MICROFLUIDIC VALVE, METHOD FOR ITS MANUFACTURE, AND USES THEREOF

Abstract

A microfluidic valve, includes arranging a substrate of a mechanically inert material to one or more physicochemical properties over time, configuring a structural portion of the valve; additive layer manufacturing to print, a succession of one or more filaments of a material with mechanical response to one or more of said physicochemical properties over time, preferably LCP, configuring a functional portion of the valve; and arranging the succession of filaments on the substrate, configuring a fluid flow rate through the valve using the application of an anti-adhesion treatment on one or more interfaces of said filaments and the substrate.

Claims

1. A method for the manufacture of a microfluidic valve, wherein said method comprises performing the following steps: arranging a substrate configuring a structural portion of the valve, wherein said substrate comprises at least one mechanically inert material to one or more physicochemical properties over time; printing a succession of one or more filaments of a mechanically responsive material to one or more of said physicochemical properties over time, wherein said mechanically responsive material comprises at least one LCP, and wherein the succession of filaments configures a functional portion of the valve; wherein said method comprises an additional step of arranging the succession of filaments of the mechanically responsive material on the substrate of a mechanically inert material by applying an anti-adhesion treatment on one or more interfaces of said filaments and the substrate; wherein the substrate of a mechanically inert material and the filaments of the mechanically responsive material at least partially configure a fluid flow rate through the valve, wherein the succession of filaments of the mechanically responsive material is arranged, in the mentioned fluid flow rate, such that the variation in one or more of the physicochemical parameters causes a disruption in the molecular order of the LCP, contracting or expanding the material along a longitudinal or transversal direction of the filaments, and leading to an increase or reduction of the fluid flow rate.

2. The method according to claim 1, wherein the succession of filaments of the mechanically responsive material is arranged, in the mentioned fluid flow rate, as a plurality of substantially parallel filaments, forming a rectangular or square surface.

3. The method according to claim 1, wherein the succession of filaments of the mechanically responsive material is arranged, in the mentioned fluid flow rate, adopting a substantially planar radial distribution, wherein each filament starts from a central region common to the rest of the filaments.

4. The method according to claim 1, wherein the succession of filaments of the mechanically responsive material is arranged, in the mentioned fluid flow rate, as a substantially planar azimuthal or spiral distribution starting from a central region common to one or more filaments.

5. The method according to claim 1, comprising an additional step of adding a coupling agent between at least one part of the filaments of the mechanically responsive material and the substrate of a mechanically inert material.

6. The method according to claim 5, wherein the coupling agent is a hybrid organic-inorganic coupling agent.

7. The method according to claim 1, wherein the anti-adhesion treatment comprises at least one of the group consisting of: the addition of a chemical agent with anti-adhesion capability to LCP; and the introduction of micro-roughness on the contact surface of the substrate of a mechanically inert material with the succession of filaments; and the use of materials with a surface energy lower than 40 mJ/m.sup.2 for the manufacture of the substrate or the succession of filaments; and the application of an anti-adhesion coating on the substrate of a mechanically inert material or on the succession of filaments; and the spatial separation of the succession of filaments with respect to the substrate.

8. The method according to claim 7, wherein the chemical agent comprises one or more long-chain aliphatic or fluorinated modifiers.

9. The method according to claim 1, comprising the additional arrangement of one or more layers of a mechanically inert material after printing the filaments of the mechanically responsive material, configuring one or more additional elements of the structural portion of the valve.

10. The method according to claim 10, comprising a step of applying an anti-adhesion treatment on one or more of the additional layers of a mechanically inert material.

11. The method according to claim 1, comprising a step of applying a curing treatment after finishing the printing of the filaments of the mechanically responsive material.

12. The method according to claim 11, wherein the step of applying a curing treatment is performed selectively in certain regions of the valve, or wherein a succession of multiple curing operations is applied on said regions.

13. The method according to claim 1, wherein the succession of filaments of the mechanically responsive material is printed with a three-dimensional shape.

14. The method according to claim 13, wherein the succession of filaments of the mechanically responsive material is printed with a conical shape.

15. A valve for regulating the flow of a fluid through a microfluidic device, wherein the valve is manufactured by a method according to claim 1.

16. The valve according to claim 15, wherein the mechanically responsive material comprises a mixture of at least one main-chain LCP with reactive acrylate groups at the end of said chain, together with one or more photoinitiators.

