EP3393661B1 - Microfluidic device and method for operating a microfluidic device - Google Patents

Description

State of the art

The invention is based on a device or a method according to the preamble of the independent claims.

In microfluidic devices, liquids are provided or transported on a chip. Such microfluidic devices can be used, for example, in so-called lab-on-a-chip systems (LOCs), in which the entire functionality of a macroscopic laboratory is accommodated on, for example, a credit card-sized plastic substrate (LOC cartridge) and complex biological, diagnostic, chemical or physical processes can be miniaturized. Many LoC systems require a variety of fluids, such as liquid reagents, such as: As salt solutions, ethanol-containing solutions, aqueous solutions, detergents or dry reagents, such as lyophilisates, salts, etc., which are required for a variety of diagnostic applications. These reagents can either be manually pipetted onto the LOC cartridge or pre-stored on the cartridge. The latter brings advantages in terms of automation, contamination risks, user-friendliness and transportability of LOC systems.

The WO 2014/090610 A1 describes a concept in which liquids are stored in tubular bags, so-called stickpacks. The stickpacks are integrated into the LOC system, where they can be opened and emptied via a deflection of a flexible membrane.

The documents DE 10 2010 001412 A1 and US 2006/275852 disclose microfluidic devices for handling fluids.

Disclosure of the invention

Against this background, a microfluidic device and a method for manufacturing and a method for operating a microfluidic device according to the main claims are presented with the approach presented here. The measures listed in the dependent claims advantageous refinements and improvements of the independent claim microfluidic device are possible.

An advantage of the described microfluidic device is that liquids, such as reagents and moisture-sensitive dry reagents for LOC applications, can be stored for a long time and can be provided if required via a mechanical element, such as a stamp, a stamp unit, or a plunger.

• einem Kammersubstrat mit einer Fluidkammer zum Aufnehmen eines Fluids;
• einem Deckelsubstrat mit einer Stempelöffnung, wobei die Stempelöffnung gegenüberliegend zu einer Fluidkammeröffnung der Fluidkammer angeordnet ist;
• einer flexiblen Membran, die zwischen dem Kammersubstrat und dem Deckelsubstrat angeordnet ist und die Stempelöffnung und die Fluidkammeröffnung überspannt;; und
• einer Stempeleinheit, die dazu ausgebildet ist, um durch die Stempelöffnung in die Fluidkammer einzufahren, um die Membran in die Fluidkammer auszulenken, um ein Ausströmen des Fluid aus der Fluidkammer zu ermöglichen, wenn das Fluid in der Fluidkammer aufgenommen ist.

A microfluidic device is presented with the following features:

• a chamber substrate having a fluid chamber for receiving a fluid;
• a lid substrate having a punch opening, the punch opening being disposed opposite to a fluid chamber opening of the fluid chamber;
• a flexible membrane disposed between the chamber substrate and the lid substrate and straddling the die opening and the fluid chamber opening; and
• a die unit configured to retract into the fluid chamber through the die opening to deflect the membrane into the fluid chamber to permit outflow of the fluid from the fluid chamber when the fluid is received in the fluid chamber.

The chamber and lid substrate may be a polymeric substrate of high barrier plastics. The Membrane is designed to be deflected at a pressure on the membrane. The membrane is highly flexible and tear-resistant in one embodiment. In one embodiment, the membrane is configured to retract to its original position upon a withdrawal of the pressure. In particular, with a large deflection of the membrane, it can also lead to plastic deformation, which is not necessarily the function in the way.

An imagined mechanical stamping unit of the microfluidic device enables reliable reagent release. Since a high force can safely be applied to the fluid chamber containing a fluid, for example, the fluid can be stored, for example, in a blister or behind a barrier film with a particularly strong layer structure, which enables safe and long-term stable storage of the fluid. The presented membrane has the advantage that the stamp unit can always remain separated from the fluid and thus reusable due to the hygienic application possibility. This can create a cost advantage. The fluid chamber may, for example, have a volume less than 30 ml, 20 ml, 10 ml, 5 ml, 1 ml or less than 0.1 ml. In addition, a mechanically movable punch unit has the advantage that the release of the reagents does not necessarily have to be gravity-driven. The stamp unit can displace the volume of reagent through the membrane into other chambers or channels, wherein the entire structure can be arbitrarily aligned, for example at 0 ° inclination, but also under, for example, 30 °, 45 ° or 60 ° tilt. This offers advantages in handling and processing of the LOC cartridge.

The fluid may be received in the fluid chamber and held in the fluid chamber by a barrier film closing the fluid chamber. In this case, the barrier film may be formed to be opened by the stamp unit, for example, to fluidly connect a channel or a rearrangement chamber with the fluid chamber. By means of such a barrier film, the fluid, such as a reagent for example, can be stored safely in the fluid chamber and can be selectively released only when required by introducing the stamp unit into the barrier film.

According to one embodiment, the fluid may be disposed in a hopper received by the fluid chamber, the barrier foil closing the hopper. Such a depositor has the advantage that a direct filling of the fluid chamber can be avoided and thus simplifies manufacturing, simplifies use and incorrect operation and the risk of contamination can be excluded. According to various embodiments, the insert container may be flexible or plastically shaped.

The insert may be formed so that it can be accommodated accurately in the fluid chamber, the material of the insert can have a higher barrier property with respect to the fluid than the chamber substrate. Thus, different fluids with different requirements for a long-term stable Vorlagerung in specially designed for the requirements of the fluids depositors are stored safely in the device. A choice of material of the chamber substrate can thus be carried out independently of suitable for fluids storage materials.

The fluid may also be disposed in a blister received from the fluid chamber, wherein the blister substantially fills a volume of the fluid chamber, the blister being shaped to be opened by the stamp unit. For example, a blister may be formed from one or more sealing films whose edges may be joined by tight sealing seams and may be a cost effective alternative to a depositor. For example, a blister made of an elastic material can simply be taken up, for example glued, in fluid chambers having different shapes.

