Patent Grant
12186745
The invention relates to a device for receiving, discharging, diluting or moving fluids as well as for adding fluid components, for separating, filtering, fractionating, enriching fluids and/or their constituents as well as for modifying fluids and their constituents and for detecting the constituents of the fluids, and which can also be described as a fluidic system, in particular a microfluidic system. The device can also be called a chip. Furthermore, the invention relates to a method for processing fluids in a fluidic system.
The intake and discharge of fluids and gases as well as their movement including mixing in fluidic systems, separation, filtering, fractionation, and enrichment of fluids and their constituents, as well as the modification of fluids and their constituents and the detection of substances, particularly in microfluidic systems, is often carried out via an externally connected pump, which is connected to the fluidic system via a fluidic interface, via syringe pumps integrated into the fluidic system or via membrane valves. All these solutions require an appropriate control device to operate the pumps or valves and are not suitable for easily implementing functions such as receiving, discharging and/or moving fluids in lab-on-a-chip systems in a simple way or even manually.
The external pumps used to manipulate lab-on-a-chip systems require a fluidic interface, which requires additional components to be used, and which, like all fluidic interfaces, involves the risk of leakage. Furthermore, additional connected devices for performing the above-mentioned partial functions pose the risk of contamination and/or falsification of the analysis results in addition to a time delay.
Syringe pumps integrated directly into fluidic systems avoid a fluidic interface to the outside, but require another element, the plunger, in order to move fluids.
Membrane valves offer the advantage that they do not require a fluidic interface or any other components and only require a pre-formed recess and a movable cover for actuation. They are configured in such a way that they can be operated pneumatically or mechanically. Generally, these membrane valves are operated by an appropriate operating device.
The intake and discharge of fluids, the distribution to different reaction cavities, the movement of fluids as well as the addition of reaction components require manual handling steps or a corresponding automation of these steps by means of large automats. This is done manually during sample collection and reagent supply by pipetting, mixing and incubation is carried out, for example, by shaking titer plates and reagents are taken from appropriate storage containers for supply. Both manual handling and automated handling require a larger number of handling steps, additional equipment such as pipettes or pipette automats as well as storage facilities for the corresponding reagents.
In microfluidic systems, handling is usually carried out via external pumps and a device is required to control the system.
The separation, filtration, enrichment and/or fractionation of fluids and their components is often performed by means of filters and/or membranes and/or density gradients in a fluid and in combination with a filtration of the vessels containing the filters/membranes and/or density gradients in order to separate the sample accordingly. Here, too, additional devices and manual handling steps are required in addition to the test vessel.
This invention combines all handling steps including reagent storage on a manually operated component.
The object of the invention is to be able to take in, dispense, dilute, transport and/or mix fluids as well as separate, filter, enrich and/or fraction fluids and their components and modify fluids and their components as well as detect the components of the fluids manually, i.e. without any further aids, as well as with corresponding devices. This should preferably be possible in fluidic systems without an external pump or suction device, preferably also manually. A particular feature of the system is that multiple intakes and discharges of fluids are possible and that desired volumes of the received and/or discharged fluid can be precisely controlled. It is also an object to provide methods for processing fluids with such fluidic systems.
A fluidic system is provided, comprising a structured component with a chamber and a channel system, which are sealed fluid-tight with a component, wherein the chamber is fluidically connected to the outside via the channel system and a fluidic interface. The component has a flexible or movable portion that can be moved into the chamber portion or beyond a plane of the chamber. The plane of the chamber is the upper boundary of the chamber on the side to the chamber, i.e. the bottom side of the component closing the chamber. By moving the flexible portion, fluids or gases can be taken in or discharged through the fluidic interface and/or moved in the fluidic system. The moving portion can be moved manually or with an appropriate operating device. One option is to push or move the flexible portion up into different positions. Particularly advantageous are the possibility of a defined fluid discharge and intake through the combination of the chamber with a small channel system, the multiple intakes and discharges of fluids as well as the possibility of manual operation.
The fluidic system preferably has an interface for a fluid reagent reservoir.
The flexible or movable portion is preferably accessible from the outside.
Particularly advantageous is the configuration of the component which closes the structured component as a foil, wherein the foil is also the moving component due to its intrinsic flexibility.
The structured component can preferably be provided with one covering component each on its top and bottom side. This allows channel systems and/or parts thereof to be arranged on both sides of the structured component and sealed with the components. Thus, the channel system can be easily inserted into the structured component on one or both sides from the respective surface and the channels on both sides can be connected by holes. In the area of the chamber, the component can be configured flexible or it can be configured as a foil, which then serves as a flexible portion in the area of the chamber, as it is flexible in its basic properties.
The dilution of the received fluid and/or the supply of reagents takes place via the emptying of a fluid reservoir connected to the structured component, which can be configured as a blister. The external geometry of the fluidic interfaces can influence the fluid intake and fluid discharge.
The volume can be defined by the corresponding outlet geometry of the fluidic interface, wherein this volume definition can be further influenced by a surface modification of the fluidic interface.
Another fluidic system is also provided, comprising a structured component with a chamber and a channel system which are hermetically sealed with a further component, the chamber being fluidically connected to the outside via the channel system and a fluidic interface. The flexible portion is formed by the walls of the chamber.
A particular advantage here is that a lateral pressing of the chamber also enables the movement of the fluid or the compression effect can be increased by the flexible chamber walls.
In addition, a further fluidic system is provided, comprising a structured component or a structured module as well as a further component which seals the chamber and the channel system hermetically and connects the chamber to the outside via the channel system and the fluidic interface. The structured component is configured in such a way that the chamber bottom is flexible and can be pushed in or expanded.
A particular advantage of this embodiment is that the bottom can be configured to be particularly flexible and can be manufactured by means of two-component injection moulding, so that a flexible component can be injection-moulded together with another component. Alternatively, the base material of the structured component can also be sufficiently flexible to guarantee the functionality of the component. An assembly of the flexible portion into the structured component is also possible.
The chamber can be connected to a fluidic interface via another channel system, wherein one of the fluidic interfaces can be closed with a cap. The closure with a cap also prevents fluid from escaping at this point.
