DEVICE FOR CONTROLLING THE DISPOSSING OF A FLUID

Description

Technical field of the invention

[0001] The present invention relates to a device for controlling the movement of a fluid, using a microfluidic component. State of the art

[0002] As is known, a microfluidic component, also called a microfluidic device or microfluidic card, includes a support, often made of a COC, PMMA or equivalent type material.

[0003] The component may include at least one microfluidic capsule. A microfluidic capsule comprises a chamber into which at least one microfluidic channel opens. The microfluidic capsule also includes a deformable membrane that is actuated by pneumatic means. By applying positive or negative pressure to a dedicated actuation channel, the membrane deforms within the chamber between at least two extreme positions.

[0004] The change from negative to positive pressure, and vice versa, causes the chamber to fill or empty. As it moves, the membrane modulates the volume of fluid present in the chamber and therefore the volume of fluid it displaces out of the chamber, or draws into the chamber.

[0005] In some applications, it may be useful to know the volume of fluid delivered or aspirated by the microfluidic capsule, and thus control the volumes of fluid to be moved.

[0006] Patent EP3148696B1 describes, in particular, a solution that includes means for measuring membrane deformation. These means can be optical and / or electrical. For example, the electrical means may include a strain gauge integrated into the membrane. The optical means, for instance, are configured to determine the angle the membrane makes relative to the support during its deformation. Based on the membrane's position, the system deduces the volume of liquid displaced by the membrane's movement.

[0007] In the case of electrical measurement methods, this previous solution has the major drawback of requiring the use of a specific instrumented membrane incorporating the strain gauge. As for optical measurement, it proves difficult to implement because the visualization must be performed perpendicularly through several layers of the component.

[0008] Therefore, there is a need for a device capable of precisely controlling the movement of a fluid within a microfluidic component, and which is: Easy to implement using readily available resources, without requiring the creation of a specific membrane; Reliable and accurate in the volume of fluid displaced; Description of the invention

[0009] This goal is achieved by a fluid displacement control device comprising: A microfluidic capsule comprising a microfluidic chamber, at least one microfluidic channel opening into said microfluidic chamber, and a deformable membrane inside said microfluidic chamber for displacing a volume of fluid out of the chamber into said microfluidic channel or drawing a volume of fluid into the microfluidic chamber; a membrane actuation device, the actuation device comprising an actuation channel opening opposite the membrane; the actuation device comprising an actuation fluid placed in the actuation channel and pneumatic actuation means connected to the actuation channel and configured to inject an actuation gas into said actuation channel in order to pressurize said actuation fluid against the membrane and deform it.A gas / liquid interface is present in said actuation channel with a position that varies according to the pressure of the injected actuation gas against the actuation liquid. The control device includes monitoring means configured to track a longitudinal displacement of said gas / liquid interface along the actuation channel, and control means configured to determine the volume of fluid displaced by the membrane as a function of said longitudinal displacement of the gas / liquid interface being tracked.

[0010] According to one particular feature, the control means are configured to compare the measured volume of displaced fluid with a setpoint value and to send a pressure command to the pneumatic actuation means in order to adapt the pressure of the injected actuation gas taking into account the difference between the measured volume of displaced fluid and the setpoint value.

[0011] According to another feature, the control means are configured to determine the pressure to be applied to the actuating gas by taking into account the difference between the measured volume of displaced fluid and the setpoint value.

[0012] According to another particularity, the control means are configured to control the pneumatic actuation means by controlling the flow of fluid displaced by the diaphragm.

[0013] Another distinctive feature is that the monitoring system includes a camera positioned to capture images of the actuation channel in which the gas / liquid interface moves.

[0014] According to another feature, the actuation channel includes a coil in which the gas / liquid interface is able to move.

[0015] According to another feature, the camera has an image capture surface and the coil is configured to be adjusted in length and section, so that it is covered along its entire length by said capture surface.

[0016] According to another peculiarity, the coil defines a volume corresponding to the minimum of the maximum volume of fluid present in the chamber when the membrane is in an extreme position called open.

