DE102011005932B4 - Fluidic system for bubble-free filling of a microfluidic filter chamber and method for bubble-free filling and method for filtering a liquid with such a system - Google Patents

Abstract

Fluidic system for bubble-free filling of a microfluidic filter chamber (10) comprising a multilayer structure made up of at least two layers (11, 14) and a microfluidic filter chamber (10) comprising a filter (3), a ventilation channel (4), an inlet channel (1) and a Outlet channel (6), the filter (3) being inserted between the inlet channel (1) and outlet channel (6), and the ventilation channel (4) branching off from the inlet channel (1), and the flow through the microfluidic filter chamber being controlled by a valve (5) in the ventilation duct (4) can be regulated, characterized in that between the two layers (11, 14) there is an elastic film (12) which acts as a valve (5).

Description

The subject matter of the present invention is a fluidic system for bubble-free filling of a microfluidic filter chamber and for filtering liquids, a method for bubble-free filling of a microfluidic filter chamber of the system according to the invention and a method for filtering liquids.

State of the art

In molecular biology and molecular diagnostics, filtration or solid phase extraction steps are often performed. The purpose can be, for example, the accumulation of bacteria or the purification of DNA fragments. Depending on the application, fabric mats or particle beds made of glass, silicates, oxides, polymers, etc. are used as filters. Filters pressed into plastic tubes (so-called tubes) are commercially available as part of kits, eg QIAquick Purification Kit from Qiagen®, such filters are known from US Pat DE10218554A1 . These filters are filled manually by pipetting and then centrifuged.

• Die Zeitersparnis bei der Durchführung des Assays. Es werden nur geringere Mengen an Reagenzien und Proben benötigt. Der Arbeitsaufwand für den Bediener wird reduziert. Es gibt weniger Möglichkeiten für den Bediener, Fehler zu machen. Das System kann portabel ausgeführt werden.

Recently, attempts have been made to integrate molecular-biological processes (so-called assays) into microfluidic systems. Such a system is also referred to as a lab-on-chip (LOC) or micro total analysis system (μTAS). The special features of a LOC system include:

• The time saved in running the assay. Only small quantities of reagents and samples are required. The workload for the operator is reduced. There is less opportunity for the operator to make mistakes. The system can be made portable.

Applications for LOC systems can be found in molecular diagnostics, in environmental analysis, etc. One way of integrating a filter into a microfluidic LOC system is in the US2002/0185431A1 described.

The pamphlets U.S. 2007/0 125 942 A1 and DE 103 45 818 A1 disclose a filter chamber having an inlet duct, an outlet duct and a filter interposed therebetween.

Disclosure of Invention

The subject matter of the invention is a fluidic system for bubble-free filling of a microfluidic filter chamber comprising a multilayer structure made up of at least two layers and a microfluidic filter chamber comprising a filter, a ventilation channel, an inlet channel and an outlet channel, the filter being inserted between the inlet channel and the outlet channel, the ventilation channel being inserted branches off from the inlet channel and the flow through the microfluidic filter chamber can be regulated by means of a valve of the ventilation channel, with a film located between the two layers acting as a valve.

The system according to the invention has the following advantageous properties: The microfluidic filter chamber can be filled without bubbles. No air bubbles are trapped during filling. This prevents the filter from becoming clogged. The filter is flown homogeneously. Liquid flows can be precisely regulated. Complete rinsing of the filter is guaranteed. There is no clogging of components or the occurrence of undesired reactions. Mixing liquids is made easier. Foam formation is prevented. The fluidic resistance of the system is kept constant. Reagents contained in the filter chamber can be exchanged in a controlled manner.

According to the invention, the microfluidic filter chamber includes a valve for the controllable passage through the ventilation channel. This serves to regulate the passage of liquid or gas.

A particular embodiment of the microfluidic filter chamber is characterized in that the ventilation channel either leads to the atmosphere or leads to a separate reservoir. This is to evacuate the air.

Another special embodiment of the microfluidic filter chamber is characterized in that the ventilation channel opens into the outlet channel after the filter. This is to evacuate the air.

In a preferred embodiment of the invention, the microfluidic filter chamber is characterized in that the inlet channel is widened before and/or after the filter. A particularly preferred embodiment of the microfluidic filter chamber is characterized in that the inlet channel is widened in front of the filter in order to ensure that liquids flow onto the filter homogeneously. A likewise particularly preferred embodiment of the microfluidic filter chamber is characterized in that the outlet channel is widened after the filter.

In a particular embodiment of the invention, one or more layers are structured planes.

