EP2905079A1 - Device for storing a fluid in a microfluidic system, method for operating and method for producing such a device - Google Patents

Abstract

The invention relates to a device (100) for pre-storing a fluid (120) in a microfluidic system. The device (100) comprises a cover element (105) and a bottom element (110) with a bottom recess (115). The bottom recess (115) is disposed opposite the lid member (105) and adapted to receive the fluid (120). Furthermore, the device (100) is provided with a closure film (125) which is arranged between the cover element (105) and the bottom element (110) at least in the area of the bottom recess (115) in order to keep the fluid (120) in the bottom recess (11). 115). In addition, the device (100) comprises at least one pressure channel (130) which is formed in the cover element (105) to direct a pressure in a region of the bottom recess (115) and at least one fluid channel (135) which is between the cover element (105) and the bottom member (110) is adapted to fluidly connect the bottom recess (115) with an outside environment of the bottom recess (115). Finally, the device (100) comprises a membrane (140) which is arranged at least in the region of the bottom recess (115) between the cover element (105) and the closure film (125) and is designed to guide the pressure into the region of the bottom recess (115) being pressed against the sealing film (125) by the pressure such that the sealing film (125) is opened.

Description

State of the art

The present invention relates to a device for pre-storing a fluid in a microfluidic system, to a method of operating such a device, and to a method for producing such a device.

The EP 1 896 180 B1 discloses a microfluidic system, also called a lab-on-a-chip system, which is equipped with flexible membranes to displace fluids within the system.

Microfluidic systems can be designed, for example, as a multilayer structure with a cavity. In this case, a membrane to be deflected can be permanently fastened locally to a lid of the cavity in order to define a volume to be displaced during a joining process.

Disclosure of the invention

Against this background, with the approach presented here, a device for pre-storing a fluid in a microfluidic system, a method for operating such a device and a method for producing such a device according to the main claims are presented. Advantageous embodiments emerge from the respective subclaims and the following description.

• ein Deckelelement;
• ein Bodenelement mit einer Bodenausnehmung, wobei die Bodenausnehmung dem Deckelelement gegenüberliegend angeordnet ist und ausgebildet ist, um das Fluid aufzunehmen;
• eine Verschlussfolie, die zumindest in einem Teilbereich der Bodenausnehmung zwischen dem Deckelelement und dem Bodenelement angeordnet ist, um das Fluid in der Bodenausnehmung zu halten;
• zumindest einen Druckkanal, der in dem Deckelelement ausgebildet ist, um einen Druck in einen Bereich der Bodenausnehmung zu leiten;
• zumindest einen Fluidkanal, der zwischen dem Deckelelement und dem Bodenelement ausgebildet ist; und
• eine Membran, die zumindest im Bereich der Bodenausnehmung zwischen dem Deckelelement und der Verschlussfolie angeordnet ist und ausgebildet ist, um bei Leiten des Drucks durch den Druckkanal durch den Druck derart verformt zu werden, dass die Verschlussfolie geöffnet wird.

The present approach provides a device for pre-storing a fluid in a microfluidic system, the device having the following features:

• a lid member;
• a bottom member having a bottom recess, the bottom recess being opposed to the lid member and configured to receive the fluid;
• a sealing film, which is arranged at least in a partial region of the bottom recess between the cover element and the bottom element in order to hold the fluid in the bottom recess;
• at least one pressure channel formed in the lid member to direct pressure into a portion of the bottom recess;
• at least one fluid channel formed between the lid member and the bottom member; and
• a membrane which is arranged at least in the region of the bottom recess between the cover element and the closure film and is designed to be deformed by the pressure during the passage of the pressure through the pressure channel such that the closure film is opened.

A microfluidic system can be understood to mean a system for analyzing the smallest amounts of sample liquids. For example, such a system can be a cartridge-like layer composite with a cover element and a base element. Under a cover element and a bottom element can each be understood a layer which is made for example of a plastic, in particular of a polymer. Under a bottom recess can be understood as a depression in the bottom element. Under a fluid may be a liquid reagent for effecting a chemical reaction in the microfluidic System understood. Under a sealing film or a membrane can be understood depending on a sheet-like flexible element such as a plastic layer or a composite layer. The sealing film or the membrane may be, for example, fluid-impermeable. The pressure can be introduced through the pressure channel into a region between the cover element and the membrane. The membrane can be pressed by the pressure against the sealing foil and further into the bottom recess.

The present approach is based on the recognition that a reagent in the form of a fluid can be stored long-term stable and space-saving in a lab-on-a-chip system by the fluid is placed in a recess of a substrate and covered by a sealing film. To provide the fluid when needed, the sealing film can be severed by pneumatic deflection of an elastic membrane. As a result, an efficient emptying of the recess is ensured even at low volumes of fluid, without separate containers for the fluid would be required.

The use of the elastic membrane as a means for opening the sealing film can prevent reagents from getting stuck in the recess, for example due to capillary forces acting between the reagents and a polymer surface. Thus, losses during emptying or even a lack of emptying can be avoided.

The device may be provided with a blister which is filled with the fluid. In this case, the blister can be arranged in the bottom recess. Furthermore, in this case, the sealing foil seal the blister fluid-tight. Under a blister can be understood a tablet package with a cup-like depression, which is sealed with the sealing film. Such a blister is easy and inexpensive to provide. Further, since the fluid is trapped in the blister, contamination of the fluid by foreign matters can be prevented.

The membrane may be configured to be further deformed by the pressure upon directing the pressure through the pressure channel after the opening of the closure film such that the fluid from the bottom recess into the fluid channel is moved. In this way, the bottom recess can be safely emptied by the deformation of the membrane.