[0017] According to another particularity, the monitoring means are of the capacitive, resistive or inductive type, and the displacement of the gas / liquid interface in the actuation channel has the effect of changing the value of a capacitance, a resistance or an inductance. Brief description of the figures

[0018] Other features and advantages will appear in the detailed description that follows, in connection with the figures listed below: THE Figures 1A to 1Crepresent the principle of implementation of a microfluidic capsule used in the invention and illustrate the operating principle of the invention; The figure 2 schematically represents the principle of implementation of the device of the invention; The Figures 3A and 3B show an example of an embodiment of the actuation channel used in the device of the invention; The figure 4 shows an example of the application of the device of the invention; Detailed description of at least one embodiment

[0019] For the remainder of this description, we define an orthonormal coordinate system X, Y, Z, with the Z-axis oriented along the vertical direction. The terms "greater than", "less than", "above" and "below" or equivalents should be understood in relation to the Z-axis. Microfluidic card and fluidic valve

[0020] Figure 1A Figure 1B Figure 1C

[0021] The invention applies to a microfluidic capsule 1 conventionally used in a microfluidic component.

[0022] Such a microfluidic component 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 component can thus be integrated into an entire microfluidic network composed of microfluidic elements such as valves, chambers, and microfluidic channels. The microfluidic network is manufactured, for example, by machining or molding.

[0023] A microfluidic component can be made in a single layer or by assembling several layers together. For example, its layers are joined together by thermal bonding. Each layer can be machined or molded to create at least a portion of the microfluidic network of the board; stacking the layers together forms the entire microfluidic network of the microfluidic board.

[0024] The microfluidic component has two opposite faces, each extending in the two dimensions X, Y, and often has a smaller thickness (a few mm for example) along Z compared to the other two dimensions.

[0025] The microfluidic component 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...

[0026] The microfluidic network of the microfluidic component may include one or more microfluidic capsules 1.

[0027] A microfluidic capsule 1 typically comprises a chamber 10 into which at least one, advantageously two, fluidic channels open, designated as the inlet fluidic channel 11 and the outlet fluidic channel 12. The microfluidic capsule also comprises a deformable membrane 13 inside the chamber. Depending on its position, the membrane 13 modulates the volume of fluid F present in the chamber. It can assume two extreme positions: An open position in which chamber 10 is full ( Figure 1A ) ; A closed position, in which chamber 10 is empty ( figure 1C ) ;

[0028] The movement of the membrane 13 inside the chamber 10 causes a movement of fluid F out of the chamber or into the chamber, depending on its direction of movement.

[0029] For the principle of the invention to function reliably, the fluid F displaced by the membrane 13 is advantageously incompressible and therefore made up of a liquid.

[0030] There figure 1B The microfluidic capsule 1 is shown with the membrane 13 in an intermediate position, located between its open and closed positions. In this intermediate position, the membrane 13 separates the chamber 10 into two distinct spaces: an upper space containing the fluid to be moved and a lower space pressurized by the actuation fluid L of the membrane 13 actuation device (see below).

[0031] Membrane 13, for example, is sandwiched between two layers of the microfluidic component and is sealed between these two layers.

[0032] Currently, deformable membranes are often made of a hyperelastic silicone-based material, such as polydimethylsiloxane (PDMS), or an elastomer like Ecoflex (registered trademark). Other materials with similar mechanical properties or those better suited to the application could be considered.

[0033] To actuate the membrane 13 between its two positions, the microfluidic component incorporates an actuation channel 20 opening opposite the membrane 13. This actuation channel 20 forms part of an actuation device for the fluidic system. Like the microfluidic circuit of the component, the actuation channel 20 is advantageously implemented, at least partially, within the body of the microfluidic component, similarly to the other channels of the component's microfluidic network. Actuation device

[0034] Figure 1A Figure 1B Figure 1C Figure 2

[0035] In the context of the invention, the actuation device comprises an actuation liquid L placed in the actuation channel 20 and pneumatic actuation means 2 connected to the actuation channel and configured to inject an actuation gas G (for example air) into said actuation channel 20 in order to pressurize said actuation liquid L against the membrane 13 to deform it.

[0036] The actuation fluid L comes directly into contact with the membrane 13 to move it, thereby pressurizing the lower space of the chamber 10 of the capsule.

[0037] The actuation channel 20 advantageously has a constant cross-section along its entire length. This cross-section is, for example, rectangular.

