Bubble deflection within microfluidic channels
By introducing a bubble deflection structure into the microfluidic device, the problem of bubble interference in the bioassay process is solved, and the bubble bypass guidance is realized, ensuring continuous flow of the fluid channel and protection of the analyte.
Patent Information
- Application Number
- CN202510871870.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2024-06-26
- Filing Date
- 2025-06-26
- Publication Date
- 2025-12-26
AI Technical Summary
In microfluidic systems, the presence of foreign objects such as bubbles can interfere with the bioassay process, affecting fluid flow and the displacement of analyte particles. Furthermore, existing technologies struggle to effectively prevent or remove bubbles.
Design a microfluidic device comprising a bubble deflection structure that deflects bubbles within a microfluidic channel, causing them to pass along a bypass path while allowing process fluid to enter the region of interest, thus preventing the bubbles from directly contacting the region of interest.
It effectively prevents bubbles from interfering with the region of interest, ensures continuous flow of process liquid and protection of analytes, avoids blockage and mixing of fluid channels, and achieves the purposeful guidance rather than removal of bubbles.
Smart Images
Figure CN121198370A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to apparatus and methods for improving bioassays by reducing interference caused by foreign objects (such as air bubbles) in microfluidic channels. Background Technology
[0002] Specifically, in bioassays, the presence of foreign objects, such as bubbles, in the liquid environment of microfluidic systems is a well-known and generally undesirable problem. Foreign objects like bubbles can have detrimental effects when they come into contact with certain components at specific points in time. For example, bubbles can disrupt laminar flow under uniform pressure and velocity, reduce the fluid's response time to changes in flow rate due to expansion / diffusion, damage cell membranes, clog channels, displace analyte particles, or concentrate analyte particles at the gas / liquid interface.
[0003] Therefore, while foreign objects (such as air bubbles or other air bubbles) can be harmful to biological processes (e.g., bioassays) in microfluidic systems, the micrometer-scale size of such systems makes the removal of these foreign objects challenging. Thus, despite the challenge, it is generally desirable to avoid such foreign objects, including air bubbles, from the outset, or at least to remove them before they enter the microfluidic system. Solid objects are typically removed by means of filtration systems, such as membrane filters, which are injected at the upstream end of the microfluidic system, i.e., so that foreign objects are removed from the liquid to be filled into the microfluidic system before the liquid enters the microfluidic channel and / or the region of interest (ROI) of such microfluidic channel system.
[0004] The appearance of bubbles can have many different causes, and it is generally desirable to understand the source of such bubbles, as preventing their appearance is often more effective than subsequently removing them. One of the initial challenges when starting a microfluidic process is clearly the complete filling of the system with liquid, i.e., the complete removal of all unwanted gases. Intelligent design of the microfluidic channel system, such as avoiding sharp angles in the microfluidic channels, can help support this initial start-up. However, even during operation, other influences, such as the porosity of the materials used in the setup components, setup leaks, and / or gases dissolved in the process fluid, can cause bubbles to reappear. Various measures, even in combination, such as using process vessel fittings with PTFE seals, degassing the (porous) materials of the process fluid and / or channel setup, and / or even potentially treating the inner surfaces of the microfluidic channels with a soft surfactant before filling the system with the process fluid, can help initially prevent or subsequently remove bubbles. Even temporarily applied pressure pulses can support bubble removal by forcing bubbles to dissolve in the process fluid. Another approach is to integrate a bubble trap into the microfluidic system. These types of bubble traps can utilize a hydrophobic membrane that removes bubbles from the process liquid and prevents leakage of aqueous process liquids. One or more of these measures can be combined depending on the specific process and setup requirements.
[0005] It is evident that, in specific situations, and not all of these measures are equally applicable. For example, while avoiding the introduction of bubbles into microfluidic systems may seem advantageous on the one hand, on the other hand, bubbles have proven to form very effective separators for different liquids in processes requiring switching between them. In cases where a process switches a liquid flow in a microfluidic system from a first type of liquid to a second type of liquid, the liquids typically mix during the transition phase (e.g., through convection and / or diffusion). The longer the channel path and the more complex the geometry of the channel structure, the greater the mixing of the two liquids during the transition phase. This often results in an inherent delay in the switching process conditions at the specific point of interest in the microfluidic channel system.
