Microfluidic device with a deformable membrane actuated by a hydraulic circuit

Abstract

The invention relates to a microfluidic device comprising: A microfluidic circuit including an inlet microfluidic channel (11) and an outlet microfluidic channel (12), and a microfluidic capsule; A hydraulic actuation circuit including an inlet hydraulic channel (21) and an outlet hydraulic channel (22); The microfluidic capsule including a chamber (10) divided into two subspaces by a deformable membrane (13), said chamber including a first subspace (100) into which the inlet microfluidic channel (11) and the outlet microfluidic channel (12) open, and a second subspace (101) into which the inlet hydraulic channel (21) and the outlet hydraulic channel (22) open; A flow control system (S) connected to the inlet hydraulic channel (21).The flow control system (S) is commanded to inject or draw an actuation fluid (L) into the second subspace (101) to move the membrane (13) inside the chamber. Figure to be published with the abbreviation: Figure 1,

Description

Title of the invention: Microfluidic device with a deformable membrane actuated by a hydraulic circuit. Technical field of the invention

[0001] The invention relates to a microfluidic device having a deformable membrane, the membrane being actuated by means of a hydraulic circuit. State of the art

[0002] A microfluidic capsule commonly used in a microfluidic board comprises a deformable membrane between two positions within a chamber to control the flow of fluid between an inlet channel and an outlet channel. This type of capsule can be used to form a peristaltic pump. The capsule is often actuated using pneumatic means connected to a control channel opening onto the membrane. Applying positive or negative pressure through this control channel deforms the membrane between its two positions within the chamber.

[0003] Using a pneumatic control system, it is difficult to control the chamber drainage flow rate. This flow rate depends on the deformation of the membrane, its elasticity, and the pressure downstream of the chamber. Depending on the application, the downstream pressure is unknown, variable, and uncontrollable, making it very difficult to drain a chamber with a fixed and controlled flow rate.

[0004] The aim of the invention is to propose a microfluidic device in which it is possible to control the drainage flow of the chamber of a microfluidic capsule, thus opening the field to new applications. Description of the invention

[0005] This goal is achieved by a microfluidic device comprising: - A microfluidic circuit comprising an inlet microfluidic channel equipped with a first valve and an outlet microfluidic channel equipped with a second valve, and a microfluidic capsule, - A hydraulic actuation circuit comprising an inlet hydraulic channel and an outlet hydraulic channel equipped with a third valve, - The microfluidic capsule comprising a chamber divided into two subspaces by a deformable membrane, said chamber comprising a first subspace into which the inlet microfluidic channel and the outlet microfluidic channel open, and a second subspace into which the hydraulic inlet channel and the hydraulic outlet channel open. - A control unit, - The device comprising: - A flow control system connected to the hydraulic inlet channel, - A fluid reservoir connected to the hydraulic outlet channel, - Said flow control system being controlled by said control unit to inject or aspirate an actuation liquid into said second subspace to move said membrane inside the chamber.

[0006] It should be noted that the deformable membrane used in the microfluidic capsule is currently made of a gas-permeable material. Maintaining it in a pneumatically controlled state would therefore lead to the formation of air bubbles, which could then propagate through the microfluidic network due to this permeability. The principle of the invention, which uses a liquid to actuate the membrane, solves this problem.

[0007] According to one particular feature, the flow control system is a syringe pump type device.

[0008] According to another feature, the device includes a fourth valve placed on the hydraulic inlet channel.

[0009] The invention also relates to a microfluidic system comprising a matrix of microfluidic devices, each microfluidic device being as defined above, said matrix comprising M column(s) and N rows, M being greater than or equal to 1 and N greater than or equal to 2, on each row and / or each column the microfluidic outlet channel of a first microfluidic device being connected to the microfluidic outlet channel of a second microfluidic device via a junction zone.

[0010] According to one particular feature, the outlet microfluidic channel of the second microfluidic device is split so as to form a shear junction zone on the microfluidic channel of the first microfluidic device.

