Microfluidic device comprising a bubble trap

Abstract

The invention provides a microfluidic device (100) comprising a fluid inlet (101), a fluid outlet (102), and a microfluidic channel (109) configured to fluidically connect the fluid inlet (101) and the fluid outlet (102), wherein (a) the microfluidic channel (109) comprises (i) a channel wall (115) defining a channel height (HC); (b) the microfluidic channel (109) comprises a bubble trap section (300) having a bubble trap section axis (Ebt) of elongation, wherein the channel wall (115) at the bubble trap section (300) comprises a bubble trap wall section (315) extending along the channel height (HC), wherein the bubble trap section (300) comprises a divider wall arrangement (310) configured to divide the microfluidic channel (109) in the bubble trap section (300) in a first passage (301) and a second passage (302); (c) the bubble trap wall section (315) and the divider wall arrangement (310) define (i) a primary first passage flow-through area (A11) and a secondary first passage flow-through area (A12) from the first passage (301), wherein the primary first passage flow-through area (A11) is configured upstream of the secondary first passage flow-through area (A12), and (ii) a primary second passage flow-through area (A21) and a secondary second passage flow-through area (A22) from the second passage (301), wherein the primary second passage flow-through area (A21) is configured upstream of the secondary second passage flow-through area (A22); wherein A11>A21 and A12 <A22.

Description

[0001] Microfluidic device comprising a bubble trap

[0002] FIELD OF THE INVENTION

[0003] The invention relates to a microfluidic device comprising a bubble trap, and a method for reducing bubbles in a liquid.

[0004] BACKGROUND OF THE INVENTION

[0005] Microfluidic devices comprising a bubble trap are known in the art. EP3401014 Al, for instance, describes a microfluidic chip including a first cells enrichment system and a second cells enrichment system is provided. Channel layouts of the first and the second cells enrichment systems are symmetric with respect to a reflection plane vertical to the microfluidic chip. Each of the first the second cells enrichment systems includes a first fluid channel, a second fluid channel, a sample channel, an inlet channel, and a filtration chamber. According to an embodiment, the micro fluidic chip further includes a reagent inlet and a reagent channel. The reagent channel bifurcates in a first branch and a second branch, wherein the first branch is in fluid communication with the filtration chamber of the first cells enrichment system, and the second branch is in fluid communication with the filtration chamber of the second cells enrichment system. According to an embodiment, the reagent channel further includes a bubble trapping chamber before bifurcating in the first branch and the second branch.

[0006] SUMMARY OF THE INVENTION

[0007] Air bubbles are a common hurdle in microfluidics. The bubbles have several possible origins: air trapping due to the geometry and various components of the system (tubing, connection, inlet, microchannels), wettability properties of the chip material, temperature variations, and injecting both an organic and an inorganic solution into the chip.

[0008] Depending on the application of the microfluidic device, bubble free flow of the liquid(s) may be desirable. For instance when applying a microfluidic device for making artificial lipid bilayers starting from an aqueous liquid and an organic liquid, unwanted bubbles in the channels may often arise at an interface between an aqueous and an organic phase, which may disrupt the contact process between monolayers. Moreover, bubbles in the liquid may result in pressure differences between parallel channels. Furthermore, gas bubbles circulating through a microfluidic system may damage equipment or may damage a (biological) sample of interest. In further applications, bubbles may block a current conduction.

[0009] Providing bubble-free flows may facilitate stable and robust microfluidic applications. To capture and / or remove air bubbles from microfluidic systems, bubble traps may be used. Known bubble traps may comprise active bubble traps, e.g., wherein a vacuum is used to assist bubble removal. Other active bubble traps may be based on the assistance of lasers or acoustic generators. Active bubble traps essentially rely on external auxiliary equipment for bubble capture and removal which may not be desired. Active bubble traps may require auxiliary equipment. The auxiliary equipment may result in complex configurations, requiring additional. Furthermore, the auxiliary equipment may move, such as rotate or translate and may be prone to wear. In contrast to that, passive bubble traps may remove bubbles without auxiliary equipment and may require no or less maintenance.

[0010] Passive bubble traps may for instance be based on buoyancy. Bubbles may float upward and temporarily reside on the liquid surface, where they may be removed. Removal may e.g., be done using a chamber wherein gas may leave the chamber at the top while the liquid may exit the chamber at the bottom. The bubble-removal efficiency of known buoyancybased bubble traps is especially limited by the fluid flow rate. Further passive bubble traps are developed or under development, among others based on surface tension and hydrodynamic forces at the gas-liquid interface. The bubble-removal efficiency of this kind of bubble trap seems to depend largely on the bubble size and the geometry of the device. Further alternatives may be based on hydrophobic porous films preventing the liquid to pass and allowing a gas to pass. These systems may especially be appropriate for aqueous liquids. However, if the pressure in the liquid is too low, the bubbles may not easily be expelled from the film pores. Moreover, if the pressure is too high, the liquid may still pass the film.

[0011] Further, in prior art systems, channels and bubble traps may have tubular configurations and / or out-of-plane configurations, requiring (additional) space (compared to on plane configurations). Yet, volumes of microfluidic systems are preferably minimized allowing them to be incorporated in chips with a minimized thickness. Furthermore, prior art bubble traps may structurally be configured as distinct devices that have to be connected to an inlet of an application device, such as an application chip, if bubble free flow is required in the application. These bubble traps may not be configured to allow direct incorporated in the application chip. Yet further disadvantages of prior art bubble traps is that they may be configured to remove bubbles only from single phase systems; that they are made of different parts that have to be assembled and / or that they are made from various different materials. The manufacturing of many prior art bubble traps systems may (therefore) be complex.

[0012] Hence, it is an aspect of the invention to provide an alternative microfluidic device, which preferably further at least partly obviates one or more of above-described drawbacks. The present invention may have as object to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0013] According to a first aspect, the invention provides a microfluidic device. In embodiments, the microfluidic device comprises a (first) fluid inlet, a (first) fluid outlet, and a (first) microfluidic channel configured to fluidically connect the (first) fluid inlet and the (first) fluid outlet. The (first) microfluidic channel may in embodiments comprise a channel wall, especially defining a channel height (He). In further embodiments, the (first) microfluidic channel may comprise a bubble trap section having a bubble trap section axis (Ebt) of elongation. In further embodiments, the channel wall at the bubble trap section may comprise a bubble trap wall section, extending along the channel height (He) (in embodiments along a total of the channel height (He)). The bubble trap wall section is in embodiments configured in the (first) microfluidic channel. In further embodiments, the bubble trap section comprises a divider wall arrangement. The divider wall arrangement may in embodiments be configured to divide the (first) microfluidic channel in the bubble trap section in a first passage and a second passage. The first passage and the second passage may be configured parallel to each other (i.e., especially not downstream or upstream from each other). In further embodiments, the bubble trap wall section and the divider wall arrangement define (i) a primary first passage flow-through area (An) and a secondary first passage flow-through area (An) (both) from (or especially in) the first passage, especially wherein the primary first passage flow-through area (An) is configured upstream of the secondary first passage flow-through area (An). Further, in embodiments, the bubble trap wall section and the divider wall arrangement may (further) define a primary second passage flow-through area (A21) and a secondary second passage flow- through area (A22) (both) from (or especially in) the second passage. In further embodiments, especially wherein the primary second passage flow-through area (A21) is configured upstream of the secondary second passage flow-through area (A22). In specific embodiments, An>A2i and An <A22.

[0014] Hence, in specific embodiments, the invention provides a microfluidic device comprising a (first) fluid inlet, a (first) fluid outlet, and a (first) microfluidic channel configured to fluidically connect the (first) fluid inlet and the (first) fluid outlet, wherein (a) the (first) microfluidic channel comprises a channel wall defining a channel height (He); (b) the (first) microfluidic channel comprises a bubble trap section having a bubble trap section axis (Ebt) of elongation, wherein the channel wall at the bubble trap section comprises a bubble trap wall section extending along the channel height (He), wherein the bubble trap section comprises a divider wall arrangement; wherein the divider wall arrangement is configured to divide the (first) microfluidic channel in the bubble trap section in a first passage and a second passage; and (c) the bubble trap wall section and the divider wall arrangement define (i) a primary first passage flow-through area (An) and a secondary first passage flow-through area (An) (both) from the first passage, wherein the primary first passage flow-through area (An) is configured upstream of the secondary first passage flow-through area (An), and (ii) a primary second passage flow-through area (A21) and a secondary second passage flow-through area (A22) (both) from the second passage, wherein the primary second passage flow-through area (A21) is configured upstream of the secondary second passage flow-through area (A22); wherein A11AA21 and A12AA22.

[0015] Such microfluidic device may be used for a variety of microfluidic applications requiring a bubble-free liquid flow. The device may comprise a bubble trap that may independently operate. The bubble trap may trap bubbles when using the microfluidic device or microfluidic application. Moreover, such a bubble trap may be integrated in the microfluidic device allowing a direct and easy integration in a microfluidic systems. The microfluidic device, especially the bubble trap, may be small compared to prior art systems. The microfluidic device may in embodiments be integrated in a chip. The microfluidic device may further allow relatively high liquid flows through the microfluidic device while still trapping the bubbles. Furthermore, the microfluidic device may be used for aqueous liquid flows as well as for organic liquid flows, multi-phase flows, and combinations of these flows. Furthermore, embodiments of the microfluidic device may be configured for tolerating harsh materials such as chloroform or acetone.

[0016] The herein described bubble trap may provide a novel passive bubble trap with an in-plane configuration and designed with an asymmetric architecture. Embodiments of microfluidic device may provide the benefit of applying a passive in-plane bubble trap to capture unwanted bubbles from the fluid flow and to reduce their impact on a successive microfluidic application in the microfluidic device. The passive in-plane configuration makes the device easy-to-fabricate. Moreover, the in-plane configuration allows configuration of the bubble traps in a thinner chip compared to tubular configurations. A passive configuration may require less parts / element and may further be more compact than active configurations. The bubble trap may have a modular configuration and may simply be integrated into any microfluidic application chip (e.g. providing a drug delivery chip wherein bubbles are trapped upstream of the drug delivery application in the same chip). Hence, connecting a separate device as bubble trap to the inlet a main (application) chip may not be required, especially simplifying the setup, and reducing a total size of the microfluidic setup. Further, embodiments of the bubble trap may handle two-phase flow, such as comprising an aqueous fluid and an organic fluid.

[0017] In embodiments, the bubbly trap may ensure stable and robust microfluidic applications in the device. The microfluidic device may further in embodiments be made of a transparent material allowing to use optical techniques to check the trapping of bubbles and / or for studying specific applications in the microfluidic device. Furthermore, the bubble trap may be configured from the same material as the application section in the chip. Embodiment of the bubble traps may be configured in a chip also comprising an application section, and especially the entire chip may be fabricated using precision machining, such as Micro CNC (using computer numerical control to automate the movement of cutting tools, ensuring accuracy and repeatability in producing high-quality parts). Moreover, in embodiments, no assembly (and manufacturing) of various different parts may be required to provide the bubble trap.

[0018] Herein, the bubble trap section may function as a bubble trap. Therefore, also the term “bubble trap” may in embodiments be used referring to the bubble trap section. The invention may thus provide a microfluidic device (or “device”) comprising a bubble trap. In a further aspect, the invention may provide a method for trapping bubbles in a microfluidic device, especially the microfluidic device of the invention.

[0019] The term “microfluidic device” may herein refer to a device for the manipulation of small amounts of fluids using channels with sizes of ten to hundreds of micrometers. Microfluidic devices are known in the art. Amongst others, the invention provides a microfluidic device comprising a microfluidic channel with a bubble trap section, e.g., for trapping bubbles from a liquid flow to provide a bubble-free liquid flow. The bubble free liquid flow may successively be used in a microfluidic application configured in the same microfluidic device, or e.g., in a further microfluidic device. The invention may in embodiments provide a microfluidic chip.

[0020] The terms “bubble trap”, “trapping bubbles”, and comparable terms especially refer to separating a gaseous phase from a liquid (flow). The gaseous phase may especially be extracted from the liquid (flow). The gaseous phase may be present as visible bubbles. The gaseous phase may also be present as minute bubbles that optionally may coalesce forming larger bubbles. The bubbles are especially separated / extracted from the (liquid) flow such that downstream of the bubble trap, the liquid may be bubble-free. The bubble may in embodiments be contained in the bubble trap after trapping the bubble. Bubble traps are known in the art, and may for instance also be called “debubblers” or “degassers”.

[0021] In embodiments, the microfluidic device may comprise a fluid inlet and a fluid outlet, such as a first (and / or a second) fluid inlet and a first (and / or a second) fluid outlet, respectively. Further, the microfluidic device may comprise a microfluidic channel configured to fluidically connect the fluid inlet and the fluid outlet. Moreover, in embodiments, the device may comprise a first microfluidic channel configured to fluidically connect the first fluid inlet and the first fluid outlet and optionally a second fluid channel configured to fluidically connect the second fluid inlet and the second fluid outlet (see also further below). The fluid outlet may be configured downstream of the fluid inlet. The fluid channel is in embodiments especially configured for guiding a fluid flow from an upstream end (especially the fluid inlet) of the fluid channel to a downstream end of the fluid channel (especially the fluid outlet).

[0022] Herein, the terms “upstream” and “downstream” may relate to an arrangement of items or features relative to the propagation of fluids from a fluid providing means (e.g., a pump or syringe) wherein relative to a first position within a flow of fluid from the fluid providing means, a second position in the flow of fluid closer to the fluid providing means is “upstream”, and a third position within the flow of fluid further away from the fluid providing means is “downstream”.

[0023] The term “microfluidic channel” may in embodiments refer to a plurality of (the same or different) microfluidic channels, e.g., to a first microfluidic channel and / or a second microfluidic channel, see also below. In embodiments, each microfluidic channel may be configured to fluidically connect an individual fluid inlet and a respective fluid outlet. For clarity reasons, herein, the fluid channel and the respective inlet and outlet may be indicated with comparable adjectives. For instance, a first microfluidic channel may fluidically connect a first fluid inlet and a first fluid outlet, a second microfluidic channel may fluidically connect a second fluid outlet and a second fluid outlet, and a further microfluidic channel may connect a further fluid inlet and a further fluid outlet. Hence, if the microfluidic channel is indicated as a “certain” microfluidic channel, this may imply that the (respective) fluid inlet and fluid outlet connected to (or “of’) the “certain” fluid channel may also be indicated as the “certain” fluid inlet and the “certain” fluid outlet, respectively.

[0024] Moreover if a specific element or section is configured in the “certain” microfluidic channel, also the specific element or section may be indicated as “certain” specific element, or “certain” section, herein for clarity reasons. For instance if a bubble trap section is configured in a first microfluidic channel, then this bubble trap may also be indicated as a “first” bubble trap section. Likewise, if a bubble trap section is configured in a second microfluidic section, this bubble trap section may also be indicated as a “second” bubble trap section. Yet, in embodiments it may also be described that the first microfluidic channel comprises a bubble trap section and the second microfluidic channel comprises a bubble trap section. This may also be understood by the skilled person such that both (the first and the second) microfluidic channels may comprise a bubble trap section (wherein the bubble trap sections may be configured alike or different in embodiments).