[0006] Bubbles (such as air bubbles) can serve as effective separators between two liquids, allowing for fairly instantaneous switching between different process conditions (associated with different process liquids) at a specific point of interest in a microfluidic system. In particular, when a process is to switch from flowing a first type of process liquid in a first process stage to flowing a second type of process liquid in a second process stage, bubbles intentionally introduced at the end of the first stage of the process, along with the subsequent second process liquid, can help prevent mixing of the first and second process liquids. Since the gas is unlikely to mix with the process liquid, depending on the channel structure and the surface tension of the process liquid at the bubble boundary, the bubble can act as a fairly stable separator between the two types of liquids as it travels through the microfluidic channel structure. This example demonstrates, and not all known techniques for preventing or removing bubbles are applicable to all situations. Summary of the Invention
[0007] Therefore, a specific technical problem of the present invention is to prevent foreign objects from having undesirable effects on specific regions of interest in microfluidic channel systems, particularly for bioassays.
[0008] This problem is solved by the invention as defined in the independent claims. Preferred embodiments are defined in the dependent claims.
[0009] Therefore, in one aspect, a microfluidic device (particularly suitable for bioassays) is proposed, comprising a microfluidic channel for guiding a process fluid from a fluid inlet (on the upstream side of the microfluidic channel) to a fluid outlet (on the downstream side of the microfluidic channel) via at least one region of interest within the microfluidic channel suitable for bioassays, in the direction of fluid flow. The region of interest can be considered as a volume within the microfluidic channel, separated from at least one sidewall of the microfluidic channel by a bubble deflection path, and is intended and suitable for bioassays in an environment provided by a process fluid. While the microfluidic channel may have a dedicated fluid inlet and a dedicated fluid outlet, thus having a dedicated direction of fluid flow, the fluid inlet and outlet may also vary their function depending on (switchable) operating modes. Therefore, the microfluidic channel can be a bidirectional channel that allows switching of the direction of fluid flow.
[0010] According to the invention, the microfluidic device further includes a bubble deflection structure (bubble deflector) arranged in a microfluidic channel and adapted to deflect bubbles entering the microfluidic channel via a fluid inlet, such that the bubbles are guided through the microfluidic channel along at least one bubble path formed outside the region of interest while allowing process liquid entering the microfluidic channel via the fluid inlet to flow through the region of interest.
[0011] In other words, at least when bubbles reach the bubble deflector from the fluid inlet side of the microfluidic channel, the bubble deflection structure is fairly permeable to the process liquid but impermeable to the bubbles. Therefore, when the process liquid penetrates the bubble deflection structure and flows at least partially through the region of interest, the bubbles entering the microfluidic channel are deflected within the channel, guiding them along their bubble path around the region of interest to pass through the microfluidic channel without disturbing the region of interest. The bubble deflection structure forms a protective barrier around the region of interest. This prevents gas from reaching the region of interest and prevents the process liquid from shifting away from it. This ensures that gas-sensitive materials located and / or fixed in the region of interest are protected from drying out and / or from the adverse effects of direct contact with gas. Because the bubble deflection structure forms a liquid-permeable protective barrier, rather than a solid impermeable wall, it has no direct effect or only minimal direct effect on the flow characteristics of the process liquid. Specifically, at least in the absence of bubbles, the flow of the process liquid can be maintained (to a large extent) laminar over a wide range of relevant flow rates.
[0012] Therefore, this invention provides a solution to prevent large objects, which may be bubbles, from contacting a defined area within a fluid channel without obstructing continuous flow and avoiding the need to completely remove all air from the system. A significant difference from existing degassing / venting and bubble trap strategies is that this invention generally does not remove air from the liquid, but rather prevents air from contacting certain areas of interest (ROI). It does not remove air, but rather guides it. This is advantageous if air should be retained in the system, for example, for targeted liquid separation. Therefore, this invention is superior to many conventional solutions that attempt to prevent gas / air from entering microfluidic systems.
[0013] The region of interest is preferably suited to contain and / or fix microscopic and / or nanoscale substances and / or objects to be treated and / or examined. Examples of substances and / or objects of interest include molecules and / or molecular layers and / or bacteria and / or cells. Substances and / or objects of interest can be fixed at the region of interest in various ways, including, for example, object traps like (partially open) cages and / or adhesive surface coatings of the region of interest.