According to another embodiment of the present approach, the fluid may be filled in the bottom recess. In this case, the sealing foil can seal the bottom recess in a fluid-tight manner. By filling required reagents directly into a lab-on-a-chip cartridge and sealing them for a long time, a particularly simple and cost-saving reagent pre-storage can be realized.

In this case, the closure film may be fixed to the bottom element in order to close the bottom recess in a fluid-tight manner. For example, the sealing foil may be attached to the bottom member such that the membrane and the sealing foil are separated by a small gap, thus preventing direct contact between the membrane and the sealing foil.

Furthermore, the sealing film may have at least one predetermined breaking point. A predetermined breaking point can be understood as meaning a material weakening of a partial region of the sealing film. For example, the predetermined breaking point can be realized by a reduced thickness of the sealing film or by a specific embossing pattern. Thus, even a relatively low pressure may be sufficient to open the sealing film by the deflection of the membrane. Furthermore, the predetermined breaking point offers the advantage of a controlled and reproducible opening of the sealing film.

The predetermined breaking point can be realized according to a further embodiment by means of laser structuring. Laser structuring can be understood as a method in which the predetermined breaking point is generated by means of electromagnetic waves in the sealing film. As a result, the predetermined breaking point can be realized particularly quickly and efficiently. For example, the closure film of a prefabricated blister can be provided in this way subsequently very easily with the predetermined breaking point.

Furthermore, the closure film can be realized with at least one polymer layer and / or at least one metal layer. By way of example, the polymer layer and the metal layer can be combined with one another in a layer composite. By such a combination of different types of layers, the sealing film can be made particularly robust.

According to a further embodiment, it is provided that the membrane is fixed to the cover element at least in the region of the fluid channel. This makes it possible to prevent the fluid channel from being narrowed or closed by a deflection of the membrane in the region of the fluid channel.

The device can also be provided with at least one further bottom recess. In this case, the further bottom recess can be arranged opposite the cover element. The fluid channel may in this case be designed to fluidly connect the bottom recess and the further bottom recess. The further bottom recess can serve, for example, to catch the fluid released when the closure film is opened.

According to one embodiment, the membrane may be fastened to the cover element in a subregion of the bottom recess located on a side of the bottom recess facing away from the fluid channel. In this case, an outlet of the pressure channel can be arranged in a subregion of the bottom recess located on a side of the bottom recess facing the fluid channel, in which the membrane is not fastened to the cover element. In this way, deformation range of the membrane can be limited.

The membrane may be configured to be deformed back upon the withdrawal of the pressure at the pressure channel after the opening of the sealing film. In addition to the withdrawal of the pressure, a negative pressure can be applied to the pressure channel. As a result of the deformation of the membrane, the membrane can rest continuously on the cover element in the region of the bottom recess. In particular, can be ensured by the back deformation that the fluid channel is released from the membrane.

The fluid channel may have a step between a first section of the fluid channel formed in the base element and a second section of the fluid channel formed in the cover element. In this case, the first section can open into the bottom recess. The first section and the second section may be parallel to each other and overlap in the area of the step. This can facilitate outflow of the fluid through the fluid channel.

The membrane may extend beyond the step. In the region of the first section of the fluid channel, the membrane may be fastened to the cover element. In the region of the second section of the fluid channel, the membrane can be movably arranged between the cover element and the bottom element. By moving the membrane in the second section towards the cover element, the fluid channel can be released in the region of the step.

According to one embodiment, during operation of the device, the fluid channel can be arranged below to move the fluid in a gravity-driven manner from the bottom recess into the fluid channel. This simplifies the construction of the device.

A method of operating said apparatus comprises a step of directing the pressure through the pressure channel to deform the membrane such that the closure sheet is opened. Preferably, the membrane is further deformed by directing the pressure through the pressure channel such that the fluid is moved from the bottom recess into the fluid channel.

In this way, the upstream fluid in the device can be displaced by a simple provision of pressure from the bottom recess in the fluid channel.

The present approach provides a method of manufacturing a device according to any of the above-described embodiments, the method comprising the steps of: Providing a bottom member having a bottom recess for receiving a fluid and a lid member having at least one pressure channel to direct pressure into a portion of the bottom recess;

Providing the fluid, a sealing film and a membrane;

Assembling the cover element and the bottom element, wherein the bottom recess is arranged opposite the cover element, at least one fluid channel is formed between the cover element and the bottom element, the fluid is arranged in the bottom recess, the closure film at least in a partial region of the bottom recess between the cover element and the bottom element is arranged to hold the fluid in the bottom recess, and the membrane is disposed at least in the region of the bottom recess between the lid member and the sealing foil, wherein the membrane is adapted to be deformed upon pressure of the pressure channel through the pressure so in that the closure film is opened.

Preferably, the membrane may be configured to be deformed by the pressure upon directing the pressure through the pressure channel after the opening of the closure film such that the fluid is moved from the bottom recess into the fluid channel.