Preferably, the integration of valves, for example capillary stopping valves, which act by changing the capillary diameter, allows the intake of defined volumes.
Preferably, a valve function is created by local modification of the surface, and/or the function of existing geometrically acting valves is enhanced a by surface modification in the valve area.
A particular advantage of this embodiment is that venting can take place when fluid is taken in through the second fluidic interface and that fluid can also be taken in and discharged at various points. The closure with the cap also prevents fluid from escaping at this point. Furthermore, it is advantageous to position the fluidic system in such a way that the discharging fluidic interface is inclined downwards when the fluid is discharged.
Preferably, the fluidic system includes a venting option for the chamber, which can be provided via an additional channel communicating with the outside or a gas-permeable membrane, and this venting device can be optionally closed.
Preferably, the fluidic system includes an inlet channel, which has a passive stopping function, for example a capillary stopping valve, a channel tapering or a corresponding surface modification, and receives a defined quantity of fluid either by a capillary effect, which can be intensified by surface modifications in the portion to be filled, or by a change in the chamber volume caused by the moving components.
The intake of very precise volumes without the use of expensive pipetting units is particularly advantageous here.
In a preferred configuration, the fluidic system includes an additional reagent reservoir. This can be formed as a blister, for example.
The particular advantage here is that several fluids or dry reagents can be mixed together and the reagent can be used to transport the received fluid or fluid in the system.
Preferably, dry reagents are provided in the structured component, which can be taken up by the flowing fluids and mixed with them.
Preferably, a reagent is provided at a defined position, which colours the fluid flowing over it and thus indicates that the position at which the reagent is present has been reached, and thus that a certain volume or dwell time has been reached.
Preferably, a magnification function is provided in the structured component at a defined position, for example in the form of a lens integrated into the structured component, in order to be able to better follow the reaching of certain positions in the channel system by the fluid and also to be able to better read colour reactions as indicator reactions.
Longer channel elements are also preferred as flow limiters in the fluid flow to enable a controlled fluid intake and fluid discharge.
In a preferred embodiment, the reagent reservoir is formed as a blister. Preferably, the reagent reservoir has a blister seat with piercing elements that pierce the fluid-tightly connected blister located above them. This embodiment can include a flap which allows a defined insertion of the flap via guide elements in the blister seat and thus a defined volume dosage. The volume dosing can also be carried out in several steps due to the particular configuration of the guide elements.
The fluid-tight closure of the fluidic interface for the fluid intake, for example via a cap, makes sense. The cap can also be equipped with a transport element, for example a mandrel or plunger, which projects into the channel and thus moves the fluid in it by means of volume displacement when the cap is placed on the fluidic interface. In addition, or alternatively, the cap can also have a flexible portion that can be pushed in or pulled out after it has been placed to move the fluid in the channel and/or channel system. When pushing, the fluid is pushed further into the channel. As the flexible portion is pulled out, fluid is moved out of the channel towards the fluidic interface. This allows small movements to be generated.
The particular advantage here is that defined fluid volumes can be discharged from the blister and this can also be done manually with high precision. In combination with a defined volume intake, an exact mixing ratio can thus be set.
In a preferred embodiment, the fluidic system has a long channel to the chamber. This long channel is particularly advantageous, as it can be used to adjust the speed of the fluid intake and to introduce reagents into the channel, which are optimally resuspended due to the long length of the channel.
In a preferred embodiment, the long channel to the chamber has additional widenings. This embodiment is particularly advantageous, as reagents can be pre-assembled in the widenings and improved mixing can be achieved through a different flow profile.
In a preferred embodiment, the fluidic system includes a cavity or detection chamber for optical readout and/or reaction which can preferably have different depths. A particular advantage here is that optical detection can be performed directly and, if the detection chamber is configured with several depths, the dynamic range can also be increased.
In a preferred embodiment, the fluidic system includes a lateral flow strip, which allows filling by the operation of the chamber. One embodiment includes a venting membrane, another one a venting channel. Particularly advantageous is the possibility of fluid intake, which can be operated manually, with the direct possibility of a read out via the lateral flow strip. Particular aeration options allow the combination of the negative pressure driven flow achieved by the chamber with the subsequent fluid movement by the suction effect of the lateral flow strip. A lateral flow strip is used for the detection of target molecules in the fluid, wherein both individual target molecules can be detected as well as different target molecules depending on the configuration of the lateral flow strip. A particular feature of the lateral flow strip is the integration of an array for parallel detection of several target molecules.
In a preferred embodiment, the fluidic system includes more than one chamber, which are connected to one another by a channel system and/or can be arranged in one or more planes. Particularly advantageous is that the flexible elements enable forwarding and reciprocating as well as active mixing by changing the chamber volumes.
In a preferred embodiment, the fluidic system includes attachments on the flexible components that are either located outside the chamber or extend into the chamber. A particularly advantage here is an exact definition of the volume to be taken in and/or discharged, which is thus independent of the force or finger size of the user even in manual operation.
In a preferred configuration, the fluidic system has reagents in the chamber. A particular advantage here is that the chamber is not only used for fluid movement, but the chamber volume can also be used directly for dissolving, reacting and mixing reagents. Dry reagents, in particular, enable the chamber to be used in a particularly advantageous way.
In a preferred embodiment, the cap for emptying the blister is directly connected to pushing elements for moving the flexible portion, if necessary, implemented integrally.
In a preferred embodiment, mixing is possible by means of moveable elements provided in the chamber, such as balls or rods, which can also be magnetic. Mixing can be additionally enhanced by structural elements in the structured component or can be performed entirely by these. A particular advantage here is that the simple configuration of the system allows particularly effective mixing in the chamber.
In a preferred embodiment, mixing takes place in the chamber by manually moving the fluidic system. A particular advantage here is that the simple configuration of the system allows manual use.
In a preferred embodiment, mixing takes place in the chamber by means of a mixing mechanism on the device side. A particular advantage here is that efficient mixing can take place.
In a preferred embodiment, the channel systems themselves include alignment marks, or alignment marks are attached next to, below or above the channel system, to allow volume indication. This marking is particularly advantageous similar to a ruler as it allows the user to read the received or discharged volume and to end or continue the intake or discharge of volumes in order to receive, discharge or move defined volumes.