[0025] In embodiments, the microfluidic channel may thus comprise a hollow channel. Especially, the microfluidic channel may be configured to provide passage for a fluid through the microfluidic device. Hence, in embodiments, fluid may be provided to the microfluidic device at the fluid inlet. During the operation of the device, in embodiments, the fluid may flow in a direction from the fluid inlet towards the fluid outlet. The fluid inlet and the fluid outlet may, in embodiments, be configured in fluidic contact with each other. The term “fluidic contact” may especially indicate that a fluid may flow between the elements which are indicated to be in fluidic contact. Especially, herein, a gas (mixture, e.g., air) or a liquid, like an aqueous solution, may flow between the two elements. The term “fluid” may in specific embodiments especially refer to a liquid (a liquid containing gas bubbles and / or a bubble-free liquid). In further specific embodiments, the term “fluid” may (also) refer to a gaseous fluid.

[0026] The microfluidic channel may, in embodiments, comprise an elongated channel, i.e., the channel may have one dimension (e.g., length) significantly larger than the other dimensions of the microfluidic channel (e.g. width, height, diameter). Especially, the microfluidic channel may comprise a channel wall. In embodiments, the channel wall may define a channel length (Lc) and a channel height (He). In embodiments, the microfluidic channel may approximate a cuboid shape. Hence, in embodiments, a cross-section of the microfluidic channel may approximate a square or rectangular shape. In such embodiments, the channel wall may define the channel height (He) and may additionally define a channel width (Wc). In embodiments, Lc>Hc, such as Lc>2*Hc, like Lc>3*Hc, especially Lc>5*Hc. Similarly, in embodiments, Lc>Wc, such as Lc>2*Wc, like Lc>3*Wc, especially Lc>5*Wc.

[0027] The channel height is especially defined perpendicular to the channel width. The channel height and the channel width may in further embodiments define a plane (“or cross- sectional plane”) perpendicular to the microfluidic channel axis (at a given longitudinal position in the microfluidic channel). When referring to a cross-section or cross-sectional area of the (microfluidic) channel (at a longitudinal position), the cross-section or cross-sectional area may especially be configured in that plane (at the longitudinal position).

[0028] In alternative embodiments, the microfluidic channel may approximate a cylindrical shape. Hence, in embodiments, a cross-section of the microfluidic channel may approximate a circular shape. In such embodiments, the channel height (He) may essentially be a (cross-sectional) diameter of the microfluidic channel. Especially, in such embodiments, the channel height (He) may be an equivalent circular diameter (De) of a cross-section (perpendicular to a direction of elongation) of the microfluidic channel. The equivalent circular diameter (or ECD) (or “circular equivalent diameter”) of an (irregularly shaped) two- dimensional shape is the diameter of a circle of equivalent area. For instance, the equivalent circular diameter of a square with side a is 2*a*SQRT(l / 7t). For a circle, the diameter is the same as the equivalent circular diameter. Would a circle in an xy-plane with a diameter D be distorted to any other shape (in the xy-plane), without changing the area size, then the equivalent circular diameter of that shape would be D.

[0029] In yet alternative embodiments, the microfluidic channel may have any other elongated shape. For example, in embodiments, a cross-section of the microfluidic channel may approximate a triangular or polygonal shape. In such embodiments, the channel height (He) may be an equivalent circular diameter (De) of a cross-section (perpendicular to a direction of elongation) of the microfluidic channel.

[0030] The channel height (He) may, in embodiments, be selected from the range of >0.5 mm, such as from the range of >1 mm, like from the range of >1.5 mm, especially from the range of >2 mm. Further, in embodiments, the channel height (He) may be selected from the range of <30 mm, such as from the range of <20 mm, like from the range of <10 mm, especially from the range of <5 mm. Similarly, in embodiments, the (channel) equivalent circular diameter (De) may be selected from the range of >0.5 mm, such as from the range of >1 mm, like from the range of >1.5 mm, especially from the range of >2 mm. Further, in embodiments, the equivalent circular diameter (De) may be selected from the range of <30 mm, such as from the range of <20 mm, like from the range of <10 mm, especially from the range of <5 mm. Analogously, in embodiments, the channel width (Wc) may be selected from the range of >0.5 mm, such as from the range of >1 mm, like from the range of >1.5 mm, especially from the range of >2 mm. Further, in embodiments, the channel width (Wc) may be selected from the range of <30 mm, such as from the range of <20 mm, like from the range of <10 mm, especially from the range of <5 mm. Furthermore, in embodiments, the channel length (Lc) may be selected from the range of >20 mm, such as from the range of >30 mm, like from the range of >40 mm, especially from the range of >50 mm. Further, in embodiments, the channel length (Lc) may be selected from the range of <150 mm, such as from the range of <100 mm, like from the range of <80 mm, especially from the range of <60 mm.

[0031] Note that, in embodiments, the channel dimensions may not necessarily be constant over the whole channel, e.g., at one cross-section the channel width may be larger than at a different cross-section (at a different longitudinal position in the channel). In other words, at one cross-section the channel may be narrower (or wider) than at a different cross-section. Hence, the herein described dimensions (Lc, He, Wc, and De) may refer to average dimensions. In further embodiments, the herein described dimensions (Lc, He, Wc, and De) may refer to a maximum value. The described dimensions may further refer to a local dimension. The (local) channel dimension(s) may herein further be defined at a given longitudinal position in the channel.

[0032] The term “longitudinal”, in “a longitudinal position” (or “longitudinal location”) may herein especially refer to a (predetermined, given, and / or determinate) position or location along a length of an elongated object, such as along a length of the microfluidic channel, or e.g., along a length of a bubble trap section, an application section, etc. A longitudinal position in the microfluidic channel may for instance refer to a (predetermined or quantifiable) position, especially cross-sectional position, along the channel axis.

[0033] The term “approximate” and its conjugations herein, such as in “to approximate a shape”, may refer to being nearly identical to, especially identical to, the following term, for example nearly identical to a circular cross-section or a semi-cylindrical shape. For example, a channel may define a cylindrical shape but for a defect. In particular, an object approximating a first shape may herein refer to: a first shape realization encompassing the object, wherein the first shape realization is defined as the smallest encompassing shape of the (2D or 3D, respectively) object wherein the first shape realization has the shape of the first shape, wherein a ratio of the area (volume) of the first shape realization to the area (volume) of the object may be < 1.2, especially < 1.1, such as <1.05, especially <1.02. For instance, a channel may approximate a semi-cylindrical shape, wherein the first shape realization may be defined as the smallest encompassing semi -cylindrical shape of the channel, wherein a ratio of the volume of the first shape realization to the volume of the channel is < 1.2, especially, especially < 1.1, such as <1.05, especially <1.02, including 1. Further, if the dimensions of the first shape are defined, the term approximate may refer to the object and the first shape being superimposable (in 2D or 3D, respectively) such that an intersection between the object and the first shape covers at least n% of the object and at least n% of the shape, wherein n is at least 90%, such as at least 95%, especially at least 98%, such as at least 99%, including 100%.

[0034] The channel wall of the microfluidic channel may in embodiments enclose a channel space. If it is described herein that a specific element is configured in the microfluidic channel this may in embodiments indicate that the specific element is configured in the channel space. The microfluidic channel may have a channel axis of elongation configured, especially perpendicular to the channel height (and channel width). The channel axis (of elongation) may further, especially be configured perpendicular to the cross-sectional plane of the channel. It is noted that the channel axis may comprise a straight axis in embodiments. The channel axis may be configured substantially linear. Yet, in alternative embodiments, the channel axis may be curved, and / or may, e.g., comprise one or more bends. The channel axis may especially comprise any arbitrarily shape. The channel axis (especially of a straight channel) may further be configured parallel to a shortest line connecting the fluid inlet to the fluid outlet via the microfluidic channel. The bubble trap section axis of elongation (or just “bubble trap section axis”) may in embodiments coincide with the channel axis (at the location of the bubble trap section axis).

[0035] The microfluidic channel may thus in embodiments comprise the bubble trap section. In embodiments, the bubble trap section may comprise the divider wall arrangement. The divider wall arrangement may in embodiments be configured parallel to the bubble trap section axis. The divider wall arrangement may in further embodiments at least partly extend along the (full) channel height. The divider wall arrangement may in embodiments have a (divider wall) height (Hsa), especially approximately equal to the channel height (Hc). In embodiments, there may be no opening or empty space between the divider wall arrangement and the channel wall in a direction parallel to the height of the divider wall arrangement. Yet, in further embodiments there may be a very small opening between the divider wall arrangement and the channel wall in a direction parallel to the height of the divider wall arrangement. Such very small opening may especially have a size of no more than 120 pm to prevent a bubble to pass through the opening. The divider wall arrangement height (and / or a height of subdivider elements, see further below) (especially at a given longitudinal position) may be at least 90%, especially at least 95%, like at least 99% (and especially no more than 100%) of the channel height (at the given longitudinal position).

[0036] The divider wall arrangement may comprise a plurality of sections or “subdivider elements” defining the divider wall arrangement, especially defining openings between the subdivider elements (see further below). It will be understood that the “height” of the divider wall arrangement at these openings may be less than the divider wall arrangement height, and may especially be zero. The divider wall arrangement may further divide the microfluidic channel in the bubble trap section in the first passage and the second passage, see also further below. Hence, the divider wall arrangement may be configured such that in a longitudinal direction and in a direction perpendicular to the channel axis, there is empty space (optionally filled with a fluid) or opening between the divider wall arrangement and the channel wall.

[0037] As indicate above, at the bubble trap section, the channel wall may comprise a bubble trap wall section. Herein, the term “bubble trap wall section” may especially refer to a section of the channel wall defined along the bubble trap section axis of elongation and configured parallel to the divider wall arrangement height. The term “bubble trap wall section” may in embodiments refer to a portion of the channel wall at the bubble trap section. It is noted that in embodiments, a total length of the divider wall arrangement (including the openings) may be equal to or smaller than a total length of the bubble trap wall section. Further, especially, the bubble trap wall section may in embodiments comprise two distinct portions of the channel wall configured at opposite sides of the divider wall arrangement. The term “bubble trap wall section” may refer to two bubble trap wall sections, each one being defined by one of the two distinct portions of the channel wall. Herein, these two wall sections or two distinct portions of the channel wall, especially of the bubble trap wall section, may also be referred to as “two opposite wall portions of the bubble trap wall section”, see also further below.

[0038] The bubble trap wall section may in further embodiments define the width of the microfluidic channel at a given longitudinal position (in the bubble trap section). Likewise, a height of the bubble trap wall section (at a given longitudinal position) may in embodiments (especially comprising a rectangular cross-section of the microfluidic channel) correspond to channel height (at the given longitudinal position).

[0039] The divider wall arrangement and the bubble trap wall section may further, in embodiments, define the first passage and the second passage. Herein, the first passage and the second passage together may also be referred to as “the (two) passages”. In embodiments the first passage may thus be defined by one of the two opposite wall portions (of the bubble trap wall section) and (“in combination with”) the divider wall arrangement, and especially the second passage may be defined by the other one of the two opposite wall portions and the divider wall arrangement.

[0040] The two passages may in embodiments be configured to provide a flow profile in the passages for allowing to trap any bubble (present in the fluid) in the bubble trap section. Based on the configuration of the bubble trap section, e.g., in embodiments, a bubble in the flow when entering the bubble trap section may flow into the second passage, whereas the liquid (part of the flow) may flow into the first passage. This different behavior (of the liquid phase and the gas phase) may be the result of a difference between (a size of) the primary first passage flow-through area An and (a size of) the primary second passage flow-through area A21. The effect may especially be observed for A21 / A11 being smaller than 1. The bubble may further be trapped (caught) in the bubble trap section, especially based on the difference between (a size of) the secondary first passage flow-through area A 12 and (a size of) the secondary second passage flow-through area A22 (arranged further downstream in the passages), especially wherein A12 / A22 is smaller than 1.

[0041] Hence, in embodiments a primary ratio A21 / A11 is (configured to be) smaller than 1, such as smaller than 0.99. The primary ratio A21 / A11 may in embodiments be equal to or smaller than 0.95, such as 0.9 at maximum, like 0.8 at maximum. The primary ratio A21 / A11 may further be at least 0.05, such as at least 0.1, especially at least 0.3. In embodiment the primary ratio A21 / A11 may be selected from the range of 0.1-0.9, such as from the range of 0.3- 0.8. The primary ratio A21 / A11 may for instance be around 0.5, e.g., 0.5 ± 20%. Based on the primary ratio, a bubble entering the bubble trap may in embodiments be facilitated to flow into the first passage (and especially not in the second passage).

[0042] A secondary ratio of A12 / A22 may in further embodiments have a value that is described above in relation to the primary ratio A21 / A11. The secondary ratio of Ai2 / A22 is in further embodiments selected from the range of 0.1-0.9, such as from the range of 0.3-0.8. The (value of the) secondary ratio may especially be selected independently from (the value of) the primary ratio. Yet, in specific embodiments, the primary ratio and the secondary ratio may have the same value.

[0043] In embodiments, A21 is configured at a primary second longitudinal position (of the microfluidic channel in the bubble trap section) and An is configured at a primary first longitudinal position (of the microfluidic channel in the bubble trap section). In specific embodiments, the primary second longitudinal position may be configured further upstream (especially closer to the fluid inlet) than the primary first longitudinal position. Further, in embodiments An and A21 are configured at the same (primary) longitudinal position in the microfluidic channel. A (minimal) distance (along the microfluidic channel axis) between the fluid inlet and A21 may in specific embodiments be equal to or less than the (minimal) distance between the fluid inlet and An. Having A21 configured at least not further away from the fluid inlet then An may further support guiding the bubble into the first passage in embodiments. In further embodiments, A22 is configured at a secondary second longitudinal position (of the microfluidic channel in the bubble trap section) and A12 is configured at a secondary first longitudinal position (of the microfluidic channel in the bubble trap section). In specific embodiments, the secondary second longitudinal position may be configured further upstream (especially closer to the fluid inlet) than the secondary first longitudinal position. In alternative embodiments, the secondary second longitudinal position may be configured further downstream than the secondary first longitudinal position. In yet further embodiments A12 and A22 may be configured at a same longitudinal (respective) position in the microfluidic channel. The secondary second longitudinal position and the secondary first longitudinal position may be the same (- secondary - longitudinal position).

[0044] In further embodiments, the flow-through area between the primary first passage flow-through area and the secondary first passage flow-through area may vary (i.e., the flow- through area may be increased or be decreased in the first passage as a function of a longitudinal position in the first passage). As a result of a flow-through area that initially (especially downstream from the primary first passage flow-through area) increases and successively (further downstream) decreases in a downstream direction (especially at locations upstream from the secondary first from flow-through area), a bubble may be trapped, especially kept, or maintained in the bubble trap section, especially in the first passage of the bubble trap section.