[0038] The membrane 13 is actuated between its two positions by means of the actuating fluid L which pressurizes the lower space of the chamber, and the actuating fluid L is displaced by pneumatic means, by application of a positive or negative pressure by means of the actuating gas G injected into the actuating channel 20.

[0039] It should be noted that the pneumatic actuation means 2 are connected directly to the actuation channel 20 in which the actuation liquid L is placed. The injected actuation gas G therefore comes directly into contact with the actuation liquid L. By the term "directly", it is meant that the gas G injected into the actuation channel 20 comes into physical contact with the actuation liquid L present in the channel and that there is no intermediate wall, specific membrane or physical barrier separating them.

[0040] Within the framework of the invention, we are interested in the gas / liquid interface INT present in the actuation channel 20.

[0041] According to the invention, the displacement of the gas / liquid interface INT is directly proportional to the volume of fluid F displaced by the membrane 13 in the microfluidic capsule. This principle applies in particular because the actuation liquid L and the fluid F displaced by the membrane 13 are incompressible. Means of monitoring and control

[0042] Figure 1A Figure 1B Figure 1C Figure 2

[0043] By following the movement of the gas / liquid interface INT inside the actuation channel 20, it is thus possible to deduce the volume of fluid displaced by the membrane 13 in the microfluidic capsule 1.

[0044] By gas / liquid interface INT, it should be understood that it can be a meniscus or a line moving along the actuation channel 20 depending on the pressure level of the gas G injected by the pneumatic actuation means 2.

[0045] The monitoring means advantageously include a camera 3 configured to follow the movement of the gas / liquid interface INT inside the actuation channel 20.

[0046] The camera 3 is coupled to control means 4 responsible for processing the images acquired by the camera 3. The control means 4 are advantageously those already used for the control of the microfluidic component.

[0047] Camera 3 is configured to acquire several images at successive times. If the pressure of the actuating gas G injected by the pneumatic actuation means 2 is changed, the gas / liquid interface INT moves. From the acquired images, the control means 4 are configured to determine, at each instant, the position of the gas / liquid interface INT and to deduce a direction of movement of the gas / liquid interface and a longitudinal displacement of this gas / liquid interface along the actuation channel 20 when the position of the gas / liquid interface varies over time.

[0048] Alternatively, other means of monitoring the movement of the gas / liquid interface INT could be used. For example, these could be electrical systems using capacitive, inductive, or resistive measurements. These methods require positioning electrodes on the internal surface of the actuation channel 20. As the gas / liquid interface INT moves, a change in capacitance, inductance, or resistance is observed. Based on this change, the control means 4 can deduce the longitudinal displacement of the gas / liquid interface INT within the actuation channel and, ultimately, the volume of fluid displaced by the membrane 13 in the microfluidic capsule 1.For example, the electrodes are deposited on the internal surface of the actuation channel 20 and electrical connection points are created on the microfluidic component to connect them to means of measuring the parameter in question (capacitance, inductance, resistance).

[0049] The volume of the actuation liquid L displaced in the actuation channel 20 (taking into account the cross-section of the actuation channel and the length between two positions of the gas / liquid interface) varies according to the direction of movement and the length of movement of the gas / liquid interface INT along the actuation channel 20.

[0050] Assuming that the cross-section of the actuation channel 20 is constant, the length of the displacement of the gas / liquid interface INT is then directly proportional to the volume of fluid displaced by the membrane 13. By monitoring the longitudinal displacement of the gas / liquid interface INT, the control means 4 can implement control of the volume of fluid displaced by the membrane 13 in the microfluidic capsule 1.

[0051] Advantageously, the control means are configured to regulate the volume of fluid displaced by the membrane 13 using a control loop. With reference to the figure 2 The way it works is, for example, as follows: A setpoint value V_cons of the volume to be moved by the microfluidic capsule 1 is injected into the inlet of the control means 4; To move this volume, the control means 4 command the pneumatic actuation means 2; When the pneumatic actuation means 2 are commanded, the gas / liquid interface INT moves along the actuation channel 20; The monitoring means (for example the camera 3 via its capture surface 30) measure at least two distinct positions taken by the gas / liquid interface INT during its movement and send data D to the control means 4; From the received data D, a software module M1 of the control means 4 determines the longitudinal displacement of the gas / liquid interface INT and deduces the actual volume V_r of fluid F displaced by the membrane 13 in the microfluidic capsule;Using a comparison module M2, the control means 4 compare the volume V_r of fluid actually displaced by the membrane 13 with the setpoint value V_cons received at the input; Taking into account the difference V_x between the actual volume V_r and the setpoint value V_cons, the control means 4 determine the pressure command P to be sent to the pneumatic actuation means 2 to make the actual volume V_r displaced converge towards the setpoint value V_cons; The control loop is repeated as long as the actual injected volume V_r does not correspond to the setpoint value V_cons;