In a preferred embodiment, multiple fluid intakes and/or fluid discharges are possible. A particular advantage here is that the fluidic system can be used for the multiple intakes and discharges of fluids.
In a preferred embodiment, fluidic interfaces are provided at the structured components which point in different directions, for example perpendicular to the plane of the fluidic system or leaving the fluidic system at a particular angle. A particular advantage here is that a particular geometry allows fluids to be taken in and/or discharged in particularly shaped surfaces or vessels.
Several fluidic interfaces are provided in a preferred embodiment. This is particularly advantageous, as fluids can then be discharged and received at different positions simultaneously or consecutively.
In combination with a distribution system, the intake and discharge can take place at several positions simultaneously or sequentially. If a mere distribution system is used, fluids can be discharged or taken in simultaneously via the movement of the flexible elements.
In a preferred embodiment, the intake and/or discharge of fluids is controlled via membrane valves. This is particularly advantageous, as it allows an individual fluid intake and/or fluid discharge at different fluidic interfaces to take place through the movement of the flexible elements in the chamber.
A particular embodiment is the integration of passive valves into the individual distribution channels in order to ensure uniform filling and thus uniform fluid transport and thus, for example, the discharge of the same volumes.
In a preferred embodiment, the intake and/or discharge of fluids is controlled via rotary valves. The rotary valves preferably have a rotary valve seat (28a) and a rotating rotary valve body (28b) with a connecting channel connecting the various parts of the channel system. This is particularly advantageous as it allows individual fluid intake and/or fluid discharge at different fluidic interfaces to take place through the movement of the flexible elements in the chamber.
In a preferred embodiment, the fluidic system is configured as a microfluidic system. The structured component is preferably and essentially made of plastic.
In the case of the flexible element, the entire component can, for example, be made of plastic foil. It is also possible to use a flexible plastic such silicone or TPE incorporated in the other components or a movable mechanical element made of any material.
The above-mentioned embodiments of the fluidic system may further include at least one functional element, which can be realized for example by a filter, a membrane, a frit, or a functional paper or similar elements.
The one or more functional elements may be realized by one or more filters, membranes, frits, paper or similar elements containing reagents or to which reagents are applied.
Reagents may be applied to the structured component and/or the at least one component and/or the one or more functional elements, and/or they can contain these reagents, for example in the form of arrays of identical or different agents.
The object is also solved by a fluidic system, comprising a structured component with a chamber and a channel system, the chamber and/or the channel system having at least one functional element, at least the chamber being sealed fluid-tightly with a component and being fluidically connected to the outside via the channel system and at least one fluidic interface, the component having a flexible or movable portion, which can be moved at least into a region of the chamber or beyond a plane of the chamber and by moving the flexible or movable portion fluids or gases can be taken in or discharged via the fluidic interface and/or moved in the fluidic system, the flexible or movable portion being movable manually or with an operating device, wherein it is possible to press the flexible or movable portion in or move the flexible or movable portion upwards.
The object is also solved by a fluidic system, comprising a structured component with a chamber and a channel system, the chamber and/or the channel system having at least one functional element, and the at least one functional element being provided with reagents, at least the chamber being sealed fluid-tightly with a component and being fluidically connected to the outside via the channel system and at least one fluidic interface, the component having a flexible or movable portion, which can at least be moved into a region of the chamber or beyond a plane of the chamber in order to take in or discharge fluids or gases via the fluidic interface by moving the flexible or movable portion and/or to move it in the fluidic system, the flexible or movable portion being movable manually or with an operating device, wherein it is possible to press the flexible or movable portion in or move the flexible or movable portion upwards.
The object is also solved by a fluidic system, comprising a structured component with a chamber and a channel system, wherein reagents are applied to the structured component and/or to the component sealing it and/or to the at least one functional element, wherein at least the chamber is sealed fluid-tightly with a component and is fluidically connected to the outside via the channel system and at least one fluidic interface, wherein the component has a flexible or movable portion, which can at least be moved into a region of the chamber or beyond a plane of the chamber in order to take in or discharge fluids or gases via the fluidic interface by moving the flexible or movable portion and/or to move it in the fluidic system, the flexible or movable portion being movable manually or with an operating device, wherein it is possible to press the flexible or movable portion in or move the flexible or movable portion upwards.
Preferably the functional element is realized by a filter, a membrane, a frit and/or a functional paper. All these examples of functional elements are at least partially passable for fluids, i.e. porous. They can be membranes and/or filters for size exclusion like laser structured membranes (track-etch) with exactly defined pore size, silicon screens, filter paper with a coarse-meshed net. Functional elements that use size exclusion and/or an adherence to the surface of the functional element are different elements like porous three-dimensional structures like frits, silicon membranes, silica membranes, three-dimensional aggregated particles, filter mats made of different materials, silica mats, PET filters, thin layer chromatography material or plasma/serum generation membranes, to name a few examples. All of these functional elements can be additionally provided with reagents to realize a specific binding of target molecules to these functional elements and a specific separation of target molecules from functional elements.
Preferably, a fluid is taken in via the fluidic interface, wherein the fluid is passed through or over or across the functional element. The fluid can then be discharged by pressurizing the chamber of the thumb pump.
Preferably, the fluid is taken in by capillary forces or surface tension caused by the surfaces of the channel system and/or the chamber and/or the fluidic interface.
Preferably the fluid is taken in by actuating the chamber of the thumb pump.
Preferably, the fluidic system has at least one valve, which is arranged in the channel system, wherein a defined volume can be taken in by integrating the valve.
Preferably, at least one functional element has a suction function, which drives the fluid intake. The suction function can be caused by a hygroscopic property of the materials of the functional element.
Preferably, the inlet can be closed with a cap.
Preferably, the inlet and outlet can be closed with a cap.
Preferably, the at least one functional element is configured such that only plasma or serum passes through the functional element when blood flows through it and other blood components are retained by the functional element, wherein the plasma or serum obtained can be discharged via the fluid outlet.
Preferably two functional elements are connected in series. This means that two functional elements with identical or different properties are arranged in the channel system.