[0014] At the region of interest, the bubble deflection structure divides the cross-section of the microfluidic channel into at least two distinct sub-segments, comprising a protected segment and a bypass segment. While the protected segment includes the region of interest, the bypass segment serves as a bubble path to guide the bubble through the microfluidic channel outside the region of interest.
[0015] To achieve a semi-permeable function with the permeability of one or more process liquids and bubble deflection properties, the bubble deflection structure may include multiple liquid inlet windows that allow process liquid from a fluid inlet in the microfluidic channel to reach the region of interest, wherein the cross-section of the liquid inlet windows is smaller than the cross-section of at least one bubble path. Thus, bubbles can more easily enter the region of interest by passing through the microfluidic channel via a bubble path outside the region of interest than by passing through the liquid inlet windows. Specifically, the cross-section of each liquid inlet window transverse to the fluid flow direction is less than 20% of the cross-section of the bubble path (bypass), preferably less than 10%, more preferably less than 5%, even more preferably less than 2%, and most preferably less than 1%, as it is located adjacent to the region of interest transverse to the fluid flow direction.
[0016] In a particularly preferred embodiment, the liquid inlet window may have a cross-section that allows analyte particles (e.g., molecules, viruses, bacteria, cells) with a diameter not greater than a predetermined particle pathway diameter in the range of at least about 10 nm, preferably at least about 100 nm, and more preferably at least about 1 μm. This means that particles with a diameter corresponding to or smaller than the predetermined particle pathway diameter of the liquid inlet window can pass through the liquid inlet window, while larger particles may be blocked / deflected. Therefore, the particle pathway diameter is a characteristic of the size (and / or shape) of the liquid inlet window that defines the maximum diameter of particles that can pass through the liquid inlet window. The specific size of the liquid inlet window can be selected depending on the desired analyte used in the region of interest. For example, for molecular analytes, the liquid inlet window may allow particles with diameters up to about 10 nm, about 20 nm, or about 50 nm to pass through. For bacteria as an analyte, the liquid inlet window may allow particles with diameters up to about 100 nm, about 200 nm, or about 500 nm to pass through. For cells as an analyte, the liquid inlet window may allow particles with diameters up to about 1 μm, about 2 μm, or about 5 μm to pass through.
[0017] Preferably, the inlet window is small enough that the bubble deflection structure prevents objects with a diameter of about 100 μm or larger, preferably about 50 μm or larger, more preferably about 20 μm or larger, even more preferably about 10 μm, and specifically preferably about 1 μm or larger, from entering the liquid inlet window. This effectively prevents the relevant bubbles from reaching the region of interest. Also in this respect, the specific size of the liquid inlet window can be selected depending on the desired analyte to be used in the region of interest. For example, in the case of molecules as the analyte, the size of the liquid inlet window can be chosen to be smaller, thereby preventing bubbles smaller than those in the case of cells as the analyte from reaching the region of interest.
[0018] In a preferred embodiment, the microfluidic channel specifically has a cross-section transverse to the (primary) fluid flow direction at at least one region of interest, such that it supports a volumetric flow rate of at least about 20 μl / min, more specifically at least about 40 μl / min, preferably in the range of about 40 μl / min to about 3.5 ml / min, more preferably in the range of about 100 μl / min to about 2 ml / min, particularly when a fluid velocity according to one of the following preferred values is applied. Specifically, in this case, the fluid velocity at the region of interest can be at least about 1 mm / s, preferably at least about 5 mm / s, more preferably at least about 10 mm / s, even more preferably at least about 50 mm / s, most preferably at least about 0.1 m / s, or even at least at least about 0.5 m / s. Preferably, the fluid velocity at the region of interest is specifically set to a value in the range of about 0.07 to about 0.74 m / s. Specifically, the microfluidic channel preferably has a cross-section of about 0.2-10 m / s. 4 μm 2 Approximately 20.10 4 μm 2 Within that range, more specifically in the range of approximately 1.10 4 μm 2 To approximately 5.10 4 μm 2 The cross section transverse to the direction of fluid flow within the range.
[0019] In this paper, the term "volumetric flow rate" is defined as the volume of fluid passing through the microfluidic channel containing the region of interest per unit time. Furthermore, the term "fluid velocity" (or "fluid velocity") is defined as the instantaneous velocity of the fluid element at a given location.