[0011] According to another feature, the microfluidic devices of the same column share the same flow control system.

[0012] According to another feature, the microfluidic devices of the matrix share the same liquid reservoir.

[0013] The invention also relates to a method for controlling the flow of a fluid, this method being implemented using a microfluidic device as defined above, the method consisting of controlling the flow control system of said microfluidic device in order to aspirate or inject an actuation liquid into the second subspace of the chamber to control a displacement of its membrane and control the displacement of said fluid towards the inside or outside of the first subspace of the chamber. Brief description of the figures

[0014] Other features and advantages will become apparent in the detailed description that follows, given in relation to the accompanying drawings in which: - Fig. 1 shows schematically the architecture of the microfluidic device of the invention; - Figures 2A to 2C illustrate a first mode of operation of the microfluidic device of the invention; - Figures 3A to 3C illustrate a first mode of operation of the microfluidic device of the invention; - Fig. 4 shows a first architecture of a microfluidic system forming a first example of application of the microfluidic device of the invention; - Fig. 5 shows a second architecture of a microfluidic system forming a second example of application of the microfluidic device of the invention;

[0015] Detailed description of at least one embodiment

[0016] The invention relates to the control of a microfluidic capsule conventionally used in a microfluidic device. This type of microfluidic device D is often used in a microfluidic board.

[0017] A microfluidic card is notably used in the medical field to analyze a fluid, such as a liquid sample (blood, for example), by connecting to an automated analyzer. The microfluidic card can thus integrate an entire microfluidic network composed of microfluidic elements such as microfluidic capsules in the form of valves or pumps, and microfluidic channels.

[0018] A microfluidic board can be made in a single layer or by assembling several layers together. For example, its layers are assembled by thermal sealing. Each layer can be machined to create at least a portion of the microfluidic network of the board, with the stacking of the layers forming the entire microfluidic network of the microfluidic board.

[0019] The microfluidic card has two opposite faces, each extending in two dimensions X, Y and has a small thickness (a few mm) along Z compared to the other two dimensions.

[0020] The microfluidic card is advantageously made of a transparent material such as COP (Cyclo-Olefin Polymer), COC (Cyclo-Olefin Copolymer), PMMA (Polymethyl Acrylic Methacrylate), PDMS (Polydimethyl Siloxane), Silicon...

[0021] The microfluidic network of the microfluidic card may include one or more microfluidic capsules.

[0022] With reference to [Fig.1], a microfluidic capsule classically comprises a chamber 10 into which an inlet microfluidic channel 11 and an outlet microfluidic channel 12 open. For readability, in the attached figures, the channels 11 and 21 are shown superimposed, but it should be understood that they can be arranged orthogonally in two planes of the card.

[0023] The microfluidic capsule also includes a deformable membrane 13 that can be positioned between at least two locations within the chamber. The membrane divides the chamber into two subspaces 100 and 101 and, depending on its position, modulates the volume ratio between the two subspaces. The first subspace 100 is, for example, positioned above the second subspace 101. The inlet microfluidic channel 11 and the outlet microfluidic channel 12 each open only into this first subspace 100 of the chamber 1. The membrane 13 can assume a first position, referred to as the lower position (as in [Fig. 1]), in which it allows the first subspace of the chamber to be filled with the fluid F via the inlet fluidic channel 11, and a second position, referred to as the upper position, in which it pushes the liquid towards the outlet fluidic channel 12.In its upper position, membrane 13, for example, is held against a wall of the cavity and blocks any passage of fluid between the two channels. The expressions "upper position" and "lower position" are of course to be considered in a non-limiting manner.

[0024] The membrane 13 is for example intercalated between two layers of the microfluidic card and is sealed between these two layers.

[0025] The membrane is for example made of a hyperelastic material such as silicone (type PDMS, Ecoflex Silpuran from wacker- registered trademarks) or TPU.