It is advantageous if a diameter of the die opening according to an embodiment is greater than half the diameter of the fluid chamber opening. The diameter of the die opening may advantageously have a diameter which corresponds to the diameter of the fluid chamber opening. Thus, the volume of the fluid chamber can almost completely displace. A stamp tip of the stamp unit can advantageously be formed so that the fluid is displaced in the fluid chamber in the direction of a channel.

In further advantageous embodiments, the stamp unit can assume geometries on the end face, which promote cracking of the barrier film in the direction of the rearrangement chamber without damaging the flexible membrane. In this case, stamp geometries which have elevations on the front side of the stamp unit are particularly advantageous in order to favor the beginning of cracking of the barrier film exactly in this area by means of local stress peaks. Upon further immersion of the stamp unit, the cracking continues and the displacement of the reagents gets a corresponding preferred direction. This allows a controlled displacement of the reagents in the rearrangement chamber.

A simple method is to allow the punch to move at a defined feed rate (typically 1 mm / min to 50 mm / min) until the face of the punch unit hits the bottom of the fluid chamber. Furthermore, it proves to be advantageous to make the process of the stamp step-shaped. The stamp unit moves in the first step until the first tear of the barrier film. In the second step, the stamp unit retracts a few millimeters to allow the reagent to escape through the resulting cracks. In the third step, the stamp unit moves to the bottom of the fluid chamber for a complete displacement of the liquid in the rearrangement chamber. Here, any further variations of the feed rate and the sequence of the travel direction of the stamp unit are conceivable in order to enable an optimal and efficient release of reagents into the rearrangement chamber.

According to the invention, the device has a channel which runs on a side of the membrane facing the chamber substrate and is fluidically connected to the fluid chamber. The channel can open into the fluid chamber. At a fluid chamber opposite end of the channel, a rearrangement chamber can be arranged for safe collection of the fluid.

In the rearrangement chamber, for example, another fluid may be upstream, which may be intended for mixing with the fluid after the release of the fluid. Alternatively, such a rearrangement chamber can also open directly into the fluid chamber.

The diameter of the punch opening may be smaller than half the diameter of the fluid chamber opening. In this case, the punch opening may be arranged adjacent to the channel. A relatively small punch opening can accommodate a correspondingly small punch unit, which in turn can make room for, for example, a further punch opening and / or for a vent opening on the side of the fluid chamber opening. Advantageously, the channel can be arranged at a certain angle of inclination of the device so that the fluid can flow off or be sucked off in a gravity-directed direction. When the plunger opening is arranged adjacent to the channel as presented, the vent opening can be arranged, for example, over the plunger opening, from where, for example, an inflow of ambient air through the vent opening can favor the outflow of the fluid.

According to the invention, the channel has a channel extension and the cover substrate has a vent opening, which opens into the channel extension, wherein the punch opening can be arranged between the vent opening and the channel, wherein the membrane does not span the vent opening.

An imaginary vent opening above the channel with connection to the channel can favor, for example, due to an established connection to the ambient air, a drainage of the fluid through the channel.

The lid substrate may include a vent opening into the fluid chamber, wherein the die opening may be disposed between the vent and the channel, wherein the membrane may span the vent. The apparatus may further comprise a further punch unit adapted to retract into the fluid chamber through the vent opening to deflect the diaphragm into the fluid chamber to allow inflow of further fluid into the fluid chamber.

A proposed approach allows the opening of a fluid chamber sealed by the barrier film, for example, and / or the opening of a blister disposed in the fluid chamber at two different locations. The approach also provides the basic prerequisite for a possibly additional air duct with connection to the vent opening and to the fluid chamber, which can allow an inflow of another fluid into the fluid chamber.

It is advantageous if, according to one embodiment, an intermediate substrate is arranged between the chamber substrate and the membrane, which has a further punch opening continuing the die opening and a vent opening continuing further vent opening and is formed to a transverse to the vent opening and into the further vent opening to generate opening air duct.

The air duct may extend in a direction facing away from the channel. An imaginary air channel can compensate for a resulting negative pressure in the fluid chamber after the stamping operation and during the outflow of the fluid by an inflow of, for example, ambient air through the air channel into the fluid chamber and thus promote the outflow of the fluid through the channel. In addition, the intermediate substrate prevents an air path for venting during active intake of the released fluid. Otherwise there is a risk that only air is sucked in instead of liquid.

The channel can run between the membrane and the intermediate substrate and open into the punch opening. This approach allows a favorable arrangement of the channel when an intermediate substrate is placed in the device.

A diameter of the fluid chamber opening may correspond to the stamp opening, wherein the fluid chamber may have a second stamp opening which corresponds to a diameter of the further vent opening. The chamber substrate may thus, except in the region of the fluid chamber opening and in the area of the second fluid chamber opening, have a fluid chamber opening side at the fluid chamber opening and the second one Fluid chamber opening are arranged extend. The chamber substrate can be formed more stable. A possibly arranged barrier film for closing the fluid chamber may, according to this embodiment, for example be glued along an inside of the fluid chamber facing the fluid chamber opening side and / or arranged between the chamber substrate and the intermediate substrate. When the barrier film is disposed between the chamber substrate and the intermediate substrate, the barrier film may span the fluid chamber opening and the second fluid chamber opening as well as the further vent opening and the further die opening of the intermediate substrate.

A fluid chamber bottom opposite the fluid chamber opening may be formed by a further barrier film. Due to the above-described increased stability of the chamber substrate on the fluid chamber opening side, the opposite fluid chamber bottom of the chamber substrate can only be formed by the further barrier film. The chamber substrate can thus be filled, for example, beforehand by the fluid chamber bottom and subsequently closed by the further barrier film. In addition, during the stamping process by the at least slightly flexible further barrier film, an internal pressure arising in the fluid chamber due to retraction of the stamp units can be compensated for by slightly moving the further barrier film in the direction of the punch movement. In this further advantageous embodiment with additional barrier film, the formation of an air path during active suction of the fluid is completely excluded, since the bottom of the fluidic chamber is connected over its entire area to the intermediate substrate.