[0020] Preferably, the bubble deflection structure may include at least one gas escaping opening toward the fluid outlet, i.e., toward the downstream direction of the microfluidic channel. Specifically, the gas escaping opening (one or more) may be larger than the liquid inlet window. For example, the cross-section of the gas escaping opening may be at least about 25%, preferably at least about 50%, and more preferably at least about 75%, of the maximum cross-section of the bubble deflection structure transverse to the fluid flow direction. When the microfluidic device is initially filled before analysis begins, the gas escaping opening supports the removal of gas from the region of interest. Therefore, the asymmetric structure of the bubble deflection structure relative to the upstream and downstream directions supports the removal of gas from the region of interest (e.g., when setting up the system initially) and prevents gas from entering the region of interest during operation of the microfluidic device.
[0021] In a preferred embodiment, the bubble deflection structure has a pointed shape facing upstream toward the fluid inlet of the microfluidic channel. The pointed shape of the bubble deflection structure enhances the splitting of incoming (large) bubbles into smaller bubbles. This enhances the smooth deflection of the bubbles and allows them to pass along one side of the region of interest but outside of it. The bubble deflection structure can narrow the effective channel width through which bubbles pass. As larger bubbles are broken down into smaller bubbles, the risk of large bubbles temporarily blocking the bubble path and / or the pressure drop along the bubble path can be reduced. This can improve the continuous (preferably laminar) flow of the process fluid even in / through the region of interest.
[0022] Preferably, the bubble deflection structure can, alone or in cooperation with one or more walls (structural and functional) of the microfluidic channel, encompass a convex space that completely contains at least one region of interest. In other words, preferably, the bubble deflection structure extends from an upstream position relative to the region of interest to a downstream position relative to the region of interest. In this respect, the bubble deflection structure can (continuously) deflect and guide bubbles from a position upstream of the region of interest (i.e., closer to the fluid inlet) to a position downstream of the region of interest (i.e., closer to the fluid outlet).
[0023] Therefore, the bubble deflection structure preferably not only protects the region of interest from bubbles arriving directly from the upstream side, but also prevents bubbles guided in the bypass along one side of the region of interest from interfering with the material located at and / or the process performed at the region of interest, until the bubbles have completely passed through the region of interest, i.e., until the bubbles leave the bypass at a location further downstream than the region of interest. Once the bubbles have passed through the bubble deflection structure, they can expand and / or move over the entire cross-section of the microfluidic channel.
[0024] Preferably, a bubble path (bypass) is formed between at least one wall of the bubble deflection structure and the microfluidic channel. Alternatively or additionally, the microfluidic device may have a first bubble deflection structure and a second bubble deflection structure, each protecting at least one region of interest, wherein a bubble path is formed between the first bubble deflection structure and the second bubble deflection structure.
[0025] In a preferred embodiment, the bubble deflection structure may include a plurality of substantially parallel pillars, each pillar being attached at its opposite ends to the opposing inner surface of the microfluidic channel. Preferably, these pillars form a fence-like structure to protect the region of interest from bubble interference. The pillars may be formed individually or may be connected to each other via connecting elements to form a network. The plurality of pillars may have substantially constant and / or identical diameters. Alternatively, the diameter of each pillar may vary over its length, for example having a larger diameter / cross-section near the connection point with the corresponding wall of the microfluidic channel. Alternatively or additionally, the bubble deflection structure may include a plurality of raised / pyramidal elements and / or hourglass-shaped elements. In yet another embodiment, the bubble deflection structure may include a continuous wall with an opening to form a liquid inlet window.
[0026] In one embodiment, the bubble deflection structure is attached at one end (segment) (e.g., the lower end) to the inner surface of a first fluid channel wall, such as the bottom wall (base wall), and at the other end (segment) (e.g., the upper end) to the inner surface of a second fluid channel wall, such as the top wall (cap) of a microfluidic channel substantially opposite the first fluid channel wall. Thus, each segment of the bubble deflection structure at its opposite ends can be stably held on the opposite wall of the microfluidic channel, thereby ensuring high stability of the entire bubble deflection structure even under high-velocity fluid flow conditions.
