Fluid analysis system including an acoustic wave generating component

Abstract

The invention relates to a fluid analysis system comprising: A microfluidic component (1) incorporating a main microfluidic circuit (10) and having a front face (12) and a rear face (13); A measurement / analysis component (2) mounted on the front face (12) of the microfluidic component (1) and comprising at least one measuring element (21) capable of being mechanically stimulated by acoustic waves; An acoustic wave generator component; The acoustic wave generator component being mounted on the rear face (13) of the microfluidic component (1). Figure to be published with the abbreviation: Figure 2A

Description

Title of the invention: Fluid analysis system including an acoustic wave generating component Technical field of the invention

[0001] The present invention relates to a fluid analysis system. State of the art

[0002] With reference to [Fig. 1], in the field of fluid analysis, it is known to connect a measurement / analysis component 2 to a microfluidic component 1 (also called a microfluidic interposer, in the sense that it accommodates the measurement / analysis component 2). The microfluidic component 1 is often made of a transparent polymer material and incorporates a main microfluidic circuit 10 formed of microfluidic channels through which flows a fluid to be analyzed itself or a fluid carrying particles to be analyzed. The measurement / analysis component 2 comprises a microfluidic measurement circuit 20 connected to the main microfluidic circuit of the microfluidic component and a measuring element 21 capable of being mechanically stimulated by acoustic waves. This type of measurement / analysis component is very often implemented in the form of a MEMS ("Micro-ElectroMechanical System") or NEMS ("Nano-ElectroMechanical System") chip.

[0003] To generate acoustic waves, it is common to use an actuation system. Several types of actuation systems can be considered, operating in particular by capacitive coupling or by piezoelectric actuation. Piezoelectric actuation is achieved using a piezoelectric element made of a ceramic. The actuation element is then called a piezoceramic element 3.

[0004] To couple the measurement / analysis component 2 with the microfluidic component 1, it is necessary to: - To establish the fluidic connection between the main microfluidic circuit 10 and the measurement microfluidic circuit 20 in order to ensure fluid transfer; - Make the electrical connections of the measurement / analysis component 2 in order to read the generated electrical signal; - Perform a mechanical actuation of the measuring element 21 of the measuring / analysis component 2;

[0005] In the case where it is desired to connect the measurement / analysis component 2 to the microfluidic component 1, the rear face 23 of the measurement / analysis component 2 is dedicated to the fluidic connection, while its front face 22 is dedicated to the connection electrical. As shown in [Fig.1], to actuate the measurement / analysis component 2, the piezoceramic element 3 is conventionally brought into direct contact with the measurement / analysis component 2 by mounting it on its front face 22.

[0006] However, in this configuration, the opaque piezoceramic element 3 prevents direct visualization of the areas of interest inside the fluidic circuits during the experiment, and also greatly complicates the handling and connection of the chip, particularly for making electrical connections.

[0007] There is therefore a need to obtain an analysis system including a microfluidic component and an acoustic wave-actuated measurement / analysis component which: - Provides visualization of fluidic circuits integrated into components; - Avoids any risk of short circuit between the electrical connection wires connecting to the measurement / analysis component and the acoustic wave generating component when it is, for example, made of piezoceramic; - Avoids any risk of damage to the electrical connection wires; Description of the invention

[0008] This goal is achieved by a fluid analysis system comprising: - A microfluidic component integrating a main microfluidic circuit and comprising a front face and a rear face, - A measurement / analysis component mounted on the front face of the microfluidic component and comprising at least one measuring element capable of being mechanically stimulated by acoustic waves, - A component that generates acoustic waves, - Characterized in that the acoustic wave generating component is mounted on the rear face of the microfluidic component.

[0009] According to one particular feature, the measurement / analysis component is a MEMS / NEMS type resonator comprising a measurement microfluidic circuit connected to the main microfluidic circuit of the microfluidic component.

[0010] According to another feature, the acoustic wave generating component is a piezoelectric component.

[0011] According to another feature, the piezoelectric component is a piezoceramic element.

[0012] According to another feature, the piezoceramic element has a two-dimensional footprint forming a projected surface in which the measurement / analysis component is inscribed.

[0013] According to another feature, the measurement / analysis component is centered on the projected surface of the piezoceramic element.

[0014] According to a particular embodiment, the system comprises several juxtaposed measuring elements, which can be acted upon by a single acoustic wave generating component.

[0015] According to another feature, the microfluidic component is made of a polymer material.

[0016] According to another feature, the microfluidic component is made of Cyclo-Olefin Copolymer or of Polymethyl Methacrylate.