17. The valve according to claim 15, wherein the LCP exhibits mechanical response to a change in lighting, temperature, humidity, pH or electromagnetic field.

18. The valve according to claim 15, wherein the LCP exhibits the capability to respond to light photothermally or photochemically.

19. The valve according to claim 18, wherein the LCP comprises azobenzene, spyropyran, diarylethene, rotaxane, absorbent nanoparticles or absorbent chromophores, such as benzophenones, rhodamines, stilbenes, coumarins, or benzotriazoles.

20. The valve according to claim 15, wherein the substrate comprises PDMS or a cyclic olefin polymer structure.

21. The valve according to claim 15, wherein the structural portion of the valve comprises: one or more anti-adhesion openings arranged between the structural portion and the mechanically responsive material of the functional portion of the valve; and/or micro-roughness arranged between the structural portion and the mechanically responsive material of the functional portion of the valve; and/or a mechanically inert material with a surface energy lower than 40 mJ/m.sup.2; and/or an anti-adhesion coating.

22. A peristaltic pump comprising a successive arrangement of two or more valves according to claim 15 or one or more valves according to claim 15 in combination with a passive flow restriction element.

23. A microfluidic system comprising a valve according to claim 15, in combination with an actuator of said valve adapted for regulating a physicochemical property to which the mechanically responsive material with mechanical configuring the functional portion of the mentioned valve is sensitive.

24. The system according to claim 23, wherein the actuator of said valve for regulating the physicochemical property comprise a lighting subsystem, a temperature regulation subsystem, a humidity regulation subsystem, a pH regulation subsystem, or an electromagnetic field regulation subsystem.

25. Use of a microfluidic valve according to claim 15 in in vitro biomedical analyses, in the manufacture of organ-on-a chip devices, in drug screening analysis, in in vitro biological studies, in the monitoring and control of environmental pollution, in biological risk detection, or in food analysis.

Description

DESCRIPTION OF THE DRAWINGS

[0057] FIG. 1 shows an example of the microfluidic valve according to the present invention, in a preferred embodiment thereof.

[0058] FIGS. 2a-2c show three examples of the two-dimensional printing pattern of a mechanically responsive material which can be used for the manufacture of a microfluidic valve of the invention, according to three preferred embodiments thereof.

[0059] FIG. 3 shows an example of the general operating principle of the microfluidic valve of the invention, according to a preferred embodiment thereof.

[0060] FIG. 4 shows an example of the microfluidic valve of the invention, according to a preferred embodiment thereof, implemented as a reverse-acting valve.

[0061] FIG. 5a shows an example of the three-dimensional printing pattern of a mechanically responsive material for the manufacture of a microfluidic valve of the invention. FIG. 5b shows a preferred embodiment thereof, implemented as a reverse-acting valve.

[0062] FIG. 6 shows a sequential arrangement of microfluidic valves according to the invention, configured as a peristaltic pump whose stages can be activated with light radiation of different wavelengths.

[0063] FIGS. 7a-7b show examples of a valve and of a peristaltic pump according to the invention, respectively, wherein the substrate thereof incorporates openings acting as anti-adhesion means.

REFERENCE NUMBERS OF THE DRAWINGS

[0064] (1) Substrate of a mechanically inert material.

[0065] (2) Filaments of a material with mechanical response.

[0066] (3) Fluid flow rate.

[0067] (4) Central printing region of the filaments of a mechanically reactive material.

[0068] (5) Additional layers of a mechanically inert material.

[0069] (6) Light.

[0070] (7) Anti-adhesion openings.

DETAILED DESCRIPTION OF THE INVENTION

[0071] As described in the preceding sections, as well as in the examples shown in FIGS. 1-7 of this document, the method for manufacturing microfluidic valves essentially comprises at least the following steps: [0072] arranging a substrate (1) configuring a structural portion of the valve, wherein said substrate (1) comprises at least one mechanically inert material to one or more physicochemical properties over time. [0073] printing a succession of one or more filaments (2) of a material with mechanical response to one or more of said physicochemical properties over time by additive layer manufacturing, wherein said material with mechanical response comprises at least one LCP, and wherein the printed filaments (2) configure a functional portion of the valve. [0074] arranging the succession of filaments (2) of the mechanically responsive material on the substrate (1) of a mechanically inert material by applying an anti-adhesion treatment on one or more contact surfaces between said filaments (2) and the substrate (1).