Preferably, the two functional elements are connected in series, wherein first one functional element is flowed through and the fluid reaches the chamber of the thumb pump. Then the fluid inlet is closed with a cap. By moving the flexible component, the fluid reaches the second functional element and is then discharged via the fluid outlet. This means that the first functional element is arranged in the channel system in front of the chamber in the flow direction from the inlet to the outlet and the second functional element is arranged behind the chamber in the flow direction or between the chamber and the fluid outlet.
Preferably, two functional elements are connected in series, wherein first the one functional element is flowed through, and then the fluid that has flowed through penetrates the second functional element and is discharged via the fluid outlet by a movement of the movable component. After the fluid has been taken in via the fluid inlet, the inlet is closed with a cap, for example.
Preferably, at least one functional element is used to generate plasma or serum.
Preferably, the first functional element is used for the generation of plasma or serum, while the second functional element removes hemolyzed red blood cells.
Preferably, a fluid reservoir is connected to the structured component, wherein the fluid is diluted within the channel system when the fluid is discharged from the fluid reservoir.
Preferably, a fluid reservoir is connected to the structured component, wherein dilution of the fluid within the channel system takes place when fluid is discharged from the fluid reservoir, wherein a defined volume can be discharged from the fluid reservoir and added to a defined volume of the fluid which has been taken in.
Preferably, a fluid reservoir is connected to the structured component, wherein dilution takes place via the fluid discharge from the fluid reservoir and wherein a defined volume from the fluid reservoir is added to a defined volume of the fluid which has been taken in and which has already passed through the functional element. This means that in the flow direction, the first functional element is arranged after the fluid inlet to carry out a first treatment of the fluid which has been taken in, and wherein a fluid reservoir is connected to the channel system to add a defined amount of a fluid present in the fluid reservoir to the fluid which has been treated by the first functional element.
In a further preferred embodiment, a fluid can be taken in via the fluidic interface, mixed with fluid in a reaction cavity and then passed over and/or through at least one functional element, wherein target molecules of the fluid remain on the functional element and the target molecules are separated and discharged via the fluidic interface (outlet, 5.2) using fluid from the fluid reservoir.
Preferably, at least one additional fluid reservoir is fluidically connected to the functional element, which allows different fluids to flow through the functional element in order to free the functional element from unwanted components or to displace the separated target molecules.
Preferably, the separation of target molecules from the at least one functional element is caused by a temperature change.
Preferably, the fluid which has been taken in is first passed through/across a first functional element, wherein particles are retained at the first functional element. These particles are then broken down into smaller particles and supplied to the next functional element, wherein some of the smaller particles produced are retained by the functional element and can subsequently be separated again, wherein the target particles are found in a different fraction of the eluate than the undesired components to be separated or further target components.
Preferably, before the target particles are separated by washing with fluid, cleaning is carried out, wherein unwanted particles are removed from the functional element.
Preferably, the particles are cells, the step of breaking down the particles being the lysis of the cells.
Preferably, biological components such as nucleic acids, proteins, metabolites and/or antibodies are extracted, concentrated and/or purified with the fluidic system according to the invention.
Preferably, the resulting target component is then passed over/across integrated reagents such as arrays, i.e. an array of catcher molecules, to bind the target molecules/target particles to the array molecules and subsequently detect them.
Preferably, the target component obtained is detected and/or identified by the system, further preferably quantitatively detected.
Preferably, single or multiple functional elements are arranged in parallel. This means that the channel system has several parallel lines in which one or more functional elements are arranged.
Preferably, the reagents applied to the structured component, component and/or functional element show a color change upon contact with fluid, indicating a fill indicator.
These reagents are preferably located on, in or at the functional element.
The fluidic system is also called a thumb pump, because the flexible component is particularly easy to operate with the thumb.
In accordance with one aspect, there is provided a fluidic system, comprising:
In accordance with another aspect, there is provided a method for processing a fluid, wherein a received fluid first flows through the first functional element and the received fluid then enters the chamber, wherein thereafter the first fluidic interface is closed and by moving a flexible portion of the chamber the fluid is forced over and/or through the second functional element and discharged via the second fluidic interface.
In accordance with another aspect, there is provided a method for processing a fluid, wherein a received fluid first flows through the first functional element and the received fluid subsequently penetrates the second functional element, wherein the received fluid is discharged by means of a movement of the movable portion via the second fluidic interface.
In accordance with another aspect, there is provided a method for processing a fluid, in which a received fluid is mixed with another fluid to produce a mixed fluid in a reaction cavity, and is subsequently guided across the at least one functional element, wherein target molecules of the mixed fluid remain on the at least one functional element, wherein the target molecules are dissolved by a fluid from a fluid reservoir and are discharged via the second fluidic interface.
In accordance with another aspect, there is provided a method for processing a fluid, wherein a received fluid is first guided across the first functional element and particles are first retained on the first functional element, these particles are then broken down into smaller particles and supplied to the second functional element, wherein a part of the smaller particles is retained by the second functional element and can then be released again.
In accordance with another aspect, there is provided a method for processing a fluid, in which, before the target particles are separated from the at least one functional element by washing with fluid from a fluid reservoir, a cleaning is carried out by rinsing undesired components out of the at least one functional element and the undesired components are thus removed from the at least one functional element.
In accordance with another aspect, there is provided a method for processing a fluid, in which the fluid is subsequently guided through a reaction cavity with integrated reagents, and the reaction cavity is configured to contain a reaction therein which allows target molecules to be detected, and/or
The present invention describes a fluidic system including a chamber which has a flexible or movable part, usually the bottom or lid, in particular embodiments also movable walls, which, by lifting or bottoming, allows the intake, discharge, displacement, dilution or mixing of fluids or gases which are connected to the chamber via at least one channel or opening. An extension of the invention is achieved either by additional elements such as filters, membranes, frits or similar elements and/or integrated reagents, which may for example be arranged in the form of an array of identical or different reagents. This enables the separation, filtering, fractionation, and enrichment of fluids and their components as well as modification of fluids and their components and the detection of the components of the fluids. The individual use and combination of the additional elements can be carried out as desired.