[0045] Likewise, the flow-through area between the primary second passage flow- through area and the secondary second passage flow-through area may vary in embodiments. As a result of a flow-through area that initially (especially downstream from the primary second passage flow-through area) increases and successively decreases in a downstream direction (especially upstream from the secondary second flow-through area), a bubble may be trapped especially kept (or maintained), in the bubble trap section in embodiments. Moreover, in embodiments a relatively large bubble may be split at the divider wall arrangement into (a bubble comprising) a first portion entering the first passage and (a bubble comprising) a second (especially smaller) portion entering the second passage, and especially the second portion may be trapped in the second passage of the bubble trap section.

[0046] In embodiments, a change in microfluidic channel width as a function of the longitudinal position in the bubble trap, may result in the varying flow-through area in the first and / or second passage.

[0047] Hence, in embodiments, the bubble trap wall section and the divider wall arrangement further define a largest intermediate first passage flow-through area (A19) from the first passage configured between the primary first passage flow-through area (An) and the secondary first passage flow-through area (An). In embodiments, A19 >An and A19 > A12. In further embodiments, the bubble trap wall section and the divider wall arrangement further define a largest intermediate second passage flow-through area (A29) from the second passage configured between the primary second passage flow-through area (A21) and the secondary second passage flow-through area (A22). In further embodiments, A29 >A2i and A29 > A22.

[0048] Further, especially, a first intermediate ratio A19 / A11 may be selected from the range of 1.2-10, especially from the range of 1.5-5. Likewise, in embodiments a second intermediate ratio A29 / A21 may be selected from the range of 1.2-10, especially from the range of 1.5-5. Based on such configuration, bubble trapping in the bubble trap section may further be assisted.

[0049] In further specific embodiments A19 / A29 > 1. The ratio A19 / A29 may in embodiments be at least two, such as at least five. The ratio A19 / A29 may in further embodiments be ten at maximum, such as eight at maximum, and in embodiments five at maximum. Embodiments having a relatively large first intermediate ratio A19 / A11 may especially keep larger bubbles in the bubble trap relative to embodiments having a smaller first intermediate ratio (especially for embodiments wherein a total length of the divider wall arrangement is about the same). Furthermore, having A19 larger than A29 may further facilitate keeping the bubble in the bubble trap. If A19 is much smaller than A29 this may result in a relatively high pressure drop for the flow going through the first passage which may result in embodiments in pushing out a bubble caught in that passage, e.g., via one or more of the gaps in embodiment comprising subdivider elements, see below).

[0050] In further embodiments a flow-through area may (gradually) reduce in size from the upstream end of one or more of the (first and second) passages to a longitudinal position comprising the respective primary (first or second) passage flow-through area. Additionally, or alternatively, the flow-through area may (gradually) increase in size (again) (staring) from the longitudinal position comprising one or more of the secondary (first and second) passage flow- through areas to the downstream end of the respective primary (first or second) passage.

[0051] In embodiments, the width of the channel in the bubble trap section may vary in in the longitudinal direction (a direction parallel to divider wall arrangement). Moreover, in further specific embodiments, a shortest distance (d7) in the bubble trap section between two opposite wall portions of the bubble trap wall section (especially arranged at opposite sides of the divider wall arrangement) is reduced in a direction from the fluid inlet (up) to a first longitudinal position, and the shortest distance (d7) (in the bubble trap section) (especially between the two opposite wall portions) is increased in a direction from a second longitudinal position to the fluid outlet. The shortest distance (d7) may especially be determined along a virtual line configured perpendicular to the bubble trap section axis. Further, especially, the first longitudinal position may comprise one or more of the primary first passage flow-through area An and the primary second passage flow-through area A21. In yet further embodiments, the second longitudinal position may comprise one or more of the secondary first passage flow- through area A 12 and the secondary second passage flow-through area A22.

[0052] In further embodiments, the divider wall arrangement may be defined by a plurality (at least two) of subdivider wall elements separated by (a) gap(s) (configured between the subdivider elements). The divider wall arrangement may in embodiments, e.g., comprise an array of k subdivider elements, and especially an array of at least two subdivider elements. In further embodiments, the subdivider elements may especially be configured parallel to the bubble trap section axis. The subdivider elements may mutually be separated by k-1 gaps between the subdivider elements. The divider wall arrangement may in embodiments comprise at least two subdivider elements, such as at least three, or at least four, or in embodiments at least six subdivider elements. In embodiments k>3, such as k> 4, like k>6. In further embodiments k< 20, especially k<10, like k< 6, The number k may in embodiments, e.g. be selected from the range of 2-10, like from the range of 2-6.

[0053] In specific embodiments, the subdivider elements may especially be configured (in a line) parallel to (or coinciding with) the bubble trap section axis. The gap(s) may be configured for allowing liquid to flow between the first and second passage via the gap. The gap may further especially be configured such that a gas bubble may especially not pass through the gaps. A size of the gap (or “gap size”), especially a shortest distance between adjacently configured subdivider element is therefore in embodiments configured to be 150 pm at maximum, like 120 pm at maximum. The gap size is in further embodiments especially at least 10 pm, such as at least 25 pm, like at least 50 pm, and in embodiments at least 75 pm. Especially, each gap defines a fluidic connection between the first passage and the second passage. The gap size between a first pair of adjacently configured. The gap size between subdivider elements may be configured independently from another gap size between other subdivider elements (or configured in another bubble trap section in the microfluidic device). The fluid connection(s) may facilitate liquid to overtake (pass) the bubble in the bubble trap section. Furthermore, the size selected for the gap size may also be related to dimensions of the flow-through areas in the respective passages affecting friction forces in and a pressure drop over the first and second passage, see also above with respect to the A19 and A29. In specific embodiments, the divider wall arrangement comprises a fragmented divider wall comprising an array of k subdivider elements configured parallel to the bubble trap section axis of elongation, wherein the subdivider elements are mutually separated by k-1 gaps between the subdivider elements; wherein k>2; especially wherein a shortest distance (d5) between adjacently configured subdivider elements is selected from the range of 50-120 pm.

[0054] In embodiments, any one of the subdivider elements may have a subdivider length (LSd) defined parallel to the bubble trap section axis of elongation (and perpendicular to the channel height (He)). In embodiments, the subdivider length may be selected from the range of 100-3000 pm, like from the range of 500-3000 pm, such as from the range of 1000-2500 pm, especially from the range of 1500-2000 pm. Further, in embodiments, the subdivider length may be selected from the range of 1000-5000 pm, such as from the range of 1500-3000 pm. A ratio of the channel width at a given longitudinal position (in the bubble trap section) to the subdivider length at the given longitudinal position may in embodiments be selected from the range of 0.1-5, like from the range of 0.25-3.

[0055] In further embodiments, the subdivider elements may comprise a tapered shape, tapering in a direction parallel to the bubble trap section axis. In specific embodiments, adjacently configured subdivider elements may taper in a direction towards each other. Tapering may positively guide a liquid flow from one of the passages to the other passage. Tapering may further prevent a bubble in the bubble trap to break-up. Tapering at the upstream end of the divider wall arrangement may in further embodiments allow increasing the flow rate without pinning the liquid phase at edges of the divider wall arrangement. The liquid phase preferably is eased to flow through the bubble trap, allowing it to overtake any bubble in the bubble trap.

[0056] Hence, in embodiments adjacently configured subdivider elements have a tapering shape tapering in a direction towards each other. In alternative embodiments, one or more of the subdivider elements have a rounded shape or a blunt shape at one or more of their extremes facing an adjacently configured subdivider element.

[0057] The subdivider element may have a subdivider width (perpendicular to the subdivider length) that may thus vary along the subdivider length (LSd). The subdivider element may in embodiments especially comprise a (maximum) subdivider width (d6) configured perpendicular to the channel height (or divider wall arrangement height) and to the subdivider length (LSd). The (maximum) subdivider width may in embodiments be selected from the range of 50-500 pm, such as from the range of 50-400 pm, especially from the range of 100-300 pm. Moreover, a ratio of the (maximum) subdivider width at a given longitudinal position (in the bubble trap section) relative to the channel width at the longitudinal position may in embodiments be selected from the range of 0.5-30, like from the range of 2-15. In further embodiments the divider wall arrangement has a tapered shape at one or more of the extremes of the divider wall arrangement (i.e., at an upstream end and / or a downstream end of the divider wall arrangement). In embodiments, this may imply that the subdivider element at the upstream end and / or the subdivider element at the downstream end of the divider wall arrangement comprises that tapered shape (tapering to the fluid inlet and / or the fluid outlet, respectively. In further embodiments, the divider wall element may not comprise a fragmented divider wall, especially may not be fragmented, and one or more of the extremes of the (unfragmented) divider wall arrangement has the tapered shape.

[0058] If the divider wall arrangement comprises a non-fragmented divider wall (arrangement) (comprising no gaps), this may also be indicated with k=l. Moreover, in embodiments, a (maximal) width of the divider wall arrangement may be selected from values described herein for the width of the subdivider element. Furthermore, a length of the divider wall arrangement comprising an unfragmented divider wall may in embodiments be in the same range as a total length of the fragmented divider wall. In embodiments, e.g. a (total) length of the divider wall arrangement may be selected from the range of 300 pm - 20000 pm, like 500 pm - 15000 pm, especially 1000 pm - 10000 pm, and in embodiments 5000 pm -15000 pm.

[0059] A height of the subdivider element may in embodiments be equal to the divider wall arrangement height (Hsa). A (total) length of (the microfluidic channel) in the bubble trap section may in embodiments correspond to the length of the divider wall arrangement.

[0060] As described above, the divider wall arrangement is in embodiments configured parallel to the bubble trap section axis. The bubble trap section axis may in embodiments be configured substantially linear, especially the bubble trap section axis may define a straight line. The bubble trap section axis (Ebt) of elongation may be a straight axis of elongation in embodiments. Additionally, or alternatively, the bubble trap section axis may in embodiments comprise a curved or bent axis. Furthermore, the bubble trap wall section may in embodiments comprise protrusions extending in the direction of the divider wall arrangement. The (extremes of) the protrusions may in embodiments in combination with the divider wall arrangement define one or more of the (primary, secondary, or intermediate) first passage flow-through areas and / or one or more of the (primary, secondary, or intermediate) second passage flow-through areas.

[0061] In further specific embodiments the divider wall arrangement is configured parallel to the bubble trap section axis of elongation, wherein the bubble trap wall section comprises protrusions extending in the direction of the divider wall arrangement, wherein (extremes of) the protrusions in combination with the divider wall arrangement define (i) the primary first passage flow-through area, (ii) the secondary first passage flow-through area, (iii) the primary second passage flow-through area, and (iv) the secondary second passage flow- through area.

[0062] In further embodiments partitions of the bubble trap wall section between the protrusions optionally define the intermediate first passage flow-through area and the intermediate second passage flow-through area.

[0063] As is described above (especially based on the described configurations), specific embodiments of (the microfluidic channel in) the bubble trap section may especially be configured asymmetrically. Such asymmetric configuration may facilitate trapping of bubbles.

[0064] The microfluidic device of the invention may in an aspect be used for a microfluidic application with a liquid (without gas bubbles). The microfluidic device may in embodiments comprise an application section (to perform the microfluidic application). The application section is in embodiments especially configured downstream from bubble trap section. Furthermore, the application section is in further embodiments further especially configured upstream of the (first) fluid outlet. In further embodiments, upstream of the application section, bubbles in the liquid may be trapped in the bubble trap section, as discussed above. In further embodiments, a number of bubbles in a liquid provided to the microfluidic device may be reduced, especially based on the bubble trap (section).

[0065] Such microfluidic device (comprising the application section) may for instance comprise a cell culturing application, especially wherein biological cells may be provided in the application section and may be cultured in the application section. The application may in further embodiments comprise the formation of (artificial) lipid layers, such as lipid bilayers. The layers may for instance be used in a microfluidic application for drug screening. In further embodiments, the bubble trap may be integrated into any arbitrarily kind of flow-rate / flow shear stress sensitive microfluidic systems (as bubble in the channels may disturb the flow). The bubble trap may e.g. be integrated in a microfluidic particle sorting / separation system or e.g. cell / spheroid trapping systems. The application section may in embodiments comprise a microfluidic particle sorting and / or separation section. In further embodiments, the application section may comprise a (especially biological) cell and / or spheroid trapping section.

[0066] Such microfluidic device may in embodiments comprise more than one microfluidic channel. In specific embodiments, especially (only) one of these microfluidic channels may comprise the application section. For reasons of explaining the microfluidic device, herein it may be described that the first microfluidic channel may comprise the application section (and especially a further microfluidic channel may not comprise the application section). It will be understood that in (further) embodiments the further (e.g., the second) microfluidic channel may comprise the application section (instead of the first microfluidic channel or next to the first microfluidic channel).

[0067] In embodiments, the microfluidic device may for instance comprise a cell culturing section configured in the (first) microfluidic channel at a location downstream from the bubble trap section. The (first) microfluidic channel may comprise the cell culturing section in embodiments.

[0068] In further embodiments, the microfluidic device may be configured for the formation of lipid bilayers. The microfluidic device may comprise a membrane formation section in embodiments. The membrane formation section may especially be configured in the (first) microfluidic channel at a location downstream from the bubble trap section. This way a bubble-free flow may be provided to the membrane formation section (especially for the formation of lipid bilayers). The (first) microfluidic channel may comprise the membrane formation section in embodiments.

[0069] Hence, in specific embodiments, the microfluidic device may further comprise an application section configured in the microfluidic channel (in embodiments in the first microfluidic channel) at a location downstream from the bubble trap section; especially wherein the application section comprises one or more of a membrane formation section, a cell culturing section, a microfluidic particle sorting and / or separation section, and a (biological) cell (especially including a spheroid) trapping application.

[0070] Hence, in specific embodiments, the (first) microfluidic channel may (further) comprise a membrane formation section at a location downstream from the bubble trap section (and especially upstream of the (first) fluid outlet).

[0071] In further embodiments the membrane formation section has a membrane formation section axis (Emfs) of elongation. Furthermore, the channel wall at the membrane formation section may (further) comprise a membrane formation wall section. In specific embodiments, the membrane formation section comprises a plurality of micropillars, wherein each of the plurality of micropillars is configured to extend along the channel height (He) (and in embodiments especially along the full channel height). The plurality of micropillars may in embodiments be configured in an n*m array parallel to the membrane formation section axis (Emfs) of elongation; especially wherein n is selected from the range of >1 and m is selected from the range of >2. The plurality of micropillars are especially configured in an n*m array of n rows * m columns. Furthermore, especially in embodiments, the n*m array may be configured to define (i) n+1 (parallelly configured) elongated subchannels within the (first) microfluidic channel and (ii) per row of the n rows m-1 fluidic connection sections (especially wherein adjacent elongated subchannels are configured fluidically connected at the m-1 fluidic connection sections configured between adjacent micropillars). In embodiments, the (n) rows may be configured parallel to the membrane formation section axis of elongation. In further specific embodiments, the plurality of micropillars each may have a maximum width (Wmax) defined in a direction perpendicular to the membrane formation section axis (Emfs) of elongation (and especially also to the channel height He). Further, especially in embodiments each of the plurality of micropillars may taper from its maximum width (Wmax) at least in directions parallel to the membrane formation section axis (Emfs) of elongation towards respective adjacent micropillars.