• Fig. 1 eine schematische Darstellung einer Vorrichtung gemäß einem Ausführungsbeispiel der vorliegenden Erfindung;
• Fig. 2a, 2b, 2c, 2d schematische Darstellungen einer Vorrichtung in verschiedenen Auslenkungszuständen gemäß einem Ausführungsbeispiel der vorliegenden Erfindung;
• Fig. 3 eine schematische Darstellung einer Vorrichtung gemäß einem Ausführungsbeispiel der vorliegenden Erfindung;
• Fig. 4a, 4b schematische Darstellungen einer Vorrichtung mit einer Sollbruchstelle gemäß verschiedenen Ausführungsbeispielen der vorliegenden Erfindung;
• Fig. 5a, 5b, 5c, 5d schematische Darstellungen einer Vorrichtung in verschiedenen Auslenkungszuständen gemäß einem Ausführungsbeispiel der vorliegenden Erfindung;
• Fig. 6a, 6b schematische Darstellungen einer Vorrichtung mit einer Sollbruchstelle gemäß verschiedenen Ausführungsbeispielen der vorliegenden Erfindung; und
• Fig. 7 ein Ablaufdiagramm eines Verfahrens zum Betreiben einer Vorrichtung gemäß einem Ausführungsbeispiel der vorliegenden Erfindung; und
• Fig. 8 ein Ablaufdiagramm eines Verfahrens zum Herstellen einer Vorrichtung gemäß einem Ausführungsbeispiel der vorliegenden Erfindung.
• Fig. 9 eine schematische Darstellung einer Vorrichtung gemäß einem Ausführungsbeispiel der vorliegenden Erfindung; und
• Figuren 10 bis 14 schematische Darstellungen einer Vorrichtung in verschiedenen Auslenkungszuständen gemäß einem Ausführungsbeispiel der vorliegenden Erfindung.

The approach presented here will be explained in more detail below with reference to the accompanying drawings. Show it:

• Fig. 1 a schematic representation of a device according to an embodiment of the present invention;
• Fig. 2a . 2b, 2c, 2d schematic representations of a device in different deflection states according to an embodiment of the present invention;
• Fig. 3 a schematic representation of a device according to an embodiment of the present invention;
• Fig. 4a, 4b schematic representations of a device with a predetermined breaking point according to various embodiments of the present invention;
• Fig. 5a, 5b, 5c, 5d schematic representations of a device in different deflection states according to an embodiment of the present invention;
• Fig. 6a, 6b schematic representations of a device with a predetermined breaking point according to various embodiments of the present invention; and
• Fig. 7 a flowchart of a method for operating a device according to an embodiment of the present invention; and
• Fig. 8 a flowchart of a method for manufacturing a device according to an embodiment of the present invention.
• Fig. 9 a schematic representation of a device according to an embodiment of the present invention; and
• FIGS. 10 to 14 schematic representations of a device in different deflection states according to an embodiment of the present invention.

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 shows a schematic representation of an apparatus 100 according to an embodiment of the present invention. The device 100 comprises a cover element 105 and a bottom element 110. The cover element 105 and the bottom element 110 are each designed plate-like. The bottom element 110 has a bottom recess 115, which is arranged opposite the cover element 105. In the bottom recess 115, a fluid 120 is upstream. In the area of the bottom recess 115, a closing foil 125 is arranged between the lid element 105 and the bottom element 110. The sealing foil 125 is designed to hold the fluid 120 in the bottom recess 115.

In the cover member 105, a pressure channel 130 is further formed. By way of example, the pressure channel 130 is realized as a passage opening. One end of the pressure channel 130 is disposed opposite the bottom recess 115.

Between the cover element 105 and the bottom element 110, a fluid channel 135 is formed, which leads from the bottom recess 115 to an outside environment of the bottom recess 115. The fluid channel 135 may, for example, be formed by a groove in the cover element 105 or the base element 110. A fluidic connection between the bottom recess 115 and the fluid channel 135 may be closed by the closure film.

In the area of the bottom recess 115, a membrane 140 is arranged between the closure film 125 and the cover element 105. By way of example, the membrane 140 further extends across an entire width of the device 100.

By means of the pressure channel 130, a pressure can be applied to a side of the membrane 140 facing away from the bottom recess 115. For example, the pressure channel 130 for this purpose with a in Fig. 1 not shown pneumatic pump connected. The membrane 140 is designed to be pressed against the closure film 125 when the pressure is applied in such a way that the closure film 125 tears open. Characterized in that the diaphragm 140 with increasing pressure both in the direction of a bottom surface of the bottom recess 115 and in the direction of the fluid channel 135 trough-shaped bulges, the fluid 120 is pressed by the bottom recess 115 in the fluid passage 135.

According to this embodiment, the fluid 120 is introduced into a blister 145. The blister 145 is disposed in the bottom recess 115. An opening of the blister 145 facing the lid member 105 is sealed with the sealing film 125. An outer edge region of the sealing film 125 protrudes beyond the blister 145. In this case, the protruding outer edge region of the closure film 125 is arranged in a groove running along an edge region of the bottom recess 115, which serves to fix the blister 145 in the bottom recess 115. Alternatively, the fluid may be, for example, based on Fig. 5a shown to be arranged directly in the bottom recess 115.

In Fig. 1 For example, an initial state of the blister 145 in the multilayer structure of a first polymer substrate 105, a polymer membrane 140 and a second polymer substrate 110 is shown.

A microfluidic device 100 for emptying an upstream fluid 120 may be configured to provide or transport fluids 120 on a chip. Such a component 100 can be used, for example, in a lab-on-a-chip system (LOC) in which the entire functionality of a macroscopic laboratory is accommodated on a plastic substrate, for example a credit card-sized plastic. Thus, complex biological, diagnostic, chemical or physical processes can be miniaturized.

A lab-on-a-chip system is designed, for example, as a polymer-based multilayer structure. Such structures include, for example, two polymer substrates 105, 110, which include cavities in the form of chambers 115 and channels 130, 135. Between the polymer substrates 105, 110, a flexible polymer membrane 140 can be arranged, which can be deflected by means of different pneumatic pressure levels in an adjacent cavity 115. Outside the cavity 115, the membrane 140 is fixed to the adjacent polymer substrates, ie lid 105 and substrate 110, connected. For example, the flexible membrane 140 may be formed to spread when applying compressed air in the entire chamber 115 and thus to displace liquids 120, for example. In this way, liquids can be transported via channels 135 from chamber to chamber on a lab-on-a-chip system and reservoirs or chambers are emptied. According to the same principle pneumatically controlled diaphragm valves can be opened or closed.