[0017] According to another feature, the system includes an electronic control board on which the acoustic wave generating component is mounted.

[0018] According to another feature, the system includes an electronic measurement card mounted on the front face of the microfluidic component, carrying a reading unit and electrical contacts linking said reading unit to the measurement / analysis component.

[0019] It should be noted that the system architecture is such that the three components are in physical contact with each other, forming a stack.

[0020] The measurement / analysis component and the acoustic wave generator component are therefore arranged on either side of the microfluidic component, which does not prevent the transmission of acoustic waves through the microfluidic component, even though the latter is often made of a polymer-type material (COC or PMMA for example), a material which would nevertheless be likely to attenuate the transmission of acoustic waves and that it incorporates a fluidic network. Brief description of the figures

[0021] Other features and advantages will appear in the detailed description in connection with the attached figures listed below: - Fig. 1 represents an architecture of a fluid analysis system conforming to the state of the art; - Figures 2A and 2B represent an architecture of a fluid analysis system according to the invention, respectively seen in cross-section and in top view by transparency; - Fig. 3 represents a system according to a variant embodiment with several oscillators with a common actuation; - Fig. 4 represents a diagram showing the frequency response of the oscillation amplitude of an SNR type measurement / analysis component in different stacking configurations; - Fig. 5 represents a diagram showing the mass detection limit obtained as a function of integration time, by measuring the Allan variance for different actuation architectures; - Fig. 6 shows an example of the assembly of the piezoceramic element used in the system of the invention;

[0022] Detailed description of at least one embodiment

[0023] The system of the invention is intended for the analysis of a fluid or particles carried by the fluid using microfluidics. As a reminder, microfluidics consists of manipulating fluids in very small volumes (typically from pL to pL) in a controlled manner. This manipulation is carried out in a microfluidic component.

[0024] Thanks to the system of the invention, it is possible, for example, to characterize at least one property (for example, mass, volume, density) of a particle. By particle, we mean, for example, a biological particle such as a cell, exosome, virus, bacterium, etc. We also mean an inorganic particle such as, for example, a particle of gold, polystyrene, silica, etc.

[0025] For the remainder of the description, an orthonormal coordinate system (X, Y, Z) is defined in order to materialize the three dimensions. Microfluidic component

[0026] [Fig.2A] and [Fig.2B]

[0027] The microfluidic component 1 can also be called a microfluidic chip, microfluidic card, microfluidic interposer, or microfluidic cartridge. It is generally flat or thin in the vertical direction (along the Z-axis) compared to its other two dimensions. It may be composed of an assembly of several layers sealed together. Advantageously, it has a rectangular shape in its two dimensions X and Y and a constant thickness along Z.

[0028] The microfluidic component 1 is defined with a front face 12 and a rear face 13, opposite the front face and separated from it by the thickness of the microfluidic component. The two front and rear faces each extend along the two axes X and Y and are advantageously planar, perpendicular to the Z axis.

[0029] The microfluidic component 1 includes a microfluidic circuit, referred to as the main microfluidic circuit 10, integrated within its thickness. This main microfluidic circuit 10 may have microfluidic channels a few micrometers in diameter, having, for example, a square cross-section. Without limitation, the main microfluidic circuit 10 may also include fluidic pumps, fluidic valves, reservoirs, or other fluidic elements (not shown) for circulating the fluid within the main microfluidic circuit 10.

[0030] The microfluidic component 1 may in particular incorporate a deformable membrane (type "Ecoflex") forming one of the layers of the microfluidic component 1, this membrane being deployable to perform a function of a fluidic element such as, for example, pumping, valve...

[0031] The microfluidic component 1 can be made from several types of materials, mostly polymer-type materials such as, for example, COC (Cyclo-Olefin Copolymer) or PMMA (Polymethyl Methacrylate). Measurement / Analysis Component

[0032] [Fig.2A] and [Fig.2B]

[0033] The measurement / analysis system of the invention also includes a measurement / analysis component 2 mounted on the microfluidic component 1. In other words, the measurement / analysis component 2 is fixed to the microfluidic component 1, on its front face 12, and makes physical contact with this front face 12. Contact can be achieved by direct contact, or advantageously via one or more seals drilled at the fluidic access points and a mechanical clamping system to ensure sealing. Alternatively, adhesive can be used as a localized bonding interface between the measurement / analysis component 2 and the microfluidic component 1, except for the fluidic access areas so as not to obstruct them.