[0072] In embodiments, the membrane formation section may be configured such that during operation of the microfluidic device (by providing fluids for membrane formation to the device) membranes (or lipid bilayers) may be formed in the membrane formation section in a direction parallel to the membrane formation section axis (Emfs) of elongation. Therefore, in embodiments, the membrane formation section may comprise a plurality of micropillars.

[0073] Herein, micropillars may refer to structures configured in the microfluidic channel (especially in the membrane formation section) and having a shape such that, in embodiments, the micropillars may have one dimension equal to one dimension of the microfluidic channel. Especially, in embodiments, (at least part of) the micropillars may have a micropillar height (HM) (equal to or) that may extend along the channel height (He). More especially, in embodiments, each of the plurality of micropillars may be configured to extend along the full channel height (He). Or alternatively, such as in embodiment indicated above, (at least part of) the micropillars may have a micropillar height (HM) (equal to or) that may extend along the full equivalent circular diameter (De). In other words, the micropillar height (HM) may be at least 95%, such as at least 98%, like at least 99%, especially at least 99.5%, including 100% of the channel height (He). Especially, in embodiments, the micropillars may each be configured in the membrane formation section such that in one dimension of the microfluidic channel (especially the channel height (He)) there may not be empty space (or an opening) between the channel wall and the micropillar. Conversely, in such embodiments, the micropillars may each be configured in the membrane formation section such that in the other dimensions of the microfluidic channel (especially the channel length (Lc) and the channel width (Wc)) there may yet be empty space (especially an opening) between the channel wall and the micropillar.

[0074] In embodiments, at the membrane formation section the channel wall may comprise a membrane formation wall section. Especially, in embodiments, the membrane formation wall section may refer to the section of the channel wall defined along the subchannel length (Lsc) and configured parallel to the micropillar height (HM).

[0075] In embodiments, the membrane formation section may thus comprise a plurality of micropillars. Especially, in embodiments, the membrane formation section may comprise at least 2 micropillars, like at least 3, such as at least 4, like at least 6, especially at least 12 micropillars. Further, in embodiments, the membrane formation section may comprise at most 80 micropillars, such as at most 60, like at most 40, especially at most 30 micropillars. Especially, in embodiments, the plurality of micropillars may be configured in an array, such as an n*m array, parallel to the membrane formation section axis (Emfs) of elongation. In specific embodiments, the plurality of micropillars may be configured in an n*m array, wherein the n rows of micropillars may be configured parallel to the membrane formation section axis (Emfs) of elongation, such that the m columns may extend along the direction of elongation. The m columns may especially extend from the channel wall (along the direction of elongation)

[0076] Herein, in embodiments, n may be selected from the range of >1, such as from the range of >2, like from the range of >3. Selecting n>2 may be advantageous as this may enable the formation and analysis of dual-stacked lipid bilayers within the microfluidic device. Especially, in embodiments, n may be selected from the range of <10, such as from the range of <8, like from the range of <6. Similarly, in embodiments, m may be selected from the range of >1, such as from the range of >2, like from the range of >3. Especially, in embodiments, m may be selected from the range of >1, such as from the range of >2, like from the range of >3. Furthermore, in embodiments, m may be selected from the range of <25, such as from the range of <20, like from the range of <15. For example, in embodiments, n=l and m=2 (i.e. there may be 2 micropillars). In an alternative example, in embodiments, n>2 and m>3, e.g. n=2 and m=3 (i.e. there may be 6 micropillars). Such embodiments may be beneficial as 6 micropillars may allow formation of up to 4 lipid bilayers, therewith enabling triplicate experiments in one single use of the microfluidic device. In a yet alternative example, in embodiments, n=2 and m=15 (i.e. there may be 30 micropillars).

[0077] In embodiments, the n*m array (of micropillars) may be configured to define n+1 (parallelly configured) elongated subchannels within the first microfluidic channels. Hence, in embodiments, the n rows of micropillars may divide the (first) microfluidic channel (at least in the membrane formation section) into n+1 elongated subchannels. In embodiments, the n+1 elongated subchannels may have a subchannel length (Lsc) defined as the largest distance between the micropillar configured closest to the first fluid inlet and the micropillar of the same row m configured closest to the fluid outlet. Especially, in embodiments, the subchannel length (Lsc) may be selected from the range of 2-30 mm, such as from the range of 5-25 mm, like from the range of 8-20 mm. The subchannel length (Lsc) especially depends on (i) the number of columns (i.e. the value of m) of the n*m array, (ii) a micropillar length (LM, see also further below), and a membrane formation distance (dM, see also further below).

[0078] For example, in embodiments where n=l there may be n+1 =2 elongated subchannels. In such embodiments, the micropillars may be configured centered, i.e., such that the microfluidic channel may be split into two elongated subchannels equal in size. However, this may not necessarily be the case.

[0079] In a further example, in embodiments where n=2 there may be n+1 =3 elongated subchannels. In such embodiments, the elongated subchannels may effectively comprise two wall-adjacent subchannels, i.e., configured adjacent to the membrane formation wall section, and one central subchannel, i.e., configured between the wall-adjacent subchannels (and may thus in itself not be configured directly adjacent to the membrane formation wall section).

[0080] Furthermore, in embodiments, the n*m array (of micropillars) may be configured to define per row of the n rows m-1 fluidic connection sections. Hence, in embodiments, between each of the m columns of micropillars an opening (such as a through hole) may exist, where fluid from the adjacent elongated subchannels may be fluidically connected. In other words, in embodiments, fluidic connections sections may be configured between micropillars of a row, such that the micropillars and the fluidic connection sections may alternate, i.e., provide an alternating pattern. Hence, in embodiments, adjacent elongated subchannels may be configured fluidically connected at the m-1 fluidic connection sections configured between adjacent micropillars. Note that, in embodiments, the fluidic connection sections of adjacent subchannels may thus coincide, such that said subchannels may be fluidically connected.

[0081] In embodiments, the membrane formation section may thus comprise micropillars configured adjacent to each other in a direction perpendicular to the direction of elongation (i.e. n rows of micropillars), such that the membrane formation section may comprise n+1 subchannels. Furthermore, the membrane formation section may thus comprise micropillars configured adjacent to each other in a direction parallel to the direction of elongation (i.e. m columns of micropillars), such that the membrane formation section may comprise m-1 fluidic connection sections.

[0082] In embodiments, the plurality of micropillars may each have a maximum width (Wmax) defined in a direction perpendicular to the membrane formation section axis (Emfs) of elongation (and perpendicular to the channel height (He)). Especially, in embodiments, the maximum width (Wmax) may be selected from the range of 25-350 pm, like from the range of 50-300 pm, such as from the range of 50-250 pm, especially from the range of 75-250 pm. Further, in embodiments, the maximum width (Wmax) may be selected from the range of 75- 200 pm, like from the range of 100-150 pm.

[0083] Further, in embodiments, the plurality of micropillars may each have a micropillar length (LM) defined parallel to the membrane formation section axis (Emfs) of elongation (and perpendicular to the channel height (He)). Especially, in embodiments, the micropillar length (LM) may be selected from the range of 25-1000 pm, like from the range of 50-1000 pm, such as from the range of 50-750 pm, especially from the range of 75-500 pm. Further, in embodiments, the micropillar length (LM) may be selected from the range of 100- 500 pm, like from the range of 200-400 pm.

[0084] In embodiments, at least part of, especially each of, the micropillars may have a width that may vary along its micropillar length (LM). Especially, in embodiments, at least part of, especially each of, the plurality of micropillars may taper from its maximum width (Wmax) along its micropillar length (LM). More especially, in embodiments, at least part of, especially each of, the plurality of micropillars may taper from its maximum width (Wmax) at least in directions parallel to the membrane formation section axis (Emfs) of elongation towards respective adjacent micropillars. As a result, in embodiments, a cross-section of the micropillars perpendicular to the micropillar height (HM) may have a shape with a varying width, such as e.g. a shape selected from the group comprising a (semi-)circular shape, an oval shape, an ovoid shape, an obovoid shape, a diamond (or rhombus or parallelogram) shape, a triangular shape, a kite shape, a trapezium shape, and a polygonal shape. In specific embodiments, one or more of the plurality of micropillars may have a diamond-like cross- sectional shape (defined in a plane perpendicular to the micropillar height (HM). Such embodiments may be beneficial as the tapering (or narrowing) corners of the diamond shapes of adjacent micropillars may allow fluids from adjacent subchannels to gently collide at the fluidic connection section between said adjacent tapering micropillars.

[0085] As described above, the subchannel length (Lsc) especially depends on (i) the number of columns (i.e. the value of m) of the n*m array, (ii) the micropillar length (LM), and a membrane formation distance ( M). Especially, in embodiments, Lsc=m*LM+(m-l)*dM. In embodiments, the micropillars may be configured at a distance from each other, such that the fluidic connection sections may be configured between the micropillars. In embodiments, during operation, lipid monolayers from the subchannels may join at the fluidic connection sections, therewith forming lipid bilayers (or membranes) at the fluidic connection sections. Therefore, in embodiments, the distance between the micropillars may be referred to as a membrane formation distance (“or a membrane length”) (d\i). In embodiments, the membrane formation distance (diu) may be selected from the range of 25-750 pm, like from the range of 25-500 pm, such as from the range of 50-500 pm, especially from the range of 75-250 pm. Further, in embodiments, the membrane formation distance (d\i) may be selected from the range of 50-250 pm, like from the range of 100-200 pm.

[0086] In exemplary embodiments, the first microfluidic channel may comprise 2*3 micropillars having a micropillar length LM) of 500 pm and being configured at a distance (i.e. the membrane formation distance (d\i) from each other of 150 pm. In such embodiments, the subchannel length (Lsc) may be 3*500 + (3-1)* 150 pm = 1800 pm. In an alternative example, in embodiments, the first microfluidic channel may comprise 2*15 micropillars having a micropillar length (LM) of 250 pm and being configured at a distance (i.e. the membrane formation distance (dM) from each other of 150 pm. In such embodiments, the subchannel length (Lsc) may be 15*250 + (15-1)* 150 pm = 5850 pm.

[0087] The membrane formation section axis of elongation (or just “membrane formation section axis”) may in embodiments coincide with the first microfluidic channel axis (in the formation section). In further embodiments, the membrane formation wall section may be configured parallel to the membrane formation section axis (Emfs) of elongation. The membrane formation section axis (Emfs) of elongation may in embodiments comprise a curved axis of elongation. Likewise, the membrane formation wall section may comprise a curved shape. In specific embodiments, the membrane formation wall section may be configured substantially linear (or “may comprise a straight wall section”). The membrane formation wall section may in embodiments have a linear configuration. The membrane formation wall section may in specific embodiments be configured as a straight wall (section). In further specific embodiments, the membrane formation section axis (Emfs) of elongation and the bubble trap section axis (Ebt) of elongation may be aligned. In alternative embodiments, the membrane formation section axis (Emfs) of elongation and the bubble trap section axis (Ebt) of elongation may be configured under an angle. In further specific embodiments, the membrane formation wall section may be configured in a wave-like shape parallel to the membrane formation section axis (Emfs) of elongation, wherein first distances (dl) defined between the membrane formation wall section at the maximum width (Wmax) of the micropillars and the membrane formation section axis (Emfs) of elongation, may be smaller than second distances (d2) defined between the membrane formation wall section at the fluidic connection sections between the micropillars and the membrane formation section axis (Emfs) of elongation.

[0088] In specific embodiments, the membrane formation wall section may be configured in a (sinusoidal or triangular) wave-like shape mirroring the tapering of the plurality of micropillars (in a row m adjacent to the wall). The membrane formation wall section is especially substantially linear. The membrane formation wall section may in embodiments comprise two parallelly configured (flat or smooth) planes (arranged at opposite sides of the membrane formation section axis). These planes may be curved in embodiments.

[0089] In further embodiments, the channel width in the membrane formation section is constant along the (entire) membrane formation section. The membrane formation wall section may be configured may especially be configured parallel to the membrane formation section axis (Emfs) of elongation. Moreover, a shortest distance between the membrane formation wall section and the membrane formation section axis (Emfs) of elongation may be constant along the membrane formation wall section.

[0090] As described above, the width of the microfluidic channel may vary along the microfluidic channel axis. The width may for instance be a function of the longitudinal position in the bubble trap section as described above. Furthermore, in embodiments the (average) channel width in the bubble trap section may further differ from the (average) width of the channel in the application section. Especially, in embodiments, the average channel width in the bubble trap section may be configured larger than in locations of the channel downstream of the bubble trap section. This may in embodiments result in a reduced flow rate in the bubble trap section relative to the application section, which may help trapping of bubbles in embodiments. Conversely, in further embodiments the channel width at locations upstream of the bubble trap may be larger than the average channel width in the bubble trap section. The channel width at locations upstream of the bubble trap may in embodiments be constant and e.g. be the same as the channel width at the upstream end of the bubble trap section.

[0091] In further specific embodiments a maximal channel width in the membrane formation section may be smaller than a maximal channel width in the bubble trap section. In further embodiments, it may be desired to provide a plurality of (different) liquid flows to the application section. For that, sequentially the plurality of liquids may be provided to the fluid inlet. Yet, it may be in embodiments also be advantageous to have a plurality of microfluidic channels in the same microfluidic device. Any one of the microfluidic channels may in embodiments especially be configured as described above. The microfluidic channels may in embodiments be configured independently from each other. The microfluidic channels may further especially be physically separated from each other. In further embodiments, the microfluidic channels may be fluidically connected to each other. Furthermore, in embodiments at least one of the microfluidic channels may comprise a bubble trap (section) as described herein. Moreover, in embodiments at least two, such as especially all of the microfluidic channels may comprise a (respective bubble trap (section) as described herein.

[0092] Hence, in specific embodiments, the microfluidic device may comprise two microfluidic channels, two fluid inlets, and two fluid outlet, wherein any one of the microfluidic channels is configured to fluidically connect one of the fluid inlets and a respective (one of the) fluid outlet, wherein the microfluidic device further comprises one or more connection channels configured to fluidically connect the microfluidic channels to each other, wherein the one or more connection channels are configured downstream from the respective bubble trap sections.

[0093] The term “microfluidic channel” may therefore in embodiments relate to a plurality of (different) microfluidic channels. As described above, the term may for instance refer to a first microfluidic channel in embodiments. Additionally, or alternatively, the term “microfluidic channel” may refer to a second microfluidic channel and / or a further microfluidic channel.

