Microfluidic valve, method of manufacture and use thereof

Abstract

The invention relates to a method for manufacturing a microfluidic valve, comprising: providing a substrate (1) of a mechanically inert material, mechanically inert over time with respect to one or more physico-chemical properties, the substrate (1) being configured with a structural part of the valve; printing, by additive layer manufacturing, a series of one or more filaments (2) of a material, mechanically responsive over time with respect to one or more physico-chemical properties, and preferably a LCP, the series of filaments (2) being configured with a functional part of the valve; and providing the series of filaments (2) on the substrate (1), configuring a fluid flow rate (3) through the valve by applying an anti-adhesion treatment on one or more interfaces of the filaments (2) and the substrate (1). In this way, a change in one or more physico-chemical parameters causes a sequential disruption of the LCP molecules, contracting or expanding their polymer chains in the longitudinal or transverse direction of the filaments (2), and causing an increase or decrease in the fluid flow rate (3).

Description

[0001] The project that gave rise to this application was funded by the EU Horizon 2020 Research and Innovation Programme, grant agreement number 829010. Technical Field

[0002] This invention belongs to the field of microfluidics. More specifically, this invention relates to a new technology for microfluidic actuators, preferably valves, which have mechanical and functional responses when subjected to external stimuli, such as changes in light intensity, temperature, pH, humidity, or electromagnetic fields. Background Technology

[0003] Microfluidic devices, also known as microfluidic chips, enable the precise processing of small amounts of fluid samples, facilitating reliable, rapid, accurate, and high-throughput analytical assays. Advances in microfluidic technology have had a significant impact on the biomedical field, fostering the development of new tools for drug screening, biological research, and on-site diagnostics, and offering great promise for personalized medicine. Beyond healthcare, microfluidic technology is also crucial in other areas requiring rapid and cost-effective analytical tools, such as environmental pollution monitoring and control, biohazard detection, and the food industry. Therefore, the microfluidic market is expected to continue growing at a CAGR of 19% over the next five years (projected to reach €9 billion in 2021).

[0004] To control fluid flow within the chip or to perform analytical tasks on the flow, most current microfluidic devices require large and expensive auxiliary equipment located outside the chip. This means that microfluidic platforms are very expensive, typically exceeding €20,000, and their operation can usually only be performed by highly skilled personnel (see, for example, J. ter Schiphorst et al., Lab Chip (2018) 18, 699). Although different existing solutions have attempted to integrate all these components into the chip itself at the laboratory level, the inherent small size and complexity of these devices, and the difficulty of handling different types of materials within them, make integrating all the necessary functions into a single device feasible only on a laboratory scale. This temporarily precludes the development of standalone microfluidic devices that are industrially feasible and commercially viable using current technology.

[0005] Regarding the mechanical responses of microfluidic devices developed to date, their ability to perform certain operations is limited, such as opening or closing channels using valves or generating controlled fluid flow using pumps. For this reason, these operations mostly rely on external auxiliary components and are performed outside the microfluidic chip itself. In prior art, which falls under the category of existing technology, the integration of active pumps and valves into microfluidic chips has been tested using electroosmotic or piezoelectric pumps, and stimulus-sensitive hydrogels that perform certain functions, similar to externally activated valves. However, the inherent small size and complexity of microfluidic devices, the high diversity of material types used in the field (where compatibility with known pumps and valves is not always possible), and the complexity of the fabrication techniques required to realize them in their final forms make it difficult, inherently costly, and, in short, infeasible for large-scale industrial production. All these limitations hinder further market penetration of microfluidic technology and limit the development of new innovative devices capable of taking microfluidic technology to a new stage.

[0006] The present invention aims to solve the above-mentioned problems by allowing the fabrication of novel microfluidic devices capable of performing different mechanical functional characteristics of a chip in response to the application of external stimuli, such as temperature, light, pH, or other physicochemical properties. In this way, the microfluidic device can be remotely controlled and dynamically operated. Summary of the Invention

[0007] To address the aforementioned limitations and problems, this invention proposes the use of liquid crystal networks or elastomers (LCNs or LCEs) to provide mechanical responsiveness to certain external stimuli (light, temperature, etc.). The LCNs and LCEs can be obtained from liquid crystal polymers (LCPs) that have undergone a polymer chain crosslinking process. The latter material can be applied in a controlled manner using add-layer manufacturing techniques, and once crosslinked, it can generate LCNs or LCEs, thereby allowing the configuration of active microfluidic valves to have mechanical responsiveness to changes in physicochemical values, such as light, humidity, pH, temperature, or electromagnetic fields. Therefore, this mechanical response allows for the regulation of fluid flow in microfluidic devices, for example, in the form of valves, to variably regulate or drive the fluid in a larger loop or system over time. Within the scope of this invention, the additive printing process of LCPs and its transformation into LCEs or LCNs with the aforementioned functional properties will be referred to as a "4D printing" process (considered a fourth dimension given their responsiveness over time).