A particular embodiment of the invention relates to a fluidic system comprising a cover, a first structured level and a second structured level, an inlet channel, an extension of the inlet channel, a filter, a valve and an outlet channel. Optionally, the fluidic system can also include a passage through a channel.

A further special embodiment of the invention relates to a fluidic system, characterized in that an elastic film is located between the first structured level and the second structured level.

In a particular embodiment, the fluidic system for bubble-free filling of a microfluidic filter chamber includes at least one additional valve.

The subject matter of the invention is also a method for bubble-free filling of a microfluidic filter chamber of the system according to the invention, comprising a filter and a ventilation channel, with a liquid being pumped through the inlet channel to the filter while the valve in the ventilation channel is open, and
then the filter is filled capillary, and then the channel area before the filter, the ventilation channel and the channel area are filled after the filter, and then the valve is closed.

The invention also relates to a method for filtering a liquid in the microfluidic filter chamber of the system according to the invention, the microfluidic filter chamber first being filled with a liquid without bubbles, by a liquid being pumped through the inlet channel to the filter while the valve in the vent channel is open, then the filter is filled capillary, then
the channel area in front of the filter, then the ventilation channel and then the channel area after the filter is filled, and then the valve is closed, and then the liquid to be filtered flows in through the inlet channel and then flows through the filter into the outlet channel.

The filter can be a fabric filter or a silica filter. For example, fabric mats or particle beds made of glass, silicates, oxides or polymers are used as filters. In principle, all filters that are suitable for fluidic systems, in particular for microfluidic systems, can be used. The radius of the filter is adapted to the dimensions of the microfluidic filter chamber. It can be between 1 and 25 mm. The radius of the filter is preferably 2 to 5 mm, particularly preferably 3.5 mm.

Fluidic channels are channels through which the liquid can flow in a microfluidic system. The dimensions of the fluidic channels are adapted to the requirements in question. The fluidic channels include the inlet channel, the outlet channel, the ventilation channel and the channel extension. The passage of the channel also belongs to the fluidic channels. The fluidic channels have, for example, a diameter or a width of 0.05 to 2 mm, preferably 0.2 to 1 mm, particularly preferably 0.3 or 0.5 mm, and a depth of 0.05 to 1.5 mm, preferably 0. 2 to 1 mm, particularly preferably 0.3 or 0.5 mm.

The ventilation channel is adjustable, i.e. the flow of liquid or gas through the ventilation channel can be regulated. The ventilation channel can be regulated via a valve. The valve can be open, partially open or closed.

Valves are used to regulate the liquid flows in a fluidic filter chamber and in the fluidic systems. For example, an elastic film sandwiched between two layers can act as a valve. Other examples of valves are rotary valves or external solenoid valves. The invention is but not limited to the valves mentioned, rather all systems are included with which a regulation of liquid or gas flows in fluidic systems is possible.

The fluidic system can be a microfluidic system. In a special embodiment, the microfluidic filter chamber is located in one layer. According to the invention, the microfluidic filter chamber is realized in a multi-layer structure. A special embodiment involves a multi-layer structure consisting of several different layers. Another special embodiment involves a multi-layer structure, which is built up from several identical layers. A multi-layer structure includes, for example, two to twenty or more layers. The microfluidic filter chamber can be located in only one layer or can extend over several layers. In a particular embodiment, the microfluidic filter chamber extends over two or three or more layers. The layer can be a polymer, for example. The layer can consist of, for example, polycarbonate, polypropylene, polyethylene, polystyrene or a cyclic polyolefin. The layer can also consist of glass or silicon. The layer can be structured, for example by means of injection molding, hot stamping, milling, sandblasting or etching. Individual layers can be deformable. For example, a layer can be a film, particularly preferably an elastic film, for example an elastomer or a thermoplastic elastomer, in particular a polyurethane-based thermoplastic elastomer. In preferred embodiments of the invention, individual layers are 0.05 to 10 mm thick. Preferably, individual layers have a thickness of 0.1 mm, 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm.

In particularly preferred embodiments of the invention, the fluidic channels are widened at certain points, i.e. they have a larger cross section or diameter there compared to the inlet channel or outlet channel. For example, the inlet channel can be widened immediately in front of the filter in order to achieve a homogeneous inflow. The outlet channel can also be widened immediately after the filter. In the case of a lateral flow, the inlet channel or outlet channel before or after the filter is widened over a length of 5 mm to 10 mm, for example. In the case of transverse flow, there is a cavity before or after the filter, for example, which has a height of between 0.5 mm and 2 mm, for example 1 mm, and a diameter of between 0.5 mm and 3 mm, for example 2 mm, which is smaller than the diameter of the filter. In a particular embodiment of the invention, so-called phase guides are located in the expansions of the fluidic channels, i.e. structures (e.g. edges) which control the filling of the channel expansion through pinning effects. Such structures can be located, for example, in the enlargement of the inlet duct in order to control the filling of the duct enlargement and to ensure uniform filling.