[0094] In specific embodiments, the microfluidic device may further comprise a membrane formation section configured in one of the microfluidic channels at a location downstream from the respective bubble trap section (and upstream of the respective fluid outlet), especially wherein the membrane formation section has a membrane formation section axis (Emfs) of elongation, wherein the channel wall at the membrane formation section comprises a membrane formation wall section.

[0095] The membrane formation section may further especially be configured as described above in relation to a microfluidic device comprising a single (first) microfluidic channel and further comprising the bubble trap section. The membrane formation section may comprise a plurality of micropillars, wherein each of the plurality of micropillars is configured to extend along the channel height (He); especially wherein the plurality of micropillars are configured in an n*m array parallel to the membrane formation section axis (Emfs) of elongation; wherein n is selected from the range of >1 and m is selected from the range of >2; wherein the n*m array is configured to define (i) n+1 elongated subchannels within the (respective) microfluidic channel and (ii) per row of the n rows m-1 fluidic connection sections; wherein the plurality of micropillars each have a maximum width (Wmax) defined in a direction perpendicular to the membrane formation section axis (Emfs) of elongation; and wherein each of the plurality of micropillars tapers from its maximum width (Wmax) at least in directions parallel to the membrane formation section axis (Emfs) of elongation towards respective adjacent micropillars.

[0096] In further embodiments, the one or more connection channels comprise a first connection channel and a second connection channel; wherein the first connection channel is configured upstream of the membrane formation section; and wherein the second connection channel is configured downstream of the membrane formation section.

[0097] Hence, the invention also provides in embodiments a microfluidic device (especially for the formation of lipid bilayers), wherein the microfluidic device comprises (i) a first fluid inlet, (ii) a first fluid outlet, (iii) a first microfluidic channel configured to fluidically connect the first fluid inlet and the first fluid outlet, (iv) a second fluid inlet, (v) a second fluid outlet, (vi) a second microfluidic channel configured to fluidically connect the second fluid inlet and the second fluid outlet, and (vii) one or more connection channels; wherein (a) each microfluidic channel comprises a channel wall defining a channel height (He); (b) each microfluidic channel comprises a bubble trap section having a bubble trap section axis of elongation; wherein (bi) the channel wall at the bubble trap section comprises a bubble trap wall section (configured in the (respective) microfluidic channel and) extending along the channel height (especially in embodiments along the full channel height), (bii) the bubble trap section comprises a divider wall arrangement, (biii) the divider wall arrangement is configured to divide the (respective) microfluidic channel in the bubble trap section in a first passage and a second passage (especially configured parallel to each other), (biv) the bubble trap wall section and the divider wall arrangement define a primary first passage flow-through area (An) and a secondary first passage flow-through area (A 12) (both) from the first passage, wherein the primary first passage flow-through area (An) is configured upstream of the secondary first passage flow-through area (An), (bv) the bubble trap wall section and the divider wall arrangement (further) define a primary second passage flow-through area (A21) and a secondary second passage flow-through area (A22) (both) from the second passage, wherein the primary second passage flow-through area (A21) is configured upstream of the secondary second passage flow-through area (A22); (c) An, A12, A21, and A22 for any one of the microfluidic channels are (independently from each other) selected such that An>A2i and An <A22; (d) the first microfluidic channel further comprises a membrane formation section at a location downstream from the bubble trap section; (e) the membrane formation section has a membrane formation section axis (Emfs) of elongation; (f) the channel wall at the membrane formation section comprises a membrane formation wall section; (g) the membrane formation section comprises a plurality of micropillars, wherein each of the plurality of micropillars is configured to extend along the (especially full) channel height (He); (h) the plurality of micropillars are configured in an n*m array parallel to the membrane formation section axis (Emfs) of elongation; wherein n is selected from the range of >1 and m is selected from the range of >2; wherein the n*m array is configured to define (hi) n+1 (especially parallelly configured) elongated subchannels within the first microfluidic channel and (hii) per row of the n rows m- 1 fluidic connection sections (especially, wherein adjacent elongated subchannels are configured fluidically connected at the m-1 fluidic connection sections configured between adjacent micropillars); wherein the plurality of micropillars each have a maximum width (Wmax) defined in a direction perpendicular to the membrane formation section axis (Emfs) of elongation (and especially also the channel height He); and wherein each of the plurality of micropillars tapers from its maximum width (Wmax) at least in directions parallel to the membrane formation section axis (Emfs) of elongation towards respective adjacent micropillars; and (j) the one or more connection channels are configured to fluidically connect the second microfluidic channel to the first microfluidic channel at a location downstream from the bubble trap sections.

[0098] In further embodiments, the one or more connection channels comprise a first connection channel and a second connection channel; wherein the first connection channel is configured upstream of the membrane formation section and wherein the second connection channel is configured downstream of the membrane formation section.

[0099] The microfluidic device may in further embodiments comprise the application section in one of the (first and second) microfluidic channels, especially at a location downstream from the respective bubble trap section (and upstream of the respective fluid outlet). In embodiments, for instance, the application section may be configured in the first microfluidic channel at a location downstream from the bubble trap section configured in the first microfluidic channel (which may also be indicated as “at a location downstream from the first bubble trap section”) (and further especially upstream of the first fluid outlet). In embodiments, the microfluidic device may comprise a material selected from the group comprising a glass material and a polymeric material. Especially, in embodiments, the microfluidic device may comprise a polymeric material, such as e.g. selected from the group comprising: polydimethylsiloxane (PDMS), a curable optical adhesive, and epoxy-based negative photoresist such as SU8 polymer. Further, in embodiments, the microfluidic device may comprise a glass material, such as e.g. a quartz (i.e. silica sand), a limestone, a dolomite, borosilicate, glass-ceramics, and recycled glass. The curable optical adhesive may especially comprise 50-70 (wt)% of a Mercaptan ester and 30-50 (wt)% Triallyl Isocyanurate. The curable optical adhesive may, e.g., comprise Norland Optical Adhesive (NOA), especially Norland Optical Adhesive 81.

[0100] The microfluidic device may, in embodiments, consist of essentially one type of material, i.e., the microfluidic device may be monolithic. Alternatively, in embodiments, the microfluidic device may comprise a combination of different materials as herein described. For example, the microfluidic device may comprise both polydimethylsiloxane (PDMS) and a curable (cured) optical adhesive (such as, e.g., Norland Optical Adhesive (NOA)). In another example, the microfluidic device may comprise both borosilicate and a curable (cured) optical adhesive (like Norland Optical Adhesive). Especially, in embodiments, the spacer wall as described above may for example comprise the curable (cured) optical adhesive, whereas the channel bottom section and / or the channel top section may comprise a glass, such as borosilicate.

[0101] In embodiments, the above described structure of the microfluidic device may be provided using a 3D printing technique, such as one or more of the group comprising: two- photon polymerization (2PP), digital light processing (DLP), stereolithography (SLA), fused deposition modelling (FDM), selective laser sintering (SLS), polyjet printing, and inkjet printing.

[0102] Further, in embodiments, the microfluidic device may comprise a light- transmissive material. Especially, in embodiments, the microfluidic device may essentially consist of light-transmissive materials. Such embodiments may be beneficial as the microfluidic device may be applicable in light-based experiments such as e.g. microscopy (confocal, optical tweezers, fluorescent imaging). Further, in embodiments, the microfluidic device may comprise a material that may have a high resistance to common solvents and reagents (e.g. chloroform, hexane, methanol, acetone and aqueous buffers) used for lipid bilayer formation. Such embodiments may be beneficial as the microfluidic device may be applicable for providing a variety of lipid bilayers in a wide range of experimental set-ups. In yet another aspect, the invention may further provide a method for reducing a number of bubbles in a liquid (“bubble reduction method”). The bubble reduction method may in embodiments comprise providing a microfluidic device described herein; and introducing a liquid via the fluid inlet in the microfluidic channel and flowing the liquid (especially comprising one or more bubbles) through one or more of the microfluidic channels (fluidically connected to the fluid inlet). The term “bubbles” especially refers to gas bubbles.

[0103] The term “a liquid” may refer to a plurality of (different) liquids. For instance, in embodiment two or more different liquids may be introduced sequentially in the microfluidic channel. Moreover, in further embodiments the microfluidic device may comprise two microfluidic channels and the same liquid is provided in both microfluidic channels. It will be understood that many different combinations are feasible.

[0104] In embodiments, the microfluidic device comprises the first microfluidic channel, and especially the liquid (such as a first liquid) is introduced in the first microfluidic channel via the first fluid inlet. In further embodiments, the microfluidic device comprises the second microfluidic channel, and especially the liquid (or a further liquid) may be introduced in the second microfluidic channel via the second fluid inlet.

[0105] In embodiments, the microfluidic device, especially the fluid outlet of the microfluidic device may be fluidly connected to a further microfluidic device and a (substantially) bubble free liquid may be provided to (an inlet of) the further microfluidic device. Additionally, or alternatively, the microfluidic device may comprise the application section, and the (substantially) bubble free liquid is provided to the application section.

[0106] The invention may in yet further embodiments provide a method for cell culturing in a microfluidic device (“cell culturing method’). In embodiments, the cell culturing method comprises providing the microfluidic device (described herein) comprising one or more microfluidic channels comprising a (respective) bubble trap section, wherein the microfluidic device further comprises an application section configured at a location downstream from the bubble trap section in the one or more microfluidic channels, wherein the application section comprises a cell culturing section configured. In specific embodiments, the cell culturing method may comprise providing (biological) cell material in one or more of the microfluidic channels in the cell culturing section; and providing a flow of a liquid comprising growth media one or more of the fluid inlets.

[0107] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention will now be described, by way of example only, with reference to the accompanying schematic drawings in which corresponding reference symbols indicate corresponding parts, and in which: Figs 1 schematically depict an embodiment of the microfluidic device of the invention; Figs 2-6 schematically depict some aspects of the invention; Fig. 7 schematically depicts an embodiment of the system of the invention; and Fig. 8 depict some further aspects of the invention The schematic drawings are not necessarily to scale.

[0108] DETAILED DESCRIPTION OF THE EMBODIMENTS

[0109] Figs 1 schematically depict an embodiment of a microfluidic device 100 of the invention. The depicted embodiment may be used for the formation of lipid bilayers. For that the device 100 comprises a membrane formation section 200 described herein as one of the optional applications sections 600. The microfluidic device 100 comprises a microfluidic channel 109. The microfluidic device 100 further comprises a fluid inlet 101 and a fluid outlet 102. The microfluidic channel 109 is configured to fluidically connect the fluid inlet 101 and the fluid outlet 102. The microfluidic channel 109 comprises a channel width Wcand a channel length Lc. The channel length Lc is especially defined from the fluid inlet 101 and to the fluid outlet 102. The channel width Wcmay vary along the channel length Lcas is demonstrated by a smaller channel width Wc at the fluid outlet relative to the channel width Wc at the fluid inlet 101. The depicted embodiment comprises a single microfluidic channel 109, which herein may also be indicated as a first microfluidic channel 110, comprising a first fluid inlet 111 and a first microfluidic outlet 112. In further embodiments the microfluidic device may comprise two microfluidic channels 109, see e.g. Fig. 4. Herein, these two microfluidic channels 109 may (also) be indicated as the first microfluidic channel 110 and a second microfluidic channel 120. Moreover, in embodiments comprising (only) a first microfluidic channel 110, the first microfluidic channel 110 may also be indicated as microfluidic channel 109. Moreover, the terms “first fluid inlet” 111 and “first fluid outlet” 112, may also be used referring the fluid inlet 101 and the fluid outlet 102 respectively of the microfluidic channel 109. Likewise, the second fluid inlet 121 and the second fluid outlet 122 of the second microfluidic channel 120 may also be referred to as fluid inlet 101 and fluid outlet 102 of the microfluidic channel 109 (see e.g. Fig. 4).

[0110] In embodiments, the microfluidic device 100 may thus comprise a fluid inlet 101, a fluid outlet 102, and a microfluidic channel 109 configured to fluidically connect the fluid inlet 101 and the fluid outlet 102. Further, in embodiments, the (first) microfluidic channel 109 (110) may comprise a channel wall 115 defining a channel height (He, seeFig. 1, subfigure II).

[0111] The schematically depicted embodiment in Fig. 1 comprises a bubble trap. Moreover, the microfluidic channel 109 comprises a bubble trap section 300 with a bubble trap section axis Ebt of elongation (herein also indicated as “bubble trap section axis Ebt“). Furthermore, the channel wall 115 at the bubble trap section 300 may comprise a bubble trap wall section as is indicated with reference number 315. The bubble trap wall section 315 may in embodiments extend along the channel height He. The depicted bubble trap section 300 further comprises a divider wall arrangement 310, dividing the microfluidic channel 109 (in the bubble trap section 300) in a first passage 301 and a second passage 302. The passages 301,302 are configured parallel to the divider wall arrangement 310 and especially at opposite sides of the divider wall arrangement 310.

[0112] Herein also the term “bubble trap” may be used refereeing to the bubble trap section 300. The bubble trap 300 is especially configured for trapping bubbles 5 in a flow provided to the fluid inlet 101. The trapping of a bubble 5 may especially be the result of changing sizes of the flow-through area in the respective passages 301,302. The term flow- through area especially refers to an open cross-section in the microfluidic channel 109 through which the fluid may flow. For instance, if no divider wall arrangement 310 would be present in the bubble trap section 300 at a specific longitudinal position, then the flow-through area would be equal to the (inner) cross-section of the microfluidic channel 109 at the specific longitudinal position. In the figure multiple flow-through areas are indicated. These flow- through areas are indicated with the references An, A19, An, A21, A29, and A22. An, A19, A12 refer to a primary first passage flow-through area, a largest intermediate first passage flow- through area, and a secondary first passage flow-through area, respectively; all configured in the first passage 301. A21, A19, and A22 refer to a primary second passage flow-through area, a largest intermediate second passage flow-through area, and a secondary second passage flow- through area, respectively; all configured in the second passage 302. The figure further depicts that the primary first passage flow-through area An is configured upstream of the secondary first passage flow-through area A12, and that the primary second passage flow-through area A21 is configured upstream of the secondary second passage flow-through area A22. Furthermore A19 is configured upstream of A12 and downstream of An, and A29 is configured upstream of A22 and downstream of A21. In the depicted embodiment, An>A2i and An <A22. Moreover, in the depicted embodiment the primary ratio A21 / A11 is about 0.5 and the secondary ratio of Ai2 / A22is about 0.5. Furthermore the intermediate passage flow through areas Ai9,A29 are both larger than the primary passage flow-through areas An, An, and larger than the secondary passage flow-through areas AII,A22 in the respective passages 301,302. Hence, A29 >A2i and A29 > A22, and A19 >An and A19 > A12 in the depicted embodiment. Furthermore, in the embodiment A19 / A29 is larger than 1. Furthermore, in embodiments, a first intermediate ratio A19 / A11 may be selected from the range of 1.5 to 5. Additionally, or alternatively a second intermediate ratio A29 / A21 may in embodiments be selected from the range of 1.5 to 5. Such dimensions may assist in trapping bubbles in the bubble trap 300.