• Bereitstellen eines Kammersubstrats mit einer Fluidkammer zum Aufnehmen eines Fluids,
• Bereitstellen eines Deckelsubstrats mit einer gegenüberliegend zu einer Fluidkammeröffnung der Fluidkammer angeordneten Stempelöffnung;
• Anordnen einer flexiblen Membran zwischen dem Kammersubstrat und dem Deckelsubstrat, wobei die Membran die Stempelöffnung und die Fluidkammer überspannt;
• Optional, Erzeugen eines Kanals auf einer dem Kammersubstrat zugewandten Seite der Membran, wobei der Kanal fluidisch mit der Fluidkammer verbunden ist; und
• Bereitstellen einer Stempeleinheit, die dazu ausgebildet ist, um durch die Stempelöffnung in die Fluidkammer einzufahren, um die Membran in die Fluidkammer auszulenken, um ein Ausströmen des Fluids aus der Fluidkammer zu ermöglichen, wenn das Fluid in der Fluidkammer aufgenommen ist.

A method for manufacturing a microfluidic device comprises the following steps:

• Providing a chamber substrate having a fluid chamber for receiving a fluid,
• Providing a lid substrate having a punch opening opposite to a fluid chamber opening of the fluid chamber;
• Disposing a flexible membrane between the chamber substrate and the lid substrate, the membrane spanning the die opening and the fluid chamber;
• Optionally, creating a channel on a side of the membrane facing the chamber substrate, the channel being fluidly connected to the fluid chamber; and
• Providing a stamper unit adapted to retract into the fluid chamber through the stamper opening to deflect the membrane into the fluid chamber to allow the fluid to flow out of the fluid chamber when the fluid is received in the fluid chamber.

A method for operating a said microfluidic device comprises the following step:
Retracting the stamper unit through the stamper opening into the fluid chamber to deflect the diaphragm into the fluid chamber to allow outflow of the fluid from the fluid chamber when the fluid is received in the fluid chamber.

• Fig. 1 eine schematische Querschnittsdarstellung einer mikrofluidischen Vorrichtung;
• Fig. 2 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung;
• Fig. 3 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung;
• Fig. 4 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung;
• Fig. 5 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit Einlegebehälter;
• Fig. 6 eine perspektivische Darstellung eines Kammersubstrats mit einer Mehrzahl von Fluidkammern;
• Fig. 7 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit einer Entlüftungsöffnung gemäß einem Ausführungsbeispiel;
• Fig. 8 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit einer Entlüftungsöffnung gemäß einem Ausführungsbeispiel;
• Fig. 9 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit einem Zwischensubstrat und einer weiteren Stempeleinrichtung;
• Fig. 10 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit einem Zwischensubstrat und einer weiteren Stempeleinrichtung;
• Fig. 11 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit einer weiteren Barrierefolie;
• Fig. 12 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit einer weiteren Barrierefolie;
• Fig. 13 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit einer weiteren Barrierefolie;
• Fig. 14 eine Querschnittdarstellung einer mikrofluidischen Vorrichtung mit einer weiteren Barrierefolie;
• Fig. 15 eine perspektivische Darstellung einer Vorrichtung mit einer Mehrzahl von Fluidkammern;
• Fig. 16 ein Ablaufdiagramm eines Verfahrens zum Herstellen einer mikrofluidischen Vorrichtung; und
• Fig. 17 ein Ablaufdiagramm eines Verfahrens zum Betreiben einer mikrofluidischen Vorrichtung.

Embodiments of the invention and other non-inventive examples are shown in the drawings and explained in more detail in the following description. It shows:

• Fig. 1 a schematic cross-sectional view of a microfluidic device;
• Fig. 2 a cross-sectional view of a microfluidic device;
• Fig. 3 a cross-sectional view of a microfluidic device;
• Fig. 4 a cross-sectional view of a microfluidic device;
• Fig. 5 a cross-sectional view of a microfluidic device with insert container;
• Fig. 6 a perspective view of a chamber substrate with a plurality of fluid chambers;
• Fig. 7 a cross-sectional view of a microfluidic device with a vent opening according to an embodiment;
• Fig. 8 a cross-sectional view of a microfluidic device with a vent opening according to an embodiment;
• Fig. 9 a cross-sectional view of a microfluidic device with an intermediate substrate and another stamping device;
• Fig. 10 a cross-sectional view of a microfluidic device with an intermediate substrate and another stamping device;
• Fig. 11 a cross-sectional view of a microfluidic device with a further barrier film;
• Fig. 12 a cross-sectional view of a microfluidic device with a further barrier film;
• Fig. 13 a cross-sectional view of a microfluidic device with a further barrier film;
• Fig. 14 a cross-sectional view of a microfluidic device with a further barrier film;
• Fig. 15 a perspective view of a device having a plurality of fluid chambers;
• Fig. 16 a flow diagram of a method for producing a microfluidic device; and
• Fig. 17 a flowchart of a method for operating a microfluidic device.

In the following description of favorable embodiments of the present invention, the same or similar reference numerals are used for the elements shown in the various figures and similar acting, with a repeated description of these elements is omitted.

Fig. 1 10 shows a schematic cross-section of a microfluidic device 100. The device 100 comprises a chamber substrate 105 with a fluid chamber 110 and a cover substrate 115 arranged adjacent to the chamber substrate 105. The cover substrate 115 is arranged between the chamber substrate 105 and a stamp unit 120. The lid substrate 115 has a punch opening 125 and the fluid chamber 110 has a fluid chamber opening 130. Between the chamber substrate 105 and the cover substrate 115, a flexible membrane 135 is arranged, which spans the fluid chamber opening 130 and the adjacently arranged punch opening 125. On a chamber substrate 105 facing the side of the membrane 135 optionally extends a channel 140 which is fluidly connected to the fluid chamber 110.