[0075] As shown in FIG. 1, the substrate (1) and the succession of filaments (2) of the mechanically responsive material at least partially configure a fluid flow rate (3) through the valve. Likewise, the succession of filaments (2) of the mechanically responsive material is arranged, in the mentioned flow rate (3), such that the variation in one or more of the physicochemical parameters (for example, by means of lighting in a given frequency range) causes a disruption in the molecular order of the LCP, contracting or expanding the material along the longitudinal or transversal direction of the filaments (2), respectively, and leading to an increase or reduction of the fluid flow rate (3).

[0076] The configuration of the flow rate (3) shown in FIG. 1 therefore adopts a channel shape and can be configured with a curved channel geometry, which is adjusted to the actuator in the actuated state or can use a planar upper part acting on a channel, opening or closing it depending on the state of the valve (non-actuated or actuated), as shown in FIG. 3. This configuration is also advantageous, since the area of the functional portion in contact with the opposite wall of the structural portion is partial, which facilitates the subsequent detachment thereof when the mechanically responsive materials return to their initial state (non-actuated).

[0077] The stiffness of the mechanically responsive material used for printing the succession of filaments (2), as well as the ratio between the thickness and the dimensions in the plane (longitudinal and/or transversal) of the resulting LCE or LCN sheet, influence the degree of deformation of the functional portion of the valve. An excessive increase in these parameters reduces deformation, negatively impacting valve performance. Preferably, the succession of filaments (2) comprises LCPs which, when printed, give rise to an LCE-type cross-linked polymer system with a Young's modulus in the order of MPa or an LCN type cross-linked polymer system with a Young's modulus in the order of GPa. The longitudinal and/or transversal dimensions of the resulting LCE or LCN sheet are typically comprised between 1-20 mm and its thickness between 50-1500 μm.

[0078] Adhesion between the substrate (1) and the succession of filaments (2) also plays a key role in valve performance and can even cancel out its functionality if said adhesion is irreversible. Although it is true that the presence of liquids can reduce adhesion between certain surfaces, adhesion between surfaces in a liquid is also known to significantly increase with contact time. This latter scenario is what occurs when liquid is expelled from the contact area between the substrate (1) and the succession of filaments (2). For this reason, preventing or controlling this adhesion by means of the application of an anti-adhesion treatment is key. Preferably, said anti-adhesion treatment comprises: [0079] the addition of a chemical agent with anti-adhesion capability to LCP, preferably one or more fluorinated modifiers or long-chain aliphatic silanes comprising, for example, nonyl trichlorosilane, octadecyl trichlorosilane, octyl trichlorosilane, fluoro-n-octyl trichlorosilane or fluoro-n-octyl trimethoxysilane; and/or [0080] the introduction of micro-roughness on the contact surface of the substrate (1) of a mechanically inert material with the succession of filaments (2) (e.g., by sandblasting using glass or metal as mechanically inert material), preferably with a mean square roughness, or mean square deviation of the profile in the order of a micron since, under these conditions, adhesion between elastomers and rigid surfaces is known to decrease considerably [Fuller et al. Proc. R. Soc. Lond. A 1975 345, 327-342]; and/or [0081] the use of materials with a surface energy lower than 40 mJ/m.sup.2 for the manufacture of the substrate (1) and/or the succession of filaments (2), such as cyclic olefin polymers (COP, 30 mJ/m.sup.2) and polydimethylsiloxane (PDMS, 19-21 mJ/m.sup.2); and/or [0082] the application of an anti-adhesion coating on the substrate (1) of a mechanically inert material and/or on the succession of filaments (2), preferably comprising one or more fluoropolymers, such as polytetrafluoroethylene (PTFE); and/or [0083] the spatial separation of the succession of filaments (2) with respect to the substrate (1).

[0084] In this way, adhesion is drastically reduced by decreasing the probability of adhesion forces due to friction between the functional portion and the structural portion of the valve, which reduces the risk of failure thereof due to the possible fixing of one portion to the other. However, in those devices without these problems of adhesion between the substrate (1) and the succession of filaments (2), it would be possible not to apply said treatments.