[0008] While the use of 4D printing methods for LCEs and LCNs is generally known (and therefore not the subject of this invention), their specific application in the manufacture of microfluidic valves has not been previously described, based on the features claimed herein. This involves printing the LCPs in a specific, fixed geometric arrangement to produce cross-linked polymer systems LCEs or LCNs, allowing for the efficient actuation of the valves in a microfluidic device. In this sense, as a result of the selected printing process, local anisotropy of the printing material is achieved, causing the long polymer chains of the LCPs to oriented in the direction of needle movement. This defines the orientation of the filaments during deposition on other materials used as a substrate, resulting in precise control of the cross-linked morphology of the LCEs or LCNs arising from the LCP chains. This allows for the subsequent execution of desired microfluidic flow regulation functions. Once configured as a valve, the reduction in the molecular order of the cross-linked LCPs caused by external stimuli such as temperature or light causes the material to contract along its main direction, in the preferred direction of the mesocrystalline units of the polymer chains, and to expand along its orthogonal direction. As a result of this behavior, the function of the valve can be tuned by appropriately selecting materials (depending on whether their properties require adjustment via physicochemical and other parameters) and a printing device that allows for the desired behavior in both space and time. Generally, the mechanical response characteristics of certain LCNs or LCEs relative to external changes are known in the prior art, and therefore such mechanical response characteristics are not part of the purpose of this invention. Similarly, this document claims protection for configurations of microfluidic valves and specific embodiments thereof. Likewise, although the term LCP is used herein to refer to inks used within the scope of this invention, the interpretation of the term includes not only polymer chains of liquid crystals, but also liquid crystal monomers and combinations thereof, and generally any material that acquires anisotropy upon deposition due to the preferred orientation of its components.

[0009] Therefore, the main object of the present invention relates to a method for manufacturing a microfluidic valve, the method comprising performing the following steps:

[0010] - A substrate is provided, the substrate configuring the structural portion of the valve, wherein the substrate comprises at least one mechanically inert material that is mechanically inert to one or more physicochemical properties over time;

[0011] - At least one mechanically responsive material is printed by adding layers, the mechanically responsive material exhibiting mechanical responsiveness to one or more of the aforementioned physicochemical properties over time, wherein said properties can be acquired before, during, or after printing. The material comprises at least one LCP, and the material is printed as a series of one or more filaments, the series of filaments configuring the functional portion of the valve.

[0012] Advantageously, the manufacturing method includes an additional step of setting the series of filaments of the mechanically responsive material on the substrate of a mechanically inert material by applying an anti-adhesion treatment at one or more interfaces of the filaments and the substrate. In this way, the substrate and the series of filaments are at least partially configured for a fluid flow rate through the valve, wherein the series of filaments of the mechanically responsive material are set at such a flow rate that a change in one or more physicochemical parameters causes a disruption of the molecular order of the LCP, causing its polymer chains to contract or expand longitudinally or laterally along the filaments, resulting in an increase or decrease in the fluid flow rate. The above embodiments should be understood to also include cases where the mechanically responsive material is directly printed onto the substrate, which is formed as part of the valve structure, similar to cases where the mechanically responsive material is temporarily printed onto a first substrate (as a manufacturing support) and subsequently transferred or attached to a second substrate, which is formed as part of the valve structure.

[0013] As a result, the valve obtained using the technology of this invention allows for precise programming of the magnitude and direction of the force applied to the flow rate, and allows for regulation of the fluid flow circulation through the microfluidic system, the flow rate being configured by the substrate and the mechanically responsive material. Therefore, it is possible to precisely control the resulting structure in space and time in a reversible and determinate manner. In this sense, through the precise design of the internal structure and the resulting forces (which can be achieved via the described 4D printing platform), this invention allows for the acquisition of complex geometries and functions that are unattainable by currently available LCP processing technologies. In addition to stretching or bending, this invention also allows for the generation of other more complex functions, such as the opening of orifices or even the rotation of the functional portion of the valve, thus providing new possibilities and functions for shape transformations in known liquid crystal (LC) actuator technology. If suitable materials are provided and fabricated with suitable functions or molecular switches, the concept of LCP 4D printing can potentially be extended to temperature and light, as well as a wide range of external stimuli, such as electric and magnetic fields, pH, or humidity. Furthermore, these actuators can be fabricated directly on other substrates or devices, or on large surfaces, bringing the proposed technology closer to industrial production. In particular, as a preferred embodiment, the printing method allows for the integration of 3D-printed mechanically responsive LCP elements with inert materials commonly used in microfluidics, such as polydimethylsiloxane (PDMS), and allows for the fabrication of adaptable composite devices, wherein the functional portion of the valve deforms and protrudes, acting as, for example, a lens. As mentioned above, PDMS is a key material in biological and medical microfluidic devices; therefore, the 4D printing method for LCP materials of the present invention represents a promising opportunity to produce dynamically adjustable systems (e.g., microfluidic pumps or valves) that can be integrated into microfluidic devices according to the specific embodiments described below.

[0014] In this sense, in a preferred embodiment of the method described in this invention, the series of filaments of the mechanically responsive material are arranged as a plurality of substantially parallel filaments at the fluid flow rate, forming a rectangular or square surface.