The chamber and the movable part are configured such that, by a movement of the movable part from its initial position, a predetermined and adjustable volume of the chamber is displaced. In this way, predetermined volumes can be received or discharged in the chamber when the moving part is returned to another position or to the initial position. In other words, the volume is predetermined by the properties of the fluidic system or can be adjusted by the configuration of the fluidic system according to the invention.
The fluidic system has a structured component 1 including a chamber 2, wherein the chamber 2 is connected to a channel system 3. The structured component 1 is essentially flat and/or plate-like. In other words, the structured component 1 has a first main side and a second main side which are parallel to each other. The chamber 2 and the channel system 3 are formed on the first main side on and/or in the surface of the structured component 1. In other words, the chamber 2 and the channel system 3 are embedded at the main side into the surface of the structured component 1. The chamber 2 and the channel system 3 thus are a recess on the surface of the structured component 1. For example, the first main side is a top side of the structured component 1, and the second main side is a bottom side of the structured component 1, wherein an orientation of the top side and the bottom side is arbitrary and by turning the structured component the top side becomes the bottom side and vice versa. Side surfaces of the structured component 1 are arranged between the top side and the bottom side of the structured component 1. The structured component 1 can, for example, be rectangular in shape. The structured component 1 can also be disc shaped. However, the structured component 1 can take on any shape as long as it is essentially flat. The structured component 1 can be formed as a platform, for example. Structured component 1 can be flat.
The chamber 2 and/or the channel system 3 thus has a top side which corresponds to the top side of the structured component 1. A bottom side of the chamber 2 and/or the channel system 3 is formed inside the structured component 1. The bottom side of the chamber 2 can also be referred to as a chamber bottom 7. The interior of the chamber 2 is formed between the top side of the chamber 2 and the bottom side, wherein the top side and bottom sides can be either the top or bottom side, depending on an orientation.
The chamber 2 and/or the channel system 3 can be configured as a recess in the structured component 1, for example on the top side or the bottom side of the structured component 1. The chamber 2 and the channel system 3 can be configured as recesses of different depths, wherein the top side and bottom sides can be either the top or bottom side, depending on an orientation.
The chamber 2 and/or the channel system 3 are fluidically connected to the outside via one or more fluidic interfaces 5. In other words, the fluidic interface 5 is an opening of the channel system 3 e.g. on a side surface of the structured component 1. The opening of the fluidic interface 5 can also be arranged on an upper side or bottom side of the fluidic system. As can be seen in
The fluidic system may have a plurality of fluidic interfaces 5, each of which is connected to the channel system 3. The fluidic interfaces 5 can be arranged at different surfaces of the structured component 1, for example the top side, bottom side or side surfaces, preferably on opposite side surfaces. In other words, the openings of the fluidic interfaces 5 may point in different directions. They can therefore have different orientations with respect to the center of the structured component 1.
A component 4 seals the channel system 3 and the chamber 2 fluid- and optionally gas-tight, so that the supply and discharge of fluids and gases can only take place via the one or more fluidic interfaces 5. In other words, the component 4 is arranged at the surface of the structured component 1 in such a way that it closes the chamber 2 and the channel system 3 on the upper side of the structured component 1. Component 4 can, for example, be glued, bonded, pressed, or welded to structured component 1 or sealed using sealing elements such as sealing soft components. Component 4 thus serves as a lid to seal the structured component 1.
In other words, at the top side of the chamber 2, the interior of the chamber 2 is bounded by the bottom side of the component 4. Component 4 can be essentially made of a transparent material to observe the course of the fluids in the channel system 3 and/or in the chamber 2.
Chamber 2 can have an essentially flat oval, rectangular or round shape. Thus, chamber 2 and/or the interior or volume of chamber 2 is defined by the structured component 1 on the one hand and by component 4 on the other hand.
Either the whole component 4 is flexible or the component 4 has a flexible or movable portion 6. As shown in
Component 4 can be for example a foil or strip and can be made of plastic or metal.
Alternative embodiments of the fluidic system are shown in
Another alternative embodiment is shown in
The structured component 1 is preferably configured with a cover foil, which has sufficient flexibility for pushing in and lifting above and/or below the chamber 2.
Preferably, the chamber 2 is configured in such a way that the flexible portion(s) 6, 7, 9 do not fill the entire chamber 2 when pushing into the chamber 2. In other words, if the flexible portion 6, 7, 9 is pressed into the chamber 2, the flexible portion will not be flush with the chamber bottom. This means that fluid or gas in the chamber 2 is not completely discharged from the chamber 2 by pushing in the flexible portion 6, 7, 9. Furthermore, a tight sealing of the flexible portions 6, 7, 9 with the chamber bottom or the adjacent channel systems 3 is not necessary for the functionality, but the movement of the flexible portions 6, 7, 9 causes the movement of the medium.
An exemplary operation of the embodiment shown in
Fluid intake: In order to take fluids/gases into the fluidic system, or more precisely into the chamber 2 of the fluidic system, the flexible portion 6 is pushed downwards from the initial position manually and/or by hand, for example with a finger of a user, or by means of an operating device. In other words, the flexible portion 6 is moved from its initial position into the chamber 2 by pressure. This means that the flexible portion 6 is pushed from the top side into the interior of the chamber 2. By pushing the flexible portion 6 into the chamber 2, the interior space of the chamber 2 is reduced. Subsequently, the fluidic interface 5 is immersed in a fluid. The flexible portion 6 moves either automatically, due to the material properties of the flexible portion 6, partially or completely back to the initial position, or is moved back to the initial position by a movement of the operating device, for example suction or lifting off. In other words, the interior of the chamber 2 is enlarged again by moving the flexible portion 6 back to its initial position. By increasing the volume of the interior space, a negative pressure is created in the chamber 2 and/or in the adjacent channel system 3, which is connected to the fluid via the fluidic interface. This means that fluid is drawn into the fluidic system by the under pressure. In other words, a part of the fluid is first drawn into the channel system 3 by the negative pressure and then, if the negative pressure is sufficiently high, also into the chamber 2. Fluid is thus taken into the fluidic system. By adjusting the volume of the interior of the chamber 2 displaced by pressing down the flexible portion 6 and/or by returning the flexible portion 6 to its initial position in a defined manner, the volume of the received fluid and/or the positioning of the fluid in the channel system 3 and/or in the chamber 2 of the fluidic system can be adjusted.