In one variant, the channel 140 extends on a side of the cover substrate 115 facing the membrane 135. The channel is then fluidly connected to the fluid chamber 110 via a through hole in the membrane 135. The diameter of the die opening 125 in this variant is advantageously smaller than the diameter of the fluid chamber opening 130, so that the channel 140 in the cover substrate 115 can be guided to a position opposite the fluid chamber opening 130.

The stamp unit 120 is shaped to retract into the fluid chamber 110 through the lid substrate 115. The stamp unit 120 according to this exemplary embodiment has, on a side facing the cover substrate 115, a rounded stamp tip which corresponds to an internal geometry of the fluid chamber 110. As the stamp unit 120 retracts into the fluid chamber, the diaphragm 135 is deflected from the rounded punch tip of the stamp unit 120 into the fluid chamber 110. When the stamp unit 120 retracts from the fluid chamber, the diaphragm 135, according to one embodiment, assumes its original position, which is shown in FIG Fig. 1 is shown again. Alternatively, the membrane 135 remains at least partially deformed after retraction of the stamp unit 120.

For example, a fluid may be contained in a blister in the fluid chamber 110. The fluid may also be filled directly into the fluid chamber, wherein the fluid chamber opening 130 may then be closed by a barrier film, so that the fluid can not flow into the channel 140. The fluid may alternatively be accommodated in an insert container accommodated in the fluid chamber 110, wherein the insert container may be closed by the barrier film.

By way of example, the microfluidic device 100 in FIG Fig. 1 shown in a position with a 0 ° inclination.

Fig. 2 shows a schematic cross section of a microfluidic device 100. These may be those based on Fig. 1 described microfluidic device 100, with the difference that the fluid chamber in Fig. 2 the barrier film 200 and the fluid 205 disposed in the fluid chamber 110. Furthermore, the device 100 has a transfer chamber 210 with a valve 215. The fluid 205 is received directly in the fluid chamber 110, with the barrier film 200 closing the fluid chamber opening, whereby the fluid 205 is securely held in the fluid chamber 110. According to this example, the fluid 205 does not completely fill the fluid chamber 110, it may contain other contents such as gas or air the fluid chamber 110 may be arranged. The fluid 205 may also be received in a blister disposed in the fluid chamber 110.

The rearrangement chamber 210 is connected to the channel 140 with the channel 140 disposed between the fluid chamber 110 and the rearrangement chamber 210. The rearrangement chamber 210 is disposed below the fluid chamber 205. The rearrangement chamber 210 has the valve 215 on a side facing away from the fluid chamber 110.

Details already described are described below with reference to Fig. 2 explained in more detail:
The LOC system 100 in the form of the microfluidic device 100 can consist of polymer-based multilayer structures in the form of the chamber substrate 105 and the cover substrate 115. The chamber substrate 105 and the lid substrate 115 have polymer-based substrates in which cavities in the form of the fluid chamber 205 and / or the channel 140 are arranged. A storage of liquids 205, hereinafter referred to as fluids 205, with small volumes below 1 ml is only conditionally possible in the fluid chamber 110 of the chamber substrate 105, since most plastics do not have sufficient barrier properties for long-term stable storage (PC, PA, US Pat. PS, PMMA). In addition, it is important that the fluid 205, such as a reagent, in the initial state is closed, z. B. by normally-closed valves 215, and on demand (on-demand) can be provided, which implies additional requirements for storage concepts. Thus, to store the fluid 205 for a long time, therefore, a separate container such as a blister pack or a tube bag in the form of the blister may be accommodated in the fluid chamber 110, whereby the chamber substrate 105 is not limited in its material selection. This implies requirements on the manufacturing process due to handling and pick-and-place processes. Advantageously, the chamber substrate 105 is made of plastics having high barrier properties, such as COP, COC, PP, PE or PET, allowing for safe fluid or reagent pre-storage in the chamber substrate 105 allows. A concept based on such plastics can on the one hand be integrated directly into the material system of the fluid chamber 110 or, on the other hand, can be fluidically connected to the fluid chamber 110 by a joining process, for example by gluing, welding or clamping.

The illustrated device 100 has a polymeric layer structure consisting of at least two polymer substrates, namely the chamber substrate 105 and the cover substrate 115, which are separated by the flexible membrane 135. In the chamber substrate 105, an upstream fluid 205 is arranged, for example in the blister, in a sealed injection-molded insert container or in an opening in the form of the fluid chamber 110 within the chamber substrate 105 sealed with the or more of the barrier films 200. To provide the upstream fluid 205 At least one stamp unit 120, for example a plunger, which can penetrate through at least one opening in the form of the stamp opening 125 in the cover substrate 115 by relative movement into the LOC in the form of the fluid chamber 110 is used.

Fig. 3 shows a schematic cross section of a microfluidic device 100. These may be those based on Fig. 2 described device, with the difference that the stamp unit 120 is inserted into the die opening and the barrier film 200 is opened by the stamp unit 120. Here, the flexible membrane 135 is deflected by the stamp unit 120 without tearing. Upon contact with the barrier film 200, a force is exerted by the stamp unit 120, which results in the tearing of a sealing film of the blister, for example, in the fluid chamber 110 and / or the barrier film 135.

Fig. 4 shows a schematic cross section of a microfluidic device 100. These may be those based on Fig. 3 described device 100, with the difference that according to this embodiment, the stamp unit 120 completely in the Fluid chamber 110 is inserted and the fluid 205 is displaced into the rearrangement chamber 210.

The fluid 205 is either in a supply chamber 210, previously referred to as rearrangement chamber 210, displaced or emptied after retraction of the stamp unit 120 in the connected microfluidic channel 140.

The result of the described approach is the advantage of a reliable provision of the fluid 205 by the mechanically actuated punch unit 120 or the plunger. In addition, the introduction of defined predetermined breaking points in, for example, the barrier film by z. As laser ablation be dispensed with, as can be exercised by the stamp unit 120 safely very large forces on the barrier film or the sealing film. It eliminates an associated additional manufacturing step. By using the mechanically actuated stamp unit 120, for example, barrier films can be used which have a strong layer structure and / or are formed very thick, for. B. by PP and metal layers, especially aluminum, these can still be broken reliably. This also favors the long-term stable storage of the fluid 205.