[0027] Preferably, the bubble deflection structure can be compressed between the inner surfaces of the first microfluidic channel wall and the second microfluidic channel wall. Specifically, before assembling the opposing microfluidic channel walls, the bubble deflection structure can initially be manufactured to have a height greater than the height of the microfluidic channel (i.e., the distance between the first and second microfluidic channel walls), such that the bubble deflection structure is sandwiched between these channel walls (e.g., the bottom and top surfaces of the channel). Specifically, the height of the bubble deflection structure can initially be 10% to 30% greater than the height of the microfluidic channel.
[0028] Preferably, the microfluidic channel has a substantially rectangular cross-section transverse to the (primary) fluid flow direction. In this regard, the preferred value for the height of the microfluidic channel ranges from about 20 μm to about 100 μm, and more preferably from about 30 μm to about 75 μm. Furthermore, the preferred value for the width of the microfluidic channel ranges from about 200 μm to about 1000 μm.
[0029] The bubble deflection structure used in this invention can be fabricated by photolithography or etching to place micron-sized structures on microfluidic channels. To allow for fine shapes at the nanometer to micrometer scale, a barrier can be created within the microfluidic system using two-photon polymerization (2PP) technology. This barrier allows unobstructed flow of liquid but retains and guides larger objects, such as gas / air bubbles, through a protected region of interest (ROI). Specifically, photonic-excited polymerization, such as two-photon polymerization (2PP), can be employed, as is known in the art. Therefore, the material of the structure can be made of or may include suitable photopolymers, such as negative IP-Dip or IP-Visio photopolymers, SU8, positive photopolymers, and / or hydrogels.
[0030] The bottom surface of the microfluidic channel used in this invention, i.e., the surface on which the bubble deflection structure can be adhered, is not particularly limited and can include any surface on which the corresponding structure can be fabricated by 2PP. Suitable materials in this regard include glass, silicon, metals (e.g., gold and / or chromium), ceramics, and / or polymers such as polydimethylsiloxane (PDMS), polypropylene (PP), and / or SU8. In a preferred embodiment, the bottom surface of the microfluidic channel and / or the top surface of the channel are made of an optically transparent material (e.g., glass) to allow microscopic (e.g., fluorescence microscopy) observation and / or analysis of the substance / object of interest within the region of interest.
[0031] In one aspect, the invention also relates to the use of the microfluidic device according to the invention, particularly when implemented in a medium embodiment of the preferred embodiments described herein, for bioassays, wherein a process fluid flows through a microfluidic channel from a fluid inlet to a fluid outlet. (Bio)substances / objects can be positioned / fixed in the region of interest for analysis, preferably under fluid flow conditions. A bubble deflection structure thereby protects the substance / object of interest from undesirable interference from bubbles that may intentionally or unintentionally enter the microfluidic device.
[0032] Specifically, for bioassay purposes, but not limited thereto, the present invention also provides a method of operating a microfluidic device according to the invention, particularly when implemented in one of the preferred embodiments described herein. This method of operation allows the process fluid to flow from a fluid inlet through a microfluidic channel to a fluid outlet. At least under these operating conditions, the bubble deflection structure can effectively protect the region of interest from interference by bubbles that may or may not have entered the microfluidic device intentionally or unintentionally.
[0033] Specifically, to analyze a substance or object of interest under fluid flow conditions, the method of operation may include fixing the substance or object of interest in a region of interest. In a preferred embodiment, the method may include filling a microfluidic channel (including the region of interest) of a microfluidic device with a first process fluid; and injecting gas (i.e., bubbles) and subsequently a second process fluid into the microfluidic channel via a fluid inlet, thereby replacing the first process fluid in the microfluidic channel with the second process fluid. Specifically, the gas (bubble) may separate the second process fluid from the first process fluid in the microfluidic channel in portions other than the bubble deflection structure. In this case, it is desirable to inject sufficiently large bubbles to fill the entire cross-section of the microfluidic channel in sections remote from the bubble deflection structure. This ensures effective separation of the first and second process fluids to avoid or reduce mixing of process fluids in portions of the microfluidic device other than the bubble deflection structure, particularly at least in those portions upstream of the bubble deflection structure. Attached Figure Description
[0034] Further details and advantages of preferred embodiments of the invention will be described with reference to the accompanying drawings, in which:
[0035] Figure 1A This is a schematic top view of a microfluidic device with a bubble deflection structure according to a preferred embodiment of the present invention;
[0036] Figure 1B yes Figure 1A A schematic side view of a microfluidic device;
[0037] Figure 2 This is a schematic top view of a microfluidic device with a bubble deflection structure according to another preferred embodiment of the present invention;
[0038] Figure 3 This is a schematic top view of a microfluidic device with a bubble deflection structure according to another preferred embodiment of the present invention;
[0039] Figure 4 This is an example of the possible arrangement of bubble deflection structures in a top view drawn to scale in an exemplary embodiment of the present invention;
[0040] Figure 5 This is a microscopic snapshot of a microfluidic device in a top view during gas injection during the transition from the first process liquid to the second process liquid; and
[0041] Figure 6 It is a sequence of 12 microscopic snapshots in a top view of a microfluidic device during the transition from a first process liquid to a second process liquid, which is separated from the first process liquid by intentionally injected bubbles. Detailed Implementation
[0042] Gases such as air (bubbles) can be used in microfluidic systems to effectively separate different aqueous solutions or other process liquids, producing a rapid transition from one process liquid to another. This invention describes a solution for preventing large objects, which may be bubbles, from contacting a defined area within a fluid channel without obstructing continuous flow and avoiding the need to completely remove all gas / air from the system.