[0015] In another preferred embodiment of the method, the series of filaments of the mechanically responsive material are arranged at the fluid flow rate in a substantially planar radial distribution, wherein each filament is arranged starting from a central region shared by the remaining filaments.

[0016] In another preferred embodiment of the method, starting from a central region shared by one or more filaments, the series of filaments of the mechanically responsive material are arranged in an azimuthal distribution with respect to the fluid flow rate, or approximately, in a substantially planar spiral distribution, which is easier to achieve in practice.

[0017] In another preferred embodiment of the method, the method includes an additional step of modifying the surface to promote adhesion between the constituent elements. This modification may include, for example, exposing the corresponding surface to ozone generated by ultraviolet (UV) radiation, oxygen plasma, or other gases. Similarly, a coupling agent may be applied between at least a portion of the mechanically responsive material and the substrate. More preferably, the coupling agent is a hybrid organic-inorganic coupling agent (e.g., aminosilane, mercaptosilane, or epoxysilane).

[0018] In another preferred embodiment of the method, the anti-adhesion treatment includes:

[0019] - Adding an anti-adhesion chemical agent to the LCP, preferably one or more fluorinated modifiers or long-chain aliphatic silanes, such as nonyltrichlorosilane, octadecyltrichlorosilane, octyltrichlorosilane, fluoro-n-octyltrichlorosilane, or fluoro-n-octyltrimethoxysilane; and / or

[0020] - Introducing micro-roughness on the contact surface between the mechanically inert substrate and the series of filaments; and / or

[0021] - Use surface energy below 40 mJ / m 2 The material is used to manufacture the substrate and / or the series of filaments; and / or

[0022] - Apply an anti-adhesion layer to the mechanically inert substrate and / or to the series of filaments; and / or

[0023] - The series of filaments are spatially separated relative to the substrate.

[0024] In another preferred embodiment of the method, the method includes attaching one or more layers of mechanically inert material after printing the mechanically responsive material, thereby configuring one or more additional elements of the structural portion of the valve. Optionally, the method may include a step of applying an anti-adhesion treatment to one or more additional layers of mechanically inert material to prevent irreversible adhesion between the layer and the substrate and / or the series of filaments.

[0025] In another preferred embodiment of the method, the method includes a step of applying a curing process after the printing of the mechanically responsive material is completed. More preferably, the curing step is selectively performed in certain areas of the valve, and / or multiple successive curing operations are applied to the areas.

[0026] In another preferred embodiment of the method, the printing of the series of filaments of the mechanically responsive material is performed in a three-dimensional shape, more preferably in a conical shape following a radial distribution. In this way, when the series of filaments is stimulated by external factors (temperature, light, etc.), the series of filaments changes its shape toward a cone with a smaller height and a wider base, thereby allowing for the realization of, for example, a reverse-acting or normally closed valve; that is, preventing the flow of the fluid in the absence of external stimulation, which would otherwise allow the fluid to flow.

[0027] A second object of the invention relates to a valve for regulating fluid flow via a microfluidic device, said valve being advantageously manufactured according to any of the embodiments described herein.

[0028] In a preferred embodiment of the valve of the present invention, the mechanically responsive material is a mixture of at least one main-chain LCP and one or more photoinitiators, wherein the main-chain LCP has reactive acrylate groups at the ends of the chain.

[0029] In another preferred embodiment of the valve described in this invention, once crosslinked and formed, the LCP exhibits a mechanical response to changes in light, temperature, humidity, pH, or electromagnetic fields. More preferably, the LCE or LCN exhibits a mechanical response to light (photochemical and photothermal). The introduction of photoactive functionality can be achieved primarily through two different strategies. On one hand, the first strategy is based on the incorporation of photoisomerization units, such as azobenzene, spiropyran, diarylethylene, or rotaxane, which, when irradiated in their absorption bands, undergo isomerization between trans and cis states. The trans state has an elongated shape, thus favoring CL order, while the cis state has a curved shape and disrupts CL order. The generation of cis isomers by light disrupts the order of the liquid crystal and destroys the mechanical properties of the system. On the other hand, the second strategy is based on the combination of molecules or absorbent nanomaterials. When irradiated in their absorption bands, they all release heat very efficiently, which is transferred to the material in which they are incorporated, in this case, the LCE, thereby generating mechanical actuation. Alternatively, absorbing chromophores that can absorb light of a specific wavelength and effectively convert light energy into heat can be used, such as benzophenone, rhodamine, stilbene, coumarin, or benzotriazole.

[0030] In another preferred embodiment of the valve described in this invention, the substrate comprises PDMS or a cyclic olefin polymer structure.

[0031] In another preferred embodiment of the valve of the present invention, the structural portion of the valve includes:

[0032] - One or more anti-adhesion openings, said one or more anti-adhesion openings being disposed between the structural portion and the mechanically responsive material of the functional portion of the valve; and / or

[0033] - Micro-roughness, wherein the micro-roughness is disposed between the mechanically responsive material of the structural portion and the functional portion of the valve; and / or

[0034] - A mechanically inert material, wherein the surface energy of the mechanically inert material is less than 40 mJ / m2; and / or

[0035] - Anti-adhesion layer.