The stamping unit 120 advantageously does not come into contact with the upstream fluid 205 during the entire release process. The flexible membrane 135 enables complete separation from the mechanical actuation mechanism in the form of the stamp unit 120 and the fluid 125 in the fluid chamber 110 a control unit to be installed and does not have to be disposed of together with the blister used, for example, or insert in the form of the hopper. As a result, both the costs for the device 100 and the costs for a drive unit remain low, since this requires no additional mechanism in order to grip a punch unit 120 accommodated on the device 100.

According to this example, the reagent pre-inventory concept is based on the chamber substrate 105 of FIG polymeric substrate with integrated fluid chamber 110 which is sealed by the barrier film. The chamber substrate 105 may be made of plastics having high barrier properties, e.g. B. PP,
PE, COC, COP, or have additional coatings such as Al, Al2O3, SiO meet the requirements for long-term storage of fluids 205 as liquid reagents. The chamber substrate 105 is connected to the flexible membrane 135 and another polymeric substrate, the lid substrate 115. As joining processes for this multi-layer structure, laser transmission welding, ultrasonic welding, thermal bonding, gluing, clamping or comparable processes are suitable. The lid substrate 135 has at least one opening in the form of the die opening 125. For the release of the fluid 205, the stamp unit 120 moves through the die opening 125, deflects the flexible membrane 135 without it tearing, and breaks the barrier film. In this case, the fluid 205 is displaced via the transfer channel in the form of the channel 140 into the rearrangement chamber 210 and is ready for further microfluidic processes. For example, the fluid 205 may be sucked when opening the valve 215 by a negative pressure in a behind it located microfluidic network. The flexible membrane 135 enables a complete fluidic separation between the fluidics in the chamber substrate 105 with all fluids 205 involved and the mechanical stamp unit 120. The stamp unit 120 is preferably formed so that it displaces the largest possible volume from the fluid chamber 110, without the Seal edges of the fluid chamber 110 so that the fluid 205 no longer enters the rearrangement chamber 210. This is best achieved if the shape of the stamp unit 120 corresponds to the inverse of the fluid chamber 110, but for example has some 100 μm tolerance on the outer walls.

Any desired geometries, dimensions and shapes are also conceivable for the stamp unit 120, which promote targeted rupture of the barrier film and / or the sealing film and directional emptying of the fluid chamber 110. For example, the stamp unit 120 can hold a recess directed to the rearrangement chamber 210 in order to promote the displacement of the fluid 205 into the rearrangement chamber 210. It can thus be minimized crosstalk of the fluid 205.

Fig. 5 shows a schematic cross section of a microfluidic device 100 with insertion tray 500. These may be based on the Fig. 2 described device 100, with the difference that the cavity 505 having insert container 500 is received by the fluid chamber 110. The fluid 205 is disposed in the cavity 505 of the loading container 500. The fluid chamber 110 has a rectangular shaped cross-section to receive the loading container 500, which also has a rectangular cross-section. The insert container 500 can be inserted with a precise fit or approximately exact fit into the fluid chamber 110. Due to the separate insert container, the channel 140 or the wall between the fluid chamber 110 and the rearrangement chamber 210 can be completely eliminated in an advantageous and space-saving embodiment. According to one example, the fluid chamber 110 and the rearrangement chamber 210 are combined into one chamber, or in other words, the rearrangement chamber 210 and the inserter bin 500, also referred to as an inserter, are not separated. Alternatively, the wall between the fluid chamber 110 and the rearrangement chamber 210 can be reduced to a small indentation, be designed as a web for holding the insertion container 500 in the fluid chamber 110, or have a passage opening forming the channel 140.

In this further advantageous example, the additional insert container 500 is integrated into the chamber substrate 105. The insert container 500 ideally has higher barrier properties than the surrounding chamber substrate 105. This insert container 500 contains the fluid 205 and is sealed to the barrier film 200. The release of the fluid 205 is identical, as described in the preceding figures. The material selection of the chamber substrate 105 remains independent of the requirements of the long-term stable reagent pre-storage according to this embodiment.

The insert container 500 can be glued, clamped, welded or integrated by other joining methods. The loading container 500 may also be easily inserted into a suitably shaped receiving chamber in the form of the fluid chamber 110 in the Chamber substrate 105 has been inserted. By properly formed, it is meant here that the fluid chamber 110 closely encloses the loading container 500. This has the advantage that the dead volume of the structure is minimized and slipping of the loading container 500 is avoided.

The loading container 500 has according to this embodiment, the cavity 505 for receiving the fluid 205, but according to an alternative embodiment, also have a plurality of such cavities 505, the z. B. each filled with different fluids 205. These cavities 505 may be arranged in the form of a bar or only in certain places, for. B. at the top, comb-like with each other. This has the advantage that in the fluid chamber 110 separating elements, for. As walls, may be arranged between the various fluids 205, which can reliably prevent mixing of the fluids 205. Furthermore, the deflection of the flexible membrane 135 by the movable punch unit causes the fluidic path to the in Fig. 6 sealed connection recesses 605 is sealed in order to prevent mixing of stored in separate fluid chambers 110 fluids 205 after their release safely.

Fig. 6 shows a perspective view of a chamber substrate 105 with a plurality of fluid chambers 110. This may be based on the Fig. 5 described chamber substrate 105, with the difference that no fluid is received in the cavities 505 of the hopper 500. According to this example, the chamber substrate 105 has four fluid chambers 110 arranged side by side. The number of fluid chambers 110 is merely exemplary, so that more or fewer than four fluid chambers 110 may be provided. Below the fluid chambers 110 four rearrangement chambers 210 are arranged. The fluid chambers 110 have the insertion container 500, wherein the insertion container 500 is formed as a four cavities 505 comprehensive insert container 500, wherein one of the cavities 505 is accommodated in each case in one of the four fluid chambers 110. According to this example, the loading container 500 has a region between the cavities 505 facing away from the rearrangement chambers 210 three connecting webs 600 on. The chamber substrate 105 has in the region corresponding to the connecting webs 600 three connecting recesses 605 for receiving the connecting webs 600.

