WO2015090339A1 - Fluidic microsystem and method of manufacturing thereof - Google Patents

Fluidic microsystem and method of manufacturing thereof Download PDF

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Publication number
WO2015090339A1
WO2015090339A1 PCT/EP2013/003834 EP2013003834W WO2015090339A1 WO 2015090339 A1 WO2015090339 A1 WO 2015090339A1 EP 2013003834 W EP2013003834 W EP 2013003834W WO 2015090339 A1 WO2015090339 A1 WO 2015090339A1
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WO
WIPO (PCT)
Prior art keywords
module
insert
substrate body
fluid conduits
receptacle
Prior art date
Application number
PCT/EP2013/003834
Other languages
French (fr)
Inventor
Jean-Christophe Baret
Jiseok Lim
Florine MAES
Valérie TALY
Original Assignee
MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. filed Critical MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
Priority to PCT/EP2013/003834 priority Critical patent/WO2015090339A1/en
Publication of WO2015090339A1 publication Critical patent/WO2015090339A1/en

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • B01L9/527—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for microfluidic devices, e.g. used for lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/025—Align devices or objects to ensure defined positions relative to each other
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/028—Modular arrangements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/04—Exchange or ejection of cartridges, containers or reservoirs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions

Definitions

  • the present invention relates to a fluidic microsystem, which comprises a substrate body with fluid conduits.
  • the invention relates to a fluidic microsystem having a modular structure.
  • the present invention relates to a method of manufacturing a fluidic microsystem, wherein a substrate body having fluid conduits is created with modular structure.
  • Applications of the invention are available in the fields of handling liquids, in particular in biochemistry, medicine, biology or chemistry.
  • Fluidic microsystems are used for the manipulation of fluids at small scales in sub-mm ranges.
  • applications of fluidic microsystems have been proposed, which include e. g. in biochemistry the manipulation and assay of single cells, genes, or enzymes, up to the manipulation of complex multicellular organisms and reconstitution of artificial organs.
  • rapid prototyping by soft-lithography is generally known which provides microfabrication methods to produce microfluidic chips with an almost infinite number of degrees of freedom.
  • miniatur ⁇ izing fluidic components down to micro-meter scale many functional modules can be integrated on a single chip, e. g. for single phase flow or multiphase flow or towards specific pre-programmed actions.
  • a glass substrate coated with the polymer PDMS (polydime- thylsiloxan) is used as a platform accommodating the MABs, which are aligned, assembled and finally, bonded on the platform substrate.
  • the conventional method has the following disadvantages .
  • laterally connecting the MBAs and suppressing leakage from the fluidic microsystem requires a bonding of the MABs not only with the platform substrate, but rather also with neighbouring MABs. Only with the lateral bonding of neighbouring MABs, sufficient forces connecting the MBAs are obtained and the fluidic microsystem is able to sustain the pressure in fluidic channels. As a disadvantage, the lateral bonding increases the complexity of the manufacturing process. Furthermore, after manufacturing the whole fluidic mi- crosystem, it is not easy to change a function thereof by replacing a single MAB. Consequently, the fluidic microsystem obtained with the conventional method is a disposable device rather than a reversible system.
  • the conventional method requires a clean work space, complex facilities and post-processing tools and a high level skill by the person manufacturing the fluidic microsystem.
  • the conventional technique requires a spin coater for applying the adhesive material on the platform substrate, a curing system for the adhesive, like e. g. an oven or a hot-plate device or an UV exposure unit. Any dust trapping during the MAB assembling and bonding has to be strictly avoided.
  • organic contamination e. g.
  • the MABs used for the conventional technique are structured with recesses on one surface thereof. In the assembled state, the recesses are closed by the adjacent surface of the substrate platform, thus providing fluid conduits in the fluidic microsystem. As the recessed surface structure of the MABs is exposed until the bonding with the platform substrate, the conventional technique is extremely sensitive against dust particles, which can be located on the exposed recessed surface or the surface of the platform substrate. Dust particles deteriorate the bonding, thus resulting in an increased risk of unintended leakage of the microsystem.
  • the objective of the invention is to provide an improved fluidic microsystem, which is capable of avoiding disadvantages of conventional techniques.
  • the objective of the invention is to provide an improved fluidic microsystem, which has a reduced manufacturing complexity, a reduced complexity of the module structure, a reversible configuration, an improved tightness against leakage, and/or an increased flexibility for adapting the microsystem to individual tasks
  • the objective of the invention is to provide an improved method of manufacturing a fluidic microsystem, whic is capable of avoiding disadvantages of conventional techniques.
  • the objective of the invention is to provide the manufacturing method with reduced complexity and/or reduced requirements as to the cleanness of the work space and the needed facilities and tools, and which can be implemented without particular skills by a user of the fluid ic microsystem.
  • a fluidic microsystem having a substrate body with fluid conduits embedded therein.
  • the sub strate body is a plate-shaped, preferably plane or curved component, which is made of a solid material, preferably a polymeric material and which includes the fluid conduits as hollow channels within the substrate body material.
  • the substrate body has a lateral extension (plane extension, along lateral directions) and a thickness extension in a thickness direction perpendicular to the lateral extension.
  • the substrate body includes at least one module receptacle, which is a through-hole in the substrate body extending in the thickness direction thereof. The at least one module receptacle is arranged such that at least one of the fluid conduits within the substrate body opens into the at least one module receptacle.
  • At least one insert module including at least one conduit section is arranged in the at least one module receptacle, respectively.
  • one insert module is arranged in each of the module receptacles, respectively.
  • the insert module is a component which is made of a solid material, preferably a polymeric material, wherein the at least one conduit section is embedded in the volume of the insert module material.
  • the at least one insert module is press-fitted in the at least one module receptacle, wherein at least one conduit section of the insert module is aligned with at least one of the fluid conduits of the substrate body.
  • the insert module is fully enclosed by the material of the substrate body in the latera] directions, so that the insert module is secured to the substrate body.
  • the above objective is solved by a method of manufacturing a flu- idic microsystem, based on providing a substrate body with fluid conduits embedded therein.
  • the fluidic mi ⁇ crosystem of the above first aspect of the invention is manufactured.
  • at least one module receptacle is formed, which extends through the substrate body in a thickness direction thereof, i.e. perpendicular to a lateral directions of a plate forming the substrate body.
  • the at least one module receptacle is formed such that at least one of the fluid conduits is connected with the receptacle, i. e. at least one of the fluid conduits opens into the at least one module receptacle.
  • each insert module with at least one conduit section is inserted into the module receptacle, respectively.
  • the at least one insert module is arranged in the respective module receptacle, i. e. the through-hole formed by the module receptacle is closed by the insert module.
  • each insert module can be simply oriented relative to the respective module receptacle, e. g. by aligning the fluid conduits and conduit sections and/or by using optical marks on the insert module and the substrate body.
  • the at least one insert module is press-fitted in the at least one module receptacle, respectively, while the at least one conduit section of the insert module is aligned with the at least one of the fluid conduits opening to the module receptacle .
  • the insert module is coupled with the associated module receptacle by a press fit connection (interference fit, friction fit) .
  • the insert module has a cross-sectional dimension, which is larger than the cross-sectional dimension of the module receptacle.
  • the module receptacle is formed undersized with regard to the cross-sectional dimension of the insert module, and the insert module is formed oversized relative to the cross-sectional dimension of the module receptacle.
  • At least one of both parts deforms, so that a continuous contact is obtained between the lateral surface of the insert module and the internal lateral surface of the substrate body within the module receptacle.
  • the mechanical stability obtained with the invention is determined by the stability of the substrate body surrounding each insert module and by a minimized dead- volume between the insert modules.
  • each insert module has a configuration, which is adapted for fulfilling a predetermined function of the respective insert module.
  • the configuration of the insert module is adapted for at least one of a physical and a chemical interaction of the insert module with the liquid in the fluidic microsystem, e. g. for a mechanical, electric, magnetic, thermal, optical and/or chemically-reactive effect on the liquid.
  • the fluidic microsystem can be provided with a specific fluidic function.
  • the inventive fluidic microsystem is a configurable and preferably even reconfigurable microfluidic device which is assembled with the substrate body and elementary functional units provided by the insert modules. Preferably, the insert modules can be replaced and/or exchanged.