[0043] Figure 1A This is a schematic top view of a microfluidic device 1 with a microfluidic channel according to a preferred embodiment of the invention, the microfluidic channel having a bubble deflection structure 10. In this embodiment, the microfluidic channel has a substantially rectangular cross-section and a channel width w between two sidewalls 28. A region of interest 16 is arranged in the microfluidic channel, in this case substantially in the middle of the microfluidic channel in the width direction. For example, during bioassays under flow conditions, the region of interest 16 may be an analyte (such as a spectroscopic object) of interest fixed in the region of interest. For this purpose, the microfluidic channel supports the flow of process liquid within the microfluidic channel along the fluid flow direction F from the fluid inlet to the fluid outlet of the microfluidic channel.
[0044] like Figure 1A As shown, in this preferred embodiment, the bubble deflection structure 10 comprises a plurality of pillars 12 forming a fence structure surrounding the region of interest 16, and leaving a bypass between the bubble deflection structure 10 and each of the sidewalls 28 of the microfluidic channel. This fence structure formed by the pillars 12 of the bubble deflection structure 10 deflects bubbles 20 entering the microfluidic channel via a fluid inlet, such that the bubbles 20 are guided through the microfluidic channel along at least one bubble path 22 formed as a bypass outside the region of interest 16. Windows / openings 18 formed in the bubble deflection structure between the pillars 12 allow process fluid entering the microfluidic channel via the fluid inlet to flow into the fence structure and through the region of interest 16. Specifically, while some windows 18 formed on the upstream side of the bubble deflection structure serve as liquid inlet windows allowing process fluid to enter the inner region of the fence structure, other windows 18 formed on the downstream side of the bubble deflection structure 10 serve as liquid outlet windows allowing process fluid to exit the inner region of the fence structure (where the region of interest 16 is located).
[0045] exist Figure 1A In the preferred embodiment shown, the bubble deflection structure has a fluid inlet facing the microfluidic channel, i.e., facing upstream. Figure 1AThe pointed shape 30 (on the left side of the bubble deflection structure 10). This pointed shape 30, formed by the apex of the bubble deflection structure 10 facing the inlet, can enhance the splitting of incoming (large) bubbles into smaller bubbles. This can enhance the smooth deflection of bubbles and allow bubbles to pass along one or both sides of the region of interest in the corresponding bypass formed between the bubble deflection structure 10 and the sidewall 28. Since these bypasses are narrower than the channel width w, the splitting of larger bubbles into smaller bubbles enhances the smooth deflection of bubbles to guide them along the bubble path 22 and reduces the risk of large bubbles temporarily blocking the bubble path. This can improve the continuous (preferably laminar) flow of the process liquid even in / through the region of interest 16.
[0046] Figure 1B It shows Figure 1A A schematic side view of a microfluidic device. Figure 1B As can be seen, in this preferred embodiment, a plurality of substantially parallel pillars are each attached at their opposite ends to the opposing inner surfaces of a substantially rectangular microfluidic channel having a channel height h. Specifically, pillars 12 are attached at one end (lower end) to the inner surface of the base wall 24 (base wall) and at their respective other ends (upper ends) to the inner surface of the top wall 26 (cap) of the microfluidic channel. Thus, each end of the bubble deflection structure can be stably held at the opposing wall of the microfluidic channel, thereby ensuring high stability of the entire bubble deflection structure 10 even under high-velocity fluid flow conditions.