[0036] A third object of the present invention relates to a peristaltic pump comprising at least one valve according to any embodiment described herein, the valve being configured in conjunction with a passive flow-limiting element; or configured as a sequential arrangement of two or more valves according to any embodiment described herein.

[0037] A fourth object of the present invention relates to a microfluidic system comprising a valve according to any embodiment described herein, coupled with an actuator of the valve, wherein the actuator includes means adapted to modulate physicochemical properties, and the mechanically responsive material forming the functional portion of the valve is sensitive to the physicochemical properties.

[0038] A fifth object of the present invention relates to the use of microfluidic valves, peristaltic pumps, or systems according to any embodiment described herein in in vitro biomedical analysis, drug screening analysis, in vitro biological research, monitoring and control of environmental pollution, biohazard detection, food analysis, or in the fabrication of on-chip organ devices. These on-chip organ devices provide physiologically relevant biomimetic models that allow for a better understanding of the specific functions and responses of tissues and organs, and thus responses to drug therapy or progression of certain pathologies, thereby contributing to the development of new tools for conducting novel physiological research, drug development and screening, toxicology, and personalized medicine.

[0039] In a preferred embodiment of the system of the present invention, the device for adjusting the physicochemical properties includes a light regulation subsystem, a temperature regulation subsystem, a humidity regulation subsystem, a pH regulation subsystem, or an electromagnetic field regulation subsystem.

[0040] Within the scope of this invention, the term "mechanical response" should be interpreted as a property of a material whose molecular structure is disrupted over time in response to one or more externally applied physicochemical quantities, such as light, temperature, humidity, pH, or electromagnetic fields. Similarly, within the scope of this invention, this property is reversible, meaning that if the applied physicochemical quantity returns to its previous state, or if applied under other conditions, or in combination with other physicochemical quantities or stimuli, it is possible for the molecular structure of the material to return to its original state. In a preferred embodiment of the invention relating to obtaining a microfluidic valve, the mechanical response characteristic should be interpreted as the ability to modify the structure of the functional portion of the valve to enable the valve to drive or regulate the fluid flow in a microfluidic device or system.

[0041] Within the scope of this invention, the phrase "mechanical inertness over time" should be interpreted as meaning that the material has essentially no mechanical reactivity over time.

[0042] Within the scope of this invention, the expression "substantially" should be interpreted as the same as or included within the range of ±10%.

[0043] Within the scope of this invention, the term "structural portion of the valve" should be interpreted as the portion configuring the shape and overall structure of the valve, which is formed of a mechanically inert material that does not undergo reversible substantial shape changes in the event of changes in one or more physicochemical parameters.

[0044] Within the scope of this invention, the term "functional portion of the valve" should be interpreted as the portion configuring the movable and actuating elements of the valve, which is formed of a mechanically responsive material that undergoes a reversible substantial shape change in response to variations in one or more physicochemical parameters.

[0045] Within the scope of this invention, the term "anti-adhesion treatment" should be interpreted as a treatment that prevents complete or partial irreversible adhesion between the following substances:

[0046] - The series of filaments of the mechanically responsive material and the substrate of the mechanically inert material; and / or

[0047] - The series of filaments of the mechanically responsive material and one or more additional layers of the mechanically inert material; and / or

[0048] - The substrate of mechanically inert material and one or more additional layers of mechanically inert material; and / or

[0049] - Two or more additional layers of mechanically inert material.

[0050] According to this interpretation, the following examples should also be understood to be included within its scope:

[0051] - Add chemical reagents with anti-adhesion capabilities to LCP;

[0052] - Introduce micro-roughness on the contact surface between the substrate of the mechanically inert material and the series of filaments and / or one or more additional layers of the mechanically inert material;

[0053] - Introduce micro-roughness in one or more of the additional layers of mechanically inert material;

[0054] - The substrate, the series of filaments, and / or one or more layers of the additional layer are fabricated using a material with low surface energy, wherein "material with low surface energy" should be understood as having a surface energy below 40 mJ / m 2 Materials;

[0055] - Apply an anti-adhesion layer to the substrate, the series of filaments and / or one or more layers of the additional layer of mechanically inert material;

[0056] - The series of filaments are spatially separated relative to one or more layers of the additional layer and / or the substrate and / or the mechanically inert material, or any other arrangement designed to limit or prevent them from adhering to the substrate and / or one or more of the additional layers (e.g., setting the contact surfaces at an angle to each other rather than parallel to each other). Attached Figure Description

[0057] Figure 1 An example of a microfluidic valve according to a preferred embodiment of the present invention is shown.

[0058] Figure 2 a-2c illustrates three examples of two-dimensional printed patterns of mechanically responsive materials according to three preferred embodiments of the invention, which can be used to manufacture the microfluidic valves of the invention.

[0059] Figure 3 An example of the general operating principle of a microfluidic valve according to a preferred embodiment of the present invention is shown.

[0060] Figure 4 An example of a microfluidic valve according to a preferred embodiment of the present invention is shown, the microfluidic valve being implemented as a reverse-acting valve.