[0085] For the suitable actuation of the valves of the invention, it is necessary to use mechanically responsive materials in the form of inks whose rheology leads, after the printing and, optionally, the curing thereof, to LCP filaments (2) with controlled morphology, according to the properties described above. To that end, said inks preferably comprise a mixture of main-chain LCPs with reactive acrylate groups at the end of the chain, together with a small amount of photoinitiator. Likewise, the mechanically responsive liquid crystal polymer preferably contains absorbent molecular units incorporated in its main chain, which are either photoresponsive (e.g., azobenzene, spyropyran, etc.), undergoing conformational changes upon absorbing light disturbing the liquid crystal order, or absorbent molecules which transform the absorbed light into heat, also disturbing the liquid crystal order. Another possibility is the incorporation of the units in the LCP ink as an additional monomer which later binds to the polymer structure. The polymer is primarily obtained by a Michael addition process, making a mixture of mesogenic diacrylates with reactive units, which are in turn mixed with n-butylamine in a molar ratio close to 1, with a diacrylate excess to ensure the formation of polymer chains, through the Michael addition reaction, with terminal acrylate groups which can subsequently react in a second step performed by photopolymerization. The amine-acrylate chemistry has been used as an example, but it is also possible to use other reactions for the formation of the reactive chains, such as the thiol-acrylate, amine-epoxy, etc., leading to the same effect. The inks thus prepared generally have viscoelastic behavior, where the easy formation of long and thin filaments (2) is possible by simply printing them from the polymer material, generating well oriented fibers, with the mesogenic monomers aligned in the printing direction. Other possibilities also include the use of photo-chemical or photo-thermal materials, such as inks containing nanoparticles or molecules which transform light into heat. The magneto-thermal effects can also be used in the scope of the invention, in different preferred embodiments thereof.

[0086] The substrate (1) of the valve preferably comprises one or more biocompatible materials, selected for example from those commonly used in microfluidic applications, such as PDMS or cyclic olefin polymer structures.

[0087] FIGS. 2a-2c show three examples of configurations adopted by the filaments (2) of the mechanically responsive material for the manufacture of different preferred embodiments of the valves of the invention. In that sense, FIG. 2a shows a succession of filaments (2) of the mechanically responsive material arranged as a plurality of substantially parallel lines, forming a rectangular or square surface. This configuration is what the valve of FIG. 1, for example, adopts. In another embodiment (FIG. 2b), the succession of filaments (2) of the mechanically responsive material is arranged adopting a substantially planar radial distribution, wherein each filament (2) starts from a central region (4) common to the rest of filaments (2). In an additional embodiment (FIG. 2c), the succession of filaments (2) of the mechanically responsive material is arranged, in the aforementioned fluid flow rate (3), as an azimuthal distribution and, as an approximation to same on a continuous path, a substantially planar spiral, starting from a central region (4) common to one or more of the filaments (2).

[0088] A potential problem with mechanically stressed composite actuators is the delamination of one or more of the materials used. To promote adhesion of the functional portion of the valve to the structural portion (at those points or regions where it is needed), specific chemicals can be applied to the latter. For example, exposing the corresponding surfaces to ozone generated by radiation ultraviolet (UV), oxygen plasma, or other gases, or treatments with hybrid organic-inorganic coupling agents for acrylate-based inks, such as 3-aminopropyltriethoxysilane, 3-aminopropyltrimethoxysilane, 3-aminopropyltrichlorosilane, 3-mercaptopropyltrimethoxysilane, 3-mercaptopropyltriethoxysilane, 3-methacryloxypropyltrimethoxysilane. This generates reactive species covalently bound to the surface, which can later be used as bonds for the acrylate inks when they are photocured, increasing the binding strength of said inks.

[0089] In other embodiments of the invention, the manufacturing method may also comprise the additional arrangement of one or more layers (5) of a mechanically inert material after printing the succession of filaments (2) with mechanical response, configuring one or more additional elements of the structural portion of the valve. Optionally, said method may comprise a step of applying an anti-adhesion treatment on one or more of the additional layers (5) of a mechanically inert material to prevent the irreversible adhesion between the layers (5), with the substrate (1), and/or with the succession of filaments (2).

[0090] In other embodiments of the invention, the manufacturing method may also comprise a step of applying a curing treatment, preferably after finishing printing the filaments (2) of the mechanically responsive material. Said curing step can be performed selectively on certain regions of the valve, wherein a succession of multiple curing operations can optionally be applied on said regions. The method of the invention also allows printing filaments (2) which deform (for example, due to an external mechanical action) before being cured. This possibility is interesting for certain complex valves or actuator designs. In other embodiments, the method of the invention also allows the printing of multi-stable structures of filaments (2), obtaining different deformations in each curing.

