of the vacuum valve 8 and the pressure valve 9 (FIG. 10), allowing the dispensing / filtration system 12 to perform both dispensing and filtering operations automatically.

[0127] For the filtration step, the movable carrier brings the aspiration head 1 into contact with the vacuum unit 7. The connector unit 7c (FIG. 10) of the vacuum unit 7 is then switched to the connected configuration by opening the pressure valve 9 (FIG. 10). If the vacuum valve 8 is also opened, negative pressure from the laboratory vacuum 15 is transmitted to the microplate 2, and liquid is aspirated into the aspiration head 1, and then through the check valve 6 (FIG. 1), through the connector unit 7c (FIG. 10) to the vacuum connection 7v (FIG. 10), and through the vacuum valve 8 (FIG. 10) into the waste container 14. To stop the filtration, the vacuum valve 8 can be closed or the connector unit 7c is switched to the disconnected configuration. This dispensing / filtration system 12 allows for automated, repeated cycles of dispensing liquid into the microplate and filtering the liquid from the microplate without the need for any manual operation of the system.

[0128] Using the novel dispensing / filtration system 12, processes such as solid phase peptide synthesis (SPPS) can be performed within the wells of a microplate 2. The microplate 2 needs to be prepared with resin beads and a suitable filter.

[0129] To add any liquids required for the process to the microplate 2, the suction head 1 is moved to the dispensing position, where the dispensing system 11 can then dispense the respective liquids into the individual wells. These liquids may be substances for unblocking both ends of the amino acids of the peptide chain being generated. These liquids may also contain the next amino acid to be connected to the peptide chain.

[0130] Also, steps requiring rinsing with water can be performed. For this purpose, first a washing substance is added to each well of the microplate 2 by using the dispensing head 11d. After that, the suction head 1 moves into the contact position together with the vacuum unit 7. Next, the liquid is filtered from the microplate 2 by applying negative pressure to the suction head 1.

[0131] After repeated cycles of binding and washing, the peptides need to be cleaved from the beads. For this purpose, the cleaved material is dispersed into the respective wells of the microplate 2 by again using the dispensing head 11d. After the cleavage reaction, the peptides in the cleaved material can also be filtered from the microplate 2 by using the suction head 1. For this purpose, the suction head 1 is again moved into contact position together with the vacuum unit 7, and filtering takes place. The liquid aspirated from the microplate 2 can be collected in a dedicated container 14.

[0132] The present invention is not limited to the above-described embodiments. Alternative embodiments of the present invention are possible. The microplate described is merely an example and may therefore have a different number of wells (e.g., 1536 wells). The microplate mount may feature different elements and / or a different number of the described elements (e.g., only two clamps and zero corners). The microplate mount may have a gasket made of a material other than PTFE, or may dispense with a gasket if the contact geometry permits. The collection reservoir body may have a different design; for example, the collection reservoir body may direct liquid into a reservoir chamber not located directly below the microplate. The collection reservoir body may also have a different volume and may be made of a material other than PEEK (e.g., stainless steel or a ceramic material). The interior surface of the collection reservoir may also have a different design, for example, including a liquid channel.

[0133] The suction vent could have a different shape and its profile could be, for example, oval or square rather than circular. The check valves presented are only possible embodiments; the valve body could have a different shape and / or size, and the spring could be another type of spring (e.g., a leaf spring). Other check valves (e.g., electromagnetically opened valves) are also possible.

[0134] The presented filtration system can be realized in different ways, for example, the vacuum connection can be connected to the connector unit by a telescoping connection so that it does not move when the connector unit is extended or retracted. The connector unit can also connect or disconnect without being extended (e.g., it can fold into place). The connector unit can also open and close the check valve by various means (e.g., by closing an electrical circuit that opens the electromagnetic check valve). The filtration system can also be realized without a connector unit, for example, with flexible tubing between the suction head and the vacuum connection that allows a sufficient range of movement of the suction head. All stabilization and support components of the filtration system can, of course, have various shapes and sizes.

[0135] Alternative embodiments exist for the dispensing / filtration system as well. The carrier may be movable along other paths (e.g., along several axes). The carrier may also include several dispensing heads. All shown shapes and (relative) sizes are meant as examples only and may therefore vary.

[0136] In summary, it should be noted that the present invention produces an aspiration head that allows simple and reliable filtration of liquids from many wells of a microplate.