Furthermore, reagents for lab-on-a-chip systems can be stored in a blister 145 or also integrated in an embroidery pack ("on-chip"). A blister 145 is a tablet package in which liquid or solid reagents are stored. Through the use of special polymer composite films with integrated barrier layers, such as aluminum layers, a long-term stable storage of liquid reagents can be ensured.

Stickpacks are tubular bag packaging in which liquid or solid reagents can be stored for a long time. In both reagent pre-storage concepts, the reagents are separately filled and sealed in their respective packages. Here, the reagents can be integrated by a kind of pick-and-place system in a respective lab-on-a-chip cartridge in the manufacturing process.

Tube bags for reagent pre-storage in lab-on-a-chip systems can be opened and emptied by pressure-driven pneumatic actuation of elastic membranes, for example.

The FIGS. 2a to 2d 12 show schematic representations of a device 100 in different deflection states according to an exemplary embodiment of the present invention. In Fig. 2a the membrane 140 is first pressed by the voltage applied to the pressure channel 130 pressure against one of the opening of the pressure channel 130 opposite region of the sealing film 125. If the pressure exerted on the closing foil 125 by the membrane 140 is high enough, the closing foil 125 breaks open and is opened by the increasing deflection of the membrane 140 in the direction of the fluid channel 135, as in FIGS FIGS. 2b to 2d shown. Here, the stored in the blister 145 Fluid 120 pushed out of the blister 145 and conveyed from the bottom recess 115 in the fluid passage 135. In Fig. 2d an inner surface of the blister 145 is completely lined with the membrane 140. Thus, as complete as possible emptying of the blister 145 is achieved.

In one embodiment, by incorporating a blister 145 in lab-on-a-chip, polymer-based, microfluidic systems, such as credit card-sized lab-on-a-chip cartridges, device 100 enables long-term stable storage and reliable delivery of reagents. To efficiently empty reagent-filled blisters 145, the sealing film 125 of the blister 145 is pressure-stressed by pneumatically deflecting an elastomeric polymer membrane 140 so that the sealing film 125 opens. The elastic polymer membrane 140 can now penetrate into the hollow body of the blister 145 and empty it efficiently.

A targeted weakening of the structure of the blister 145 in the region of the mechanical load leads to a reproducible opening and can be produced, for example, by a preceding structuring of the sealing film 125 by removing an inner and, if present, outer polymer layer of the sealing film 125 realized as a composite film Without a barrier layer, such as aluminum, the sealing film 125 is severed. Thus, a strength of the sealing film 125 is significantly reduced in this area. Thus, a predetermined breaking point is generated without affecting the barrier properties of the sealing film 125.

A flexible polymer membrane 140 may be used with blisters 145 having a fill volume of, for example, less than 10 ml, less than 5 ml, or less than 1 ml. In this case, by penetrating the polymer membrane 140, small reagent volumes can be displaced and the blister 145 can be emptied efficiently.

The emptying of the reagent 120 is in this case not gravity-driven, so that a safe and reproducible emptying of the reagent 120 is ensured, regardless of a position and location of the entire lab-on-a-chip cartridge.

Thus, a mechanical actuator such as a plunger for emptying the blister 145 may be dispensed with.

Reagent pre-storage in blisters 145 is more space-saving than reagent pre-storage in stick-packs since more volumes per unit area can be stored in blisters 145, i. h., blisters 145 have a smaller footprint. This may be particularly advantageous in lab-on-a-chip cartridges with integrated reagent pre-storage ("on-chip") of several liquid reagents.

By a one-sided structuring of a polymeric sealing layer of a polymer composite film 125, an opening direction of the blister 145 can be influenced according to an exemplary embodiment of the present invention, for example by dissolving the polymer composite film 125 only in the region of the structuring. Thus, the polymer composite film 125 has a preferred direction, whereby an efficiency of the emptying of the blister 145 can be increased.

In addition, the membrane 140 can be fixed in certain areas. This ensures that the diaphragm 140 does not compress the complete blister 145 and in particular does not close the region in front of the channel 135. This allows a safe and defined exit of the reagent 120.

Fig. 3 shows a schematic representation of an apparatus 100 according to an embodiment of the present invention. In Fig. 3 is a top view of the in the FIGS. 1 to 2d shown device 100 shown. The cover element 105, the bottom element 110, the bottom recess 115 and the closure film 125 are each embodied as rectangular. The blister 145 is exemplified with an elliptical cup in which the fluid 120 is filled. The cup is covered in a fluid-tight manner by the closure film 125, wherein the closure film 125 protrudes beyond a base surface of the cup. The fluid channel 135 extends, for example, along a longitudinal axis of the blister 145. The pressure channel 130 is offset laterally from a center of the blister 145 and in a region remote from the fluid channel 135 Floor recess 115 arranged. Thus, upon application of the pressure to the pressure channel 130, a deflection of the diaphragm 140 in the direction of the fluid channel 135 is made possible.

Exemplary is in Fig. 3 a channel 135 on the right side of the blister 145 for the discharge of the reagent 120 introduced. The blister 145 is located in a recess 115 within the polymer substrate 110. If an overpressure is now applied via the pressure channel 130 in the polymer substrate 105, the polymer membrane 140 begins to deflect and press onto the sealing film 125 of the blister 145. If a critical pressure is reached, the sealing film 125 begins to tear. Finally, the polymer membrane 140 can penetrate into the entire volume of the blister 145 and displace the contents of the blister 145, such as a liquid, into the outlet channel 135. In the region of the outlet channel 135, the membrane 140 is fixed to the polymer substrate 110, for example by laser welding, so that the membrane 140 does not depress the outlet in this area and the reagent 120 can not escape.