[0026] The inlet microfluidic channel 11 is equipped with a first valve Vfl_1 and the outlet microfluidic channel 12 is equipped with a second valve Vfl_2. The first valve and the second valve are advantageously of the pneumatic type and are each controlled respectively to allow or block the filling of the chamber 10, and to allow or block the evacuation of the chamber, according to the actuation of the membrane 13.

[0027] According to the invention, to actuate the membrane 13 between its two positions, the microfluidic device uses a hydraulic circuit. The hydraulic circuit comprises an inlet hydraulic channel 21 opening into the second subspace 101 of the chamber 10 and an outlet hydraulic channel 22 also opening into the second subspace of the chamber 101. In the context of the invention, the membrane 13 is actuated between its two positions by means of an actuation fluid L present in the hydraulic circuit. This actuation fluid L is pressurized or depressurized to push or pull the diaphragm 13 between its two positions.

[0028] The inlet hydraulic channel 21 is also advantageously equipped with a third valve Vhl_1 and the outlet hydraulic channel 22 is equipped with a fourth valve Vhl_2.

[0029] The valves are advantageously of the pneumatic type. They may be valves using the same deformable diaphragm 13 as that of the microfluidic capsule.

[0030] It should be noted that the microfluidic circuit is intended for the circulation of the fluid F whose circulation we wish to control, this being advantageously a liquid that can contain one or more reactants, and that the hydraulic circuit is intended for the circulation of the actuation liquid L necessary for the actuation of the membrane 13 of the capsule.

[0031] Fluid F and actuation fluid L are physically separated and never come into contact with each other, being separated by membrane 13 at chamber 10. Fluid F is intended to occupy the first subspace 100 of chamber 10 of the capsule, and actuation fluid L is intended to occupy the second subspace 101 of chamber 10 of the capsule. Thus, actuation fluid L is never in physical contact with fluid F, as they are separated by the presence of membrane 13.

[0032] Within the framework of the invention, the microfluidic device also includes a flow control system S connected to the inlet hydraulic channel 21 and a liquid reservoir R connected to the outlet hydraulic channel 22.

[0033] The flow control system S functions as a hydraulic pump with a controlled flow rate. It can, for example, be a syringe pump (as shown in the accompanying figures), a peristaltic pump, or any other pump mechanism whose flow rate can be controlled over a wide pressure range. The objective of this system is indeed to control the quantity of actuating fluid L in the hydraulic circuit in order to control the movement of the diaphragm 13, and ultimately to control the flow rate of the fluid F present in the microfluidic circuit.

[0034] The actuating fluid reservoir R is advantageously pressurized either under positive pressure or negative pressure. This allows the diaphragm 13 to be actuated by pressure alone, without using the flow control system S (as in the prior art).

[0035] The microfluidic device also includes a control unit UC, associated with pneumatic control means MP to control each valve and configured to control the flow control system S and the reservoir R.

[0036] The control unit is configured to control the flow control system S so as to be able to adjust the flow and pressure of the actuating fluid L in the hydraulic circuit and therefore the position of the diaphragm 13 in the capsule.

[0037] In a non-limiting manner, two modes of operation of the device of the invention are presented below.

[0038] In the figures, the valves shown in dark grey are in the closed state (they do not allow the fluid or actuating liquid to pass through) and the valves shown in light grey are in the open state (they allow the fluid or actuating liquid to pass through). First mode of operation

[0039] [Fig.2A]

[0040] [Fig.2B]

[0041] [Fig.2C]

[0042] Initially, all valves are closed and the diaphragm is held in the high position (as in [Fig.1]).

[0043] El - [Fig.2A]: Valve Vhl_l and valve Vfl_l are controlled in the open state. The flow control system S is controlled in suction mode to draw a volume identical to that of chamber 10. The diaphragm 13 is thus moved to its lower position. The fluid F present in the microfluidic circuit is therefore drawn into the first subspace 100 of the chamber.