Figure 7 shows a cross section of a microfluidic device 100 with a vent opening 700 according to an inventive embodiment. These may be the ones based on Fig. 3 described device 100, with the difference that the punch opening 125 is smaller than in Fig. 3 is formed and arranged in the region of the channel 140, and that the channel 140 has a channel extension 705, which has the vent opening 700.

The channel extension 705 extends according to this embodiment in a direction away from the channel 140, the punch opening 125 is arranged between the channel extension 705 and the channel 140. The channel extension 705 is also disposed between the fluid chamber 110 and the diaphragm 135. The channel extension 705 according to this embodiment extends over a height 710 of the fluid chamber 110, wherein the vent opening 700 opens transversely to the channel extension 705 in an out of the height 710 disposed end of the channel extension 705. The vent opening 700 runs on a side of the fluid chamber 110 facing away from the stamp opening 100 according to this exemplary embodiment, parallel to the stamp opening 125.

According to this exemplary embodiment, a blister is embedded in the chamber substrate 105 in such a way that two sealed sealing areas 715 of the blister rest on a surface provided in the chamber substrate 105 and can be glued there, for example. The lid substrate 115 has the vent opening 700, under which the membrane 135 is opened on.

The punch opening 125 is closed by the membrane 135. The stamp unit 120 can penetrate through the die opening 125 into the assembly in the form of the device 100 and pierce the barrier film 200 as well as the sealing film surrounding the blister. The fluid 205 may then be discharged through the channel 140. This exemplary embodiment has the particular advantage that it is possible to dispense with an additional provision chamber in the form of the rearrangement chamber. Thus, this allows Embodiment, a particularly space-saving possibility for Vorlagerung the fluid 205th

Fig. 8 shows a cross section of a microfluidic device 100 with a vent opening 700 according to an inventive embodiment. These may be the ones based on Fig. 7 described device 100, with the difference that the punch unit 120 is again led out of the device 100 according to this embodiment, whereby the diaphragm 135 is retracted in the region of the die opening 125 and the fluid 205 flows into the channel 140.

Fig. 9 shows a cross section of a microfluidic device 100 with an intermediate substrate 900 and another stamp unit 905. These may be based on the Fig. 7 described device 100, with the difference that the channel 140 has no channel extension and the vent opening 700 is disposed in a region of the height 710. The intermediate substrate 900 is disposed between the chamber substrate 105 and the lid substrate 115. The intermediate substrate 900 has a further vent opening 910 and a further punch opening 915.

The further punch opening 915 continues the punch opening 125, and the further vent opening 910 continues the vent opening 700. The intermediate substrate 900 is shaped to form an air channel 920 opening into the further venting channel 910. The air channel 920 is arranged transversely to the further venting channel 910 on a side of the membrane 135 facing the fluid chamber 110. The air duct 920 extends in a direction away from the punch opening 125. The further stamp unit 905 is introduced into the fluid chamber 110 through the vent opening 700 and the further vent opening 910 according to this exemplary embodiment. The further stamping device 905 opens according to this embodiment, the barrier film 200 and / or the sealing film of the example received blister in a region in which the fluid 205 at the in Fig. 9 shown position is not arranged. According to this For example, the two sealing regions 715 are arranged between the chamber substrate 105 and the intermediate substrate 900. According to this example, a second plunger in the form of the further stamp unit 905 is used to push a second opening into the barrier film 200 and / or the sealing film of a blister. Since blisters are not completely filled due to their production, it is particularly advantageous to make the second opening at a location of the stickpack, ie the blister, behind which there is air or gas. This example has the particular advantage that the blister can be ventilated via the air duct 920 and thus a particularly high emptying efficiency is achieved.

In an alternative example, the fluid 205 is directly preceded in the fluid chamber 110, which is sealed by the barrier film 200. The arrangement is chosen so that the barrier film 200 is connected in the sealing areas 715 areally with the chamber substrate 105. For fluid release, the two mechanical punch units 120, 905 are moved into the anticipated openings in the form of the punch opening 125 and the vent opening 700 in the lid substrate 115 and the further punch opening 915 and the further vent opening 910 in the intermediate substrate 900 and divert the flexible membrane 135. In this case, the barrier film 200 is broken open in the region of the additional punch opening 915 and the further vent opening 910. If the stamp devices 120, 905 are moved back again, the venting path in the form of the air duct 920 and the fluidic path in the form of the channel 140 are released.

An example polymeric sealing layer of the barrier film 200 has the particular advantage that the mechanical deformation after retraction of the mechanical stamp devices 120, 905 is maintained, which ensures the blockade-free opening of the channel 140 and the pneumatic air channel 920. It is also particularly advantageous to design the further stamping unit 905 so that it penetrates the barrier film 200 in front of the stamping unit 120. In this way, it is ensured that any overpressure occurring within the fluid chamber 110 can escape before the stamp unit 120 penetrates. With different execution The stamp units 120, 905 can continue to be a simultaneous actuation.

Fig. 10 shows a cross section of a microfluidic device 100 with an intermediate substrate 900 and another stamp unit 905. These may be based on the Fig. 9 described device 100, with the difference that the punch device 120 and the further stamping device 905 are led out of the device 100 according to this embodiment, whereby the diaphragm 135 is retracted in the region of the punch opening 125 and in the region of the vent opening 700, whereby the fluid 205 flows into the channel 140 and another fluid from the environment of the device 100 flows through the air channel 920 in the fluid chamber 110. This example has the particular advantage that after the barrier film has been torn open and the stamp units have been retracted, the reagent can be actively sucked through the channel 140, at the same time the risk of creating an air path up to the vent 700 (as in FIG 7 and FIG. 8 ) is reduced to a minimum. The emergence of an air path for venting 700 would in the worst case, an active suction of the released reagent is no longer possible.