[0061] Figure 5a An example of a three-dimensional printed pattern of a mechanically responsive material used to manufacture the microfluidic valve of the present invention is shown; Figure 5b A preferred embodiment of the microfluidic valve is shown, wherein the microfluidic valve is implemented as a reverse-acting valve.

[0062] Figure 6 The diagram illustrates a sequential arrangement of microfluidic valves according to the invention, the microfluidic valves being configured as peristaltic pumps, the stages of which can be activated by light radiation of different wavelengths.

[0063] Figures 7a-7b Examples of a valve and a peristaltic pump according to the invention are shown respectively, wherein the substrate includes an opening serving as an anti-adhesion device.

[0064] Reference numbers in the attached figures :

[0065] (1) A substrate of mechanically inert material.

[0066] (2) Filaments of materials with mechanical response.

[0067] (3) Fluid velocity.

[0068] (4) The central printing area of ​​the filaments of the mechanically responsive material.

[0069] (5) Additional layer of mechanically inert material.

[0070] (6) Light.

[0071] (7) Anti-adhesion opening. Detailed Implementation

[0072] As described in the preceding sections, and in this article Figure 1 In the example shown in -7, the method for manufacturing a microfluidic valve essentially includes at least the following steps:

[0073] - A substrate (1) is provided, wherein the substrate (1) is configured with the structural part of the valve, wherein the substrate (1) includes at least one mechanically inert material that is mechanically inert to one or more physicochemical properties over time.

[0074] - A series of one or more filaments (2) of mechanically responsive material are printed by adding layers, the mechanically responsive material being mechanically responsive to one or more physicochemical properties over time, wherein the mechanically responsive material includes at least one LCP, and wherein the series of filaments (2) are configured as functional parts of a valve.

[0075] - A series of filaments (2) of a mechanically responsive material are disposed on a substrate (1) of a mechanically inert material by applying an anti-adhesion treatment at one or more interfaces of the filaments (2) and the substrate (1).

[0076] like Figure 1 As shown, the substrate (1) and a series of filaments (2) of the mechanically responsive material are at least partially configured to allow for a fluid flow rate (3) through the valve. Similarly, the series of filaments (2) of the mechanically responsive material are configured to allow for a fluid flow rate (3) such that a change in one or more physicochemical parameters (e.g., by irradiation within a given frequency range) causes a disruption of the molecular order of the LCP, causing the material to contract or expand, respectively, along the longitudinal or transverse direction of the filaments (2), and resulting in an increase or decrease in the fluid flow rate (3).

[0077] Therefore, as Figure 3 As shown, Figure 1 The flow rate (3) shown is configured with a channel shape and can be configured with a curved channel geometry that is adjusted according to the actuator in the actuated state, or the upper part of the plane can act on the channel to open or close the channel depending on the state of the valve (unactuated or actuated). This configuration is also advantageous because the area of ​​contact between the functional part and the relative wall of the structural part is localized, which facilitates the subsequent separation of the mechanically responsive material when it returns to its initial state (unactuated).

[0078] The stiffness of the mechanically responsive material used to print a series of filaments (2), and the ratio between the thickness and planar (longitudinal and / or transverse) dimensions of the resulting LCE or LCN sheet, affect the degree of deformation of the functional parts of the valve. Excessive increases in these parameters reduce deformation and negatively impact valve performance. Preferably, the series of filaments (2) comprises LCPs that, when printed, produce an LCE-type crosslinked polymer system with a Young's modulus on the order of MPa or an LCN-type crosslinked polymer system with a Young's modulus on the order of GPa. The longitudinal and / or transverse dimensions of the resulting LCE or LCN sheet are typically between 1 and 20 mm, and its thickness is between 50 and 1500 µm.

[0079] The adhesion between the substrate (1) and the series of filaments (2) also plays a crucial role in the valve's performance, and if the adhesion is irreversible, it can even negate the valve's function. Although the presence of liquid does reduce the adhesion between certain surfaces, it is still known that the adhesion between surfaces in liquid increases significantly with increasing contact time. This latter situation occurs when liquid drains from the contact area between the substrate (1) and the series of filaments (2). Therefore, it is crucial to prevent or control this adhesion by applying an anti-adhesion treatment. Preferably, the anti-adhesion treatment includes:

[0080] - Adding an anti-adhesion chemical agent to the LCP, preferably one or more fluorinated modifiers or long-chain aliphatic silanes, including, for example, nonyltrichlorosilane, octadecyltrichlorosilane, octyltrichlorosilane, fluorooctyltrichlorosilane, or fluoro-n-octyltrimethoxysilane; and / or

[0081] - Introducing micro-roughness (e.g., by sandblasting using glass or metal as the mechanical inert material) on the contact surface between the substrate (1) of the mechanically inert material and a series of filaments (2), preferably having a mean square roughness or mean square deviation of the profile on the order of micrometers, because under these conditions the adhesion between the elastomer and the rigid surface is known to be significantly reduced [Fuller et al. Proc. R. Soc. Lond. A 1975 345, 327-342]; and / or

[0082] - Use surface energy below 40 mJ / m 2 Materials used to manufacture the substrate (1) and / or a series of filaments (2), such as cyclic olefin polymers (COP, 30 mJ / m 2 ) and polydimethylsiloxane (PDMS, 19-21 mJ / m 2 ); and / or

[0083] - Apply an anti-adhesion layer, preferably comprising one or more fluoropolymers, such as polytetrafluoroethylene (PTFE), to a substrate (1) of mechanically inert material and / or to a series of filaments (2); and / or

[0084] - A series of filaments (2) are spatially separated from the substrate (1).