[0052] Furthermore, since the flow rate of a fluid corresponds to its volume over time, it should be noted that it would also be possible to control the fluid flow rate delivered by the microfluidic capsule 1. To achieve this, the control means 4 can control the pneumatic actuation means 2 based on flow rate rather than volume. Specifically, it would be possible to control the microfluidic capsule to ensure that it delivers fluid F at a constant flow rate. For this purpose, the control means 4 are configured to execute a flow-based control loop. The principle of this control would be similar to that described above for volume-based control. Actuation channel architecture

[0053] Figure 3A Figure 3B

[0054] Advantageously, the actuation channel 20 is made in the form of a serpentine.

[0055] The coiled design effectively addresses the constraint related to the camera's capture surface 30. The gas / liquid interface INT to be monitored must remain within the camera's capture surface 30. Furthermore, since this capture surface 30 is limited in size, it may be advantageous to have a sufficiently long actuation channel to displace the largest possible total volume. Moreover, the resolution related to the volume displaced by the membrane can be optimized by adjusting the channel's cross-section.

[0056] Depending on the cross-section of the actuation channel 20, the extent of the camera capture surface 30 and the maximum volume of fluid to be moved by the membrane 13 in the microfluidic capsule, we can then determine the length that the actuation channel 20 must have to always remain in the field of the camera 3.

[0057] For example, with a capture surface of 30 of 4x6 mm² (length X and width Y on the figure 3A ) and an actuation channel 20 having a rectangular cross-section 400µm wide (y1 on the figure 3B ) and 500µm deep (z1 on the figure 3B ), a 34.2mm serpentine actuation channel 20 will allow tracking the displacement of a 6.8µl fluid volume. Depending on the resolution level of the camera 3, it will then be possible to monitor the displaced fluid volume F with varying degrees of precision.

[0058] For example, with a camera resolution of 100µm, the accuracy on the measurement of the volume of fluid displaced by the membrane will be 0.02µl (0.30%) and with a camera resolution of 50µm, the accuracy on the measurement of the volume of fluid displaced by the membrane will be 0.01µl (0.15%).

[0059] Another example configuration is the following: Actuation channel having a rectangular cross-section of 500µm in width y1 and 800µm in depth z1: A 28.5mm coil enters the field of view of the capture surface (4x6mm²) of camera 3 and allows tracking the displacement of a fluid volume of 11.4µl. With a camera resolution of 100µm, the accuracy of the volume measurement is 0.08µl (0.36%); with a camera resolution of 50µm, the accuracy of the volume measurement is 0.04µl (0.18%).

[0060] It should be noted that it would also be possible to play on the length of the actuation channel 20 and therefore of the coil by employing a diverging lens, by using a wide field camera, i.e. with a larger capture surface 30, and / or possibly by using several juxtaposed cameras. Applications Figure 4

[0061] Controlling the volume of fluid displaced by membrane 13 in the microfluidic capsule may prove useful in certain applications.

[0062] One initial application could be in the field of organoids-on-a-chip, typically for perfusing organoids with low and controlled flow rates. Thus, for the perfusion of a biological object, a very low flow rate of culture medium (on the order of 1 µl / min) is passed near the biological object to provide it with nutrients and remove its secretions.

[0063] Another application, illustrated by the figure 4 This can consist of creating concentration profiles by mixing two aqueous compounds. Two microfluidic capsules 1a, 1b are placed in parallel, and at least one of them is volume-controlled according to the principle of the invention described above. On the figure 4Each capsule is controlled, for example, via a separate actuation channel 20a, 20b, arranged in a serpentine configuration. From the images acquired (via the two capture surfaces 30a, 30b), the control means 3 regulate the fluid flow rate delivered by each capsule 1a, 1b by controlling the pneumatic actuation means 2. Each capsule 1a, 1b delivers its fluid to a common channel 21. Depending on the volume delivered by each capsule, a fluid with a specific concentration profile is formed in this common channel 21.