The FIGS. 4a and 4b 12 show schematic representations of a device 100 with a predetermined breaking point 400 according to various embodiments of the present invention. In contrast to Fig. 3 is the one in the FIGS. 4a and 4b shown sealing foil 125 each executed with a predetermined breaking point 400. In Fig. 4a For example, the closing foil 125 has an arrow-shaped incision in the form of two lines arranged at a right angle to each other, wherein an arrowhead of the incision points in the direction of the fluid channel 135. The lines may, for example, also be arranged at an acute or obtuse angle to one another. The predetermined breaking point 400 is realized in a region of the sealing film 125 opposite the pressure channel 130.

In Fig. 4b is the predetermined breaking point 400 realized by a material removal of the sealing film 125 in the region of the pressure channel 130. The predetermined breaking point 400 is designed as an example circular, wherein a center of the predetermined breaking point 400 corresponds to a center of a channel cross section of the pressure channel 130.

By introducing the predetermined breaking point 400 in the sealing foil 125, a necessary pressure for opening the blister 145 can be greatly reduced. In addition, the expression becomes more reproducible since an entry point for the polymer membrane 140 can be defined.

The sealing film 125 for sealing the blister 145 is, for example, a polymer composite of a polymeric sealing layer 125 made of polypropylene (PP) or polyethylene (PE), a barrier layer, for example of metal or aluminum, and a polymeric protective layer, for example of polyethylene terephthalate (US Pat. PET). For the production of a defined predetermined breaking point 400, the sealing film 125 can be selected with respect to its thickness and the mechanical properties of the various composite films so that a mechanical pressure of the elastic membrane 140 is sufficient to seal the sealing film 125 at low pressure, for example from 0.5 bar to 5 bar, open. This is achieved by selecting the multilayer structure of the sealing foil 125 as thin as possible. For example, a thickness of the barrier layer is between 10 .mu.m and 50 .mu.m and a thickness of the sealing layer between 5 .mu.m and 50 .mu.m. On a protective layer of the sealing film 125 can optionally be dispensed with.

According to an exemplary embodiment of the present invention, the predetermined breaking point 400 is produced on the sealing film 125 of the blister 145 by laser structuring, in particular by lasers having a wavelength in the UV range. Laser structuring can weaken the sealing film 125 locally and in a defined manner by partially removing the protective layer, the sealing layer and / or the barrier layer of the sealing film 125. For this purpose, thicker sealing foils are suitable. For example, the barrier layer, the sealing layer and the protective layer can each be designed with a thickness between 5 μm and 500 μm, since the weakening of the sealing film 125 in the area of the predetermined breaking point 400 by thickness reduction is sufficient for a subsequent opening by deflection of the membrane 140.

The sealing or protective layer may be partially or completely removed in the region of the predetermined breaking point 400, as in FIG Fig. 4b shown. In particular, however, the barrier layer is not completely severed here, otherwise the barrier properties of the entire blister 145 would be reduced. In order to ensure a sufficient barrier property of the sealing film 125, for example, a barrier layer of aluminum has a minimum thickness of 12 microns. This corresponds to a value that is customary for packaging films.

The generation of the predetermined breaking point 400 by laser structuring has the advantage that ready-made standard blisters can be post-processed with the laser without heating up the reagent 120 located therein. In addition, thick sealing films 125 with particularly good barrier properties can thus be used, which would be difficult to open without such a predetermined breaking point 400.

Fig. 4a shows by way of example a path along which the structure of the sealing foil 125 has been weakened by laser processing. Upon application of a mechanical pressure, the sealing film 125 begins to open by the deflection of the polymer membrane 140 at the predetermined breaking point 400, wherein the membrane 140 occupies the entire volume of the blister 145 after a short time and thus displaces the reagent in a defined direction.

According to another embodiment, the predetermined breaking point or surface may be created by removing the polymer layers on one side or on both sides of the metal barrier layer. This can be done for example by means of a hot stamp which evaporates the polymer layer or the polymer layers in the region of a contact surface. Advantageously, the sealing film 125 may be processed with the stamp prior to making the blister 145. As a result, heating of the reagent 120 is avoided. Furthermore, thus a large area of film can be processed in parallel.

Fig. 4b FIG. 12 shows by way of example a region 400 within which one or more polymer layers of the sealing film 125 have been removed in order to weaken the structure. As a result, the sealing film 125 already opens in the region of the predetermined breaking point 400 when a low pressure is applied.

The required starting material in the form of the polymer substrates 105, 110 and the required structures in the polymer substrates 105, 110 can be produced for example by milling, injection molding, hot stamping or laser structuring. The breakthroughs of the polymer membrane can be generated by punching or laser structuring.

The FIGS. 5a to 5d 12 show schematic representations of a device 100 in different deflection states according to an exemplary embodiment of the present invention. The deflection states correspond to those in the FIGS. 2a to 2d shown deflection states. Unlike the FIGS. 2a to 2d However, the fluid 120 is not filled in a blister, but directly into the bottom recess 115. The bottom recess 115 is sealed fluid-tight by the sealing film 125. Here, the sealing film 125 is fixed in the edge region of the bottom recess 115 on the bottom element 110 and arranged at a small distance from the membrane 140.

The device 100 optionally further comprises a further bottom recess 500, which is fluidically connected to the bottom recess 115 via the fluid channel 135. Alternatively, the fluid channel 135, as in FIG Fig. 1 shown to be led out of the device 100. The further bottom recess 500, like the bottom recess 115, is arranged opposite the cover element 105. The membrane 140 extends between the further bottom recess 500 and the cover element 105. Furthermore, the device 100 comprises a further fluid channel 505, which is embodied, for example, in the cover element 105 in order to fluidically connect the further floor recess 500 to an external environment of the device 100. The further fluid channel 505 is in the FIGS. 5a to 5d closed by the membrane 140.