[0085] In this way, the adhesive force is significantly reduced by decreasing the likelihood of adhesive forces arising from friction between the functional and structural parts of the valve, which reduces the risk of failure due to one part potentially sticking to another. However, in devices that do not have these adhesion problems between the substrate (1) and the series of filaments (2), the aforementioned treatment may not be applied.

[0086] To properly drive the valve of the present invention, it is necessary to use a mechanically responsive material in the form of ink, whose rheological properties, according to the aforementioned properties, result in LCP filaments (2) with a controlled morphology after printing and optional curing. For this purpose, the ink preferably comprises a mixture of a main-chain LCP with a small amount of photoinitiator, the main-chain LCP having reactive acrylate groups at the ends of the chain. Similarly, the mechanically responsive liquid crystal polymer preferably contains absorber units incorporated into its main chain, which are either photoresponsive (e.g., azobenzene, spiropyran, etc.) undergoing a conformational change upon absorbing light that disrupts the liquid crystal order, or absorber units that convert absorbed light into heat that also disrupt the liquid crystal order. Another possibility is to introduce these units into the LCP ink as additional monomers, which are then incorporated into the polymer structure. This polymer is primarily obtained via Michael addition, preparing a mixture of mesocrystalline diacrylates with reactive units, which is then mixed with n-butylamine at a molar ratio close to 1. The excess diacrylate ensures the formation of polymer chains with terminal acrylate groups via Michael addition, which can then react in a second step via photopolymerization. The amine-acrylate chemical reaction is used as an example, but other reactions, such as thiol-acrylate, amine-epoxy, etc., can also be used to form a reaction chain, resulting in the same effect. The inks thus prepared typically exhibit viscoelastic behavior, where fine, long filaments (2) are easily formed by simply printing them from polymeric materials, producing well-oriented fibers with mesocrystalline monomers aligned in the printing direction. Other possibilities include the use of photochemical or photothermal materials, such as inks containing nanoparticles or molecules that convert light into heat. In its various preferred embodiments, the magnetocaloric effect can also be used within the scope of the invention.

[0087] The base (1) of the valve preferably comprises one or more biocompatible materials, such as materials commonly used in microfluidic applications, such as PDMS or cyclic olefin polymer structures.

[0088] Figure 2 a-2c illustrates three examples of configurations used for the filaments (2) of the mechanically responsive material in the manufacture of valves according to different preferred embodiments of the present invention. In this sense, Figure 2 Figure a shows a series of filaments (2) of a mechanically responsive material, the series of filaments arranged in multiple substantially parallel lines to form a rectangular or square surface. This configuration is, for example, Figure 1 The valve used. In another embodiment ( Figure 2 b) A series of filaments (2) of the mechanically responsive material are arranged in a substantially planar radial distribution, wherein each filament (2) begins from a central region (4) shared by the other filaments (2). In another embodiment ( Figure 2 c), starting from the central region (4) shared by one or more filaments (2), a series of filaments (2) of mechanically responsive material are arranged in an azimuthal distribution at the aforementioned fluid velocity (3), and are arranged in a substantially planar spiral distribution on a continuous path.

[0089] A potential problem with mechanical stress composite actuators is the delamination of one or more materials used. To promote adhesion between the functional and structural parts of the valve (at those points or areas where adhesion is desired), specific chemicals can be applied to the latter. For example, the corresponding surfaces can be exposed to ozone generated by ultraviolet (UV) radiation, oxygen plasma, or other gases, or treated with a mixture of organic-inorganic coupling agents for acrylate-based inks, such as 3-aminopropyltriethoxysilane, 3-aminopropyltrimethoxysilane, 3-aminopropyltrichlorosilane, 3-mercaptopropyltrimethoxysilane, 3-mercaptopropyltriethoxysilane, and 3-methacryloyloxypropyltrimethoxysilane. This produces reactive substances that are covalently bonded to the surface, and when these reactive substances are photocured, they can subsequently act as bonds for the acrylate inks to increase the bonding strength of the inks.

[0090] In other embodiments of the invention, the manufacturing method may further include attaching one or more layers (5) of a mechanically inert material after printing a series of filaments (2) having a mechanical response, thereby configuring one or more additional elements of the structural portion of the valve. Optionally, the method may include the step of applying an anti-adhesion treatment to one or more additional layers (5) of mechanically inert material to prevent irreversible adhesion between layers (5), between layers (5) and the substrate (1), and / or between layers (5) and the series of filaments (2).