In particular, when the microfluidic filter chambers are integrated into the microfluidic system, the channel leading to the filter is widened before and after the filter in order to achieve a homogeneous inflow of the filter in these systems. This expansion is preferably achieved by a variable cross section of the channels leading to the filter. These channels are, for example, funnel-shaped open towards the filter.

In the microfluidic filter chamber, the channel area in front of the filter is completely filled first. The air bubbles can escape through the adjustable vent channel when the valve is open. This enables bubble-free filling of the filter and the filter chamber. This prevents the filter from quickly filling with capillaries when it is being filled, thus preventing the air in front of the filter in the duct extension from escaping. If the air cannot escape, air bubbles remain trapped before and possibly also after the filter. These air bubbles disturb the homogeneous inflow of the filter and can also lead to complete or partial clogging of the filter and/or to foaming, which makes it impossible to completely rinse out the filter. In a special embodiment of the microfluidic filter chamber, the ventilation channel opens into the channel area after the filter. As a result, this area is also filled without bubbles and an additional fluidic connection is saved.

The microfluidic filter chamber can be used in all fluidic systems in which a filter is used, for example in polymeric lab-on-chip (LOC) and micro-total analysis systems (µTA systems) for molecular diagnostics.

• 1a Schematische Darstellung einer mikrofluidischen Filterkammer 10 Ausführungsform 1.
• 1b Schematische Darstellung einer mikrofluidischen Filterkammer 10 Ausführungsform 2.
• 2 Schematische Darstellung eines fluidischen Systems (Querschnitt).
• 3 Schematische Darstellung eines fluidischen Systems (Draufsicht).
• 4 Schematische Darstellung eines fluidischen Systems (Seitenansicht).

Further advantages and advantageous configurations of the objects according to the invention are illustrated by the drawings and explained in the following description. It should be noted that the drawings are for descriptive purposes only and are not intended to limit the invention in any way. Show it

• 1a Schematic representation of a microfluidic filter chamber 10 embodiment 1.
• 1b Schematic representation of a microfluidic filter chamber 10 embodiment 2.
• 2 Schematic representation of a fluidic system (cross-section).
• 3 Schematic representation of a fluidic system (top view).
• 4 Schematic representation of a fluidic system (side view).

1a shows a schematic view of a microfluidic filter chamber 10 in a first embodiment with inlet channel 1, channel extensions 2 and 13, filter 3, ventilation channel 4, valve 5 and outlet channel 6, the ventilation channel 4 either leading to the atmosphere or leading to a separate reservoir. The inlet channel 1 is widened towards the filter 3 leading to the channel widening 2 located in front of the filter 3 . The filter 3 connects to the channel extension or within the channel. The channel extension 13 after the filter 3 follows the filter 3 . The channel enlargement 13 is enlarged in cross section compared to the outlet channel 6 . The channel extension 2 before the filter 3 and the channel extension 13 after the filter 3 are each funnel-shaped. The funnel-shaped configuration is such that the larger cross section of the funnel-shaped configuration is arranged towards the filter 3 . The channel extension 2 in front of the filter 3 has a ventilation channel 4 . The ventilation channel 4 has a valve 5 . The valve 5 regulates the flow of liquid or gas through the vent channel 4.

1b shows a schematic view of the microfluidic filter chamber 10 in a second embodiment with inlet channel 1, channel extensions 2 and 13, filter 3, ventilation channel 4, valve 5, outlet channel 6, with the ventilation channel 4 opening into the outlet channel 6 after the filter 3.

According to the first embodiment, the inlet channel 1, the channel extension 2 before the filter 3, the filter 3, the channel extension 13 after the filter 3 and the outlet channel 6 are also arranged in the second embodiment in such a way that the inlet channel funnel-shaped into the channel extension 2 before the Filter 3 leads, and the channel extension 13 after the filter 3 opens into the outlet channel 6. In the second embodiment, the ventilation duct 4 is connected both to the duct widening 2 before the filter 3 and to the duct widening 13 after the filter 3 . The ventilation channel 4 has a valve 5 . The flow through the ventilation channel 4 from the channel extension 2 before the filter 3 and the channel extension 13 after the filter 3 can be regulated by the valve 5 .

The inlet channel 1 in front of the filter 3 and/or the outlet channel 6 after the filter 3 can be enlarged compared to the cross-section of the rest of the inlet channel 1 and outlet channel 6.