[0091] As an example of preferred embodiment of the invention, regarding to a light-sensitive valve (6), it is possible to use a PDMS substrate (1) on which the LCP filaments (2) are printed. The LCP-PDMS composite system can be manufactured by 3D printing the LCP material onto the PDMS, the latter being configured in the form of a film, chip, or a previously manufactured chip precursor part. Additional PDMS material can be added and cured to complete the process of manufacturing the chip. The 3D-printed LCP element can also be embedded within or on the underside of the PDMS. For example, the filaments of the mechanically light-responsive material (6) can be 3D printed, to create a membrane with its LCP director orientation parallel to the direction of the channel in the PDMS block, on top of the thin PDMS membrane base of the channel (as shown in FIG. 1). Considering the expansion induced by the light (6) in the direction perpendicular to the LCP director, the lighting on the active LCP element causes the expansion of the membrane along the direction perpendicular to the channel. If it is confined between two sufficiently thick fixed walls, the band bends, blocking the flow of fluid through the channel, therefore acting as a valve, according to the object of the invention.

[0092] In another preferred embodiment of the invention, the non-actuated valve closes the channel. Light actuation (6) opens the valve, allowing the liquid to flow as shown in the embodiment represented in FIG. 4, therefore configuring a reverse-acting valve design.

[0093] As an alternative to the printing of the succession of filaments (2) with essentially flat configurations (such as the ones shown in FIGS. 1-4), it is also possible to print said filaments (2) with a three-dimensional shape, preferably with a conical shape following a radial distribution such as the one shown in FIG. 5a. In this way, when the succession of filaments (2) is stimulated by an external agent (temperature, light, etc.), the shape of said succession of filaments (2) is modified into a cone of smaller height and wider base, allowing the realization of reverse-acting valves such as the one shown in FIG. 5b. In the absence of an external stimulus, this type of valve prevents the flow of the fluid, which is otherwise allowed.

[0094] In other preferred embodiments of the invention, it is possible to manufacture more complex actuators with the proposed method. For example, it is possible to configure a succession of two or more valve-type elements, located individually, forming a peristaltic pump as shown in FIG. 6. In said embodiment, the mechanically responsive materials of the functional portion can be independently actuated with three light beams illuminating each of them separately. Alternatively, they can be manufactured with materials sensitive to different wavelengths (e.g., red (R), green (G), and infrared (IR) in said figure), and/or with each valve being actuated by different lights (6). An independent control of each valve is thereby provided, facilitating the realization of peristaltic movements in the flow rate (3) thereof, by means of a suitable sequence of lighting events. Irradiation with suitable intensities and sequences of light (6) thus causes a unidirectional flow of the fluid. In other embodiments of the invention, it is possible to configure the peristaltic pump as a combination of one or more valves according to any of the embodiments described herein and a passive flow restriction element.

[0095] Other embodiments shown in FIGS. 7a-7b depict a valve design wherein the structural portion of said valve (and, preferably, its substrate (1)) comprises one or more openings (7) which act as anti-adhesion means, given that the use of geometries minimizing contact between parallel surfaces reduces adhesion therebetween.

[0096] Lastly, another object of the invention relates to a microfluidic system comprising a valve as herein described in combination with an actuator of said valve, wherein said actuator comprises means adapted for regulating a physicochemical property to which the mechanically responsive material comprising the functional portion of the mentioned valve is sensitive. Examples of said actuators can be:

[0097] Light: Light can be applied by means of the use of light sources such as LEDs or lasers which can preferably form part of an external device controlling the microfluidic chip.

[0098] Temperature: The chip can incorporate resistive elements close to the LCE/LCN, so that when a current is applied, heat is dissipated, and the valve is actuated. In this case, the chip could have contact electrodes which are connected to an external control module. Alternatively, the chip can incorporate a light-absorbing sheet adjacent to the LCE which can transform light radiation into heat in the LCE and activate it.

[0099] Electrical: By incorporating additives both in the LCE/LCN and in an adjacent sheet which provide resistivity to the material, such as carbon nanotubes, carbon black, etc., it is possible to heat the LCE/LCN by applying current and thereby actuate the system.

[0100] Humidity or pH: Materials that incorporate, for example, hydrogen bonds are used both in the LCE/LCN and in an adjacent sheet for this purpose. The application of solutions with a suitable pH can weaken these bonds, changing the mechanical properties.

[0101] Magnetothermal: By incorporating additives both in the LCE/LCN and in an adjacent sheet that provide magneto-thermal properties to the material, such as iron nanoparticles, it is possible to heat the LCE/LCN by applying a magnetic field and thus actuate the system.