[0047] Figure 2 A schematic top view of a microfluidic device 1 with a bubble deflection structure 10 according to another preferred embodiment of the invention is shown. In this exemplary embodiment, the region of interest 16 is located away from the center of the microfluidic channel in the width direction. Similarly, the bubble deflection structure 10 is positioned away from this center. In particular, in this embodiment, the bubble deflection structure 10 is arranged at one sidewall 28 of the microfluidic channel. Furthermore, the bubble deflection structure 10 structurally and functionally cooperates with said sidewall 28 to deflect bubbles 20, guide them along bubble paths 22, and prevent them from interfering with the region of interest 16. Similar to the embodiment in FIG1, process fluid is allowed to enter the internal region of the bubble deflection structure 10, and thus into the region of interest 16. Figure 2 The embodiments do not provide bubble splitting functionality.
[0048] Figure 3 A schematic top view of a microfluidic device 1 with a bubble deflection structure 10 according to another preferred embodiment of the present invention is shown. This embodiment is again quite similar to the embodiment in FIG1 regarding the region of interest and the placement of the bubble deflection structure. Therefore, for further details, please refer to the above. Figure 1A and Figure 1B The description.
[0049] However, in this embodiment, the bubble deflection structure 10 includes a gas escape opening 32 facing the fluid outlet, i.e., facing downstream of the microfluidic channel. Figure 3 (Right side of the image). When the microfluidic device 1 is initially filled before analysis begins, the gas escaping opening 32 supports the removal of gas from the region of interest 16 and prevents gas from entering the region of interest 16 during operation with the microfluidic device 1 flowing in the direction F.
[0050] In all embodiments shown in the figures, the bubble deflection structure 10 extends from an upstream position relative to the region of interest 16 to a downstream position relative to the region of interest 16. Therefore, the bubble deflection structure 10 deflects incoming bubbles 20, preventing them from directly reaching the region of interest 16 from the upstream side of the microfluidic channel. Furthermore, utilizing this preferred geometry, the bubble deflection structure 10 guides the bubbles 20 around the region of interest 16, at least until they reach a position further downstream than the region of interest 16. This reduces the risk that bubbles may interfere with the region of interest.
[0051] Figure 4 An example of a possible arrangement of bubble deflection structures is shown in a scaled top view according to an exemplary embodiment of the invention. In this embodiment, the bubble deflection structures cover two regions of interest. Figure 4 The fluid inlet in the middle faces to the right. Figure 5 It corresponds to Figure 4 A top-view microscopic snapshot of the microfluidic device during gas injection during the transition from the first process liquid to the second process liquid.
[0052] In more detail, this specific embodiment is characterized by a pointed design towards the incoming fluid flow and a more rounded design towards the outlet. This design enhances the breaking up of large bubbles injected into the microfluidic channel and allows them to glide through the protected area in a continuous buffered flow. The gaps (windows) between the columns are large enough to allow unobstructed laminar flow within the protected structure, i.e., in the region of interest, and the entry of smaller objects below 30-50 μm. The higher pressure on the bubbles passing between the structure and the channel sidewalls necessitates closer proximity between the columns to prevent air ingress. Once past the region of interest, the bubbles can re-inflate to fill the entire channel and are flushed away by a continuous high-pressure buffered flow. Figure 6 The snapshot sequence shows the entire process of injecting bubbles to separate the first process liquid from the second process liquid, but with the overall fluid flow direction from left to right. Figure 6 Snapshot "5" in the snapshot sequence basically corresponds to Figure 5 The situation in the middle.
[0053] In summary, this invention achieves a rapid transition between different liquids in a microfluidic system through gas separation, without the harmful effects of gas on a specific ROI. Various techniques, including those used for cell sorting, characterization, and culture, are being used in microfluidic systems with potential applications of this invention.