[0044] E2 - [Fig.2B]: Valve Vfl_1 is closed and valve Vfl_2 is open. The flow control system S is controlled in injection mode at a set flow rate and for a set volume less than or equal to the volume of chamber 10. The fluid F is therefore injected with a controlled flow rate downstream of chamber 10, via the outlet microfluidic channel 12.

[0045] E3 - [Fig.2C]: All valves are closed and diaphragm 13 is in the high position.

[0046] A new cycle can be programmed according to the same principle. Second mode of operation

[0047] [Fig.3A]

[0048] [Fig.3B]

[0049] [Fig.3C]

[0050] Initially, all valves are closed and the diaphragm 13 is held in the high position (as in [Fig.1]).

[0051] E10 - [Fig.3A]: Valve Vfl_l and valve Vhl_2 are controlled in the open state. Reservoir R is placed under vacuum. This vacuum forces the membrane into position. 13 in the lower position and to aspirate the fluid F into the first subspace 100 of the chamber.

[0052] E20 - [Fig.3B]: Valve Vfl_l and valve Vhl_2 are controlled in the closed state. Valve Vfl_2 and valve Vhl_l are controlled in the open state. The flow control system S is controlled in injection mode at a set flow rate to inject a volume of actuation fluid L less than or equal to the volume of chamber 10. The fluid F is therefore injected with a controlled flow rate downstream of chamber 10, via the outlet microfluidic channel 12.

[0053] E30 - [Fig.3C]: All valves are closed and diaphragm 13 is in position high.

[0054] A new cycle can be programmed according to the same principle.

[0055] Furthermore, it is possible to combine several microfluidic devices as described above according to different architectures, in order to fulfill different applications. Two such architectures are described below. First architecture

[0056] [Fig.4]

[0057] According to this first architecture, two microfluidic devices D1, D2 as described above are placed in parallel. The two microfluidic outlet channels of the two capsules are connected to each other in a junction zone Z, leading to a common microfluidic channel.

[0058] This architecture can be used to mix two distinct fluids Fl, F2. This allows control of the flow rate delivered by each microfluidic capsule to the junction zone Z and therefore to the common microfluidic channel.

[0059] In this configuration, the reservoir R can be common to both devices.

[0060] Each unit is equipped with its own flow control system SI, S2.

[0061] For example, the first fluid Fl is an aqueous solution and the second fluid F2 is oil. By controlling the fluid flow at each device using its flow control system, it is possible to create a fluid F3 in the form of a droplet emulsion at the Z junction zone. The size of the droplets formed in the common microfluidic channel is a function of the two flow rates imposed by the two flow control systems SI, S2.

[0062] The valves of each device D1, D2 are such as those described above and their controls are carried out according to the first operating mode or the second operating mode described above. Second architecture

[0063] [Fig.5]

[0064] It is possible to duplicate the principle described above to several devices forming a matrix, with several columns and several rows. For example, a matrix with M column(s) and N rows is defined, where M is greater than or equal to 1 and N is greater than or equal to 2.

[0065] Each device is referenced with an index i_J, with i ranging from 1 to M and j ranging from 1 to N. On [Fig.5], two columns are represented.

[0066] In this architecture, each Dij device is dedicated to controlling the injection of a distinct fluid.

[0067] By way of example, all devices present on the same line j are connected to each other via a junction zone leading to a common microfluidic channel at the output.

[0068] All microfluidic devices in the same column share, for example, their flow control system Si (SI and S2 on [Fig.5]).

[0069] The pressurized liquid reservoir R is, for example, common and shared by all the devices Dij of the matrix.

[0070] On each line j, the microfluidic outlet channel of the device Dij is split so as to connect to the microfluidic outlet channel of the device Di + 1J in shear.

[0071] Figure 5 shows a matrix having two columns (M=2) and N rows. With such a matrix, the operating principle is described below.

[0072] Initially, all valves are closed and all membranes are held in the raised position.

[0073] According to the first operating mode or the second operating mode described above, the first subspace 100 of the chamber of each device is filled with the fluid controlled by each device.