Mixing fluids: The received fluid is mixed by first drawing fluid into the chamber 2, that means fluid is first taken into the fluidic system. Then either the flexible component 6 is moved or the fluidic system itself is moved. The fluidic system is moved, for example, by tilting the fluidic system several times. A fast shaking should be avoided to avoid the generation of air bubbles in the received fluid. The movement mixes the fluids in the fluidic system.
Discharge of fluids: Fluids are discharged from the fluidic system by pushing the flexible component 6 and/or the flexible components into the chamber 2. In other words, the volume or the interior of the chamber 2, which is bounded by the flexible component, is reduced by pushing the flexible component. The fluid, which is either in the chamber 2 or in the channel system 3, is discharged from the fluidic system according to the volume displaced by the movement of the flexible portion 6, i.e. by pressing the flexible portion 6 into the chamber 2. This means that the displaced fluid is discharged from the chamber 2 via the channel system 3 through the fluidic interface 5. The volume of the fluid discharged may correspond to the volume of the interior of the chamber 2 by which the chamber 2 is shrunk by pushing in the flexible portion 6. In this case, fluid volumes can be discharged several times. Multiple discharging can be achieved by pushing the flexible portion 6, 7, 9 step by step further into the chamber 2 and/or the interior of the chamber 2. Multiple discharging can also be achieved by first pressing the flexible portion 6, 7, 9 into the chamber 2 once and then moving the flexible portion 6, 7, 9 out of the chamber 2 by itself or by moving it out of the chamber 2 with the aid of an operating device as described above. The outward movement is accompanied by a backflow of at least part of the fluid in the channel system 3 connected to the chamber 2. The outward movement is followed by a repeated push of the flexible portion 6, 7, 9 into the chamber 2 for another fluid discharge. In other words, by repeatedly and alternately pushing into the chamber 2 and moving out of the chamber 2 of the flexible portion 6, 7, 9, a pumping movement and/or pumping functionality is performed. This leads to a repeated and alternating fluid intake and fluid discharge.
Closure of the fluidic interface 5 for sampling: A cap 14 closes the fluidic interface 5 for sampling. The cap 14 may also have integral projections that protrude into the channel system 3 when the cap is placed on the fluidic interface 5. This allows fluid in the channel system 3 to be displaced and forced into the rest of the channel system 3.
Preferably, one fluidic interface 5 is configured as an inlet 5.1 of the fluidic system, and another fluidic interface 5 is configured as an outlet 5.2 of the fluidic system. The inlet 5.1, and the outlet 5.2 are preferably formed at the structured components 1. The two fluidic interfaces 5.1 and 5.2 are formed on one side, preferably at an end face or narrow side of the chip (fluidic system). This means that the inlet and the outlet are arranged on one side of the system. This makes it possible to close the inlet and outlet with a cap 14, also known as a jumper.
The cap 14 is preferably attached to the fluidic system, preferably to the structured component 1. One or more caps 14 may be attached.
In a preferred configuration, only one cap 14 is provided, which can be attached to either the inlet 5.1 or the outlet 5.2. This can then be used to selectively take in fluid at the inlet or discharge fluid at the outlet.
The one or more caps 14 are attached to the chip (fluidic system) by a flap 44.
Addition of fluid: The complete or partial emptying of a fluid reservoir 16 transports the collected sample through a fluid and allows dilution or addition of reagents.
The flexible portion 6 can thus be pushed below a plane defined by the top side of the structured component 1 into the chamber 2, or more precisely into the interior of the chamber 2, by external pressure due to its flexibility. On the other hand, the flexible portion 6 can be pulled out of the interior of the chamber 2 again by pulling from the outside, for example by means of a negative pressure or an attached device. This means that it can be moved beyond the plane defined by the top side of the structured component 1.
From these basic functionalities, i.e. the intake of fluid into the fluidic system, the discharge of fluid from the fluidic system and the mixing of fluid in the fluidic system, the following characteristics result for the fluidic system:
The intake, dilution, discharge, dosing and/or transport of fluids is possible. Fluid that has been taken into the fluidic system can be transported and stored using the fluidic system. A multiple intake and multiple discharge of fluids is possible. Mixing of fluids is possible.
The fluidic system can be used as a pipette with functions of fluid intake, fluid discharge and multiple intake and discharge of fluids, due to the configuration of the fluidic system according to the above-described embodiments and by the configuration of the chamber 2 and the flexible portion 6, 7, 9. The pipette can be operated completely manually without any further aids or by means of an operating device.
As shown in
The fluids can be mixed by moving the fluidic system, moving the flexible portion 6, 7, 9, or by inserting mixing elements. The mixing elements, for example balls made of silicone, hard plastic balls, metallic components or other particles, can be moved by manual movement of the fluidic system. Alternatively, or additionally, the mixing can be carried out by means of mixing elements made of magnetic materials, which are moved from the outside by a device for mixing.
Furthermore, the volume of the received fluid can be determined by means of passive valves in channel system 3, for example capillary stop valves and channel tapers 41, see
A further option for extending the chamber functionality is the insertion of a lateral flow strip 23, as shown in
As shown in
In general, the following applies to the fluidic system according to the present invention: all processes described for the use of fluids are equivalent to gases and a combination of fluid and gaseous substances is also possible with this fluidic system, for example the systematic supply of gases to fluids.
A further embodiment form is shown in
A further embodiment is shown in
A further embodiment is shown in
As shown in
A flow restrictor 43 is integrated in the channel system 3 upstream of chamber 2, which is meander-shaped and/or can include channel tapers 41 (not shown here), with which the flow velocity of the fluid can be controlled and/or reduced. A reservoir interface 17 with a fluid reservoir is connected to the channel system 3.