As a result of the deflection of the diaphragm 140 when the pressure at the pressure channel 130 is applied, the fluid 120 is displaced from the bottom recess 115 via the fluid channel 135 into the further bottom recess 500. Here, the membrane 140 is fixed in the region of the fluid channel 135 and in the region of the further bottom recess 500 on the cover element 105.

Fig. 6a, 6b 12 show schematic representations of a device 100 with a predetermined breaking point 400 according to various embodiments of the present invention. In the Figures 6a and 6b is a top view of the in the FIGS. 5a to 5d shown device 100 shown. In contrast to Fig. 4a is the in Fig. 6a shown breaking point 400 realized by a cross-shaped incision in the sealing film 125 and the in Fig. 6b shown predetermined breaking point 400 realized by a star-shaped incision in the sealing foil 125. The fluid channel 135 and the further fluid channel 505 extend into the Figures 6a and 6b by way of example along a common longitudinal axis.

Such a concept enables a direct and long-term stable reagent pre-storage in polymer-based, microfluidic lab-on-a-chip systems and a reliable provision of reagents 120. According to one embodiment of the present invention, a pneumatically actuatable lab-on-a-chip system with a polymeric multilayer structure with integrated flexible membrane 140 realized. A device 100 integrated in the system is configured to effectively protect the long-term storage vapor-permeable flexible membrane 140 from reagent contact up to a deployment time. For the polymer cavities 115, 500, for example, highly diffusion-resistant plastics with a suitable wall thickness are used whose properties can be improved by additional coatings. Depending on the service life requirements, less diffusion-proof plastics can be adequately finished with high quality coatings.

To keep reagents stable for a long time in lab-on-a-chip systems, the reagents are filled into polymer-based cavities 115 and sealed with a polymer composite film 125. By a pneumatic deflection of an elastic polymer membrane 140, the sealing film 125 is stressed by pressure and finally opened, which is ensured by a predetermined breaking point 400 of the sealing film 125. The elastic polymer membrane 140 then penetrates into the cavity 115 and the reagent 120 is displaced via a channel 135 into a supply chamber 500. Thus, the reagent 120 can be stored directly in the system for a long-term stability and virtually loss-free and released as needed.

Such a direct reagent pre-storage is significantly more space-saving than a pre-storage in stick packs or blisters and can be realized with lower production costs.

By a direct filling of corresponding cavities 115 with reagents 120 to be stored by means of a dispenser installation, assembly can be simplified and reduced.

Direct reagent pre-storage can reduce the risk of contamination of the entire lab-on-a-chip system by eliminating the need for separate containers of stick packs or blisters from outside the system.

On a mechanical actuator for emptying, such as a stamp, can be dispensed with. By means of an on-chip pneumatic actuation, the reagents can be arranged arbitrarily on the lab-on-a-chip system, whereby additional contamination risks are reduced from the outside.

In FIGS. 5a to 6b cross sections and an operation of the direct storage concept are shown. A multilayer structure consists of an upper polymer substrate 105, a flexible membrane 140 and a lower polymer substrate 110. In the cavity 115, a liquid 120 is arranged upstream. The cavity 115 is sealed with a long-term stable sealing film 125 with integrated predetermined breaking point 400. This allows a long-term stable storage of the reagent 120th

The sealing between long-term stable sealing film 125 and cavity 115 can be realized inter alia by gluing, ultrasonic sealing, thermal sealing or laser welding. If an overpressure is applied via the channel 130, the membrane 140 is deflected and pressed onto the sealing foil 125. If a critical pressure, for example between 1 bar and 5 bar, is reached, the sealing film 125 begins to crack, as in FIG Fig. 5c shown. Finally, the polymer membrane 140 penetrates into the entire volume of the cavity 115 and displaces the contents of the cavity 115 via the outlet passage 135 into the delivery chamber 500, as in FIG Fig. 5d shown.

By introducing a predetermined breaking point 400 in the sealing film 125, a reproducible opening of the sealing film 125 can be ensured without the barrier properties of the film 125 being significantly impaired. If the predetermined breaking point 400 is produced by laser structuring, the laser should not be moved repeatedly over the same center point, since otherwise the barrier layer in the center may under certain circumstances be completely removed.

A polymer substrate 105, 110 is made of, for example, thermoplastics such as polycarbonate (PC), polypropylene (PP), polyethylene (PE), polymethyl methacrylate (PMMA), cyclo-olefin polymer (COC) or cyclo-olefin copolymer (COP).

The polymer membrane 140 is made, for example, of elastomer, thermoplastic elastomer, thermoplastics or hot-melt adhesive films.

The sealing film 125 may be, for example, commercial polymer composite films of polymeric sealing and protective layers, such as polyethylene, polypropylene, polyamide (PA) or polyethylene terephthalate, and a barrier layer. The barrier layer is usually vapor-deposited aluminum. However, other high barrier layers such as silica (SiO ₂ ), ethylene-vinyl alcohol copolymer (EVOH), biaxially oriented polypropylene (BOPP), Parylene, Aquacer or Lipocer may also be used.

A thickness of the polymer substrate is, for example, between 0.5 mm and 5 mm.

A thickness of the polymer membrane 140 is, for example, between 5 μm and 300 μm.

A thickness of the barrier layer is, for example, between 5 μm and 500 μm or between 10 μm and 500 μm.

A respective thickness of the polymer layer and the protective layer is for example between 5 μm and 500 μm.

A volume of the blister 145 is for example between 100 μl and 1000 μl.

In addition to the exemplary embodiments shown, any other geometric connections between the polymer membrane 140 and a polymer substrate are possible in order to favor a preferred direction of the membrane 140 and a deflection of the membrane 140.