[0113] In Fig. 1, further two opposite wall portions 3151, 3152 of the bubble trap wall section 315 are indicated. The opposite wall portions 3151, 3152 may especially be arranged at opposite sides of the divider wall arrangement 310. In the depicted embodiment, a shortest distance d7 between two opposite wall portions 3151, 3152 of the bubble trap wall section 315 reduces in a direction from the fluid inlet 101 up to a first longitudinal position 316 (see also Fig. 3). The first longitudinal position 316 may in embodiments comprise the primary first passage flow-through area An. The first longitudinal position 316 may in further embodiments comprise the primary second passage flow-through area A21. In the depicted embodiment, the first longitudinal position 316 comprises the primary first passage flow-through area An and the primary second passage flow-through area A21, see also Fig. 3 in which the bubble trap wall section 300 of Fig. 1 is depicted further zoomed in. It is noted that in alternative embodiments the primary second passage flow-through area A21 may be configured closer to the fluid inlet 101 than the primary first passage flow-through area An.

[0114] In these figures, the shortest distance d7 between the two opposite wall portions 3151,3152 further increases (in the bubble trap section 300) in a direction from a second longitudinal position 317 to the fluid outlet 102. The second longitudinal position 317 in the depicted embodiment comprise the secondary first passage flow-through area A12 and the secondary second passage flow-through area A22.

[0115] In embodiments, such as depicted in Fig. 1, the microfluidic channel 109 further comprise a membrane formation section 200 having a membrane formation section axis Emfs of elongation. In embodiments, the channel wall 115 at the membrane formation section 200 may comprise a membrane formation wall section 215. The membrane formation section 200 may, in embodiments (such as highlighted in the cut-out in Fig. 1 and in Fig. 2), comprise a plurality of micropillars 210. Especially, each of the plurality of micropillars 210 may be configured to extend along the (full) channel height He. Especially, the plurality of micropillars 210 may be configured in an n*m array parallel to the membrane formation section axis Emfs of elongation. Especially, n may be selected from the range of >1 (n=2 as depicted in Fig. 1), and m may be selected from the range of >2 (m=15 as depicted in Fig. 1). Further, in embodiments, the n*m array may be configured to define n+1 (parallelly configured) elongated subchannels 110a, 110b, 110c... within the microfluidic channel 109. Additionally, in embodiments, the n*m array may be configured to define per row of the n rows m-1 fluidic connection sections 105. Further, in embodiments, adjacent elongated subchannels 110a, 110b, 110c... may be configured fluidically connected at the m-1 fluidic connection sections 105 configured between adjacent micropillars 210. It is noted that herein, the membrane formation section 200 may in embodiments especially be explained being configured in a first microfluidic channel 110,109.

[0116] As depicted in the cut-out in Fig. 1 and in Fig. 2, in embodiments, the plurality of micropillars 210 each may have a maximum width Wmax defined in a direction perpendicular to the membrane formation section axis Emfs of elongation (and perpendicular to the channel height He). Especially, in embodiments, the maximum width Wmax may be selected from the range of 50-300 pm. Moreover, in embodiments, the micropillars 210 may have a micropillar length Lmdefined parallel to the membrane formation section axis Emfs of elongation. Especially, in embodiments, the micropillar length Lmmay be selected from the range of 50- 1000 pm. Further, in embodiments, each of the plurality of micropillars 210 may taper from its maximum width Wmax at least in directions parallel to the membrane formation section axis Emfs of elongation towards respective adjacent micropillars 210. Especially, as depicted here, one or more of the plurality of micropillars 210 may have a diamond-like cross-sectional shape (in a plane perpendicular to the height He).

[0117] Fig. 1, subfigure II, schematically depicts a side view of the microfluidic device 100 in a cross-sectional plane perpendicular to the membrane formation section axis Emfs of elongation as depicted in Fig. 1, subfigure I. As depicted here, in embodiments, the channel wall 115 may be facetted. Especially, in embodiments, the channel wall 115 may comprise four facets. More especially, in such embodiments, the channel wall 115 may comprise a channel bottom section 140, a channel top section 150, and a spacer wall 160 configured to connect the channel bottom section 140 to the channel top section 150. Hence, in such embodiments, the spacer wall 160 may define the channel height He, especially, the channel height He may be defined between the channel bottom section 140 and the channel top section 150. Furthermore, in such embodiments, (where the microfluidic channel 109 may have a rectangular (or polygonal) cross-sectional shape) the membrane formation wall section 215 may refer to the spacer wall 160 defined along the subchannel length Lsc. Moreover, in such embodiments, the bubble trap wall section 315 may refer to the spacer wall 160 defined in the bubble trap section 300.

[0118] Figs 1 and Fig. 3, further depict that the divider wall arrangement 310 may comprise a fragmented divider wall 310 in embodiments. The fragmented divider wall in these figures comprises an array of four (aligned) subdivider elements 311 (configured parallel to the bubble trap section axis Ebt. The four subdivider elements 311 are mutually separated by three gaps 312 (between the subdivider elements 311). The embodiment thus is an example of a fragmented divider wall comprising an array of k subdivider elements, wherein k = 4. In Fig. 1, subfigure II, also a shortest distance d5 between adjacently configured subdivider elements 311 is indicated. Such shortest distance d5 may herein also be indicated as “gap size” d5. The gap size ds is preferably configured to allow a liquid phase to flow between the two passages 301,302, and to prevent a bubble 5 to move between the passages 301,302. The gap size d5 may in embodiments be in the range of 10 to 150 pm, especially in the range of 50-120 pm.

[0119] Fig. 1, subfigure II, and Fig. 3 further depict subdivider elements 311 having a subdivider length Lsa, especially defined parallel to the bubble trap section axis Ebt of elongation (or parallel to the divider wall arrangement 310). The subdivider length Lsa may in embodiments be selected from the range of 100-3000 pm. The subdivider element 311 may in embodiments further comprise a (maximum) subdivider width d6 configured perpendicular to the subdivider length Lsa (and to the channel height He (or divider wall arrangement height Hsa). The width d6 may in embodiments refer to a maximum width d6, such as in the depicted embodiments, wherein the subdivider elements 311 taper towards their extremes. In the depicted embodiment, adjacently configured subdivider elements 311 have a tapering shape tapering in a direction towards each other. Furthermore in the embodiment (also) the divider wall arrangement 310 has a tapered shape at extremes of the divider wall arrangement 310 (i.e. at an upstream end and at a downstream end of the divider wall arrangement 310.

[0120] Furthermore, as depicted in Fig. 1 (and also in Fig. 4) in embodiments a maximal width of the microfluidic channel 109,110 at the membrane formation section 200 (for instance configured at the upstream end of the membrane formation section 200) may be smaller than a maximal width of the microfluidic channel 109,110 at the bubble trap section 300 (for instance configured at the upstream end of the bubble trap section 300).

[0121] Furthermore, as depicted in Fig. 2, a first distance dl may be defined between the membrane formation wall section 215 at the maximum width Wmax of the micropillars 210 and the membrane formation section axis Emfs of elongation. Conversely, a second distance d2 may be defined between the membrane formation wall section 215 at the fluidic connection sections 105 between the micropillars 210 and the membrane formation section axis Emfs of elongation. Furthermore, a third distance d3 may be defined between the membrane formation wall section 215 at the maximum width Wmax of the micropillars 210 and the micropillars 210 of an adjacent row m of the n*m array. Conversely, a fourth distance d4 may be defined between the membrane formation wall section 215 and the fluidic connection sections 105 between the micropillars 210 of that row m.

[0122] As depicted in Fig. 2, subfigure II, in embodiments, the membrane formation wall section 215 may be configured substantially linear. Hence, in such embodiments, the first distance dl may essentially be equal to both the second distance d2 and the fourth distance d4. Fig. 2, subfigure II, further may also depict an embodiment of the device 100 wherein the membrane formation wall section 215 is configured substantially linear. As is shown in the embodiment with two elongated subchannels 110a, 110b. In other embodiments, such embodiment (wherein the membrane formation wall section 215 substantially linear) the membrane formation section 200 may comprise more than two elongated subchannels 110a, 110b, 110c,....

[0123] Alternatively, in embodiments, such as depicted in Fig. 2, subfigure I, the membrane formation wall section 215 may be configured in a (sinusoidal or triangular) wavelike shape parallel to the membrane formation section axis Emfs of elongation (see subfigure I). Especially, in embodiments as depicted in Fig. 1 and Fig. 2, subfigure I, the membrane formation wall section 215 may be configured in a (sinusoidal or triangular) wave-like shape mirroring the tapering of the plurality of micropillars 210 (in a row m adjacent to the wall 215). Hence, in such embodiments, the first distances dl may be smaller than the second distances d2. Similarly, in such embodiments, the third distances d3 may be smaller than the fourth distances d4.

[0124] Furthermore, in embodiments, the n+1 elongated subchannels 110a, 110b, 110c... may have a subchannel length Lsc defined as the largest distance between the micropillar 210 configured closest to the (first) fluid inlet 101 and the micropillar 210 of the same row m configured closest to the fluid outlet 102.

[0125] Moreover, in embodiments, the microfluidic device 100 may have a height H and a width W defined in a plane perpendicular to the membrane formation section axis Emfs of elongation (i.e. as shown in the figure the dimension extending perpendicularly from the drawing / paper), and a length L defined parallel to the membrane formation section axis Emfs of elongation. Additionally, or alternatively, in embodiments, the microfluidic device 100 may have a height H and a width W defined in a plane perpendicular to the bubble traps section axis Ebt of elongation (i.e. as shown in the figure the dimension extending perpendicularly from the drawing / paper), and a length L defined parallel to the bubble trap section axis Ebt of elongation. Especially, in embodiments, L>2*H and W>2*H.

[0126] In embodiments, the (first) microfluidic channel 109(, 110) may further comprise a (first) bubble trap 300 configured downstream of the (first) fluid inlet 101 (,111) and upstream of the membrane formation section 200, as is for instance depicted in Fig. 1. In that embodiment, the formation section axis Emfs of elongation and the bubble trap section axis Ebt of elongation are aligned. In alternative embodiments the formation section axis Emfs of elongation and the bubble trap section axis Ebt of elongation may be configured at an angle to each other (yet both being configured in the same plane), as is for instance depicted in one of the microfluidic channels 109, i.e. the one indicated with reference 110, in Fig. 4.

[0127] Especially, as depicted in Fig. 3, the divider wall arrangement 310 may be configured parallel to the bubble trap section axis Ebt of elongation and especially the bubble trap section axis Ebt of elongation is configured substantially linear (which may herein also be indicated as the axis of elongation comprises “a straight axis of elongation”). The bubble trap wall section 315 in Fig. 3 comprises protrusions 320 extending in the direction of the divider wall arrangement 310. Moreover, (extremes of) the protrusions 320 in combination with the divider wall arrangement 310 define the primary first passage flow-through area An, the secondary first passage flow-through area An, the primary second passage flow-through area A21 and the secondary second passage flow-through area A22 in the depicted embodiment. Furthermore, Fig. 3 further depicts an embodiment wherein partitions of the bubble trap wall section 315 between the protrusions 320 define the intermediate first passage flow-through area A19 and the intermediate second passage flow-through area A29.

[0128] Moreover, as depicted in Fig. 4, in embodiments, the microfluidic device 100 may further comprise a second fluid inlet 121, a second fluid outlet 122, a second microfluidic channel 120 configured to fluidically connect the second fluid inlet 121 and the second fluid outlet 122, and one or more connection channels 400. In embodiments, the one or more connection channels 400 may be configured to fluidically connect the second microfluidic channel 120 to the first microfluidic channel 110.

[0129] Fig. 4 may at the same time also depict an embodiment comprising two microfluidic channels 109 (also indicated with references 110 and 120, referring to the first microfluidic channel and the second microfluidic channel, respectively), two fluid inlets 101 (also indicated with references 111 and 121 (for the first and second flid inlet, respectively), and two fluid outlets 102 (indicated with references 112 and 122 for the first and second fluid outlet, respectively), wherein any one of the microfluidic channels 109 is configured to fluidically connect one of the fluid inlets 101 and a respective fluid outlet 102, wherein the microfluidic device 100 further comprises one or more connection channels 400 configured to fluidically connect the microfluidic channels 109 to each other, wherein the one or more connection channels 400 are configured downstream from the respective bubble trap sections 300.

[0130] In the depicted embodiment, each microfluidic channel 109 (110,120) comprises a channel wall 115 defining a respective channel height He. Furthermore, each microfluidic channel 109 (110,120) may comprise a respective bubble trap section 300 having a bubble trap section axis Ebti of elongation. It is noted that the respective bubble trap section axes Ebti of elongation may be configured at an angle. Moreover, the bubble trap section axes Ebti of elongation may be configured at an angle with the membrane formation section axis Emf of elongation configured in the same microfluidic channel 109,110 as is depicted in the figure.

[0131] Further, for each of the microfluidic channels 109 (110,120) (i) the channel wall 115 at the bubble trap section 300 may comprise a respective bubble trap wall section 315 extending along the respective channel height He; (ii) the bubble trap section 300 may comprise a respective divider wall arrangement 310 configured to divide the respective microfluidic channel 109 (110, 120) in the bubble trap section 300 in a first passage 301 and a second passage 302; and (iii) the bubble trap wall section 315 and the respective divider wall arrangement 310 may define (a) a respective primary first passage flow-through area An and a respective secondary first passage flow-through area An (in the first passage 301), with the primary first passage flow-through area An being configured upstream of the secondary first passage flow- through area An, and (b) a respective primary second passage flow-through area A21 and a respective secondary second passage flow-through area A22 (in the second passage 301), with the primary second passage flow-through area A21 being configured upstream of the secondary second passage flow-through area A22. In embodiments are the respective An, An, A21, and A22 for any one of the microfluidic channels 109 independently from each other selected such that An>A2i and An<A22. Hence, in embodiment An (as well as An, A21, A19, etc.) of the first microfluidic channel 110 and An(as well as An, A21, A19, etc.) of the second microfluidic channel 120 may have a different value. Hence, each bubble trap section 300 in the respective microfluidic channels 109 may have been configured independently from each other as described in relation to the microfluidic device with a single microfluidic channel 109 (for instance as depicted in Fig. 1). Especially, the one or more connection channels 400 each have (i) a channel axis CA, (ii) a first joint 401 of the respective connection channel 400 and the (first) microfluidic channel 109,110 and (iii) a second joint 402 of the respective connection channel 400 and the second microfluidic channel 109,120. Further, in embodiments, the one or more connection channels 400 each have a total channel length LRC defined along the channel axis CA between (i) the first joint 401 and (ii) the second joint 402. Especially, in embodiments, the total channel length LRC may be selected from the range of 2-50 mm. In further embodiments, the one or more connection channels 400 each have an equivalent cross-sectional circular diameter DRC defined perpendicular to the channel axis CA of the connection channel 400. In embodiments, the equivalent cross-sectional circular diameter DRC may be selected from the range of 50-500 pm.