  • the invention suppresses the need for patterning, soft molding and bonding when details on a chip have to be set or modified.
  • the inventive fluidic microsystem has two parts, the substrate body providing a base-platform used as a scaffold and the at least one insert module providing the functional unit which is combined by 'plug-and-play' . Tests by the inventors have shown that the inventive fluidic microsystem sustains typical pressures in microfluidic experiments, e. g. for producing droplets of different sizes using T-junction modules with different designs assembled successively on a 3x3 modular substrate body.
  • the invention is based on the combination of the at least one insert module which is pre-manufactured and assembled separately in the substrate body.
  • the user can define the structures of the fluidic microsystem and preferably even change a detail of the fluidic microsystem without the need to redo a photolithography step.
  • the chip-oriented rapid prototyping method of the invention contributes to a standardization of fluidic microsystems. Large series of insert modules (functional elements) can be manufactured, and the integration of the final chip being the task of the end-user.
  • each of the insert modules has a limited functional ity
  • the insert modules can be assembled at will to produce complex functionalities over the whole fluidic microsystem.
  • advantages can be obtained similar to the advantages o electrical test boards designed for creating and testing electric circuits from a finite set of functional elements.
  • the at least one module receptacle is made with an inner size, which is smaller than an outer size of the respective insert module before the insertion thereof into the module receptacle. Accordingly, as long as the insert module has a relaxed condition outside the module receptacle, it is larger than the module receptacle.
  • this size deviation supports the formation of the secure press-fit of the insert module and the module receptacle.
  • the size deviation is selected in dependency on the elasticity of at least one of the substrate body material and the insert module material.
  • the size deviation is at least 50 ⁇ in diameter, in particular at least 200 ⁇ in diameter.
  • the substrate body includes multiple module receptacles each being provided with one insert module.
  • the module recep- tacles are connected via fluid conduits within the substrate body, and the fluid conduits are coupled via the conduit sections and optionally further functional elements of the insert modules.
  • a complete fluidic microsystem can be created in dependency on the particular task defined by a us- er of the microsystem.
  • the fluidic microsystem has a fluidic connection scheme and a fluidic function being determined by selecting and setting specific insert modules in the module receptacles.
  • at least one of the substrate body and the at least one insert module is made of an elastically deformable polymer material.
  • the use of the elastically deformable polymer material facilitates the insertion of the insert module into the respective module receptacle and the creation of the liquid tight press-fit connection even if the insert module or the module receptacle is created with some tolerance in terms of dimension and shape.
  • the elastically deformable polymer material which comprises e. g. PDMS (Polydime- thylsiloxane) , or silicone rubber, polyurethanes , and thermoplastic elastomers, or a combination of those, supports a shape matching of the insert module and the module receptacle .
  • the substrate body is made of a stiff solid material, preferably a stiff polymer material, like e.
  • the at least one insert module is made of the elastically deformable polymer material.
  • the stiff solid material has a lower elasticity compared with the material of the insert module.
  • the at least one insert module is separably connected with the substrate body.
  • the separable connection means that the insert module can be inserted into the module receptacle and removed therefrom without a damage or change of the dimension or shape of the insert module or the module receptacle.
  • the coupling of the insert module and the respective module receptacle can be separated by drawing the insert module out of the module receptacle. Drawing the insert module can be done e. g.
  • the insert module can protrude from the surface of the substrate body, so that it can be drawn from the module receptacle by hand or using a gripping tool.
  • a general advantage of the invention results from the fact that the insert module and the respective module receptacle can be made with respective outer and inner shapes, which can differ from each other.
  • the inner shape of the module receptacle and the outer shape of the insert module are matched to each other.
  • the inner and outer shapes are geometrically similar.
  • this embodiment of the invention improves the homogeneity of the press-fit connection.
  • the elastic forces creating the press-fit connection are distributed homogeneously along the lateral circumference of the insert module. Accordingly, the risk of an unintended liquid leakage can be minimized.
  • the inner and outer shapes can have an elliptic cross-sectional contour, i. e. the insert module and the respective module receptacle have a shape of elliptic cylinders.
  • This variant of the invention may have advantages in terms of a compact design of the fluidic microsystem.
  • the inner and outer shapes can have a polygonal cross- sectional contour, e. g. a rectangular or even quadratic cross-sectional shape.
  • the polygonal contour has rotation symmetry.
  • the inner and outer shapes of the module receptacle and the insert module have a circular cross-sectional contour. Accordingly, the module receptacle provides a hollow circular cylinder, while the insert module provides a compact circular cylinder.
  • the circular shape has particular advantages in terms of a rotation capability of the insert module.
  • the insert module can be rotated with an axis perpendicular to the lateral extension of the substrate body, thus allowing a coupling of the at least one conduit section of the insert mod ⁇ ule with different ones of the fluid conduits within the substrate body.
  • the circular shape allows a continuous rotation so that an arrangement is possible wherein the fluid conduits of the substrate body are blocked by the insert module.
  • all module receptacles can have the same inner shape and dimension, the same inner shape and different dimensions, and/or different shapes and different dimensions.
  • the insert modules can be manufactured with shapes and dimensions in correspondence to all of these variants.
  • multiple design options are available for connecting fluid conduits within the substrate body via conduit sections within the insert module.
  • at least three fluid conduits open into the at least one module receptacle.
  • three fluid conduits open into the module receptacle with mutual angles of 90°.
  • Two of the at least three fluid conduits can be connected with one conduit section of the insert module, while at least one of the fluid conduits can be closed by the body of the insert module.
  • the insert module can be used as a fluidic switch connecting or blocking fluid conduits within the substrate body.
  • the at least one insert module includes at least one functional element, a high degree of flexibility in terms of designing the function of the inventive fluidic microsys- tern is obtained.
  • the functional element includes at least one of at least one electrode, at least one pump, at least one tube connector, at least one container, at least one injector, at least one outlet, at least one linker, at least one T-junction, at least one flow-focussing junction, at least one nozzle and at least one incubation line.
  • One insert module may include one of these functional elements, or some of these functional elements can be combined within one insert module.
  • the fluid conduits in the substrate body have a transverse arrangement including fluid conduits extending in a first lateral direction along the planar extension of the substrate body and further including fluid conduits extending in a second lateral direction along the planar extension of the substrate body.
  • the first and second lateral directions are perpendicular relative to each other.
  • the module receptacles are formed at intersection points of the fluid conduits extending in the first and second directions and the insert modules inserted in the module receptacles connect the fluidic conduits in the substrate body depending on the conduit sections within the insert modules.
  • the substrate body is manufactured with the following steps.
  • the method can be implemented correspondingly with a substrate body having a curved shape.
  • a substrate cover plate is provided, which preferably is a planar solid plate with a smooth, unstructured surface.
  • a substrate conduit plate is provided, which is a planar plate having a structured surface including recesses.
  • the recesses have longitudinal shapes ac- cording to the shapes of the fluid conduits to be obtained within the substrate body.
  • the substrate body is formed by bonding both components, wherein the recesses in the surface of the substrate conduit plate are closed by the substrate cover plate. Accordingly, the fluid conduits are formed within the inner volume of the substrate body.
  • the at least one module receptacle is formed by providing a through-hole in the substrate body, e. g. by drilling or punching.
  • the at least one insert module is manufactured according to the following steps. Firstly, a module base slab and a module conduit slab are provided, each with a plane shape.
  • the module base slab is formed with a non-structured surface, while the module conduit slab is formed with a structured surface including recesses.
  • the recesses are designed for providing the conduit sections in the complete insert module to be ob- tained.
  • the module base slab and the module conduit slab are bonded together, wherein the recesses in the structured surface of the module conduit slab are closed and the conduit sections are formed by the closed recesses.
  • the at least one module is obtained by punching at least one portion from the bonded slabs including the at least one conduit section. Punching can be obtained with a punching tool having a size and shape of the insert module to be obtained.
  • the module conduit slab is formed by soft lithography.
  • the insert modules can be manufactured directly by molding of elastically deformable polymers.
  • This embodiment of the invention can have advantages for creating the insert modules with more complex, e. g. irregular shapes.
  • the inventors have demonstrated a system for chip-oriented rapid prototyping making use of a stiff scaffold, made of e. g. PMMA, and functional units, made of e. g. PDMS .