[0054] Figure label:
[0055] 1. Microfluidic devices
[0056] 10. Bubble deflection structure
[0057] 12 columns
[0058] 16 Areas of Interest
[0059] 18 windows / openings
[0060] 20 bubbles
[0061] 22. Bubble Path
[0062] 24 base wall / base wall
[0063] 26 Top Wall / Cover
[0064] 28 sidewalls
[0065] 30-pointed structure / bubble separator
[0066] 32 Gas Escape Opening
[0067] F. Fluid flow direction
[0068] h Channel height
[0069] w Channel width
Claims
1. A microfluidic device (1) for bioassay, comprising: A microfluidic channel for guiding process fluid from a fluid inlet to a fluid outlet of the microfluidic channel via at least one region of interest (16) within the microfluidic channel for bioassay in the fluid flow direction (F); A bubble deflection structure (10) is arranged in the microfluidic channel and adapted to deflect bubbles (20) entering the microfluidic channel via the fluid inlet, such that, while allowing process liquid to flow through the microfluidic channel via the fluid inlet through the region of interest (16), the bubbles (20) are guided through the microfluidic channel along at least one bubble path (22) formed outside the region of interest (16).
2. The microfluidic device (1) according to claim 1, wherein the microfluidic device is used for bioassay of micro and / or nanoscale substances and / or objects to be treated and / or examined, wherein the microfluidic channel includes at least one region of interest (16) adapted to contain and / or immobilize the micro and / or nanoscale substances and / or objects to be treated and / or examined.
3. The microfluidic device (1) according to claim 2, wherein the at least one region of interest is adapted to contain and / or immobilize molecules and / or molecular layers and / or bacteria and / or cells.
4. The microfluidic device (1) according to claim 2, wherein the at least one region of interest is adapted to contain and / or immobilize micro and / or nanoscale materials and / or objects by means of an object trap and / or an adhesive surface coating.
5. The microfluidic device (1) according to any one of the preceding claims, wherein the bubble deflection structure (10) includes a plurality of liquid inlet windows (18) for allowing process liquid from the fluid inlet of the microfluidic channel to reach the region of interest (16), wherein the cross-section of the liquid inlet window (18) is smaller than the cross-section of the at least one bubble path (22).
6. The microfluidic device (1) according to claim 5, wherein the liquid inlet window (18) has a cross-section that allows analyte particles with a diameter not greater than a predetermined particle passage diameter to pass through, the predetermined particle passage diameter being in the range of at least about 10 nm, preferably at least about 100 nm, more preferably at least about 1 μm.
7. The microfluidic device (1) according to claim 5 or 6, wherein the inlet window (18) is small enough that the bubble deflection structure (10) prevents objects with a diameter of about 100 μm or larger, preferably about 50 μm or larger, more preferably about 20 μm or larger, even more preferably about 10 μm or larger, and most preferably about 1 μm or larger from entering the liquid inlet window (18).
8. The microfluidic device (1) according to any one of the preceding claims, wherein the microfluidic channel has a cross-section transverse to the fluid flow direction (F), the cross-section being approximately 0.2-10 mm in diameter. 4 μm 2 Approximately 20.10 4 μm 2 Within that range, more specifically in the range of approximately 1.10 4 μm 2 To approximately 5.10 4 μm 2 Within the range.
9. The microfluidic device (1) according to any one of the preceding claims, wherein the bubble deflection structure (10) includes at least one gas escaping opening toward the fluid outlet.
10. The microfluidic device (1) according to any one of the preceding claims, wherein the bubble deflection structure (10) has a pointed shape (30) facing the fluid inlet.
11. The microfluidic device (1) according to any one of the preceding claims, wherein the bubble deflection structure covers a convex space that completely encompasses the at least one region of interest.
12. The microfluidic device (1) according to any one of the preceding claims, wherein the bubble path (22) is formed between the bubble deflection structure (10) and at least one wall (28) of the microfluidic channel.
13. The microfluidic device (1) according to any one of the preceding claims, wherein the bubble deflection structure (10) comprises a plurality of substantially parallel pillars (12), each pillar being attached to an opposing inner surface of the microfluidic channel.
14. Use of a microfluidic device according to any one of claims 1 to 13 for bioassay.
15. A method of operating a microfluidic device according to any one of claims 1 to 13, comprising: The process fluid is allowed to pass from the fluid inlet through the microfluidic channel to the fluid outlet.
16. The method of claim 15, comprising: The microfluidic channels of the microfluidic device (1) are submerged in a first process liquid; as well as Gas and subsequently a second process liquid are injected into the microfluidic channel via the fluid inlet, thereby replacing the first process liquid in the microfluidic channel with the second process fluid.