[0034] The measurement / analysis component 2 includes a microfluidic circuit called a measurement circuit 20 which connects fluidly to the main microfluidic circuit 10 when the measurement / analysis component 2 is mounted on the front face 12 of the microfluidic component 1.

[0035] The measurement / analysis component 2 is, for example, a mechanical oscillator.

[0036] The measurement / analysis component 2 thus comprises a measuring element 21 capable of being mechanically excited by acoustic waves. This measuring element 21 may consist of a beam capable of being set into vibration when excited.

[0037] By way of example, the mechanical oscillator can be an SMR / SNR type resonator (for "Suspended MicroChannel Resonator" and "Suspended Nanochannel Resonator") used for example for weighing nano or microparticles (inorganic, or biological).

[0038] A mechanical resonator 1 (SMR or SNR) comprises at least one fixed part and a suspended part, forming the measuring element 21, connected to the fixed part and capable of vibrating when excited. It also comprises the microfluidic measurement circuit 20 integrated into its suspended part, this microfluidic circuit comprising at least one fluidic channel hollowed out inside its suspended part, covered with sealed walls on all four sides (top, bottom, sides) and intended to be used for injecting a fluid into which, for example, one or more particles to be characterized are placed.

[0039] The suspended part is excited by external means at the resonance frequency or at a higher natural mode frequency. In this type of resonator, the vibration is generally carried out out of plane, but alternatively it can be generated in plane, or even in torsion.

[0040] The measurement / analysis component 2 is advantageously in the form of a right prism, for example a parallelepiped (a chip in electronic terminology). It is mounted in a suitable housing formed on the front face of the microfluidic component 1.

[0041] The measuring / analyzing component 2 may include electrical contacts to which a reading unit is connected. This unit is responsible for reading the electrical signals generated by the measuring / analyzing component when it is energized. The reading unit may be implemented on an electronic board 5 (PCB – “Printed Circuit Board” – visible in top view [Fig. 2B]), with the electrical contacts of the measuring / analyzing component 2 connected to electrical pads of the reading unit assembled on the board 5, for example, via electrical connecting wires. This electronic board 5 may be a dedicated electronic board, separate from the one used for controlling the piezoceramic element 3.

[0042] The measuring element 21 of the measuring / analyzing component 2 is capable of being excited by means of acoustic waves, created by an acoustic wave generating component. Acoustic wave generating component

[0043] [Fig.2A] and [Fig.2B]

[0044] The acoustic wave generating component is a piezoelectric component. It is advantageously made in the form of a piezoceramic element 3. It could also be a SAW (for "Surface Acoustic Wave") or PMUT (for "Piezoelectric Micromachined Ultrasonic Transducer") type device.

[0045] The acoustic wave generator component includes electrical connections to receive electrical control pulses and is thus configured to generate the desired acoustic waves.

[0046] The piezoceramic element 3 is, for example, in the form of a rectangular plate having electrical contact tabs.

[0047] In [Fig. 2B], the piezoceramic element 3 is shown in transparency. It should be understood that it is positioned under the microfluidic component 1.

[0048] A control unit is associated with the piezoceramic element 3. It is for example made on an electronic board 4 mounted on the rear face of the piezoceramic element 3. Component stacking

[0049] [Fig.2A] and [Fig.2B]

[0050] According to the invention, the system is configured to form a stack along the Z-axis. In this stack, we have: - The microfluidic component 1 which has its rear face 13 and its front face 12; - The measurement / analysis component 2 is mounted on the front face 12 of the microfluidic component 1, so as to come into contact with it. The microfluidic measurement circuit 20 is fluidically connected to the main microfluidic circuit 10 of the microfluidic component 1; - The acoustic wave generating component, for example formed from the piezoceramic element 3, mounted on the rear face 13 of the microfluidic component 1;

[0051] The system may also include the electronic card 4 having a front face on which the piezoceramic element 3 is soldered and the electronic card 5 dedicated to reading the signals emanating from the measurement / analysis component 2.

[0052] Advantageously, the acoustic wave generating component has a footprint in both dimensions X and Y forming a projected surface along the Z axis. The measurement / analysis component 2 also has a footprint in both dimensions X and Y whose surface is included in the projected surface of the acoustic wave generating component.

[0053] Advantageously also, the measurement / analysis component 2 is centered with respect to the acoustic wave generating component and has a smaller footprint along the X and Y dimensions than the acoustic wave generating component. Special project

[0054] [Fig.2A], [Fig.2B] and [Fig.6].