  • the system provides tight connection between functional elements for customer-oriented integration of microfluidic chips.
  • the system is technologically interesting as the functional units are simple and can in principle be mass produced while the integration by the user will lead to an almost infinite set of possible devices, testable in very short time and at low cost.
  • the inventive system truly has plug-and-play capability.
  • the platform and the modules are all pre-made, and no post processing after plugging the modules in the platform is needed. Also, making a microfluidics can be done by even naked-hand in normal office like working space.
  • Figure 1 schematic views of a basic configuration of a pre ⁇ ferred embodiment of the fluidic microsystem according to the invention
  • Figure 2 a perspective view of a preferred embodiment of the fluidic microsystem according to the invention.
  • Figure 3 xamples of insert modules used in the embodiment f Figure 2;
  • Figure 4 schematic plan view illustrations of insert modules used according to preferred embodiments of the in- vention;
  • Figure 5 a schematic illustration of manufacturing a substrate body of the fluidic microsystem according to the invention.
  • Figure 6 a schematic illustration of manufacturing a insert modules of the fluidic microsystem according to the invention.
  • fluidic microsystems having insert modules and receptacle sections with circular cross-sections. It is emphasized that the invention correspondingly can be implemented with other shapes, e. g. elliptical, polygonal or even irregular shapes. Furthermore, the invention is not restricted to the materials and dimensions of the fluidic microsystem, which are mentioned in the following as preferred examples. The skilled person is capable of designing the fluidic microsystem, in particular selecting appropriate materials and dimensions, in dependency on the requirements of the particular task of the fluidic microsystem to be manufactured. As an example, the fluid conduits within the substrate body can be provided with modified shapes, e. g. curved or more complex shapes.
  • Insert modules are not necessarily arranged at an intersection of fluid conduits. Alternatively, insert modules can be integrated along a path of a fluid conduit. Furthermore, coupling the fluidic microsystem to additional fluidic plants is not described in detail. This coupling can be done using appro- priate tubing which is connected with the fluidic conduits in the substrate body, e. g. via inlet or outlet insert modules or via direct connection with the substrate body.
  • inventive fluidic microsystems can be adapted for fulfilling any task of a fluidic microsystem as it is known in conventional fluidic applications. Accordingly, process features, like selecting liquids or flow parameters or fluidic functions, are not described in detail as far as they are known from prior art techniques.
  • Embodiments of the invention are described in the following with reference to an orthogonal coordinate system, including x- and y-axes extending in a substrate body plane, and a z- axis perpendicular to the substrate body plane.
  • the z-axis corresponds to the thickness direction of the substrate body.
  • Figure 1 shows a first basic configuration of an inventive fluidic microsystem 100, including one single module receptacle 12 and one single insert module 20, with a cross- sectional view in a condition before ( Figure 1A) and after ( Figure IB) the insertion of an insert module into a module receptacle and with a cross-sectional view along line C - C of Figure IB in the condition after the insertion of the insert module in the module receptacle ( Figure 1C) .
  • the fluidic microsystem 100 comprises the substrate body 10 including fluid conduits 11 and the module receptacle 12.
  • the substrate body 10 has a planar shape extending along the x-y- plane of Figure 1. While the implementation of the invention with one single module receptacle and one single insert module is possible as shown in Figure 1, alternative embodiments with multiple module receptacles and module insert modules are preferred as shown e. g. in Figure 2.
  • the substrate body 10 is provided with a carrier plate 13, which is a solid support for the. fluidic microsystem. It is noted that the carrier plate 13 is an optional feature of the invention. If the material of the substrate body 10 has a sufficient mechanical stiffness, e. g. if the substrate body 10 is made of PMMA, the carrier plate 13 can be omitted.
  • the fluid conduits 11 comprise straight channels extending along the planar shape through the substrate body 10.
  • the channels open to the module receptacle 12.
  • the fluid conduits 11 have a rectangular cross-sectional shape and a cross-sectional dimension in the range of 10 ⁇ to 1 mm.
  • the thickness of the substrate body 10 is about 5 mm.
  • the module receptacle 12 comprises a cylindrical through-hole extending in the thickness-direction ( z-direction) of the substrate body.
  • the module receptacle 12 can extend through the whole thickness of the substrate body (as shown in Figure 1A) or through a part of the substrate body 10 only. In the latter case, the depth of the module receptacle 12 would be selected such that the fluid conduits 11 open into the module receptacle 12 with a distance from a bottom thereof.
  • the diameter of the module receptacle 12 is e. g. 4,7 mm.
  • the insert module 20 is a cylindrical component, which is made of an elastically deformable polymer, like e. g. PDMS.
  • the diameter of the insert module 20 is e. g. 5 mm, i. e. 300 ⁇ ⁇ larger than the inner diameter of the module receptacle 12.
  • the deviation Ar between the inner diameter of the module receptacle 12 and the outer diameter of the in- sert module 20 in a relaxed condition is in the range between 50 ⁇ to 500 ⁇ .
  • the insert module 20 includes a conduit section 21 and op- tionally a functional element 22.
  • the conduit section 21 has cross-sectional dimensions equal to the shape and dimension of the fluidic conduits 11 of the substrate body 10. Depending on the application of the fluidic microsystem, the conduit section 21 can have cross-sectional dimensions larger or smaller than the shape and dimension of the fluidic conduits 11.
  • the functional element 22 is schematically shown only. It comprises e. g. an electrode or a pump or any other compo ⁇ nent, which is to be used in the fluidic microsystem 100 (see examples in Figure 3) .
  • FIG. 2 shows a second basic configuration of an inventive fluidic microsystem 100 including multiple module receptacles 12 and multiple insert modules 20.
  • the fluid conduits 11 have a transverse arrangement of straight channels intersecting each other.
  • First and second groups of fluid conduits 11.1, 11.2 extend along the x- and y-directions, resp..
  • the module receptacles 12 are formed at intersections points of the first group and second groups of fluid conduits 11.1, 11.2, resp..
  • Insert modules 20 are inserted at the module recepta- cles 12, wherein some insert modules have a certain fluidic function, and the remaining module receptacles 12 are filled with blind inserts 30.
  • the blind inserts 30 are formed with a material, size and shape like the insert modules, but without a conduit section, so that the blind inserts 30 simply block the fluid conduits opening into the respective module receptacles 12.
  • the fluidic microsystem 100 has been configured for a droplet dispersion production of oil droplets, made of fluorinated oil with surfactant (HFE7500, Novec) with 0.5% PEG-PFPE block-copolymer ( Sigma-Aldrich, custom synthesis), in an aqueous continuous phase, e. g. water.
  • the insert modules 20 comprises an oil inlet module 23, an aqueous phase inlet module 24, a T junction module 25 for the droplet dispersion production and a dispersion outlet module 26.
  • the remaining module receptacles 12 are tightly closed with the blind inserts 30.
  • the inlet and outlet modules are formed as shown with exemplary reference to the oil inlet module 23 in Figure 3A.
  • the oil inlet module 23 comprises a conduit section 21 coupled with one of the fluid conduits 11.1, while the remaining fluid conduits are blocked by the cylindrical body of the oil inlet module 23.
  • the oil inlet module 23 comprises a chamber 23.1 and a connection hole 23.2, where a tube of a liquid supply or another microsystem can be coupled.
  • the T junction module 25 is formed as shown in Figure 3B. It includes three conduit sections 21 which are coupled with the fluid conduits 11.1, 11.2 and which form a T-junction with an integrated nozzle (e. g. as shown in Figures 4G, H) for droplet production.
  • Tests have shown, that the same platform can be used to produce droplets of different sizes by simply replacing the functional element (T junction modules 25 with different nozzles diameters, e. g. 100 ⁇ , 60 ⁇ and 40 ⁇ ) .
  • the produc- tion reliability has been shown by testing the system with different flow rates, e. g. with a fixed flow rate for the water phase as 10 ⁇ /min, and the flow rates of the oil phase with a range of 10 to 100 ⁇ /min.
  • the inventive fluidic microsystem 100 has been demonstrated as a reconfigurable, leakage-free system for multiphase flow working at a typical pressure reached in microfluidic chips (e. g. typically of order 1 bar) .