Fig. 7 shows a flowchart of a method for operating a device, as described with reference to the preceding figures, according to an embodiment of the present invention.

In this case, in a step 701, the pressure is provided at an end of the pressure channel facing away from the membrane. By passing the pressure through the pressure channel, the membrane is deformed. The pressure is maintained at least until the sealing film is opened by the deformation of the membrane. If the pressure subsequently continues to be maintained, the fluid is moved from the bottom recess into the fluid channel due to a further deformation of the membrane.

Fig. 8 shows a flowchart of a method for producing a device, as described with reference to the preceding figures, according to an embodiment of the present invention.

In a step 801, a bottom member is provided with a bottom recess for receiving a fluid. Furthermore, a cover element is provided with at least one pressure channel.

In a step 803, the fluid, a sealing film and a membrane are provided.

In a step 805, the lid member and the floor member are joined together. In this case, the bottom recess is arranged opposite the cover element, at least one fluid channel is formed between the cover element and the bottom element, the fluid is arranged in the bottom recess, the closure film is arranged at least in a partial region of the bottom recess between the cover element and the bottom element in order to supply the fluid in the bottom recess hold, and arranged the membrane at least in the region of the bottom recess between the lid member and the closure film. In this case, the diaphragm is designed to be deformed by the pressure when the pressure passes through the pressure channel such that the closure film is opened and the fluid is moved from the bottom recess into the fluid channel.

Fig. 9 shows a schematic representation of an apparatus 100 according to an embodiment of the present invention. In this case, the device 100 is shown in a plan view. The device 100 is of fundamental construction according to the basis of Fig. 3 constructed device. The sealing film 125 has at least one predetermined breaking point. According to this exemplary embodiment, a predetermined breaking point 400 extends as a line through a section of the sealing film 125 opposite the pressure channel 130. A further predetermined breaking point 400 extends on a side facing the fluid channel 135 in an arcuate manner around the section of the sealing film 125 opposite the pressure channel 130.

The FIGS. 10 to 14 show schematic cross-sectional views of in Fig. 9 in various deflection states of the membrane 140 according to an embodiment of the present invention.

Based on FIGS. 9 to 14 In the following, an embodiment of the present invention will be described in detail.

According to this exemplary embodiment, the device 100 is embodied as a lab-on-a-chip system, for example in the form of a cartridge. In the Bottom recess 115, a fluid, for example, at least one reagent stored. The sealing film 125 is designed as a sigla film.

The described approach makes it possible to save reagents 120 in a space-saving manner directly in the respective LoC system 100, e.g. in the form of a cartridge, to store long-term stable and provide on demand, without separate containers, such as stick packs or blisters for the reagents 120 are required.

As already on the basis of FIGS. 1 to 8 described, we also according to this embodiment, the reagent 120 stored directly in the bottom recess 115 and stored long-term stable with a sealing film 125. The sealing film 125 has a local predetermined breaking point 400, which can be produced by laser ablation, without impairing the barrier properties of the sealing film 125. According to this embodiment, can on a second bottom recess, as shown in the FIGS. 5a to 5d is shown to be omitted. This offers an enormous savings potential of the area consumption of the preliminary storage concept. A complete deflection of the flexible membrane 140 into the bottom recess 115 for displacing the reagent 120 into a second bottom recess is thus not necessary. According to this exemplary embodiment, an alignment of the chambers, in particular the bottom recess 115 and the fluid channel 135, plays a major role, since the reagent 120, after the sealing foil 125 has been broken open, should be gravity-driven in the area of an outlet valve 505 coupled to the fluid channel 135 in order to actively suck off the reagent 120 to allow. The outlet valve 505 may be arranged, for example, on an end of the fluid channel 135 facing away from the bottom recess 115.

In Fig. 9 the plan view of the concept is shown. The pneumatic compressed air inlet 130 is located directly above the predetermined breaking point 400 to allow the deflection of the flexible membrane 140 at this location. The predetermined breaking point 400 can also consist of any other geometric shapes. In the in Fig. 9 shown as an advantageous embodiment of the predetermined breaking point 400 is a controlled folding of the sealing foil 125 favors and thus enables a reproducible fluidic connection in the opening operation to the outlet valve 505.

In Fig. 10 is the initial state, which corresponds to the storage state of the reagent 120, the Vorlagerungskonzepts shown. In this case, the membrane 140 is not formed.

In Fig. 11 an initial pneumatic actuation of the flexible membrane 140 through the pressure channel 135 in the form of a pneumatic feed line 135 is shown. In a region 145, the flexible membrane 140 is connected to the cover element 105 in the form of a pneumatic layer 105, which prevents a deflection of the membrane 140 in this area.

In Fig. 12 the membrane 140 is shown in a state in which the membrane 140 is formed so far that the sealing film 125 tears in the region of the predetermined breaking point 400 by the pneumatic and mechanical stress by the flexible membrane 140 and the membrane 140 starts, the sealing film 125 to the To displace edges of the bottom recess 115 and expose the opening of the fluid channel 135 to the outlet valve 505.

In Fig. 13 a state is shown in which via the pneumatic supply line 135 negative pressure is applied, whereby the deflection of the flexible membrane 140 is released again. The reagent 120 can now collect gravitationally in the region of the outlet valve 505.

In Fig. 14 an embodiment is shown in which the reagent release is not intended to be gravity driven. For this purpose, the outlet valve 505 can be opened and the reagent 120 can be actively sucked in for further microfluidic processing.

For producing the device 100, the following may be used as material examples as polymer substrate 105, 110, for example thermoplastics (eg PC, PP, PE, PMMA, COP, COC), as polymer membrane 130 elastomer, thermoplastic elastomer, thermoplastics or heat-sealing films, as sealing film 125 commercially available polymer films, polymer composite films polymeric sealing and protective layers (eg PE, PP, PA, PET) with a barrier layer in the Normally vapor deposited aluminum, but also other high barrier layers such as SiO2, EVOH, BOPP, Parylene, Aquacer, Lipocer be used.