The inlet 5.1 and the outlet 5.2 can be closed with a cap 14, which is attached to the chip by a flap 44. Preferably, only one cap 14 is provided, which can be fitted alternately on the inlet 5.1 or the outlet 5.2 to selectively enable the chip to receive fluids when the inlet 5.1 is open, i.e. without the cap 14, and the outlet 5.2 is closed with a cap 14. Thus, a required negative pressure can be built up to take in a fluid via the fluidic interface 5.1 (inlet). After the intake and corresponding analysis in the chip, the fluid should be discharged again. To this end, the cap 14 is placed on the inlet 5.1 and the inlet 5.1 is sealed fluid-tight. The fluid can then be discharged via the outlet 5.2. Thus, the cap 14 can be used to switch between two functions of the chip.
In a further configuration, it is possible to attach several caps 14 to the chip, for example to allow the chip to be transported or stored, wherein either the inside of the chip is protected from contamination and/or leakage of fluids present inside is prevented.
A fluidic system is provided, comprising a structured component 1 having a chamber 2 and a channel system 3, wherein at least the chamber 2 is closed in a fluid-tight manner by a component 4 and is fluidically connected to the outside via the channel system 3 and a fluidic interface 5, wherein the component 4 has a flexible or movable portion 6 which can be moved at least into a portion of the chamber 2 or beyond a plane of the chamber 2, wherein by a movement of the flexible or movable portion 6 fluids or gases can be taken in or discharged through the fluidic interface 5 and/or moved in the fluidic system, and wherein the flexible or movable portion 6 is movable by hand or with an operating device, and a pushing or an elevating of the flexible or movable portion 6 is possible.
A fluidic system is provided, comprising a flat structured component 1 with a chamber 2 and a channel system 3, wherein at least the chamber 2 is closed fluid-tightly with at least one component 4, wherein the chamber 2 is fluidically connected to the outside via a channel system 3 and at least one fluidic interface 5, wherein the component 4 and/or the structured component 1 has a flexible or movable portion 6, which at least partially adjoins the chamber 2, wherein the flexible or movable portion 6 is configured to be pressed into or moved out of the chamber 2 manually or with an operating device so that fluids or gases are taken into or discharged via the at least one fluidic interface 5 and/or moved in the fluidic system.
A fluidic system may comprise a structured component 1 having a chamber 2 and a channel system 3, wherein the chamber 2 and the channel system 3 are closed in a fluid-tight manner by a component 4, wherein the chamber 2 is fluidically connected to the outside via the channel system 3 and the fluidic interface 5, and wherein the structured component 1 has a flexible or movable portion 6 forming side walls of said chamber 2.
A fluidic system may comprise a structured component 1 having a chamber 2 and a channel system 3, a component 4 which closes the chamber 2 and the channel system 3 in a fluid-tight manner, wherein the chamber 2 is connected to the outside via the channel system 3 and a fluidic interface 5, and wherein the structured component 1 is configured such that a bottom of the chamber 7 is flexibly configured and pressable.
Preferably, the flexible or movable portion 6 is formed on at least one side wall of the chamber 2 within the structured component 1.
In these embodiments of the fluidic system, the chamber 2 can be connected to another fluidic interface 5, preferably via a further channel system 3. Preferably at least one of the fluidic interfaces 5 can be closed with a cap 14.
The fluidic system may further comprise a venting device for the chamber 2, wherein the venting device is arranged such that venting can take place via an additional channel 25 connected to the outside or a gas-permeable membrane 24.
The fluidic system may further comprise an inlet channel which has a passive stopping function and is filled either by capillary action or by a change in the chamber volume caused by the flexible or movable components and takes in a defined quantity of fluid.
The fluidic system may also include an additional reagent reservoir 16. The additional reagent reservoir can be configured as a blister 16.
The reagent reservoir 16 may include a blister seat 17 having piercing elements 18 adapted to pierce the blister 16 fluid-tightly connected above the piercing elements 18, a flap 19, which is pushable in a defined manner using guide elements 20 in the blister seat 17, wherein a defined volume dosage is possible.
Preferably, a channel 3 leading to the chamber 2 can have widenings or expansions 22.
Preferably, a cavity or detection chamber 21 for optical readout and/or reaction observation can be connected to the channel system 3, preferably having different depths. The outwardly facing surface of the cavity can be transparent to allow a reaction of the fluid by the incident light and/or an optical readout of the reaction or constituents present in the detection chamber 21.
The component 4 and/or the structured component 1 can be transparent at least in some areas. This allows observation of the movement of the fluid within the channel system 3. Depending on the analyses to be performed, the component 4 and/or the structured component 1 can also be opaque at least in some areas to prevent a reaction of the fluid with the incident light.
Preferably, the fluidic system may have a lateral flow strip 23, the filling of which is made possible by an operation of the chamber 2, wherein a venting membrane 24 and/or a venting channel 25 is connected to the lateral flow strip 23.
Preferably, the fluidic system can have at least two chambers 2, wherein the at least two chambers 2 are directly connected to each other via a channel system 3a.
Preferably, the fluidic system may have attachments 11, 12, 13 on the flexible or movable component 6, which are either located outside the chamber 2 or extend into the chamber 2.
Preferably, the chamber 2 may contain reagents.
Preferably, the fluidic system may include movable elements introduced into the chamber 2 for mixing. Preferably, mixing of fluids takes place within the chamber 2 by a manual movement of the fluidic system and/or by a mixing device.
The channel system 3 may have alignment marks, which are arranged next to, below or above the channel system 3, and which enable a volume indication.
With the fluidic system it is possible to perform multiple fluid intake and/or fluid discharge.
Preferably, there may be several fluidic interfaces 5 pointing in different directions or arranged on different sides of the fluidic system or leaving the fluidic system at a predetermined angle.
Preferably, the fluidic system may have a rotary valve 28, which can be used to control the intake and/or discharge of fluids.
Preferably, the fluidic system may have one or more membrane valves 27 connected to the channel system 3, with which the intake and/or discharge of fluids can be controlled.
The fluidic system may preferably have a passive stop function, which is configured as a capillary stop valve, a channel tapering and/or a surface modification.
Preferably, the reagent reservoir 16 may have guide elements 20, which allow multi-stage volume dosing.
Preferably, the fluidic system may have a cap as a fluid-tight seal of the fluidic interface 5.