  • the advantages with regard to tuning droplet size can be fur- ther extended to other aspects, such as having localized wettability alterations in the insert modules 20, which would make the production of double emulsions relatively straightforward.
  • the single insert modules 20 could be made available as hydrophilic or hydrophobic, in addition to having several dimensions.
  • the inventive fluidic . microsystem 100 can also provide solutions for on-chip storage modules, valves and three-dimensional assembly. Electrodes for sorting and coalescence also, for example as described in "Lab on a Chip" vol. 9, 2009, p. 1850, can be inserted for example using the microsolidics technique described by Siegel et al . in "Angew. Chem.” vol. 45, 2006, p. 6877-6882.
  • insert modules 20 are shown in Figure 4, which comprise an inlet or outlet module (Figure 4A) , linker modules (Figures 4B, C) , a T-junction module ( Figure 4D) , a flow focussing module (Figure 4E) , an incubation line module ( Figure 4F) and nozzle modules, e. g. for a flow-focussing droplet generator ( Figure 4G) or for a T-Junctions droplet generator ( Figures 4H) .
  • Insert modules according to Figure 4 can be combined within a single insert module. Each module carries a specific connectivity to the substrate body, blocking undesired connections. Fabricating the substrate body 10 and the insert modules 20
  • the preferred embodiment of the inventive fluidic microsystem 100 is composed of a micro- machined rigid, platform (the substrate body 10) made of PMMA and elastic insert modules 20 which are fabricated by conventional soft lithography in Polydimethylsiloxane (PDMS, the functional units) as described in the following with reference to Figures 5 and 6.
  • the substrate body 10 is made of a substrate cover plate 15 and a substrate conduit plate 16, which comprise PMMA thin sheets (3 mm thick) as shown in Figure 5A.
  • the substrate cover plate 15 has a plane, smooth surface, while the substrate conduit plate 16 is formed with a structured surface includ- ing recesses 17.
  • the recesses 17 comprise two sets of parallel lines of width 500 ⁇ and depth 500 ⁇ which are micro- machined using a high precision drill (e. g. DMU 50, manufacturer DMG Mori Seiki) .
  • the substrate conduit plate 16 is then bonded with the second flat' PMMA substrate cover plate 15, e. g. by a thermal bonding process as shown in Figure 5B.
  • the plates 15, 16 are plasma-treated in an 0 2 plasma-chamber (manufacturer e. g. Diener) for 30 s at 0.4 mbar and 140 W.
  • the bond- ing is performed at a temperature of e. g. 98°C, with an applied force of 5 kN during 30 min.
  • the bonded plates are then cooled down to room temperature at a rate of e. g. approximately -l°C/min to slowly relax thermal stresses.
  • Nine through holes (diameter 4.6 mm) providing the module receptacles 12 are drilled in the substrate body 10 as shown in Figure 5C, and the substrate body 10 is cleaned by ethanol to remove debris generated during drilling process.
  • the functional insert modules 20 are made of a module conduit slab 27 and a module cover slab 29 bonded together as shown in Figure 6.
  • the module conduit slab 27 is fabricated using standard soft lithography (see e. g. Y. N. Xia et al. in "An- nual Rev. Mater. Sci., vol. 28, 1998, p. 153 - 184).
  • a master slab is created in a 25 ⁇ deep SU-8-3025 resist by shining UV light through a transparency mask (manufacturer: Selba, Switzerland) .
  • the mask is designed with is formed with a structured surface including protruding elements, in particu- lar structures and connection branches, and circular align ⁇ ment marks 28.1 (see Figure 4) spaced by 90 degrees angles from the centre of the circle.
  • the module conduit slab 27 is then replicated in PDMS from the master slab so that the protruding elements form recesses 28 ( Figure 6A) .
  • Connection holes 28.1 can be punched in the PDMS if required by the design, for example in the case of inlets and outlets ( Figure 6B) .
  • functional elements can be integrated at this stage of the process at the positions of the insert modules to be obtained.
  • a module cover slab 29 is a second PDMS slab, which is casted on a flat wafer, and both PDMS slab 27, 29 are bonded together after 02-plasma treatment ( Figure 6B) .
  • the recesses 28 are closed by the module cover slab 29, thus providing the con- duit sections of the insert modules to be obtained.
  • the PDMS insert modules 20 are cut from the bonded slabs 27, 29, using e. g. a 5 mm diameter biopsy punch. Alignment of the channels with the biopsy punch is obtained for allowing the alignment of the conduit sections 21 of the insert modules 20 with the fluid conduits of the substrate body.
  • the diameter of the module receptacles was chosen by the inventors after testing through-holes diameters ranging from 4 to 5 mm with 100 ⁇ steps. A preferred combination of diameters 5 mm (biopsy hole) and .6 mm (module re ⁇ ceptacle) has been found to provide a tight sealing between the PMMA substrate body and the PDMS insert module 20.
  • the error of the punching position would cause misalignment between the insert modules and the substrate body.
  • the inven ⁇ tors have found that malfunctions due to this error can be easily avoided, even by using a simple alignment procedure.
  • a paper guide can be used having the size and pitch of the de- sign. Even with this procedure, properly functional systems are obtained, because the tolerance is finally given by the dimensions of the fluid conduits in the substrate body.
  • the rotational tolerance for alignment between the fluid con- duits 11 in the substrate body 10 and the conduits sections 21 in the insert modules 20 is given by the respective channels in the substrate body 10 and the insert modules 20.
  • the rotational tolerance can calculated as e. g. 12° based on the geometrical dimension.
  • the translational tolerance is mainly defined by an eccentric error during fabrication of the in ⁇ sert module.
  • the tolerances are sufficient to make the con ⁇ nection alignment by eye.
  • the expanded channel design at the interface of the module and platform, and additional align- key around the module help to alignment during plug-in.
  • the insert modules 20 are introduced into the re ⁇ spective module receptacles 12.
  • the PMDS insert modules 20 can be lubricated by fluorinated oil prior to the insertion into the substrate body 10.
  • a PMMA substrate body 10 with 3> ⁇ 3 module receptacles 12 and a set of insert modules 20 have been used to produce droplets at a T-junction.
  • Two types of insert modules 20 have been assembled as described above with reference to Figures 2 and 3.

Abstract

A fluidic microsystem (100) comprises a substrate body (10) with fluid conduits (11), wherein the substrate body (10) includes at least one module receptacle (12) extending in a thickness direction of the substrate body (10) and at least one of the fluid conduits (11) opens into the at least one module receptacle (12), at least one insert module (20) with at least one conduit section (21) is arranged in the at least one module receptacle (12), resp., the at least one insert module (20) is press-fitted in the at least one module receptacle (12) and the at least one conduit section (21) is aligned with the at least one of the fluid conduits (11) of the substrate body (10). Furthermore, a method of manufacturing a fluidic microsystem is described.

Description

Fluidic microsystem and method of manufacturing thereof
Field of the invention
The present invention relates to a fluidic microsystem, which comprises a substrate body with fluid conduits. In particular, the invention relates to a fluidic microsystem having a modular structure. Furthermore, the present invention relates to a method of manufacturing a fluidic microsystem, wherein a substrate body having fluid conduits is created with modular structure. Applications of the invention are available in the fields of handling liquids, in particular in biochemistry, medicine, biology or chemistry.
Background art
Fluidic microsystems are used for the manipulation of fluids at small scales in sub-mm ranges. Over the past twenty years, by miniaturization and automatization, applications of fluidic microsystems have been proposed, which include e. g. in biochemistry the manipulation and assay of single cells, genes, or enzymes, up to the manipulation of complex multicellular organisms and reconstitution of artificial organs. In the practical development of microfluidics, rapid prototyping by soft-lithography is generally known which provides microfabrication methods to produce microfluidic chips with an almost infinite number of degrees of freedom. By miniatur¬ izing fluidic components down to micro-meter scale, many functional modules can be integrated on a single chip, e. g. for single phase flow or multiphase flow or towards specific pre-programmed actions.
However, the flexibility at the core of the soft-lithography techniques relies on manufacturing capabilities such as clean rooms, found in specific laboratories and in technological industries equipped with microfabrication techniques. The lack of availability of microfluidic chips very often limits small business units or academic laboratories to develop mi- crofluidic tools adapted to their needs.