• 6. Eine erste Flüssigkeit, z.B. Lösung oder Suspension, wird durch den Einlasskanal 4 zum Filter 3 gepumpt. Das Ventil 5 ist geöffnet.
• 7. Der Filter 3 befüllt sich kapillar. Im Bereich der Kanalerweiterung 2 befindet sich zunächst noch Luft.
• 8. Da der Flusswiderstand des Filters 3 deutlich größer ist als der des Entlüftungskanals 4, wird nun zunächst die Kanalerweiterung 2 vor dem Filter 3 und ein Teil des Entlüftungskanals 4 befüllt.
• 9. Das Ventil 5 wird geschlossen.
• 10. Das System ist komplett befüllt und der Filtrierungsvorgang beginnt.

The functioning of the microfluidic filter chamber 10 in the first embodiment is as follows:

• 6. A first liquid, eg solution or suspension, is pumped through the inlet channel 4 to the filter 3. The valve 5 is open.
• 7. The filter 3 fills up capillary. In the area of duct extension 2 there is initially still air.
• 8. Since the flow resistance of the filter 3 is significantly greater than that of the venting channel 4, the channel extension 2 in front of the filter 3 and a part of the venting channel 4 are now filled first.
• 9. Valve 5 is closed.
• 10. The system is completely filled and the filtration process begins.

• 7. Eine erste Flüssigkeit, z.B. Lösung oder Suspension, wird durch den Einlasskanal 1 zum Filter 3 gepumpt. Das Ventil 5 ist geöffnet.
• 8. Der Filter 3 befüllt sich kapillar. Im Bereich der Kanalerweiterung 2 befindet sich zunächst noch Luft.
• 9. Da der Flusswiderstand des Filters 3 deutlich größer ist als der des Entlüftungskanals 4, wird nun zunächst die Kanalerweiterung 2 vor dem Filter 3 und der Entlüftungskanal 4 befüllt.
• 10. Durch den Entlüftungskanal 4 wird die Kanalerweiterung 13 nach dem Filter 3 befüllt.
• 11. Das Ventil 5 wird geschlossen.
• 12. Das System ist komplett befüllt und der Filtrierungsvorgang beginnt.

The functioning of the microfluidic filter chamber 10 in the second embodiment is as follows:

• 7. A first liquid, eg solution or suspension, is pumped through the inlet channel 1 to the filter 3. The valve 5 is open.
• 8. The filter 3 fills up capillary. In the area of duct extension 2 there is initially still air.
• 9. Since the flow resistance of the filter 3 is significantly greater than that of the venting channel 4, the channel extension 2 in front of the filter 3 and the venting channel 4 are now filled first.
• 10. The channel extension 13 after the filter 3 is filled through the ventilation channel 4.
• 11. Valve 5 is closed.
• 12. The system is completely filled and the filtration process begins.

The second embodiment, i.e. the embodiment in which the venting channel 4 opens into the outlet channel 6 after the filter 3, also has the advantage that the channel extension 13 after the filter 3 is completely filled through the venting channel 4. Since the flow resistance of the ventilation channel 4 is significantly lower than that of the filter 3, this filling process takes place without bubbles and significantly faster than through the filter.

It is possible to fill the filter chamber 10 with a second liquid after the filtration has ended, thereby replacing the first liquid. For this purpose, the second liquid is pumped through the filter 3 in the simplest case. With this procedure, however, there is a risk that residues of the first liquid will remain in the channel extensions (2, 13) before and after the filter 3, which residues can interfere with reactions that take place later. These residues can be removed by briefly opening the ventilation channel 4 again and flushing it with liquid 2 .

2 shows a possible embodiment of the invention in cross section. The microfluidic filter chamber 10 is part of an embodiment of the microfluidic system according to the invention. The microfluidic filter chamber 10 is realized in a multilayer structure made of three polymer substrates 9 , 14 , 11 and an elastic foil 12 , which is located between the first, structured layer 11 and the second, structured layer 14 . The three layers are arranged one on top of the other, with the third layer 9 being arranged over the second layer 14 and the second layer 14 being arranged over the first layer 11 .

2 shows an inlet channel 1, with channel extension 2, filter 3, channel duct 7, additional valve 8, diameter w1 of the channel duct 7, depth t1 of the fluidic inlet channel 1, thickness t2 of the third layer 9, thickness t3 of the second layer 14, thickness t4 of the third layer 11

3 shows the same embodiment of the invention as FIG 2 , but in plan view. The microfluidic filter chamber 10 is part of a microfluidic system.