[0055] Experimentally, a first prototype of the system was produced, including a microfluidic component 1, a mechanical oscillator of the SNR type (made in the form of an SNR chip) mounted on the front face 12 of the microfluidic component 1 to play the role of the measurement / analysis component 2 and a piezoceramic element 3 mounted on the rear face 13 of the microfluidic component 1 and playing the role of the acoustic wave generator component.

[0056] The microfluidic component 1 is in the form of a plate or card made of a COC (Cyclo-Olefin Copolymer) or PMMA (Polymethyl Acrylic Methacrylate) type plastic polymer, which is machined using a precision machining center. The machining of this part is carried out on both sides: - On the rear face 13 to draw the microfluidic channels of the main microfluidic circuit 10 which will then be closed using an adhesive film (for example of the "MicroAmp" type); - On the front face 12, to make the housings to accommodate the SNR chip and the electronic card 5 allowing the reading of the signal from the SNR chip;

[0057] The plastic plate advantageously contains several holes to accommodate screws, on the one hand to ensure the leak-proof fluid connection using flexible seals and on the other hand to ensure the retention of the piezoceramic element 3 in contact with the rear face 13 of the microfluidic component 1.

[0058] With reference to [Fig. 6], two additional parts 30, 31 are, for example, also machined from COC or PMMA type plastic and are integrated into the system to maintain the piezoceramic element 3 in physical contact with the rear face 13 of the microfluidic component 1, at the desired location. The piezoceramic element 3 is then sandwiched between these two parts 30, 31, which are screwed together. The assembly between these two contacting parts provides, in particular, a housing for the electronic board 4 dedicated to controlling the piezoceramic element 3.

[0059] Once the parts are prepared, it is necessary to ensure the electrical connections enabling the reading of the SNR chip signal. This can be done by a "wire bonding" step, which electrically connects the metal contacts of the SNR chip to the metal contacts of the readout electronic board 5. The fluidic connection is then established to allow the circulation of fluids within the microfluidic component 1 and within the SNR chip.

[0060] It is also possible to ensure firm contact between the SNR chip and the microfluidic component 1 using a clamping piece (not shown), screwed onto both sides of the SNR chip to hold it in place. This piece, machined from transparent plastic and possibly containing an observation hole, does not obstruct the visualization of the parts of interest of the MEMS chip. Experimentation

[0061] [Fig.4] and [Fig.5].

[0062] To test the proper functioning of the system, the protocol consists of testing the frequency response of the SNR chip when the main microfluidic circuit 10 is filled with air. A frequency sweep is then performed to determine the resonant frequency of the SNR chip and its quality factor. It can thus be observed that the waves generated by the piezoceramic element are indeed transmitted to the SNR chip through the COC support formed by the microfluidic component 1. However, a moderate decrease in amplitude (less than an order of magnitude) of the response should be noted compared to that obtained when the piezoceramic element is directly mounted on the SNR chip ([Fig. 4]).

[0063] This can be explained in three ways: - The transmission of mechanical waves occurs through an additional thickness (that of the microfluidic component), which generates a dissipation of the waves and therefore a slight decrease in the efficiency of the actuation. - Since the microfluidic channels are hollow and not filled, and located directly under the SNR chip, the transmission of mechanical waves is less important. - The mechanical contact between the SNR chip and the microfluidic component is ensured here by a simple double-sided adhesive, which can help to dissipate some of the waves.

[0064] However, the quality factor, performance index, does not appear to be negatively affected by actuation of the SNR chip through the microfluidic component.

[0065] The SNR chip is then operated in closed loop (i.e. its resonant frequency is read continuously and the signal applied to the piezoceramic element 3 is constantly updated according to any frequency fluctuations).

[0066] An Allan variance experiment is performed to obtain the average frequency noise of the SNR chip, which is then translated into a mass detection limit. After 10 minutes of frequency noise data acquisition, it is possible to calculate the Allan variance of the SNR chip. This value allows for an estimation of the chip's lower mass detection limit, as a function of the integration time of the feedback loop. This detection limit depends on numerous factors, including the chip's actuation efficiency. This experiment is performed by applying the same actuation voltage to the piezoceramic for actuation in direct contact with the SNR chip (according to the prior art - [Fig. 1]) and for remote actuation through the microfluidic component according to the invention.

[0067] With reference to the diagram in [Fig.5], it can be seen that the Allan variance is similar for all the architectures tested, and a very small change in the mass detection limit is noted when the SNR chip is actuated through the microfluidic component according to the architecture of the invention.