Manufacturing a fluidic microsystem with a modular structure has been proposed by S . M. Langelier et al. in "Lab on a Chip", volume 11, 2011, p. 1679-1687, and M. Rhee et al . in "Lab on a Chip", volume 8, 2008, p. 1365-1373. With this method, individual microfluidic assembly blocks (MABs) are assembled for forming a complete fluidic microsystem. The MABs are prefabricated with specific structures and functions and fluidic interfaces, which allow a coupling of the MABs. A glass substrate coated with the polymer PDMS (polydime- thylsiloxan) is used as a platform accommodating the MABs, which are aligned, assembled and finally, bonded on the platform substrate. The conventional method has the following disadvantages .
Firstly, laterally connecting the MBAs and suppressing leakage from the fluidic microsystem requires a bonding of the MABs not only with the platform substrate, but rather also with neighbouring MABs. Only with the lateral bonding of neighbouring MABs, sufficient forces connecting the MBAs are obtained and the fluidic microsystem is able to sustain the pressure in fluidic channels. As a disadvantage, the lateral bonding increases the complexity of the manufacturing process. Furthermore, after manufacturing the whole fluidic mi- crosystem, it is not easy to change a function thereof by replacing a single MAB. Consequently, the fluidic microsystem obtained with the conventional method is a disposable device rather than a reversible system. Secondly, the conventional method requires a clean work space, complex facilities and post-processing tools and a high level skill by the person manufacturing the fluidic microsystem. In particular, the conventional technique requires a spin coater for applying the adhesive material on the platform substrate, a curing system for the adhesive, like e. g. an oven or a hot-plate device or an UV exposure unit. Any dust trapping during the MAB assembling and bonding has to be strictly avoided. Finally, organic contamination, e. g.
caused by fingerprints, on the PDMS pieces or platform can affect the bonding and surface properties.
The MABs used for the conventional technique are structured with recesses on one surface thereof. In the assembled state, the recesses are closed by the adjacent surface of the substrate platform, thus providing fluid conduits in the fluidic microsystem. As the recessed surface structure of the MABs is exposed until the bonding with the platform substrate, the conventional technique is extremely sensitive against dust particles, which can be located on the exposed recessed surface or the surface of the platform substrate. Dust particles deteriorate the bonding, thus resulting in an increased risk of unintended leakage of the microsystem.
A further modular system has been proposed by P. K. Yuen et al. in "Lab on a Chip", volume 8, 2008, p. 1374-1378.
However, this system has technical difficulties linked to the need of intermediate connecting blocks.
Objective of the invention
The objective of the invention is to provide an improved fluidic microsystem, which is capable of avoiding disadvantages of conventional techniques. In particular, the objective of the invention is to provide an improved fluidic microsystem, which has a reduced manufacturing complexity, a reduced complexity of the module structure, a reversible configuration, an improved tightness against leakage, and/or an increased flexibility for adapting the microsystem to individual tasks Furthermore, the objective of the invention is to provide an improved method of manufacturing a fluidic microsystem, whic is capable of avoiding disadvantages of conventional techniques. In particular, the objective of the invention is to provide the manufacturing method with reduced complexity and/or reduced requirements as to the cleanness of the work space and the needed facilities and tools, and which can be implemented without particular skills by a user of the fluid ic microsystem.
Summary of the invention
These objectives are solved with a fluidic microsystem and a method of manufacturing a fluidic microsystem comprising the features of the independent claims, respectively. Advantageous embodiments and applications of the invention are defined in the dependent claims.
According to a first general aspect of the invention, the above objective is solved by a fluidic microsystem having a substrate body with fluid conduits embedded therein. The sub strate body is a plate-shaped, preferably plane or curved component, which is made of a solid material, preferably a polymeric material and which includes the fluid conduits as hollow channels within the substrate body material. The substrate body has a lateral extension (plane extension, along lateral directions) and a thickness extension in a thickness direction perpendicular to the lateral extension. According to the invention, the substrate body includes at least one module receptacle, which is a through-hole in the substrate body extending in the thickness direction thereof. The at least one module receptacle is arranged such that at least one of the fluid conduits within the substrate body opens into the at least one module receptacle.
Furthermore, according to the invention, at least one insert module including at least one conduit section is arranged in the at least one module receptacle, respectively. Preferably, one insert module is arranged in each of the module receptacles, respectively. The insert module is a component which is made of a solid material, preferably a polymeric material, wherein the at least one conduit section is embedded in the volume of the insert module material. Furthermore, the at least one insert module is press-fitted in the at least one module receptacle, wherein at least one conduit section of the insert module is aligned with at least one of the fluid conduits of the substrate body. The insert module is fully enclosed by the material of the substrate body in the latera] directions, so that the insert module is secured to the substrate body.
According to a second general aspect of the invention, the above objective is solved by a method of manufacturing a flu- idic microsystem, based on providing a substrate body with fluid conduits embedded therein. Preferably, the fluidic mi¬ crosystem of the above first aspect of the invention is manufactured. According to the invention, at least one module receptacle is formed, which extends through the substrate body in a thickness direction thereof, i.e. perpendicular to a lateral directions of a plate forming the substrate body. The at least one module receptacle is formed such that at least one of the fluid conduits is connected with the receptacle, i. e. at least one of the fluid conduits opens into the at least one module receptacle.
Furthermore, according to the invention, at least one insert module with at least one conduit section is inserted into the module receptacle, respectively. The at least one insert module is arranged in the respective module receptacle, i. e. the through-hole formed by the module receptacle is closed by the insert module. Advantageously, each insert module can be simply oriented relative to the respective module receptacle, e. g. by aligning the fluid conduits and conduit sections and/or by using optical marks on the insert module and the substrate body. Furthermore, according to the invention, the at least one insert module is press-fitted in the at least one module receptacle, respectively, while the at least one conduit section of the insert module is aligned with the at least one of the fluid conduits opening to the module receptacle .
According to a main advantage of the invention, the insert module is coupled with the associated module receptacle by a press fit connection (interference fit, friction fit) . With reference to the lateral directions of the substrate body, the insert module has a cross-sectional dimension, which is larger than the cross-sectional dimension of the module receptacle. The module receptacle is formed undersized with regard to the cross-sectional dimension of the insert module, and the insert module is formed oversized relative to the cross-sectional dimension of the module receptacle. When the insert module is pressed into the module receptacle, both parts interfere with each other's occupation of space. At least one of both parts deforms, so that a continuous contact is obtained between the lateral surface of the insert module and the internal lateral surface of the substrate body within the module receptacle. The mechanical stability obtained with the invention is determined by the stability of the substrate body surrounding each insert module and by a minimized dead- volume between the insert modules.
Advantageously, each insert module has a configuration, which is adapted for fulfilling a predetermined function of the respective insert module. Preferably, the configuration of the insert module is adapted for at least one of a physical and a chemical interaction of the insert module with the liquid in the fluidic microsystem, e. g. for a mechanical, electric, magnetic, thermal, optical and/or chemically-reactive effect on the liquid. Thus, by selecting at least one appropriate insert module and introducing it into at least one of the module receptacles, the fluidic microsystem can be provided with a specific fluidic function.
Thus, the inventors have introduced a new concept of modular microfluidics providing a plug-and-play construction of the fluidic microsystem. The inventive fluidic microsystem is a configurable and preferably even reconfigurable microfluidic device which is assembled with the substrate body and elementary functional units provided by the insert modules. Preferably, the insert modules can be replaced and/or exchanged. The invention suppresses the need for patterning, soft molding and bonding when details on a chip have to be set or modified. The inventive fluidic microsystem has two parts, the substrate body providing a base-platform used as a scaffold and the at least one insert module providing the functional unit which is combined by 'plug-and-play' . Tests by the inventors have shown that the inventive fluidic microsystem sustains typical pressures in microfluidic experiments, e. g. for producing droplets of different sizes using T-junction modules with different designs assembled successively on a 3x3 modular substrate body.
The invention is based on the combination of the at least one insert module which is pre-manufactured and assembled separately in the substrate body. The user can define the structures of the fluidic microsystem and preferably even change a detail of the fluidic microsystem without the need to redo a photolithography step. The chip-oriented rapid prototyping method of the invention contributes to a standardization of fluidic microsystems. Large series of insert modules (functional elements) can be manufactured, and the integration of the final chip being the task of the end-user.