[0091] In other embodiments of the invention, the manufacturing method may further include a curing step, preferably after the filament (2) of the mechanically responsive material has been printed. The curing step may be selectively performed on certain regions of the valve, wherein multiple successive curing operations may be selectively performed on said regions. The method of the invention also allows the printing of the filament (2) which deforms prior to curing (e.g., due to external mechanical action). This possibility is significant for certain complex valve or actuator designs. In other embodiments, the method of the invention also allows the printing of a multi-stable structure of the filament (2), such that the filament (2) achieves different deformations in each curing.

[0092] As an example of a preferred embodiment of the present invention, regarding the photosensitive valve (6), a PDMS substrate (1) on which LCP filaments (2) are printed can be used. The LCP-PDMS composite system can be manufactured by 3D printing LCP material onto PDMS, which is configured as a thin film, chip, or a previously manufactured chip precursor component. Additional PDMS material can be added and cured to complete the chip manufacturing process. The 3D-printed LCP element can also be embedded within or beneath the PDMS. For example, filaments of a mechanophotoresponsive material (6) can be 3D printed to create a film on top of a thin PDMS film substrate of a channel, the LCP pointing vector of which is aligned parallel to the channel direction in the PDMS block (e.g., Figure 1 (As shown). Considering the expansion caused by light (6) in a direction perpendicular to the LCP direction vector, illumination on the active LCP element causes the membrane to expand in a direction perpendicular to the channel. According to the purpose of the invention, if the membrane is confined between two sufficiently thick fixed walls, the band will bend to block the fluid flow through the channel, thus acting as a valve.

[0093] In another preferred embodiment of the invention, such as Figure 4 As shown in the embodiment, the non-driven valve closes the passage. The optically driven (6) valve opens, allowing liquid flow, thus a reverse-acting valve design is configured.

[0094] As a print with a basic flat structure (such as...) Figure 1-4 As an alternative to the series of filaments (2) shown, the filaments (2) with a three-dimensional shape can also be printed, preferably as shown. Figure 5a The diagram shows a conical shape following a radial distribution. In this way, when a series of filaments (2) are stimulated by external factors (temperature, light, etc.), the shape of the series of filaments (2) is modified into a cone with a smaller height and a wider base, to allow for the realization of... Figure 5b The example shown is a reverse-acting valve. This type of valve prevents fluid flow in the absence of external stimuli; otherwise, fluid would be able to flow.

[0095] In other preferred embodiments of the invention, more complex actuators can be manufactured using the proposed method. For example, a series of two or more individually positioned valve-type elements can be configured to form, as shown in the figure below. Figure 6 The peristaltic pump is shown. In the embodiment described, the mechanically responsive material of the functional part can be independently excited by irradiating each of them with three beams of light, respectively. Alternatively, the mechanically responsive material of the functional part can be manufactured by using materials sensitive to different wavelengths (e.g., red (R), green (G), and infrared (IR) in the figure) and / or by each valve driven by different light (6). This provides independent control of each valve, facilitating the realization of peristaltic movement at a flow rate (3) through a suitable sequence of luminescence events. Thus, irradiation with light (6) of suitable intensity and sequence results in unidirectional flow of fluid. In other embodiments of the invention, it is possible to configure the peristaltic pump as a combination of one or more valves and passive flow-limiting elements according to any embodiment described herein.

[0096] Figures 7a-7b Other embodiments shown describe a valve design in which, given the use of geometry that minimizes contact between parallel surfaces and reduces adhesion between them, the structural portion of the valve (and preferably its base (1)) includes one or more openings (7) that serve as anti-adhesion devices.

[0097] Finally, another object of the present invention relates to a microfluidic system comprising a valve as described herein, coupled with an actuator thereof, wherein the actuator includes means adapted to modulate physicochemical properties, and a mechanically responsive material comprising a functional portion of the valve is sensitive to these physicochemical properties. Examples of the actuator may be:

[0098] Light: Light can be applied by using light sources such as LEDs or lasers, which can preferably be part of the external devices that control the microfluidic chip.

[0099] Temperature: The chip can include a resistive element near the LCE / LCN to dissipate heat and drive the valve when current is applied. In this case, the chip can have contact electrodes connected to an external control module. Alternatively, the chip can incorporate a light-absorbing sheet near the LCE, which can convert light radiation into heat in the LCE and activate it.

[0100] Electrical: By adding additives to the LCE / LCN and adjacent sheets to provide resistivity for materials such as carbon nanotubes and carbon black, the system can be driven by heating the LCE / LCN by applying an electric current.

[0101] Humidity or pH: For this purpose, materials with hydrogen bonds are used in LCE / LCN and adjacent sheets. Applying a solution with a suitable pH will weaken these bonds, thereby altering the mechanical properties.

[0102] Magnetothermal: By adding additives to the LCE / LCN and adjacent sheets, materials such as iron nanoparticles are given magnetothermal properties, and the system can be driven by heating the LCE / LCN by applying a magnetic field.