3 shows an inlet duct 1, with duct extension 2, filter 3, ventilation duct 4, valve 5, outlet duct 6, duct duct 7, additional valve 8, radius R1 of the duct extension 2, radius R2 of the filter 3 and width w2 of the outlet duct 6.

4 shows the same embodiment of the invention as FIG 2 and 3 , but in side view. The microfluidic filter chamber 10 is part of a microfluidic system. It is implemented in a multi-layer structure consisting of three polymer substrates 9 , 14 , 11 and an elastic film 12 which is located between the first, structured level 11 and the second, structured level 14 .

4 shows the inlet port 1, with port extension 2, filter 3, ventilation port 4, valve 5, outlet port 6, port duct 7 and additional valve 8.

• 8. Flüssigkeit strömt durch den Einlasskanal 1 ein. Das Ventil 5 ist geöffnet.
• 9. Die Flüssigkeit wird durch eine Durchführung 7 in die zweite, strukturierte Ebene 14 gelenkt und erreicht die Kanalerweiterung 2.
• 10. Der Filter 3 wird kapillar benetzt.
• 11. Die Flüssigkeit strömt durch den Belüftungskanal 4, der eine weitere Durchführung und ein Ventil 5 beinhaltet, in die erste, strukturierte Ebene 11 zurück und erreicht die Rückseite des Filters 3.
• 12. Die an der Rückseite des Filters 3 gelegene Kanalerweiterung wird befüllt.
• 13. Das Ventil 5 wird geschlossen.
• 14. Die Flüssigkeit strömt durch den Filter 3 in den Auslasskanal 6.

The functioning of the 2 , 3 and 4 embodiment shown is as follows:

• 8. Fluid flows in through inlet port 1. The valve 5 is open.
• 9. The liquid is directed through a passage 7 into the second, structured level 14 and reaches the channel enlargement 2.
• 10. The filter 3 is wetted capillary.
• 11. The liquid flows back through the ventilation channel 4, which contains a further passage and a valve 5, into the first, structured level 11 and reaches the back of the filter 3.
• 12. The channel extension on the back of filter 3 is filled.
• 13. Valve 5 is closed.
• 14. The liquid flows through the filter 3 into the outlet channel 6.

$$\text{t3}=1.5\text{mm}\text{, t4}=1.5\text{mm}\text{.}$$

Examples of typical dimensions in the 2 , 3 and 4 shown fluidic system are: $$\text{R1}=2.5\text{mm}\text{, R2}=3.5\text{mm}\text{,w1}=0.5\text{mm}\text{,w2}=0.3\text{mm}\text{, t1}=0.3\text{mm}\text{,t2}=1.5\text{mm}\text{,}$$

$$\text{t3}=1.5\text{mm}\text{, t4}=1.5\text{mm}\text{.}$$

Claims (6)

Fluidic system for bubble-free filling of a microfluidic filter chamber (10) comprising a multilayer structure made up of at least two layers (11, 14) and a microfluidic filter chamber (10) comprising a filter (3), a ventilation channel (4), an inlet channel (1) and a Outlet channel (6), with the filter (3) being inserted between the inlet channel (1) and outlet channel (6), and with the ventilation channel (4) branching off from the inlet channel (1) and with the flow through the microfluidic filter chamber being controlled by a valve (5 ) in the ventilation duct (4) can be regulated, characterized in that between the two layers (11, 14) there is an elastic film (12) which acts as a valve (5). fluidic system claim 1 , characterized in that the ventilation channel (4) either leads to the atmosphere or leads to a separate reservoir. fluidic system claim 1 , characterized in that the ventilation channel (4) opens into the outlet channel (6). Fluidic system according to one of Claims 1 until 3 , characterized in that the inlet channel (1) and / or the outlet channel (6) have a variable cross-sectional area. Method for bubble-free filling of a microfluidic filter chamber (10) in a fluidic system according to one of Claims 1 until 4 , wherein the microfluidic filter chamber (10) comprises a filter (3) and a ventilation channel (4), wherein a liquid is pumped through the inlet channel (1) to the filter (3) while the valve (5) in the ventilation channel (4) is open , and the filter (3) is filled capillary and the channel area (2) before the filter (3) and a part of the ventilation channel (4) is filled, the channel area (13) then being filled after the filter (3) and then the valve (5) is closed. Method for filtering a liquid with a microfluidic filter chamber (10) in a fluidic system according to one of Claims 1 until 4 , wherein first the microfluidic filter chamber (10) bubble-free according to the method claim 5 is filled, and then the liquid to be filtered flows in through the inlet channel (1) and then flows through the filter (3) into the outlet channel (6).

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