Although each of the insert modules has a limited functional ity, the insert modules can be assembled at will to produce complex functionalities over the whole fluidic microsystem. Thus, advantages can be obtained similar to the advantages o electrical test boards designed for creating and testing electric circuits from a finite set of functional elements.
According to a preferred embodiment of the invention, the at least one module receptacle is made with an inner size, which is smaller than an outer size of the respective insert module before the insertion thereof into the module receptacle. Accordingly, as long as the insert module has a relaxed condition outside the module receptacle, it is larger than the module receptacle. Advantageously, this size deviation supports the formation of the secure press-fit of the insert module and the module receptacle. Generally, the size deviation is selected in dependency on the elasticity of at least one of the substrate body material and the insert module material. Preferably, the size deviation is at least 50 μιη in diameter, in particular at least 200 μιη in diameter. The main advantages of the fluidic microsystem are obtained, if the substrate body includes multiple module receptacles each being provided with one insert module. The module recep- tacles are connected via fluid conduits within the substrate body, and the fluid conduits are coupled via the conduit sections and optionally further functional elements of the insert modules. Thus, a complete fluidic microsystem can be created in dependency on the particular task defined by a us- er of the microsystem. The fluidic microsystem has a fluidic connection scheme and a fluidic function being determined by selecting and setting specific insert modules in the module receptacles. According to a further advantageous embodiment of the invention, at least one of the substrate body and the at least one insert module is made of an elastically deformable polymer material. Advantageously, the use of the elastically deformable polymer material facilitates the insertion of the insert module into the respective module receptacle and the creation of the liquid tight press-fit connection even if the insert module or the module receptacle is created with some tolerance in terms of dimension and shape. The elastically deformable polymer material, which comprises e. g. PDMS (Polydime- thylsiloxane) , or silicone rubber, polyurethanes , and thermoplastic elastomers, or a combination of those, supports a shape matching of the insert module and the module receptacle . According to a particularly preferred embodiment of the invention, the substrate body is made of a stiff solid material, preferably a stiff polymer material, like e. g. PMMA (Polymethylmethacrylate), or cyclic olefin copolymer (COC) , polyacrylate, UV-curable photopolymers , or a combination of those, while the at least one insert module is made of the elastically deformable polymer material. The stiff solid material has a lower elasticity compared with the material of the insert module. This embodiment of the invention has advantages in terms of the provision of the substrate body as a stable platform providing a scaffold for accommodating the at least one insert module. Accordingly, the further use of the inventive fluidic microsystem and the integration thereof in a larger fluidic plant are facilitated.
According to a further advantageous embodiment of the invention, the at least one insert module is separably connected with the substrate body. The separable connection means that the insert module can be inserted into the module receptacle and removed therefrom without a damage or change of the dimension or shape of the insert module or the module receptacle. The coupling of the insert module and the respective module receptacle can be separated by drawing the insert module out of the module receptacle. Drawing the insert module can be done e. g. with a blade tool introduced between the abutting lateral surfaces of the insert module and the module receptacle and/or by forming the insert module with an axial dimension (size along the thickness direction of the substrate body) , which is larger than the depth of the module receptacle, in particular larger than the thickness of the substrate body. With the latter variant, the insert module can protrude from the surface of the substrate body, so that it can be drawn from the module receptacle by hand or using a gripping tool.
A general advantage of the invention results from the fact that the insert module and the respective module receptacle can be made with respective outer and inner shapes, which can differ from each other. In particular with the application of the elastically deformable polymer material, eventual deviations in shape can be tolerated. However, according to a further preferred embodiment of the invention, the inner shape of the module receptacle and the outer shape of the insert module are matched to each other. The inner and outer shapes are geometrically similar. Advantageously, this embodiment of the invention improves the homogeneity of the press-fit connection. The elastic forces creating the press-fit connection are distributed homogeneously along the lateral circumference of the insert module. Accordingly, the risk of an unintended liquid leakage can be minimized.
Advantageously, multiple variants of geometrically similar inner and outer shapes of the module receptacle and the insert module are available. Preferably, non-complex geometric figures are selected. Thus, according to a first example, the inner and outer shapes can have an elliptic cross-sectional contour, i. e. the insert module and the respective module receptacle have a shape of elliptic cylinders. This variant of the invention may have advantages in terms of a compact design of the fluidic microsystem. According to a second variant, the inner and outer shapes can have a polygonal cross- sectional contour, e. g. a rectangular or even quadratic cross-sectional shape. Preferably, the polygonal contour has rotation symmetry. This allows a step-wise rotation of the insert module within the module receptacle, e. g. for coupling the at least one conduit section of the insert module with different ones of the fluid conduits in the substrate body. Furthermore, according to a particularly preferred variant, the inner and outer shapes of the module receptacle and the insert module have a circular cross-sectional contour. Accordingly, the module receptacle provides a hollow circular cylinder, while the insert module provides a compact circular cylinder. The circular shape has particular advantages in terms of a rotation capability of the insert module. The insert module can be rotated with an axis perpendicular to the lateral extension of the substrate body, thus allowing a coupling of the at least one conduit section of the insert mod¬ ule with different ones of the fluid conduits within the substrate body. The circular shape allows a continuous rotation so that an arrangement is possible wherein the fluid conduits of the substrate body are blocked by the insert module.
It is to be noted that, if the substrate body has multiple module receptacles, all module receptacles can have the same inner shape and dimension, the same inner shape and different dimensions, and/or different shapes and different dimensions. The insert modules can be manufactured with shapes and dimensions in correspondence to all of these variants.
As a further advantage of the invention, multiple design options are available for connecting fluid conduits within the substrate body via conduit sections within the insert module. With a preferred basic configuration, at least three fluid conduits open into the at least one module receptacle. As an example, three fluid conduits open into the module receptacle with mutual angles of 90°. Two of the at least three fluid conduits can be connected with one conduit section of the insert module, while at least one of the fluid conduits can be closed by the body of the insert module. By changing the orientation of the insert module within the module receptacle, the insert module can be used as a fluidic switch connecting or blocking fluid conduits within the substrate body.
If, according to a particularly preferred embodiment of the invention, the at least one insert module includes at least one functional element, a high degree of flexibility in terms of designing the function of the inventive fluidic microsys- tern is obtained. Preferably, the functional element includes at least one of at least one electrode, at least one pump, at least one tube connector, at least one container, at least one injector, at least one outlet, at least one linker, at least one T-junction, at least one flow-focussing junction, at least one nozzle and at least one incubation line. One insert module may include one of these functional elements, or some of these functional elements can be combined within one insert module.
Preferably, a matrix arrangement of the insert modules and module receptacles is provided. With this embodiment of the invention, the fluid conduits in the substrate body have a transverse arrangement including fluid conduits extending in a first lateral direction along the planar extension of the substrate body and further including fluid conduits extending in a second lateral direction along the planar extension of the substrate body. Preferably, the first and second lateral directions are perpendicular relative to each other. The module receptacles are formed at intersection points of the fluid conduits extending in the first and second directions and the insert modules inserted in the module receptacles connect the fluidic conduits in the substrate body depending on the conduit sections within the insert modules.
Preferably, the substrate body is manufactured with the following steps. Reference is made to a preferred embodiment with a plane shape of the substrate body. The method can be implemented correspondingly with a substrate body having a curved shape. Firstly, a substrate cover plate is provided, which preferably is a planar solid plate with a smooth, unstructured surface. Furthermore, a substrate conduit plate is provided, which is a planar plate having a structured surface including recesses. The recesses have longitudinal shapes ac- cording to the shapes of the fluid conduits to be obtained within the substrate body. With the substrate cover plate and the substrate conduit plate, the substrate body is formed by bonding both components, wherein the recesses in the surface of the substrate conduit plate are closed by the substrate cover plate. Accordingly, the fluid conduits are formed within the inner volume of the substrate body. Subsequently, the at least one module receptacle is formed by providing a through-hole in the substrate body, e. g. by drilling or punching.