Fig. 11 shows a cross section of a microfluidic device 100 with another barrier film 1100. These may be based on Fig. 9 described device, with the difference that the fluid chamber bottom is formed by the further barrier film 1100, and that the fluid chamber 110 has a second punch opening 1105. The fluid chamber opening 130 has a diameter corresponding to the die opening 125. The fluid chamber opening 130 is arranged on a side of the fluid chamber 110 facing the channel 140. The second fluid chamber opening 1105 has a diameter corresponding to the vent opening 700. The second fluid chamber opening 1105 is fluidically connected to the further vent opening 910. According to this example, the fluid chamber 110 has a rectangular cross-section. The chamber substrate 105 according to this embodiment extends over the punch opening side including the fluid chamber opening 130 and the second punch opening 1105. The Barrier film 200 is disposed between the chamber substrate 105 and the intermediate substrate 900, with the barrier film 200 spanning the fluid chamber opening 130 and the second die opening 1105. The barrier film 200 is opened in the area of the fluid chamber opening 130 and in the region of the second fluid chamber opening 1105 by the stamp unit 120 and the further stamp unit 905.

The following are details already executed based on Fig. 11 described in more detail:
According to this example, the chamber substrate 105 is sealed on both sides with the barrier films 200, 1100. The double-sided sealed chamber substrate 105 with integrated fluid 205 is attached to the multi-layer structure of the device 100 via a joining step, for example by gluing and / or welding and / or clamping, such that the punch opening 125 and the vent opening 700 are in an axis with the apertures in the form the fluid chamber opening 130 and the second fluid chamber opening 1105 are located. This has the particular advantage that when the fluid is released, the mechanical stamp units 120, 905 break the barrier film 200 in a defined manner, with no air path being able to form between the channel 140 and the air duct 920, since the chamber substrate 105 travels airtight over a planar joining surface 1100 in the remaining area the intermediate substrate 900 is connected.

For the release of the fluid 205, the mechanical stamp devices 120, 905 can be moved back and the fluid 205 ready to be actively attracted, for example, in the fluidic channel 140. This results in the advantage that the further barrier film 200 limits the pressure increase within the fluid chamber 110 when the stamp devices 120, 905 are pressed in by a slight bulging. This reduces the risk of leakage when opening.

Fig. 12 shows a cross section of a microfluidic device 100 with the other barrier film 1100. These may be based on the Fig. 11 described device 100, with the Difference that the stamping device 120 and the further stamping device 905 are again led out of the device 100, whereby the diaphragm 135 is retracted in the region of the punch opening 125 and in the region of the vent opening 700, whereby the fluid 205 flows into the channel 140 and the other fluid from the environment of the device 100 through the air channel 920 flows into the fluid chamber 110.

Fig. 13 shows a cross section of a microfluidic device 100 with the other barrier film 1100. These may be based on the Fig. 11 described apparatus, with the difference that the barrier film 200 according to this embodiment is disposed on an inner side of the fluid chamber 110 such that it spans the fluid chamber opening 130 and the second fluid chamber opening 1105. The barrier film 200 is opened according to this exemplary embodiment by the stamp unit 120 and the further stamp unit 905.

According to this example, the barrier film 200 is sealed on the inside of the fluid chamber 110, so that no air path between the channel 140 and the air channel 920 can form here as well. The chamber substrate 105 is directly connected to the multi-layer structure of the device 100, so the intermediate substrate 900 via the joining surface 1110 positively or non-positively, for. B. by gluing and / or welding and / or terminals. The barrier film 200 can also be sunk locally in the chamber substrate 105 in the region of the fluid chamber opening 130 and the second fluid chamber opening 1105.

The required polymer substrates, ie the starting material, and the required structures in the polymer substrates can be produced for example by milling, injection molding, hot stamping, deep drawing and / or laser structuring.

Material examples for the individual components of the devices 100 described with reference to the preceding figures follow.

Materials for the chamber substrate 105 and the lid substrate 115 may be thermoplastics, e.g. PC, PA, PS, PP, PE, PMMA, COP, COC.

Materials for the tray 500 may be thermoplastics, for. PC, PA, PS, PP, PE, PMMA, COP, COC and / or glass.

Materials for the stamping device 120 and the further stamping device 905 may include thermoplastics, for. PC, PA, PS, PP, PE, PMMA, COP, COC, and / or metals such as steel or brass, as well as elastomers.

Coatings of reservoirs, such as fluid chamber 110, may be made with Al, Al 2 O 3, SiO 2.

Materials for membrane 135 may be elastomer, thermoplastic elastomer (TPU, TPS), thermoplastics, or heat sealable films.

As a barrier film 200 and sealing film commercially available polymer composite films of polymeric sealing and protective layers can be used, for. As PE, PP, PA, PET and as a barrier layer, usually vapor-deposited aluminum, but also other high barrier layers such as EVOH, BOPP.

The following are exemplary dimensions of elements of the embodiments:
The thickness of the chamber substrate 105 and the lid substrate 115 may be 0.5 to 5 mm. The thickness of the diaphragm 135 may be 5 to 300 μm. In a multilayer structure of the barrier films 200, a thickness of the barrier layer (usually Alu) 5 microns to 500 microns, a thickness of the polymer layer 5 microns to 500 microns, a thickness of the protective layer 5 microns to 500 microns and an elastic layer on the sealing film 50 microns to 2 mm.

The volume of the blister can be 100 to 10000 μl.

Cuboid shapes, cylindrical shapes, cubic shapes and any other suitable shapes and geometries are suitable as forms for the stamp devices 120, 905.

Fig. 14 shows a cross section of a microfluidic device 100 with the other barrier film 1100. These may be based on the Fig. 12 described device 100, with the difference that the barrier film 200 is disposed on the inside of the fluid chamber 110.

Fig. 15 shows a perspective view of a device 100 having a plurality of fluid chambers 110. This may be one of the basis of Fig. 11 to 14 act described devices 100. According to this example, the chamber substrate 105 has four adjacent fluid chambers 110.