[0068] Figures 4 and 5 also take into account an architecture in which the piezoceramic element 3 is on the rear face 13 and the system includes a clamping device to hold the stack in place. Measurement / analysis system

[0069] [Fig.3].

[0070] It is also possible to use the principle of the invention on a complete analysis system in which a single acoustic wave generating component (for example, a single piezoceramic element 3) is mounted on the rear face 13 of the same microfluidic component 1 to actuate several oscillators manufactured on one chip or on several distinct juxtaposed chips 2a, 2b, mounted on the front face 12 of the microfluidic component 1.

[0071] In this configuration, the chip or chips 2a, 2b mounted on the front face 12 of the microfluidic component 1 are arranged so as to be placed in the projected surface of the acoustic wave generating component so that all the oscillators can be acted upon by the same piezoceramic element 3.

[0072] It is indeed possible to actuate several oscillators by means of a single piezoceramic element 3, provided that the resonance frequency of each oscillator is sufficiently differentiated from the others, and that their quality factor is sufficiently high so that the actuating of one oscillator does not disturb another juxtaposed oscillator, and that there is no crosstalk between these oscillators, if ever their respective resonance frequencies were too close to each other.

[0073] This system has several advantages. It is indeed possible to: - Perform several analyses in parallel on the same sample, on the same microfluidic component 1; - To test the influence of several treatment conditions on the same sample.

[0074] Furthermore, as already indicated above, the microfluidic component 1 can have a complex architecture with fluidic elements such as pumps, valves, and reservoirs, actuated, for example, by a membrane integrated into the stack of layers of the microfluidic component. This type of architecture is described in particular in the publication referenced below: Achard, Y. Fouillet, Quantitative biological assays with on-chip calibration using versatile architecture and collapsible chambers, Sensors and Actuators B: Chemical, Volume 261, 2018, Pages 106-114, ISSN 0925-4005,

[0076] https: / / doi.org / ! 0.1016 / j.snb.2018.01.111.

[0077] The solution of the invention thus makes it possible to remotely actuate a measurement / analysis component 2 sensitive to acoustic waves mounted on the front face 12 of a microfluidic component 1 by bringing into contact, against the rear face 13 of the microfluidic component, a suitable acoustic wave generator component, controlled to emit acoustic waves. This principle applies even when the microfluidic channels of the main microfluidic circuit 10 are empty.

[0078] With this configuration, it is possible to continue observing the main microfluidic circuit, to facilitate the electrical connections of the components and to implement several separate measurement / analysis chips juxtaposed, mounted on the front face of a single microfluidic component.

Claims

Demands

1. A fluid analysis system comprising: - A microfluidic component (1) defined with a front face (12) and a rear face (13), opposite the front face and separated from it by the thickness of the microfluidic component, said microfluidic component having a main microfluidic circuit (10) integrated within its thickness, - A measurement / analysis component (2) mounted on the front face (12) of the microfluidic component (1) so as to come into contact with it and which includes at least one measuring element (21) capable of being mechanically stimulated by acoustic waves, - An acoustic wave generator component controlled to generate the acoustic waves for stimulating said measuring element (21), - Characterized in that: - The acoustic wave generator component is mounted on the rear face (13) of the microfluidic component (1),- The acoustic wave generating component has a two-dimensional footprint forming a projected surface in which the measurement / analysis component (2) is inscribed.

2. System according to claim 1, characterized in that the measurement / analysis component (2) is a MEMS / NEMS type resonator comprising a measurement microfluidic circuit (20) connected to the main microfluidic circuit (10) of the microfluidic component (1).

3. System according to claim 1 or 2, characterized in that the acoustic wave generating component is a piezoelectric component.

4. System according to claim 3, characterized in that the piezoelectric component is a piezoceramic element (3).

5. System according to claim 4, characterized in that the measurement / analysis component (2) is centered on the projected surface of the piezoceramic element.

6. System according to any one of claims 1 to 5, characterized in that it comprises several juxtaposed measuring elements, actuable by a single acoustic wave generating component.

7. System according to any one of claims 1 to 6, characterized in that the microfluidic component (1) is made of a polymer material.

8. System according to claim 7, characterized in that the microfluidic component (1) is made of Cyclo-Olefin Copolymer or Polymethyl Methacrylate.

9. System according to any one of claims 1 to 8, characterized in that it comprises an electronic control card (4) on which the acoustic wave generating component is mounted.

10. System according to any one of claims 1 to 9, characterized in that it comprises an electronic measuring card (5) mounted on the front face (12) of the microfluidic component, carrying a reading unit and electrical contacts linking said reading unit to the measuring / analyzing component (2).