Preferably, the cap 14 may have a flexible portion that is configured to be pushed in or pulled out after it is placed on the fluidic interface, thereby moving the fluid in the channel system 3.
Preferably, the gas-permeable membrane and/or the venting device is configured to be closeable.
Preferably, the at least two chambers 2 are arranged in one and/or several planes.
The movable mixing elements are preferably configured as balls or rods.
Preferably, the fluidic system includes structural elements in the chamber 2 and/or in the channel system 3 to enhance mixing.
Preferably, the fluidic interface 5 has an outlet 10, wherein the volume of a discharged fluid drop is determined by means of a geometry of the outlet 10.
The fluidic system may have a plurality of fluidic interfaces 5, which are connected to a distribution system 26 in the structured component 1, wherein the plurality of fluidic interfaces 5 can be selectively controlled.
Preferably, the channel system 3 and/or the fluidic interface 5 is configured in such a way that an autonomous fluid intake into the fluidic system takes place by means of the capillary forces of the channel system 3 at the fluidic interface 5.
Preferably, the fluidic system may have an inlet 5.1 and an outlet 5.2 located on one side of the system, with a cap 14 attached to the fluidic system, preferably to the structured component 1, which can be fitted to either the inlet 5.1 or the outlet 5.2 to allow a fluid to be taken in at the inlet 5.1 or discharged at the outlet 5.2.
Preferably, the fluidic system may have a reservoir interface 17, by means of which a fluid reservoir 16 can be connected to the structured component 1. The reservoir interface 17 can be fluidically connected to the channel system 3 and/or to the chamber 2.
The channel system 3 can have valves, which allow the intake of defined volumes of fluid. The valve function can be created and/or enhanced by surface functionalization.
Dry reagents are preferably arranged or stored in the channel system 3, wherein the dry reagents are taken in by the flowing fluids and mixed with them.
Preferably, a reagent is placed at a defined position in or on the channel system 3 and colors fluid flowing over it, so that reaching a position and thus reaching a certain volume or a defined dwell time is indicated.
Preferably, a magnifying device is arranged at at least one defined position above or below the channel system 3 or the chamber 2 so that reaching at least one defined position in the channel system 3 can be detected by fluid and/or by a color reaction. The magnifying device can be configured as a lens.
The fluidic system may preferably have extended channel elements as flow limiters 43, which are inserted into the fluid flow of the channel system 3 to enable controlled fluid intake and discharge.
The reservoir interface 17 can include a flap 19 to allow defined volumes to be extracted from the blister 16.
Preferably, geometric elements or attachments 11, 12, 13 are provided to enable a defined movement of the flexible portion 6, 7, 9.
The flap 19 and the geometric elements or attachments 11, 12 configured as pressure elements are preferably connected, combined and/or coupled with each other on the flexible or movable portion 6, 7, 9.
A multi-channel distribution system 26 may be provided, which opens into a corresponding number of fluidic interfaces 5 to allow simultaneous intake and discharge of fluids.
Equal distribution of fluids in the distribution system 26 can be supported by integrated passive valves 27.
The channel system 3 and/or the distribution system 26 connected thereto may have one or more valves 27, 28 to allow a defined fluid delivery from individual fluid interfaces 5.
The fluidic interface 5 can passively absorb fluid without moving the flexible or movable portion 6, 7, 9.
The above-mentioned embodiments can have one or more functional elements. This results in the following embodiments:
The one or more functional elements 45 such as filters, membranes, frits, paper or similar elements are located in or on the structured component.
These functional elements 45 can be attached in such a way that they are flooded vertically (
The flow can be in one direction only (
The flow can be active or passive. A pressure or a vacuum can be applied. However, a passive exchange via concentration gradients or interactions between the areas separated by the functional element 45 is also possible. A cavity 47 can be located above the functional element 45, which is part of the channel system 3, wherein the functional element 45 is fluidically connected to the channel system 3.
Furthermore, this invention comprises a combination of several of these functional elements on the thumb pump.
The thumb pump experiences a further extension of its function if, according to the invention, reactants are applied in or on the functional elements, such as a filter, a membrane, frits, a paper or similar elements, in order to react with the medium or fluid flowing through it and/or with the components or fluid on one or another side of the chamber.
A time-delayed resuspension of reagents is particularly advantageous if the functional element is intended to first retain particles/components and then to react with the reagents.
According to the invention, reagents can be applied to the structured component 1 or the at least one component 4 (lid, bottom), wherein in a particularly preferred variant these reagents are provided as an arrangement or array 48. An array can be formed by the same or different reagents, e.g., DNA molecules, antibodies, apatmers, etc., as a capture molecule; this can be a DANN or protein array.
The area of the applied reagents is called the reaction space and can thus be part of the channel system 3 and/or an expansion (reaction cavity, cavity 47) or recess of the channel system.
Alternatively or additionally, these reagents can also be applied to one or more functional elements 45, such as filter, membrane, frit, paper or similar elements (
This allows the use of the thumb pump e.g. for biological detection reactions, wherein the functionality of the thumb pump can be extended by fluid reservoirs 16 applied to the thumb pump.
A preferred embodiment is shown in
Another embodiment is shown in
In contrast to
By discharging fluid from a fluid reservoir 16, e.g. in the form of a blister, fluid is added to the fluid that has already passed through the functional element 45. The addition of fluid from the blister 16 is only carried out after passing through the functional element 45, i.e. a mixture of fluid and added fluid is achieved after processing the fluid in the functional element 45. This mixing can be achieved either by adding the fluid itself and/or by moving the thumb pump or the flexible portion 6. The mixed fluid can then be passed through another functional element 45 by pressurization and discharged via the further fluidic interface (5.2, outlet) by pressurizing the chamber 2. For this purpose, preferably the fluidic interface 5.1 serving as inlet is closed with a cap 14 after the fluid has been taken in. This means that when the fluid is added from blister 16, the 5.1, inlet is closed.
A further embodiment is shown in
A further embodiment is shown in
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2018 111 822.8 | May 2018 | DE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/062679 | 5/16/2019 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2019/219844 | 11/21/2019 | WO | A |
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