[0064] A third application using an architecture similar to that of the figure 4One example is the creation of droplets using two immiscible compounds (oil and water, for example). A first capsule contains water, and a second capsule contains oil, with the outlets of each capsule converging into a common channel. The device of the invention is fitted to each capsule, and the volume of fluid delivered by each capsule to the common channel is controlled using the principle of the invention. By regulating the pressure in each capsule, droplets are formed in the common channel.

[0065] As indicated above, the principle of the invention allows control of the volume of fluid displaced by the membrane 13, but it is also possible to control the flow rate. In the latter case, by monitoring the displacement of the gas / liquid interface INT, it is possible to control the displacement of the membrane 13 to deliver the fluid at a constant flow rate. Benefits

[0066] The invention is therefore a simple solution for efficiently tracking the volume of fluid F displaced by a membrane 13 of a microfluidic capsule 1.

[0067] When using a camera 3, this solution avoids the need for significant modifications to the microfluidic component's structure and prevents additional component costs. The methods employed are simple and often already available for controlling the microfluidic component. The microfluidic component can, in particular, be directly mounted on an instrumented support that carries the pneumatic actuation means 2 and the camera 3.

[0068] The solution of the invention is also easily implementable in already known applications.

Claims

1. Device for controlling the displacement of a fluid (F) including: - A microfluidic capsule (1) including a microfluidic chamber (10), at least one microfluidic channel (11) opening into said microfluidic chamber (10), and a deformable diaphragm (13) inside said microfluidic chamber for displacing a volume of fluid out of the chamber into said microfluidic channel or drawing a volume of fluid into the microfluidic chamber, - A device for actuating the diaphragm (13), the actuating device including an actuating channel (20) opening out opposite the diaphragm, - Characterized in that: - The actuating device includes an actuating liquid (L) arranged in the actuating channel (20) and pneumatic actuating means (2) connected to the actuating channel (20) and configured to inject an actuating gas (G) into said actuating channel (20) to pressurize said actuating liquid against the diaphragm (13) and to deform it, - A gas / liquid interface (INT) being present in said actuating channel (20) with a variable position dependent on the pressure of the actuating gas (G) injected against the actuating liquid, - The control device includes monitoring means configured to track a longitudinal movement of said gas / liquid interface (INT) along the actuating channel (20), and control means (4) configured to determine the volume of fluid displaced by the diaphragm as a function of said longitudinal movement of the gas / liquid interface (INT) being tracked.

2. Device according to Claim 1, characterized in that the control means (4) are configured to compare the measured displaced fluid volume (V_r) with a setpoint value (V_cons) and to send a pressure command (P) to the pneumatic actuating means (2) in order to adjust the pressure of the injected actuating gas (G) in consideration of the difference between the measured displaced fluid volume (V_r) and the setpoint value (V_cons).

3. Device according to Claim 2, characterized in that the control means (4) are designed to determine the pressure to be applied to the actuating gas taking into account the difference between the measured displaced fluid volume (V_r) and the setpoint value (V_cons).

4. Device according to one of Claims 1 to 3, characterized in that the control means (4) are configured to control the pneumatic actuating means (2) by controlling the flow rate of fluid (F) displaced by the diaphragm (13).

5. Device according to one of Claims 1 to 4, characterized in that the monitoring means include a camera (3) positioned to capture images of the actuating channel (20) in which the gas / liquid interface (INT) is moving.

6. Device according to Claim 5, characterized in that the actuating channel (20) includes a serpentine channel in which the gas / liquid interface (INT) can move.

7. Device according to Claim 6, characterized in that the camera (3) includes an image capture surface (30) and in that the serpentine channel is configured to be adjusted in length and in section so that its entire length is covered by said capture surface (30).

8. Device according to Claim 7, characterized in that the serpentine channel defines a volume corresponding at least to the maximum volume of fluid present in the chamber when the diaphragm (13) is in an extreme position referred to as open.

9. Device according to one of Claims 1 to 4, characterized in that the monitoring means are capacitive, resistive or inductive means, and in that the movement of the gas / liquid interface (INT) in the actuating channel (20) modifies a capacitance, resistance, or inductance value.