[0074] By controlling the two flow control systems SI, S2, each dedicated to a separate column, N mixing operations are performed sequentially on each row of the matrix. The mixing is carried out row by row, one after the other. While one row is active, the others can remain on standby, i.e., inactive. It is also possible to wash the microfluidic circuits of the devices on the inactive rows. In this case, a microfluidic washing circuit (not shown) can be connected to them.

[0075] It is also possible to provide a multi-way fluid distribution valve at the outlet of each flow control system. Each valve can then be controlled to connect the flow control system S to a particular device in the column or to several devices in the column.

[0076] This second architecture is of particular interest in the case of the formulation of LNPs (lipid nanoparticles). This application requires the ability to mix a solution containing lipids very quickly with an aqueous solution. The size of the nanoparticles produced depends on the geometry of the component and the flow rates of the two solutions. Therefore, it is essential to control the injection rates. These rates are on the order of several mL / min. The production of a few hundred nanoparticles through reactions must therefore be very rapid.

[0077] The invention has many advantages, including: - It allows precise control of the fluid flow of a microfluidic capsule, via the use of a hydraulic circuit; - Device D has a configuration in which the microfluidic part containing the reactants and the hydraulic control part are physically separated, avoiding any risk of contamination and reducing the surface area in contact with the reactants, which reduces the system cleaning times; - The device of the invention is adapted to be duplicated in rows and columns, to form a matrix dedicated to a particular application; - The solution of the invention opens the field to various applications, such as the creation of drops of different sizes, by controlling the flow rates, or the creation of nanoparticles;

Claims

Demands

1. A microfluidic device comprising: - A microfluidic circuit having an inlet microfluidic channel (11) equipped with a first valve and an outlet microfluidic channel (12) equipped with a second valve, and a microfluidic capsule, - A hydraulic actuation circuit having an inlet hydraulic channel (21) and an outlet hydraulic channel (22) equipped with a third valve, - The microfluidic capsule having a chamber (10) divided into two subspaces by a deformable membrane (13), said chamber having a first subspace (100) into which the inlet microfluidic channel (11) and the outlet microfluidic channel (12) open, and a second subspace (101) into which the inlet hydraulic channel (21) and the outlet hydraulic channel (22) open, - A control unit (CU), - Characterized in that it comprises: - A flow control system (S) connected on the inlet hydraulic channel (21),- A liquid reservoir (R) connected to the hydraulic outlet channel (22), - Said flow control system (S) being controlled by said control unit (UC) to inject or draw an actuation liquid (L) into said second subspace (101) to move said membrane (13) inside the chamber.

2. Device according to claim 1, characterized in that the flow control system (S) is a syringe-pusher type device.

3. Device according to claim 1 or 2, characterized in that it comprises a fourth valve placed on the inlet hydraulic channel (21).

4. Microfluidic system, characterized in that it comprises a matrix of microfluidic devices, each microfluidic device being as defined in any one of claims 1 to 3, said matrix comprising M column(s) and N rows, M being greater than or equal to 1 and N greater than or equal to 2, and in that on each row and / or each column the microfluidic outlet channel of a first microfluidic device is connected to the microfluidic outlet channel of a second microfluidic device via a junction zone.

5. System according to claim 4, characterized in that the outlet microfluidic channel of the second microfluidic device is split so as to form a shear junction zone on the microfluidic channel of the first microfluidic device.

6. System according to claim 4 or 5, characterized in that the microfluidic devices of the same column share the same flow control system (SI, S2).

7. System according to any one of claims 4 to 6, characterized in that the microfluidic devices of the matrix share a common liquid reservoir (R).

8. A method for controlling the flow of a fluid (F), characterized in that it is implemented using a microfluidic device as defined in any one of claims 1 to 3, and in that it consists of controlling the flow control system (S) of said microfluidic device in order to draw or inject an actuating liquid (L) into the second subspace (101) of the chamber (10) to control a displacement of its membrane (13) and to control the displacement of said fluid (F) towards the inside or outside of the first subspace (100) of the chamber.

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