Furthermore, with a preferred embodiment of the invention, the at least one insert module is manufactured according to the following steps. Firstly, a module base slab and a module conduit slab are provided, each with a plane shape. The module base slab is formed with a non-structured surface, while the module conduit slab is formed with a structured surface including recesses. The recesses are designed for providing the conduit sections in the complete insert module to be ob- tained. Subsequently, the module base slab and the module conduit slab are bonded together, wherein the recesses in the structured surface of the module conduit slab are closed and the conduit sections are formed by the closed recesses. Finally, the at least one module is obtained by punching at least one portion from the bonded slabs including the at least one conduit section. Punching can be obtained with a punching tool having a size and shape of the insert module to be obtained. Preferably, the module conduit slab is formed by soft lithography.
Alternatively, the insert modules can be manufactured directly by molding of elastically deformable polymers. This embodiment of the invention can have advantages for creating the insert modules with more complex, e. g. irregular shapes. In summary, the inventors have demonstrated a system for chip-oriented rapid prototyping making use of a stiff scaffold, made of e. g. PMMA, and functional units, made of e. g. PDMS . The system provides tight connection between functional elements for customer-oriented integration of microfluidic chips. The system is technologically interesting as the functional units are simple and can in principle be mass produced while the integration by the user will lead to an almost infinite set of possible devices, testable in very short time and at low cost.
The inventive system truly has plug-and-play capability. The platform and the modules are all pre-made, and no post processing after plugging the modules in the platform is needed. Also, making a microfluidics can be done by even naked-hand in normal office like working space.
Description of the drawings
Further advantages and details of the invention are described in the following with reference to the attached drawings, which show in
Figure 1: schematic views of a basic configuration of a pre¬ ferred embodiment of the fluidic microsystem according to the invention;
Figure 2: a perspective view of a preferred embodiment of the fluidic microsystem according to the invention;
Figure 3: xamples of insert modules used in the embodiment f Figure 2; Figure 4 : schematic plan view illustrations of insert modules used according to preferred embodiments of the in- vention;
Figure 5: a schematic illustration of manufacturing a substrate body of the fluidic microsystem according to the invention; and
Figure 6: a schematic illustration of manufacturing a insert modules of the fluidic microsystem according to the invention.
Description of the preferred embodiments
Features of preferred embodiments of the invention are de¬ scribed in the following with exemplary reference to fluidic microsystems having insert modules and receptacle sections with circular cross-sections. It is emphasized that the invention correspondingly can be implemented with other shapes, e. g. elliptical, polygonal or even irregular shapes. Furthermore, the invention is not restricted to the materials and dimensions of the fluidic microsystem, which are mentioned in the following as preferred examples. The skilled person is capable of designing the fluidic microsystem, in particular selecting appropriate materials and dimensions, in dependency on the requirements of the particular task of the fluidic microsystem to be manufactured. As an example, the fluid conduits within the substrate body can be provided with modified shapes, e. g. curved or more complex shapes. Insert modules are not necessarily arranged at an intersection of fluid conduits. Alternatively, insert modules can be integrated along a path of a fluid conduit. Furthermore, coupling the fluidic microsystem to additional fluidic plants is not described in detail. This coupling can be done using appro- priate tubing which is connected with the fluidic conduits in the substrate body, e. g. via inlet or outlet insert modules or via direct connection with the substrate body.
The inventive fluidic microsystems can be adapted for fulfilling any task of a fluidic microsystem as it is known in conventional fluidic applications. Accordingly, process features, like selecting liquids or flow parameters or fluidic functions, are not described in detail as far as they are known from prior art techniques.
Embodiments of the invention are described in the following with reference to an orthogonal coordinate system, including x- and y-axes extending in a substrate body plane, and a z- axis perpendicular to the substrate body plane. The z-axis corresponds to the thickness direction of the substrate body.
Embodiments of the fluidic microsystem
Figure 1 shows a first basic configuration of an inventive fluidic microsystem 100, including one single module receptacle 12 and one single insert module 20, with a cross- sectional view in a condition before (Figure 1A) and after (Figure IB) the insertion of an insert module into a module receptacle and with a cross-sectional view along line C - C of Figure IB in the condition after the insertion of the insert module in the module receptacle (Figure 1C) .
The fluidic microsystem 100 comprises the substrate body 10 including fluid conduits 11 and the module receptacle 12. The substrate body 10 has a planar shape extending along the x-y- plane of Figure 1. While the implementation of the invention with one single module receptacle and one single insert module is possible as shown in Figure 1, alternative embodiments with multiple module receptacles and module insert modules are preferred as shown e. g. in Figure 2.
The substrate body 10 is provided with a carrier plate 13, which is a solid support for the. fluidic microsystem. It is noted that the carrier plate 13 is an optional feature of the invention. If the material of the substrate body 10 has a sufficient mechanical stiffness, e. g. if the substrate body 10 is made of PMMA, the carrier plate 13 can be omitted.
The fluid conduits 11 comprise straight channels extending along the planar shape through the substrate body 10. The channels open to the module receptacle 12. As an example, the fluid conduits 11 have a rectangular cross-sectional shape and a cross-sectional dimension in the range of 10 μπι to 1 mm. The thickness of the substrate body 10 is about 5 mm.
The module receptacle 12 comprises a cylindrical through-hole extending in the thickness-direction ( z-direction) of the substrate body. The module receptacle 12 can extend through the whole thickness of the substrate body (as shown in Figure 1A) or through a part of the substrate body 10 only. In the latter case, the depth of the module receptacle 12 would be selected such that the fluid conduits 11 open into the module receptacle 12 with a distance from a bottom thereof. The diameter of the module receptacle 12 is e. g. 4,7 mm.
The insert module 20 is a cylindrical component, which is made of an elastically deformable polymer, like e. g. PDMS. The diameter of the insert module 20 is e. g. 5 mm, i. e. 300 μιη larger than the inner diameter of the module receptacle 12. Preferably, the deviation Ar between the inner diameter of the module receptacle 12 and the outer diameter of the in- sert module 20 in a relaxed condition is in the range between 50 μπι to 500 μηα.
The insert module 20 includes a conduit section 21 and op- tionally a functional element 22. The conduit section 21 has cross-sectional dimensions equal to the shape and dimension of the fluidic conduits 11 of the substrate body 10. Depending on the application of the fluidic microsystem, the conduit section 21 can have cross-sectional dimensions larger or smaller than the shape and dimension of the fluidic conduits 11. The functional element 22 is schematically shown only. It comprises e. g. an electrode or a pump or any other compo¬ nent, which is to be used in the fluidic microsystem 100 (see examples in Figure 3) .
When the insert module 20 is inserted into the substrate body 10 (see Figures IB and 1C) , a press-fit connection with the substrate body 10 is obtained. The conduit section 21 is aligned with the fluidic conduits 11, so that a fluidic chan- nel is formed, which extends from the substrate body 10 through the insert module 20 again to the substrate body 10. Liquids flowing through the channel can be subjected to the effect of the functional element 22, when they pass the in¬ sert module 20.
Figure 2 shows a second basic configuration of an inventive fluidic microsystem 100 including multiple module receptacles 12 and multiple insert modules 20. The fluid conduits 11 have a transverse arrangement of straight channels intersecting each other. First and second groups of fluid conduits 11.1, 11.2 extend along the x- and y-directions, resp.. The module receptacles 12 are formed at intersections points of the first group and second groups of fluid conduits 11.1, 11.2, resp.. Insert modules 20 are inserted at the module recepta- cles 12, wherein some insert modules have a certain fluidic function, and the remaining module receptacles 12 are filled with blind inserts 30. The blind inserts 30 are formed with a material, size and shape like the insert modules, but without a conduit section, so that the blind inserts 30 simply block the fluid conduits opening into the respective module receptacles 12.