As an exemplary dimension of the embodiments, a thickness of the polymer substrate 105, 110 may be 0.5 to 5 mm, a volume preceded in cavities 115 may be 5 μl to 10 ml, a thickness of the polymer membrane 140 may be 5 to 300 μm, and a multilayer structure of the sealing film 125 a barrier layer (usually Alu) having a thickness of 10 microns to 500 microns, a polymer layer having a thickness of 5 microns to 500 microns and a protective layer having a thickness of 5 microns to 500 microns.

In addition to the embodiments shown, any other geometric connections between polymer membrane 140 and polymer substrate 105, 110 are possible in order to favor the preferred direction of the membrane 140 and its deflection.

The required polymer substrates 105, 110 as starting material, and the required structures in the polymer substrates 105, 110 can be produced for example by milling, injection molding, hot stamping or laser structuring. The breakthroughs of the polymer membrane 125 can be generated by punching or laser structuring.

The embodiments described and shown in the figures are chosen only by way of example. Different embodiments may be combined together or in relation to individual features. Also, an embodiment can be supplemented by features of another embodiment.

Furthermore, the method steps presented here can be repeated as well as executed in a sequence other than that described.

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 is both the first feature as well as the second feature and according to another embodiment, either only the first feature or only the second feature.

Claims (15)

Device (100) for pre-storing a fluid (120) in a microfluidic system, the device (100) having the following features: a lid member (105); a bottom member (110) having a bottom recess (115), the bottom recess (115) being opposed to the lid member (105) and adapted to receive the fluid (120); a closure sheet (125) disposed at least in a portion of the bottom recess (115) between the lid member (105) and the bottom member (110) for holding the fluid (120) in the bottom recess (115); at least one pressure channel (130) formed in the lid member (105) to direct pressure into a portion of the bottom recess (115); at least one fluid channel (135) formed between the lid member (105) and the bottom member (110); and a diaphragm (140) disposed at least in the region of the bottom recess (115) between the lid member (105) and the sealing film (125) and adapted to be deformed by the pressure when the pressure through the pressure passage (130) is directed be that the sealing film (125) is opened. The device (100) of claim 1, wherein the diaphragm (140) is adapted to be deformed by the pressure upon directing the pressure through the pressure channel (130) after opening the closure foil (125) such that the fluid (120 ) is moved from the bottom recess (115) into the fluid channel (135). Device (100) according to claim 1 or 2, with a blister (145) which is filled with the fluid (120), wherein the blister (145) in the bottom recess (115) is arranged and closed by the sealing film (125) fluid-tight , Device (100) according to one of the preceding claims, in which the fluid (120) is filled into the bottom recess (115), wherein the closure film (125) closes the bottom recess (115) in a fluid-tight manner. Apparatus (100) according to claim 4, wherein the sealing foil (125) is fixed to the bottom member (110) to fluid-tightly close the bottom recess (115). Device (100) according to one of the preceding claims, in which the closure film (125) has at least one predetermined breaking point (400). Apparatus (100) according to claim 6, wherein the predetermined breaking point (400) is realized by means of laser structuring. Device (100) according to one of the preceding claims, wherein the membrane (140) is fixed to the cover element (105) at least in the region of the fluid channel (135). Device (100) according to one of the preceding claims, wherein the bottom element (110) has at least one further bottom recess (500), wherein the further bottom recess (500) is arranged opposite the cover element (105), and wherein the Fluid channel (135) is formed to fluidly connect the bottom recess (110) and the further bottom recess (500). Device (100) according to one of the preceding claims, wherein the membrane (140) in a located on a side remote from the fluid channel (135) side of the bottom recess (115) portion of the bottom recess (115) is attached to the lid member (105). Apparatus (100) according to any one of the preceding claims, wherein the membrane (140) is adapted to be deformed upon withdrawal of pressure at the pressure channel (130) after opening of the closure film (125). Device (100) according to one of the preceding claims, in which the fluid channel (135) forms a step between a first section of the fluid channel (135) formed in the base element (110) and a second section of the fluid channel (135) formed in the cover element (105) ) having. Device (100) according to claim 13, in which the membrane (140) extends beyond the step and is fastened to the cover element (105) in the region of the first section of the fluid channel (135) and in the region of the second section of the fluid channel ( 135) is movably disposed between the lid member (105) and the bottom member (110). Method for operating a device (100) according to one of the preceding claims, the method comprising the following steps: Directing (701) the pressure through the pressure channel (130) to deform the membrane (140) such that the closure film (125) is opened. A method of manufacturing a device (100) according to any one of claims 1 to 13, said method comprising the steps of: Providing (801) a bottom member (110) having a bottom recess (115) for receiving a fluid (120) and a lid member (105) having at least one pressure channel (130) to direct pressure into a portion of the bottom recess (115); Providing (803) the fluid (120), a closure film (125) and a membrane (140); Assembling (805) the cover element (105) and the bottom element (110), the bottom recess (115) being arranged opposite the cover element (105), at least one fluid channel (135) being formed between the cover element (105) and the bottom element (110) is arranged, the fluid in the bottom recess (115), the closure film (125) at least in a partial region of the bottom recess (115) between the lid member (105) and the bottom member (110) is arranged to the fluid (120) in the Bottom recess (115) to hold, and the membrane (140) at least in the region of the bottom recess (115) between the cover member (105) and the closure film (125) is arranged, wherein the membrane (140) is formed to conduct pressure be deformed by the pressure channel (130) by the pressure so that the sealing film (125) is opened.

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