[0132] In further embodiments, the one or more connection channels 400 may comprise a first connection channel 410 and a second connection channel 420. Especially, in embodiments, the first connection channel 410 may be configured upstream of the membrane formation section 200 (and downstream of the bubble trap 300). Moreover, in embodiments, the second connection channel 420 may be configured downstream of the membrane formation section 200.

[0133] The one or more connection channels 400 may, in embodiments, be configured essentially linear (not depicted). Alternatively, in embodiments, the one or more connection channels 400 may, in embodiments, be configured curved (not depicted). In specific embodiments, such as depicted in Fig. 4, at least one of the one or more connection channels 400 may be configured in a zigzag pattern.

[0134] In further embodiments, the second microfluidic channel 109,120 may comprise a (second) bubble trap section 300 configured downstream of the second fluid inlet 101,121 and upstream of the one or more connection channels 400.

[0135] Yet further, in embodiments, the microfluidic device 100 may further comprise a first exit 10, a second exit 20, and further connection channels 405. In embodiments, the first exit 10 and the second exit 20 may each be configured fluidically connected to the first microfluidic channel 109,110 via the (respective) further connection channels 405.

[0136] It is noted that Fig. 4 depicts an embodiment with two microfluidic channels 109. Yet further microfluidic devices may have more than two microfluidic channels 109.

[0137] The invention further provides a method for reducing the number of bubbles in a liquid (“bubble reduction method”). The bubble reduction method may in embodiments comprise providing the microfluidic device 100 and introducing a liquid 9 via the liquid inlet 101 in the microfluidic channel 109 and flowing the liquid 9 through one or more of the microfluidic channels 109. In this way the liquid 9 flows through the bubble trap section 300 and the one or more bubbles 5 may be trapped in the bubbles trap section 300, especially providing a bubble-free liquid 5 downstream from the bubble trap section 300. The bubble-free liquid may in embodiments successively be directed to an application section 600 in the microfluidic device, such as to a culturing section 700 or a membrane formation section 200, see further Figs. 8.

[0138] In specific embodiments, the invention provides a method for the formation of artificial cell lipid bilayers. Especially, in embodiments, the method may comprise a (first) stage comprising providing organic solvent 1 comprising lipids to the (first) fluid inlet 101 (111) of the microfluidic device 100. Subsequently, in embodiments, the first stage may comprise providing a flow of (first) aqueous phase 2 (optionally comprising microbeads) to the (first) fluid inlet 101 (111) of the microfluidic device 100 to obtain an aqueous phase-organic phase interface 3 (between the organic solvent 1 and the (first) aqueous phase 2), such as depicted in Fig. 5. Further, in embodiments, the method may comprise a second stage comprising applying a pressure to the (first) fluid inlet 101 (111) (at least) until the aqueous phase-organic phase interface 3 may be forced past the membrane formation section 200 via the n+1 elongated subchannels 110a, 110b, 110c.... By forcing the aqueous phase-organic phase interface 3 past the membrane formation section 200 via the n+1 elongated subchannels 110a, 110b, 110c. . ., in embodiments, lipid bilayers (or membranes) 250 may be formed at the fluidic connection sections 105.

[0139] In specific embodiments, the method for the formation of artificial cell lipid bilayers may comprise the bubble reduction method.

[0140] The invention may also provide a use of the microfluidic device 100 for (high- throughput) drug screening.

[0141] Furthermore, in embodiments, the invention provides a method for (high- throughput) active compound screening on artificial lipid bilayers. In embodiments, the method may comprise a first stage comprising providing lipid bilayers 250 in the microfluidic device 100 (by performing the above described method). Especially, in embodiments, the first stage may comprise after providing organic solvent 1 comprising lipids to the (first) fluid inlet 101 (111), providing a flow of first aqueous phase 2 (optionally comprising microbeads) to the (first) fluid inlet 101 (111) to obtain lipid bilayers 250 between the micropillars 210. Additionally, in embodiments, the first stage may comprise providing a flow of second aqueous phase 4 comprising an active compound to the second fluid inlet 121, and halting the flow of second aqueous phase 4 when one of the one or more connection channels 400 (especially the first connection channel 410) may be reached.

[0142] The method may, in embodiments, further comprise a second stage comprising after lipid bilayer formation blocking the second fluid outlet 122, halting the flow of first aqueous phase 2, and restarting the flow of second aqueous phase 4 to the microfluidic device 100 to provide the active compound to the formed lipid bilayers 250 (via the one or more connection channels 400. Yet further, in embodiments, the method may comprise a third stage comprising analyzing the lipid bilayer 250 and / or the active compound (using optical characterization techniques) during the second stage and / or after the second stage.

[0143] Fig. 6 schematically depicts an embodiment of the bubble reduction method. Moreover, the figure may depict an embodiment of the bubble reduction method comprised by method for the formation of artificial cell lipid bilayers and / or comprised by the method for (high-throughput) active compound screening on artificial lipid bilayers described above. In the figure a part of a microfluidic channel 109,110 comprising the bubble trap section 300 is schematically depicted during carrying out the method at three successive moments in time. The initial moment is schematically depicted in microfluidic channel 109,110 indicated with the Roman I, the successive moment in time is schematically depicted in microfluidic channel 109,110 indicated with the Roman II, and the last moment in time is schematically depicted in microfluidic channel 109,110 indicated with the Roman III.

[0144] The figures schematically depicts that before the initial moment (I), an organic solvent 1 (e.g. comprising lipids) comprising microbeads was introduced in the microfluidic channel 109,110 (via the fluid inlet 101,111) and subsequently a flow of aqueous phase 2 was introduced. When changing from the organic solvent 1 supply to the supply of the aqueous phase 2, a bubble 5 may accidentally have been introduced in the microfluidic flow channel 109,110. At the initial moment (I) this results in the presence of the organic solvent 1 (configured furthest upstream), the bubble 5 (configured in the middle), and the aqueous phase 2 (configured furthest downstream), in the microfluidic channel 109, 110 at a location upstream of the bubble trap section 300.

[0145] After continuing the introduction of the aqueous phase 2, the organic solvent 1 flows into the bubble trap 300 through the first passage 301 and the second passage 302 and once the bubble 5 arrives at the bubble trap 300, the bubble 5 will flow into the first passage 301 (having a larger primary flow through area than the second passage 302), whereas the aqueous phase 2 flows into the second passage 302. This is schematically indicated in the microfluidic channel indicated with II. Note that when comparing Fig. 6 with Fig. 1 and Fig. 3, that the flow the passages 301,302 are configured differently.

[0146] A bit later in time, see the figure for the last moment in time (III), the aqueous phase 2 has overtaken the bubble 5 in the bubble trap 300. Successively, the bubble 5 may remain in the bubble trap section 300, and a bubble free liquid is provided at locations downstream of the bubble trap section 300.

[0147] In the depicted embodiment, a bubble is introduced between the provision of the organic solvent 1 and the provision of the aqueous phase 2. Such bubble 5 may easily be introduced when changing the supply to the microfluidic channel 109,110, and may e.g. also be introduced when changing between two aqueous phases 2 or between two organic solvents 1. Moreover also when providing a single liquid 9 to the microfluidic channel 109,110, the liquid 9 may comprise one or more bubbles 5 that preferably are removed. The bubble trap 300 may also be used for this kind (of combinations) of liquids. Having a single liquid 9 instead of different liquids 9 may further help removing bubbles 5. The bubble trap method may in further embodiments also be used for other liquids 9 than depicted in Fig. 6.

[0148] Furthermore, in embodiments, providing organic solvent 1 comprising lipids to the (first) inlet 101 (111) of the microfluidic device 100 may comprise providing a volume X selected from the range of 0.3-100 pL of organic solvent 1 comprising lipids.

[0149] The invention may further provide a kit of parts for the formation of lipid bilayers. In embodiments, the kit of parts may comprise the microfluidic device 100, (one or more syringe pumps), a holder comprising an organic solvent 1 (and optionally comprising lipids), a holder comprising a first aqueous phase 2 (optionally comprising microbeads)(, and optionally a holder comprising a second aqueous phase 4).

[0150] As depicted in Fig. 7, in embodiments, the invention may further provide a system 1000 for performing optical measurements on artificial lipid bilayers. In embodiments, the system 1000 may comprise the microfluidic device 100. Moreover, in embodiments, the system 1000 may comprise a fluid managing device 50. The fluid managing device 50 may especially be fluidically connected with the microfluidic device 100. Especially, in embodiments, the fluid managing device 50 may be configured to provide fluids (such as one or more of the organic solvent 1, the first aqueous phase 2, and the second aqueous phase 4) to the fluid inlet 101, such as to the first fluid inlet 111 and / or second fluid inlet 121, of the microfluidic device 100. Additionally or alternatively, in embodiments, the fluid managing device 50 may be configured to dispose of fluids exiting from one or more of the fluid outlets 102, (e.g., from the first fluid outlet 112 and / or the second fluid outlet 122), the first exit 10, and the second exit 20. Furthermore, in embodiments, the system 1000 may comprise an optical measurement device 500. In embodiments, the optical measurement device 500 may be configured to provide radiation to the microfluidic device 100. Additionally or alternatively, in embodiments, the optical measurement device 500 may be configured to detect radiation emitted from the microfluidic device 100.

[0151] Fig. 8 depicts very schematically some further embodiments of the microfluidic device 100, comprising an application section 600 and / or fluidically connected to a further microfluidic device comprising the application section 600. In the embodiment at the top, Fig.8, subfigure I, the microfluidic device 100 comprises three microfluidic channels 109, each fluidically connecting a respective fluid inlet 101 and fluid outlet 102. Each of the channels 109 comprises a respective bubble trap section 300 configured upstream of the application section 600. In the depicted embodiment, the application section 600 comprises an embodiment of a cell culturing section 700. The three microfluidic channels 109 in the cell culturing section 700 are indicated with the references 701, 702, 703. The two shared channel walls 704 configured between the three channels 701,702,703 in the cell culturing section 700 may, e.g., be configured to stimulate a growth of biological tissue at the walls 704.

[0152] The depicted embodiment of the microfluidic device 100 is an example of a microfluidic device 100 comprising one or more microfluidic channels 109, wherein the application section 600 comprises a cell culturing section 700 configured in the one or more microfluidic channels 109. The embodiment may e.g. be used in the cell culturing method describe herein. In the method, cell material may for instance be provided in one of the microfluidic channels 109 in the culturing section 700, especially the one with reference number 702. Successively a flow of a liquid 9 comprising growth media may be provided in one or more of the fluid inlets 101, especially the fluid inlets 101 through which the growth media may be provided in the cell culturing section 700 to the channels 701 and 703 configured adjacent to the channel 702 comprising the cell material. A such the cells may be cultured.

[0153] In Fig. 8, subfigure II, a further embodiment of a microfluidic device 100 comprising an application section 600 configured in the microfluidic channel 109 at a location downstream from the bubble trap section 300 is depicted. As will be understood, the application section 600 not necessarily needs to be configured in the same microfluidic device 100, which is schematically indicated by the / / breaking the image of the microfluidic channel 109 and by the broken lines around the bubble trap section 300 part and the application section 600 part. Hence, Fig. 8, subfigure II, may also depict an embodiment of the microfluidic device 100 comprising a bubble trap 300 configured fluidically connected to a further microfluidic device comprising an application section. Especially, a fluid outlet 102 of the microfluidic channel 109 may then be fluidically be connected to the further microfluidic device.

[0154] The applications section 600 in the embodiment comprises a microfluidic particle sorting and / or separation section 800. After separation and / or sorting a part of the fluid flow introduced in the inlet 101 of the microfluidic device 100 may be directed to one of the two outlets 102, whereas another part may be directed to the other one of the outlets 102.

[0155] EXPERIMENTS

[0156] A microfluidic device 100 comparable to the embodiment depicted in Fig. 1 was fabricated in house as described in the following materials and method section. Successively, experiments were conducted to validate the bubble trap 300.

[0157] Fabrication of molds for the microfluidic device - Conventional lithography (etching SU-8) was implemented to make a master mold. To make a minor PDMS mold, the following steps were followed: PDMS and its curing agent (SYLGARD 184®) with 10: 1 ratio were well mixed, degassed in vacuum, and then casted on the master mold and degassed again. Afterwards it was cured in an oven at 85°C during 8 hours. Finally, the PDMS was diced out from the master mold and surface silanization (tri-chloro (lH,lH,2H,2H-perfluorooctyl)silane (PFOTS, Sigma-Aldrich)) was performed in a desiccator under vacuum. For the silanization, 50 pL of the silane in a glass tube was connected to the vacuumed chamber with a well-sealed connector for at least 2 hours such that the silane is vaporized and treats the surface of the mold.

[0158] Device fabrication protocol - The microfluidic device was fabricated by casting N0A81 (Norland Products) on the PDMS mold and placing the tip of a custom-made k-type thermocouple from Alumel and Chromel wires (TFAL-003 and TFCY-003, Omega) inside the liquid NOA. Then, a clean glass slide was deposited on top of the liquid NOA. The flow cell was then exposed to UV (Promed UVL-36 with four UV-9W-L bulbs) for 5 minutes. Afterwards, the PDMS minor mold was removed, inlet / outlet ports were drilled, and the channels were closed by bonding a cover slip previously spin-coated with NOA81 (partially UV-cured for 60 seconds). Finally, a 10-minute UV exposition was applied, and the device was then baked for 8 hours on an 85 °C hot plate.

[0159] Validation of the bubble trap - Two types of experiments were performed to validate the bubble trap. In the first experiments trapping of bubbles 5 in the bubble trap section 300 was directly studied by visually observing the flow through the first and second passage 301,302 in the bubble trap section 300. In the next experiments, trapping of bubbles 5 was indirectly studied by studying the effect of the presence of the bubble trap 300 upstream of the membrane formation section 200 on the flow of the fluid through the two elongated subchannels 110a, 110b in the membrane formation section 200 in the fabricated device 100.

[0160] Experiment 1 - Direct study of the capability to trap bubbles.