Fig. 16 FIG. 12 shows a flowchart of a method 1600 for manufacturing a microfluidic device. This can be one of the basis of Fig. 1 to 5 act described devices. In a step of providing 1605, a chamber substrate having a fluid chamber for receiving a fluid is provided. In a further step of providing 1610, a lid substrate is added with a punch opening opposite to a fluid chamber opening of the fluid chamber. In a step of placing 1615, a flexible membrane is placed between the chamber substrate and the lid substrate, with the membrane spanning the die opening and the fluid chamber. In a further step of the production 1620, a channel extending on a side of the membrane facing the chamber substrate is produced which is fluidically connected to the fluid chamber. The step of producing 1620 may be performed at an appropriate time of the method, for example, prior to the step of providing lid substrate 1610 so that in the providing step 1610, the lid substrate having the channel may already be provided. In a step of arranging 1625, a stamp unit is arranged to be formed is to retract into the fluid chamber through the die opening to deflect the membrane into the fluid chamber to allow the fluid to flow out of the fluid chamber into the channel when the fluid is received in the fluid chamber.

Fig. 17 FIG. 12 shows a flowchart of a method 1700 for operating a microfluidic device. This can be one of the basis of Fig. 1 to 5 act described devices.

In a step of retraction 1705, a stamper unit is retracted into the fluid chamber through the stamper opening to deflect the membrane into the fluid chamber to allow the fluid to flow out of the fluid chamber into the channel when the fluid is received in the fluid chamber. In one example, the force is applied by a stamp unit that is actuated in an optional step 1710. The actuation can be carried out, for example, using a mechanical or electromechanical actuator.

If an exemplary embodiment comprises a "and / or" link between a first feature and a second feature, then this is to be read so that the embodiment according to one embodiment, both the first feature and the second feature and according to another embodiment either only first feature or only the second feature.

Claims (12)

1. Microfluidic device (100) having the following features:

   a chamber substrate (105) with a fluid chamber (110) for accommodating a fluid (205);

   a cover substrate (115) with a punch opening (125), wherein the punch opening (125) is arranged opposite a fluid chamber opening (130) of the fluid chamber (110);

   a flexible diaphragm (135) which is arranged between the chamber substrate (105) and the cover substrate (115) and spans the punch opening (125) and the fluid chamber (110); and

   a punch unit (120) which is designed to move into the fluid chamber (110) through the punch opening (125) in order to deflect the diaphragm (135) into the fluid chamber (110) in order to allow the fluid (205) to flow out of the fluid chamber (110) when the fluid (205) is accommodated in the fluid chamber (110), characterized by a channel (140) which extends on a side of the diaphragm (135) facing the chamber substrate (105) and which is fluidically connected to the fluid chamber (110), wherein the channel (140) has a channel extension (705), and the cover substrate (115) has a venting opening (700) which opens into the channel extension (705), wherein the punch opening (125) is arranged between the venting opening (700) and the channel (140), and wherein the diaphragm (135) does not span the venting opening (700).
2. Device (100) according to Claim 1, characterized in that the fluid (205) is accommodated in the fluid chamber (110) and is kept in the fluid chamber (110) by a barrier film (200) which closes off the fluid chamber (110), wherein the barrier film (200) is formed to be opened by the punch unit (120).
3. Device (100) according to Claim 2, characterized in that the fluid (205) is arranged in an insert container (500) which is accommodated by the fluid chamber (110), wherein the barrier film (200) closes off the insert container (500).
4. Device (100) according to one of the preceding claims, characterized in that the fluid (205) is arranged in a blister which is accommodated by the fluid chamber (110), wherein the blister substantially fills a volume of the fluid chamber (110), wherein the blister is formed to be opened by the punch unit (120).
5. Device (100) according to one of the preceding claims, characterized in that a diameter of the punch opening (125) is greater than half the diameter of the fluid chamber opening (130).
6. Device (100) according to Claim 1, characterized in that the diameter of the punch opening (125) is less than half the diameter of the fluid chamber opening (130), wherein the punch opening (125) is arranged adjacent to the channel (140).
7. Device (100) according to Claim 6, characterized in that the cover substrate (115) has a venting opening (700) which opens into the fluid chamber (110), wherein the punch opening (125) is arranged between the venting opening (700) and the channel (140), wherein the diaphragm (135) spans the venting opening (700), and in that the device (100) has a further punch unit (905) which is designed to move into the fluid chamber (110) through the venting opening (700) in order to deflect the diaphragm (135) into the fluid chamber (110) in order to allow a further fluid to flow into the fluid chamber (110).
8. Device (100) according to Claim 7, characterized in that, between the chamber substrate (105) and the diaphragm (135), there is arranged an intermediate substrate (900) which has a further punch opening (915), extending the punch opening (125), and has a further venting opening (910), extending the venting opening (700), and which is formed to create an air channel (920) extending transversely with respect to the venting opening (700) and opening into the further venting opening (910) .
9. Device (100) according to Claim 8, characterized in that the channel (140) extends between the diaphragm (135) and the intermediate substrate (900) and opens into the punch opening (125).
10. Device (100) according to either of Claims 8 and 9, characterized in that a diameter of the fluid chamber opening (130) corresponds to the punch opening (125), wherein the fluid chamber (110) has a second fluid chamber opening (1105) which corresponds to a diameter of the further venting opening (910).
11. Device (100) according to one of Claims 8 to 10, characterized in that a fluid chamber base opposite the fluid chamber opening (130) is formed by a further barrier film (1100).
12. Method (1700) for operating a microfluidic device (100) according to one of the preceding claims, wherein the method has the following step:
    moving-in (1705) of the punch unit (120) of the microfluidic device (100) into the fluid chamber (110) of the microfluidic device (100) through the punch opening (125) in order to deflect the diaphragm (135) into the fluid chamber (110) in order to allow the fluid (205) to flow out of the fluid chamber (110) when the fluid (205) is accommodated in the fluid chamber (110).

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