Microfluidic device with deformable membrane operable 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).- Said flow control system (S) being commanded to inject or aspirate an actuation fluid (L) into said second subspace (101) to move said membrane (13) inside the chamber.

Description

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 consists of a deformable membrane that moves between two positions within a chamber to control fluid flow between an inlet 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 rate. This rate depends on the membrane's deformation and elasticity, as well as 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] US patent application US2008 / 311585A1 describes a microfluidic device suitable for controlling chemical reactions.

[0005] 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

[0006] 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 and outlet microfluidic channels open, and a second subspace into which the inlet and outlet hydraulic channels open; a control unit; the device comprising: a flow control system connected to the inlet hydraulic channel; a liquid reservoir connected to the outlet hydraulic channel.The flow control system is controlled by the control unit to inject or draw an actuation fluid into the second subspace to move the membrane inside the chamber.

[0007] 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.

[0008] One particular feature of the flow control system is that it is a syringe pump type device.

[0009] Another distinctive feature of the device is that it includes a fourth valve located on the hydraulic inlet channel.

[0010] 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.

[0011] According to a particular feature, the microfluidic outlet channel of the second microfluidic device is split in such a way as to form a shear junction zone on the microfluidic channel of the first microfluidic device.

[0012] Another distinctive feature is that the microfluidic devices in the same column share the same flow control system.

[0013] Another distinctive feature is that the microfluidic devices of the matrix share a common liquid reservoir.

[0014] 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

[0015] Other features and advantages will appear in the detailed description that follows, in conjunction with the attached drawings, in which: There Figure 1 schematically illustrates the architecture of the microfluidic device of the invention; The figures 2A to 2C illustrate a first mode of operation of the microfluidic device of the invention; The figures 3A to 3C illustrate a first mode of operation of the microfluidic device of the invention; The figure 4 shows a first architecture of a microfluidic system forming a first example of application of the microfluidic device of the invention; The figure 5 shows a second architecture of a microfluidic system forming a second example of application of the microfluidic device of the invention; 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 fabricated as a single layer or by assembling multiple layers. For example, the layers can be bonded together using thermal sealing. Each layer can be machined to create at least a portion of the board's microfluidic network; stacking the layers allows for the formation of the complete 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 can include one or more microfluidic capsules.

[0022] With reference to the figure 1A 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 10. The membrane 13 can assume a first position, called the lower position (as on the figure 1), in which it allows the first subspace of the chamber to be filled with fluid F via the inlet fluidic channel 11, and a second position, called the high position, in which it pushes the liquid towards the outlet fluidic channel 12. In its high position, the membrane 13 is, for example, held against a wall of the cavity and blocks any passage of liquid between the two channels. The terms "high position" and "low position" are, of course, to be considered in a non-limiting manner.

[0024] Membrane 13, for example, is sandwiched between two layers of the microfluidic card and 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 Vf1_1 and the outlet microfluidic channel 12 is equipped with a second valve Vf1_2. The first and second valves are advantageously pneumatic and are each controlled respectively to allow or block the filling of 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 diaphragm 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 101 of the chamber. In the context of the invention, the diaphragm 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. The inlet hydraulic channel 21 is also advantageously equipped with a third valve Vh1_1 and the outlet hydraulic channel 22 is equipped with a fourth valve Vh1_2.

[0028] The valves are advantageously of the pneumatic type. They may be valves using the same deformable diaphragm 13 as that of the microfluidic capsule.

[0029] 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.

[0030] Fluid F and actuation fluid L are physically separated and never come into contact with each other, as they are 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 never comes into physical contact with fluid F, as they are separated by membrane 13.

[0031] 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.

[0032] The flow control system S functions as a hydraulic pump with a controlled flow rate. It could, for example, be a syringe pump (as shown in the attached 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 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.

[0033] The reservoir R of the actuation fluid L is advantageously pressurized either under positive pressure or negative pressure. This allows the diaphragm 13 to be actuation by pressure alone, without using the flow control system S (as in the prior art).

[0034] 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.

[0035] The control unit UC 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.

[0036] Two modes of operation of the device of the invention are presented below, without limitation.

[0037] 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 Figure 2A Figure 2B Figure 2C

[0038] Initially, all valves are closed and the diaphragm is held in the raised position (as on the figure 1 ).

[0039] E1 - Figure 2A The Vh1_1 valve and the Vf1_1 valve 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.