[0161] To experimentally observe the capability of catching bubbles 5 in the bubble trap 300, an organic liquid 1 was flown through the microfluidic channel 109. Successively, the supply of the organic liquid 1 was stopped and removed from the fluid inlet 109 and replaced by a supply of an aqueous liquid 2. During switching the supply from the organic liquid 1 to the aqueous liquid 2 an amount of gas was introduced in the fluid inlet 101. When flowing the aqueous liquid 2 through the channel, the aqueous liquid 2 advances the organic liquid 1 and in the bubble tap section 300 it is observed that initially organic liquid 1 flows through both passages 301,302 of the bubble trap 300, next it is observed that a bubble 5 is entrapped between the organic liquid 1 and the aqueous liquid 2. When entering the bubble trap 300, the gas bubble 5 flows into the first passage 301 with the larger cross-sectional area, and the aqueous liquid 2 flows into the other passage 302 with the smaller flow through-area. Successively, the bubble 5 remains in the bubble trap 300, whereas the liquid phase 9 continued flowing through the bubble trap 300. During the experiments, the amount of gas introduced between the organic 1 and aqueous liquid 2 has been varied. In some further experiments, some additional gas (bubbles 5) was introduced while flowing the aqueous liquid 2 through the channel 109. Based on the visual observation it was concluded that all gas bubbles 5 were successfully caught in the bubble trap 300. In Fig. 6 trapping of a very large gas bubble 5 is schematically depicted. For other large bubbles it was observed that sometimes a small fraction of the bubble 5 was disconnected from the large bubble 5 and entered the second passage 302 (whereas the remainder of the bubble 5 entered the first passage 301) Also the small fraction did not leave the bubble trap 300 and was caught in the second passage 302.

[0162] Experiment 2 - Indirect study of the capability to trap bubbles.

[0163] Bubbles 5 in a liquid 9 flowing in an application section 600 may result in pressure fluctuations and irregular flow pattern. This may, e.g., in embodiments comprising a membrane formation section 200, result in a disruption of the pressure balance at the fluidic connection sections 105 between the micropillars 210 causing a cross-flow passing through the fluidic connection sections 105. To test the capability of the bubble trap 300 to reduce the number of bubbles 5 in the liquid 9, a liquid 9 (comprising gas bubbles 5) was flown through the membrane formation section 200 of the fabricated microfluidic device 100. As a result of a pressure fluctuation, the velocity of the flow around the fluidic connection sections 105 between the micropillars 210 was analyzed in the fabricated microfluidic device 100. When the pressure is not balanced on either side of the fluidic connection sections 105, a flow can pass through the fluidic connection sections 105. With a balanced pressure, the flow on the midline of the fluidic connection sections 105 is expected to be parallel to the channel 101 orientation, with no significant flow passing through the fluidic connection sections 105.

[0164] To measure the local flow velocities in the fluidic connection sections 105, a polystyrene bead of 2 pm diameter was optically trapped at the center of the fluidic connection sections 105, while liquid 9 was flown through the microfluidic channel 101 from the fluid outlet 102 (for the case with no bubble trap 300) and from the fluid inlet 101 (for the case with the bubble trap 300). While a flow of 2 pL / min was applied with a syringe pump, the displacement of the microbeads from the center of the optical trap was measured for a 6-second period and converted to flow velocity for both cases (N = 3 experiments for each case). Without the bubble trap 300, the velocity perpendicular to the membrane formation axis Emfs of elongation (vy) reached 1216±153 pm / s, which indicated that fluid flows across the fluidic connection sections 105 because of a pressure imbalance between the subchannels in the membrane formation section 200 caused by the presence of bubbles 5 in the device 100. With the bubble trap 300 however, bubbles 5 were trapped upstream in the device 100 and no bubble 5 could reach the membrane formation section 200 to disturb the flow pattern. A significantly lower vyof 16±9 pm / s was found in the case of using a bubble trap 300, which demonstrated that the pressure in the subchannels in the membrane formation section was almost equal. This pressure balance shows the benefits of using the bubble trap 300 for further applications that are sensitive to pressure fluctuations and flow variations in the channel 101.

[0165] The term “plurality” refers to two or more. Furthermore, the terms “a plurality of’ and “a number of’ may be used interchangeably. The terms “substantially” or “essentially” herein, and similar terms, will be understood by the person skilled in the art. The terms “substantially” or “essentially” may also include embodiments with “entirely”, “completely”, “all”, etc. Hence, in embodiments the adjective substantially or essentially may also be removed. Where applicable, the term “substantially” or the term “essentially” may also relate to 90% or higher, such as 95% or higher, especially 99% or higher, even more especially 99.5% or higher, including 100%. Moreover, the terms ’’about” and “approximately” may also relate to 90% or higher, such as 95% or higher, especially 99% or higher, even more especially 99.5% or higher, including 100%. For numerical values it is to be understood that the terms “substantially”, “essentially”, “about”, and “approximately” may also relate to the range of 90% - 110%, such as 95%-105%, especially 99%-l 01% of the values(s) it refers to. The term “comprise” also includes embodiments wherein the term “comprises” means “consists of’. The term “and / or” especially relates to one or more of the items mentioned before and after “and / or”. For instance, a phrase “item 1 and / or item 2” and similar phrases may relate to one or more of item 1 and item 2. The term "comprising" may in an embodiment refer to "consisting of' but may in another embodiment also refer to "containing at least the defined species and optionally one or more other species".

[0166] Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

[0167] The devices, apparatus, or systems may herein amongst others be described during operation. As will be clear to the person skilled in the art, the invention is not limited to methods of operation, or devices, apparatus, or systems in operation.

[0168] The term “further embodiment” and similar terms may refer to an embodiment comprising the features of the previously discussed embodiment, but may also refer to an alternative embodiment.

[0169] It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design many alternative embodiments without departing from the scope of the appended claims.

[0170] In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim.

[0171] Use of the verb "to comprise" and its conjugations does not exclude the presence of elements or steps other than those stated in a claim. Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, “include”, “including”, “contain”, “containing” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0172] The article "a" or "an" preceding an element does not exclude the presence of a plurality of such elements.

[0173] The invention may be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed computer. In a device claim, or an apparatus claim, or a system claim, enumerating several means, several of these means may be embodied by one and the same item of hardware. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0174] The invention also provides a control system that may control the device, apparatus, or system, or that may execute the herein described method or process. Yet further, the invention also provides a computer program product, when running on a computer which is functionally coupled to or comprised by the device, apparatus, or system, controls one or more controllable elements of such device, apparatus, or system.

[0175] The invention further applies to a device, apparatus, or system comprising one or more of the characterizing features described in the description and / or shown in the attached drawings. The invention further pertains to a method or process comprising one or more of the characterizing features described in the description and / or shown in the attached drawings. Moreover, if a method or an embodiment of the method is described being executed in a device, apparatus, or system, it will be understood that the device, apparatus, or system is suitable for or configured for (executing) the method or the embodiment of the method, respectively. The various aspects discussed in this patent can be combined in order to provide additional advantages. Further, the person skilled in the art will understand that embodiments can be combined, and that also more than two embodiments can be combined. Furthermore, some of the features can form the basis for one or more divisional applications.

Claims

CLAIMS:

1. A microfluidic device (100) comprising a fluid inlet (101), a fluid outlet (102), and a microfluidic channel (109) configured to fluidically connect the fluid inlet (101) and the fluid outlet (102), wherein: the microfluidic channel (109) comprises (i) a channel wall (115) defining a channel height (He); the microfluidic channel (109) comprises a bubble trap section (300) having a bubble trap section axis (Ebt) of elongation, wherein the channel wall (115) at the bubble trap section (300) comprises a bubble trap wall section (315) extending along the channel height (He), wherein the bubble trap section (300) comprises a divider wall arrangement (310); wherein the divider wall arrangement (310) is configured to divide the microfluidic channel (109) in the bubble trap section (300) in a first passage (301) and a second passage (302); the bubble trap wall section (315) and the divider wall arrangement (310) define (i) a primary first passage flow-through area (An) and a secondary first passage flow-through area (An) from the first passage (301), wherein the primary first passage flow-through area (An) is configured upstream of the secondary first passage flow-through area (An), and (ii) a primary second passage flow-through area (A21) and a secondary second passage flow-through area (A22) from the second passage (301), wherein the primary second passage flow-through area (A21) is configured upstream of the secondary second passage flow-through area (A22); wherein An>A2i and An<A22.

2. The microfluidic device (100) according to claim 1, wherein a primary ratio A21 / A11 is selected from the range of 0.3-0.8, and wherein a secondary ratio of A12 / A22 is selected from the range of 0.3-0.8, and wherein a distance between the fluid inlet and A21 is equal to or less than the distance between the fluid inlet and An.

3. The microfluidic device (100) according to any one of the preceding claims, wherein the bubble trap wall section (315) and the divider wall arrangement (310) further define (i) a largest intermediate first passage flow-through area (A19) from the first passage (301) configured between the primary first passage flow-through area (An) and the secondary first passage flow-through area (A12), and (ii) a largest intermediate second passage flow-through area (A29) from the second passage (302) configured between the primary second passage flow-through area (A21) and the secondary second passage flow-through area (A22); wherein A29 >A2i and A29 > A22; and wherein A19 >An and A19 > A12.

4. The microfluidic device (100) according to claim 3, wherein a first intermediate ratio A19 / A11 is selected from the range of 1.5 to 5, and wherein a second intermediate ratio A29 / A21 is selected from the range of 1.5 to 5.

5. The microfluidic device (100) according to any one of the preceding claims, wherein a shortest distance (d7) in the bubble trap section (300) between two opposite wall portions (3151, 3152) of the bubble trap wall section (315) is reduced in a direction from the fluid inlet (101) to a first longitudinal position (316), and wherein the shortest distance (d7) in the bubble trap section (300) is increased in a direction from a second longitudinal position (317) to the fluid outlet (102), wherein the first longitudinal position (316) comprises one or more of the primary first passage flow-through area (An) and the primary second passage flow- through area (A2i),and the second longitudinal position (317) comprises one or more of the secondary first passage flow-through area (A12) and the secondary second passage flow- through area (A22).

6. The microfluidic device (100) according to any one of the preceding claims, wherein the divider wall arrangement (310) comprises a fragmented divider wall comprising an array of k subdivider elements (311) configured parallel to the bubble trap section axis (Ebt) of elongation, wherein the subdivider elements (311) are mutually separated by k-1 gaps (312) between the subdivider elements (311), wherein k >2; wherein a shortest distance (d5) between adjacently configured subdivider elements (311) is selected from the range of 50-120 pm.

7. The microfluidic device (100) according to any one of the preceding claims, wherein the divider wall arrangement (310) is configured parallel to the bubble trap section axis (Ebt) of elongation, and wherein the bubble trap wall section (315) comprises protrusions (320) extending in the direction of the divider wall arrangement (310), wherein the protrusions (320) in combination with the divider wall arrangement (310) define the primary first passage flow-through area (An), the secondary first passage flow-through area (A12), the primary second passage flow-through area (A21) and the secondary second passage flow-through area (A22).

8. The microfluidic device (100) according to any one of the preceding claims, wherein the microfluidic channel (109) further comprises a membrane formation section (200) at a location downstream from the bubble trap section (300); wherein the membrane formation section (200) has a membrane formation section axis (Emfs) of elongation, wherein the channel wall (115) at the membrane formation section (200) comprises a membrane formation wall section (215); the membrane formation section (200) comprises a plurality of micropillars (210), wherein each of the plurality of micropillars (210) is configured to extend along the channel height (He); and the plurality of micropillars (210) are configured in an n*m array parallel to the membrane formation section axis (Emfs) of elongation; wherein n is selected from the range of >1 and m is selected from the range of >2; wherein the n*m array is configured to define (i) n+1 elongated subchannels (110a, 110b, 110c. . .) within the microfluidic channel (109) and (ii) per row of the n rows m-1 fluidic connection sections (105); wherein the plurality of micropillars (210) each have a maximum width (Wmax) defined in a direction perpendicular to the membrane formation section axis (Emfs) of elongation; and wherein each of the plurality of micropillars (210) tapers from its maximum width (Wmax) at least in directions parallel to the membrane formation section axis (Emfs) of elongation towards respective adjacent micropillars (210).

9. The microfluidic device (100) according to claim 8, wherein the membrane formation wall section (215) is configured substantially linear.

10. The microfluidic device (100) according to any one of the claims 1-7, comprising two microfluidic channels (109), two fluid inlets (101), and two fluid outlet (102), wherein any one of the microfluidic channels (109) is configured to fluidically connect one of the fluid inlets (101) and a respective fluid outlet (102), wherein the microfluidic device (100) further comprises one or more connection channels (400) configured to fluidically connect the microfluidic channels (109) to each other, wherein the one or more connection channels (400) are configured downstream from the respective bubble trap sections (300).

11. The microfluidic device (100) according to claim 10, further comprising a membrane formation section (200) configured in one of the microfluidic channels (109) at a location downstream from the respective bubble trap section (300); whereinthe membrane formation section (200) has a membrane formation section axis (Emfs) of elongation, wherein the channel wall (115) at the membrane formation section (200) comprises a membrane formation wall section (215); the membrane formation section (200) comprises a plurality of micropillars (210), wherein each of the plurality of micropillars (210) is configured to extend along the channel height (He); the plurality of micropillars (210) are configured in an n*m array parallel to the membrane formation section axis (Emfs) of elongation; wherein n is selected from the range of >1 and m is selected from the range of >2; wherein the n*m array is configured to define (i) n+1 elongated subchannels (110a, 110b, 110c. . .) within the microfluidic channel (109) and (ii) per row of the n rows m-1 fluidic connection sections (105); wherein the plurality of micropillars (210) each have a maximum width (Wmax) defined in a direction perpendicular to the membrane formation section axis (Emfs) of elongation; and wherein each of the plurality of micropillars (210) tapers from its maximum width (Wmax) at least in directions parallel to the membrane formation section axis (Emfs) of elongation towards respective adjacent micropillars (210); and the one or more connection channels (400) comprise a first connection channel (410) and a second connection channel (420); wherein the first connection channel (410) is configured upstream of the membrane formation section (200); and wherein the second connection channel (420) is configured downstream of the membrane formation section (200).

12. The microfluidic device (100) according to any one of the preceding claims 1- 7, further comprising an application section (600) configured in the microfluidic channel (109) at a location downstream from the bubble trap section (300); wherein the application section (600) comprises one or more of a membrane formation section (200), a cell culturing section (700), a microfluidic particle sorting and / or separation section (800), and a cell trapping application.

13. A method for reducing a number of bubbles in a liquid, the method comprises: providing a microfluidic device (100) according to any one of the preceding claims; and introducing a liquid (9) via the fluid inlet (101) in the microfluidic channel (109) and flowing the liquid (9) through the microfluidic channel (109).

14. A method for cell culturing in a microfluidic device, the method comprising: providing the microfluidic device (100) according to claim 12 wherein the microfluidic device (100) comprises one or more microfluidic channels (109), wherein the application section (600) comprises a cell culturing section (700) configured in the one or more microfluidic channels; providing cell material in one or more of the microfluidic channels (109) in the culturing section (700); and providing a flow of a liquid (9) comprising growth media in one or more of the fluid inlets (101).

15. Use of the microfluidic device according to any one of the claims 1-11 for a microfluidic application with a liquid (9), wherein upstream of an application section (600), bubbles (5) in the liquid (9) are trapped in the bubble trap section (300).

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