Claims

1. A method for manufacturing a microfluidic valve, wherein the method includes performing the following steps: - A substrate (1) is provided, wherein the substrate (1) is configured with the structural portion of the valve, wherein the substrate (1) comprises at least one mechanically inert material, the mechanically inert material being defined as a material that does not undergo reversible substantial shape changes when one or more physicochemical properties change over time; - A series of filaments (2) of a mechanically responsive material, the mechanically responsive material being defined as a material that undergoes a reversible substantial shape change in response to a change in one or more physicochemical parameters, wherein the mechanically responsive material comprises at least one liquid crystal polymer (LCP), and wherein the filaments (2) are configured as functional portions of the valve; Its features are, The method includes an additional step of applying an anti-adhesion treatment at one or more interfaces between the filament (2) and the substrate (1) while depositing the filament (2) on the substrate (1); The substrate (1) and the filament (2) are at least partially configured with a fluid flow channel (3) through the valve, wherein the filament (2) is arranged within the fluid flow channel (3) such that a change in at least one physicochemical parameter causes the mechanically responsive material to contract or expand along the longitudinal or transverse direction of the filament (2) to regulate the fluid flow rate through the channel (3).

2. The method according to claim 1, wherein the filaments (2) are arranged in the fluid flow channel (3) as a plurality of substantially parallel filaments (2) to form a rectangular or square surface.

3. The method according to claim 1, wherein the filaments (2) are arranged in a substantially planar radial distribution in the fluid flow channel (3), wherein each filament (2) is arranged starting from a central region (4) shared with the other filaments (2).

4. The method according to claim 1, wherein, Starting from a central region (4) shared by one or more filaments (2), the filaments (2) are arranged in a substantially planar azimuth or spiral distribution in the fluid flow channel (3).

5. The method of claim 1, further comprising the additional step of adding a coupling agent between at least a portion of the filament (2) and the substrate (1).

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

7. The method of claim 1, wherein the anti-adhesion treatment comprises at least one selected from the group consisting of: - Add a chemical reagent with anti-adhesion properties to the filament; and - Before depositing the filaments (2), micro-roughness is introduced on the contact surface of the substrate (1); and - Select a surface energy below 40 mJ / m 2 The material used to manufacture the substrate (1) and / or the filaments (2); and / or - Apply an anti-adhesion layer to the substrate (1) and / or the filament (2); and / or - The filaments (2) are arranged on the substrate (1) to provide spatial separation.

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

9. The method of claim 1, further comprising the step of arranging one or more layers (5) of mechanically inert material after printing the filament (2), such that one or more additional elements of the structural portion of the valve are configured.

10. The method of claim 9, further comprising the step of applying an anti-adhesion treatment to one or more additional layers (5).

11. The method of claim 1, comprising the step of applying a curing process after the printing of the filament (2) is completed.

12. The method of claim 11, wherein the curing process is selectively performed in certain areas of the valve, or wherein the curing process comprises applying a series of curing operations to certain areas of the valve.

13. The method according to claim 1, wherein the filaments (2) are printed sequentially to form a three-dimensional shape.

14. The method according to claim 13, wherein the filaments (2) are sequentially printed to form a tapered shape.

15. A valve for regulating the flow rate of fluid through a microfluidic device, characterized in that, The valve is manufactured by the method according to claim 1.

16. The valve of claim 15, wherein the mechanically responsive material comprises a mixture of at least one main-chain LCP and one or more photoinitiators, wherein the main-chain LCP has reactive acrylate groups at the ends of the chain.

17. The valve of claim 15, wherein the LCP exhibits a mechanical response to changes in light, temperature, humidity, pH, or electromagnetic field.

18. The valve according to claim 15, wherein the LCP exhibits the ability to respond to light (6) in a photothermal and / or photochemical manner.

19. The valve of claim 18, wherein the LCP comprises azobenzene, spiropyran, diarylethylene, rotaxane, absorbent nanoparticles, and / or absorbent chromophores.

20. The valve of claim 15, wherein the substrate comprises a polydimethylsiloxane (PDMS) or cyclic olefin polymer structure.

21. The valve according to claim 15, wherein, The structural portion of the valve includes: - One or more anti-adhesion openings (7), said one or more anti-adhesion openings (7) being disposed between the structural portion and the mechanically responsive material of the functional portion of the valve; and / or - Micro-roughness, wherein the micro-roughness is disposed between the mechanically responsive material of the structural portion and the functional portion of the valve; and / or - A mechanically inert material, wherein the surface energy of the mechanically inert material is less than 40 mJ / m 2 ; and / or - Anti-adhesion layer.

22. A peristaltic pump comprising two or more valves as described in claim 15 and / or a combination of one or more valves as described in claim 15 with a passive flow-limiting element, arranged sequentially.

23. A microfluidic system comprising a valve according to claim 15, the valve being coupled to an actuator for regulating at least one physicochemical parameter, the mechanically responsive material configuring the functional portion of the valve to be sensitive to the at least one physicochemical parameter.

24. The system of claim 23, wherein the actuator comprises an illumination subsystem, a temperature regulation subsystem, a humidity regulation subsystem, a pH regulation subsystem, or an electromagnetic field regulation subsystem.

25. The use of the microfluidic valve according to claim 15, the peristaltic pump according to claim 22, or the system according to claim 23, wherein the use is applied in in vitro biomedical analysis, device fabrication of organs on a chip, drug screening analysis, monitoring and control of environmental pollution, biological risk detection, or food analysis.

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