[0040] E2 - Figure 2B Valve Vf1_1 is closed and valve Vf1_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.

[0041] E3 - Figure 2C : All valves are closed and diaphragm 13 is in the high position.

[0042] A new cycle can be programmed according to the same principle. Second mode of operation Figure 3A Figure 3B Figure 3C

[0043] Initially, all valves are closed and diaphragm 13 is held in the raised position (as on the figure 1 ).

[0044] E10 - Figure 3A The Vf1_1 and Vh1_2 valves are controlled in the open state. The reservoir R is depressurized. This depressurization forces the diaphragm 13 into the lowered position and draws the fluid F into the first subspace 100 of the chamber. E20 - Figure 3BValves Vf1_1 and Vh1_2 are controlled in the closed state. Valves Vf1_2 and Vh1_1 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.

[0045] E30 - Figure 3C : All valves are closed and diaphragm 13 is in the high position.

[0046] A new cycle can be programmed according to the same principle.

[0047] Furthermore, it is possible to combine several microfluidic devices as described above in different architectures, in order to fulfill various applications. Two such architectures are described below. First architecture Figure 4

[0048] 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.

[0049] This architecture can be used to mix two distinct fluids F1, 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.

[0050] In this configuration, the reservoir R can be shared by both devices. Each unit is equipped with its own flow control system S1, S2.

[0051] For example, the first fluid F1 is an aqueous solution and the second fluid F2 is oil. By controlling the fluid flow rate 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 S1 and S2.

[0052] The valves of each device D1, D2 are such as those described above and their controls are carried out according to the first mode of operation or the second mode of operation described above. Second architecture Figure 5

[0053] It is possible to replicate the principle described above to several devices forming a matrix, with several columns and several rows. For example, we define a matrix with M column(s) and N rows, where M is greater than or equal to 1 and N is greater than or equal to 2.

[0054] Each device is referenced with an index i_j, with i ranging from 1 to M and j ranging from 1 to N. On the figure 5 Two columns are shown.

[0055] In this architecture, each device Di_j is dedicated to controlling the injection of a distinct fluid.

[0056] As an example, all devices on the same line j are connected to each other via a junction zone leading to a common microfluidic channel at the output.

[0057] All microfluidic devices in the same column share, for example, their flow control system Si (S1 and S2 on the figure 5 ).

[0058] The pressurized liquid reservoir R is, for example, common and shared by all the devices Di_j in the matrix.

[0059] On each line j, the microfluidic outlet channel of the device Di_j is split so as to connect to the microfluidic outlet channel of the device Di+1_j in shear.

[0060] There figure 5 shows a matrix with two columns (M=2) and N rows. With such a matrix, the operating principle is described below.

[0061] Initially, all valves are closed and all membranes are held in the raised position.

[0062] 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.

[0063] By controlling the two flow control systems S1 and 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 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.

[0064] 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 specific device in the column or to several devices in the column.

[0065] This second architecture is of particular interest for the formulation of LNPs (lipid nanoparticles). This application requires the ability to rapidly mix a lipid-containing solution 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, precise control of the injection rates is essential. These rates are on the order of several mL / min. The production of a few hundred µL of reaction material must thus be extremely rapid.

[0066] The invention offers numerous advantages, including: It allows for precise control of the fluid flow rate of a microfluidic capsule, via the use of a hydraulic circuit; Device D has a configuration in which the microfluidic part containing the reagents and the hydraulic control part are physically separated, preventing any risk of contamination and reducing the surface area in contact with the reagents, thus reducing 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 diverse applications, such as the creation of droplets of different sizes, by controlling flow rates, or the creation of nanoparticles;

Claims

1. Microfluidic device comprising: - A microfluidic circuit including 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 including an inlet hydraulic channel (21) and an outlet hydraulic channel (22) equipped with a third valve, - 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 control unit (CU), - Characterized by the fact thatIt comprises: - A flow control system (S) connected to the inlet hydraulic channel (21), - A liquid reservoir (R) connected to the outlet hydraulic 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 pump type device.

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

4. Microfluidic system, characterized in thatit 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 microfluidic outlet channel of the second microfluidic device is duplicated 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 (S1, S2).

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

8. Method for controlling the flow rate 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 aspirate or inject an actuation fluid (L) into the second subspace (101) of the chamber (10) to control a displacement of its membrane (13) and control the displacement of said fluid (F) into or out of the first subspace (100) of the chamber.

Images