Claims

1. An aspiration head for aspirating liquid from a microplate equipped with a filter, said aspiration head comprising: - collection containers, a microplate mount for locking the microplate in place and sealing the connection between the aspiration head and the microplate, the microplate mount having an opening facing towards the collection vessel; - a suction vent in the collection container, the collection container, the microplate mount, and the suction vent are positioned such that mounting the microplate on the microplate mount creates a continuous cavity between the microplate and the collection container, and applying negative pressure to the suction vent causes the liquid in the microplate to be drawn through the filter, through the opening in the microplate mount, and into the collection container.

2. 2. The aspiration head according to claim 1, characterized in that the microplate mount comprises a gasket, in particular a polytetrafluoroethylene (PTFE) gasket.

3. 3. The suction head of claim 1 or 2, wherein the inner surface of the collection container is sloped, and the suction vent is located within the collection container at the bottom of the slope.

4. A suction head according to any one of claims 1 to 3, characterized in that the suction vent includes a check valve for preventing leakage of liquid from the suction head when the check valve is in a closed position.

5. 5. The suction head of claim 4, wherein the check valve opens when a pushing force from outside the suction head is applied to a spring-loaded body inside the check valve.

6. 6. The aspiration head according to claim 1, wherein the contact geometry of the aspiration head on the outer surface opposite the microplate mount matches the receiving geometry of the microplate mount of the aspiration head.

7. The suction head according to any one of claims 1 to 6, wherein the maximum height of the suction head is less than 30% of the maximum width of the suction head.

8. 8. A filtration system comprising a suction head according to any one of claims 1 to 7 and a vacuum unit connectable to the suction vent of the suction head, the vacuum unit comprising a vacuum connection connectable to a vacuum source.

9. 9. The filtration system of claim 8, wherein the vacuum unit includes a vacuum valve having an open configuration and a closed configuration, the open configuration opening the connection to the suction head and the closed configuration closing the connection.

10. 10. The filtration system of claim 8 or 9, wherein the suction head is movable independently of the vacuum unit within a range, the range including at least one contact position of the suction head, and the filtration system is configured such that the vacuum unit is connected to the suction head.

11. 11. The filtration system of claim 10, wherein the vacuum unit includes a connector unit, and while the suction head is placed in a contact position with the vacuum unit, the connector unit has a connection configuration in which it is connected to the suction vent of the suction head and a non-connection configuration in which it is not connected to the suction head, and the connector unit is switchable from the connection configuration to the non-connection configuration and from the non-connection configuration to the connection configuration.

12. 12. The filtration system of claim 11, wherein the connector unit can be switched from the disconnected configuration to the connected configuration and from the connected configuration to the disconnected configuration by being moved toward or away from the suction head.

13. A dispensing and filtration system comprising the filtration system according to any one of claims 8 to 12 and a dispensing unit for automatic dispensing of liquid into a microplate, wherein the dispensing unit comprises a movable carrier for the microplate, and the suction head is mounted on the carrier.

14. A dispensing and filtering system as described in claim 13 in combination with claim 9, comprising a control unit that controls the automatic dispensing of liquid into the microplate, the movement of the carrier, and the opening and closing of the vacuum valve.

15. A dispensing and filtration system as described in claim 14 in combination with claim 11 or 12, characterized in that the control unit also controls the switching of the connector unit between the connected configuration and the disconnected configuration.

16. 1. A method for automated injection of liquids into and filtration of liquids from a microplate, the method comprising: - providing a dispensing unit having a movable carrier; - providing a suction head, said suction head comprising: - collection containers, a microplate mount for locking the microplate in place and sealing the connection between the aspiration head and the microplate, the microplate mount having an opening facing towards the collection vessel; - providing a suction head including a suction vent in the collection container; - providing a filter-equipped microplate; - mounting the filter-equipped microplate onto the aspiration head to create a continuous cavity between the microplate and the collection vessel; - placing the suction head on the movable carrier of the dispensing unit; - injecting liquid into a number of wells in the microplate using the dispensing unit; applying negative pressure to the aspiration vent of the aspiration head to filter the liquid from the microplate into the collection vessel.

17. - moving the movable carrier with the suction head from a dispensing position to a contact position with a vacuum unit; - switching the connector unit of the vacuum unit from a disconnected configuration to a connected configuration; - switching the connector unit from the connected configuration to the disconnected configuration after filtering the liquid from the microplate; 17. The method of claim 16, further comprising:

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