With an exemplary application of the invention, the fluidic microsystem 100 has been configured for a droplet dispersion production of oil droplets, made of fluorinated oil with surfactant (HFE7500, Novec) with 0.5% PEG-PFPE block-copolymer ( Sigma-Aldrich, custom synthesis), in an aqueous continuous phase, e. g. water. The insert modules 20 comprises an oil inlet module 23, an aqueous phase inlet module 24, a T junction module 25 for the droplet dispersion production and a dispersion outlet module 26. The remaining module receptacles 12 are tightly closed with the blind inserts 30. The inlet and outlet modules (23, 24 and 26) are formed as shown with exemplary reference to the oil inlet module 23 in Figure 3A. The oil inlet module 23 comprises a conduit section 21 coupled with one of the fluid conduits 11.1, while the remaining fluid conduits are blocked by the cylindrical body of the oil inlet module 23. Furthermore, the oil inlet module 23 comprises a chamber 23.1 and a connection hole 23.2, where a tube of a liquid supply or another microsystem can be coupled. The T junction module 25 is formed as shown in Figure 3B. It includes three conduit sections 21 which are coupled with the fluid conduits 11.1, 11.2 and which form a T-junction with an integrated nozzle (e. g. as shown in Figures 4G, H) for droplet production. Tests have shown, that the same platform can be used to produce droplets of different sizes by simply replacing the functional element (T junction modules 25 with different nozzles diameters, e. g. 100 μιη, 60 μιτι and 40 μιη) . The produc- tion reliability has been shown by testing the system with different flow rates, e. g. with a fixed flow rate for the water phase as 10 μΐ/min, and the flow rates of the oil phase with a range of 10 to 100 μΐ/min. Thus, the inventive fluidic microsystem 100 has been demonstrated as a reconfigurable, leakage-free system for multiphase flow working at a typical pressure reached in microfluidic chips (e. g. typically of order 1 bar) .
The advantages with regard to tuning droplet size can be fur- ther extended to other aspects, such as having localized wettability alterations in the insert modules 20, which would make the production of double emulsions relatively straightforward. The single insert modules 20 could be made available as hydrophilic or hydrophobic, in addition to having several dimensions. The inventive fluidic . microsystem 100 can also provide solutions for on-chip storage modules, valves and three-dimensional assembly. Electrodes for sorting and coalescence also, for example as described in "Lab on a Chip" vol. 9, 2009, p. 1850, can be inserted for example using the microsolidics technique described by Siegel et al . in "Angew. Chem." vol. 45, 2006, p. 6877-6882.
Further examples of insert modules 20 are shown in Figure 4, which comprise an inlet or outlet module (Figure 4A) , linker modules (Figures 4B, C) , a T-junction module (Figure 4D) , a flow focussing module (Figure 4E) , an incubation line module (Figure 4F) and nozzle modules, e. g. for a flow-focussing droplet generator (Figure 4G) or for a T-Junctions droplet generator (Figures 4H) . Features of insert modules according to Figure 4 can be combined within a single insert module. Each module carries a specific connectivity to the substrate body, blocking undesired connections. Fabricating the substrate body 10 and the insert modules 20
The preferred embodiment of the inventive fluidic microsystem 100 (e.g. according to Figure 2) is composed of a micro- machined rigid, platform (the substrate body 10) made of PMMA and elastic insert modules 20 which are fabricated by conventional soft lithography in Polydimethylsiloxane (PDMS, the functional units) as described in the following with reference to Figures 5 and 6. The substrate body 10 is made of a substrate cover plate 15 and a substrate conduit plate 16, which comprise PMMA thin sheets (3 mm thick) as shown in Figure 5A. The substrate cover plate 15 has a plane, smooth surface, while the substrate conduit plate 16 is formed with a structured surface includ- ing recesses 17. The recesses 17 comprise two sets of parallel lines of width 500 μπ\ and depth 500 μιη which are micro- machined using a high precision drill (e. g. DMU 50, manufacturer DMG Mori Seiki) . The substrate conduit plate 16 is then bonded with the second flat' PMMA substrate cover plate 15, e. g. by a thermal bonding process as shown in Figure 5B. Before bonding, the plates 15, 16 are plasma-treated in an 02 plasma-chamber (manufacturer e. g. Diener) for 30 s at 0.4 mbar and 140 W. The bond- ing is performed at a temperature of e. g. 98°C, with an applied force of 5 kN during 30 min. The bonded plates are then cooled down to room temperature at a rate of e. g. approximately -l°C/min to slowly relax thermal stresses. Nine through holes (diameter 4.6 mm) providing the module receptacles 12 are drilled in the substrate body 10 as shown in Figure 5C, and the substrate body 10 is cleaned by ethanol to remove debris generated during drilling process.
The functional insert modules 20 are made of a module conduit slab 27 and a module cover slab 29 bonded together as shown in Figure 6. The module conduit slab 27 is fabricated using standard soft lithography (see e. g. Y. N. Xia et al. in "An- nual Rev. Mater. Sci., vol. 28, 1998, p. 153 - 184). A master slab is created in a 25 μπι deep SU-8-3025 resist by shining UV light through a transparency mask (manufacturer: Selba, Switzerland) . The mask is designed with is formed with a structured surface including protruding elements, in particu- lar structures and connection branches, and circular align¬ ment marks 28.1 (see Figure 4) spaced by 90 degrees angles from the centre of the circle. The module conduit slab 27 is then replicated in PDMS from the master slab so that the protruding elements form recesses 28 (Figure 6A) . Connection holes 28.1 can be punched in the PDMS if required by the design, for example in the case of inlets and outlets (Figure 6B) . Furthermore, functional elements can be integrated at this stage of the process at the positions of the insert modules to be obtained.
A module cover slab 29 is a second PDMS slab, which is casted on a flat wafer, and both PDMS slab 27, 29 are bonded together after 02-plasma treatment (Figure 6B) . The recesses 28 are closed by the module cover slab 29, thus providing the con- duit sections of the insert modules to be obtained.
The PDMS insert modules 20 are cut from the bonded slabs 27, 29, using e. g. a 5 mm diameter biopsy punch. Alignment of the channels with the biopsy punch is obtained for allowing the alignment of the conduit sections 21 of the insert modules 20 with the fluid conduits of the substrate body. The diameter of the module receptacles (substrate body holes) was chosen by the inventors after testing through-holes diameters ranging from 4 to 5 mm with 100 μπι steps. A preferred combination of diameters 5 mm (biopsy hole) and .6 mm (module re¬ ceptacle) has been found to provide a tight sealing between the PMMA substrate body and the PDMS insert module 20. The error of the punching position would cause misalignment between the insert modules and the substrate body. The inven¬ tors have found that malfunctions due to this error can be easily avoided, even by using a simple alignment procedure. A paper guide can be used having the size and pitch of the de- sign. Even with this procedure, properly functional systems are obtained, because the tolerance is finally given by the dimensions of the fluid conduits in the substrate body.
The rotational tolerance for alignment between the fluid con- duits 11 in the substrate body 10 and the conduits sections 21 in the insert modules 20 is given by the respective channels in the substrate body 10 and the insert modules 20. The rotational tolerance can calculated as e. g. 12° based on the geometrical dimension. The translational tolerance is mainly defined by an eccentric error during fabrication of the in¬ sert module. The tolerances are sufficient to make the con¬ nection alignment by eye. The expanded channel design at the interface of the module and platform, and additional align- key around the module help to alignment during plug-in.
Finally, the insert modules 20 are introduced into the re¬ spective module receptacles 12. The PMDS insert modules 20 can be lubricated by fluorinated oil prior to the insertion into the substrate body 10. For manufacturing the fluidic mi- crosystem 100 of Figure 2, a PMMA substrate body 10 with 3><3 module receptacles 12 and a set of insert modules 20 have been used to produce droplets at a T-junction. Two types of insert modules 20 have been assembled as described above with reference to Figures 2 and 3.
The features of the invention disclosed in the above description, the drawings and the claims can be of significance both individually as well as in combination for the realization of the invention in its various embodiments.

Claims

Claims 1. Fluidic microsystem (100), having a substrate body (10) with fluid conduits (11),
characterized in that
- the substrate body (10) includes at least one module receptacle (12) extending in a thickness direction of the sub- strate body (10) , wherein at least one of the fluid conduits (11) opens into the at least one module receptacle (12), and
- at least one insert module (20) with at least one conduit section (21) is arranged in the at least one module receptacle (12), resp., wherein
- the at least one insert module (20) is press-fitted in the at least one module receptacle (12) and the at least one conduit section (21) is aligned with the at least one of the fluid conduits (11) of the substrate body (10) .
2. Fluidic microsystem according to claim 1, wherein
- the at least one module receptacle (12) has an inner size which is smaller than an outer size of the at least one insert module (20) in a relaxed condition before arrangement in the at least one module receptacle (12) .
3. Fluidic microsystem according to one of the foregoing claims, wherein
- the substrate body (10) includes multiple module receptacles (12) each including one insert module (20) .
4. Fluidic microsystem according to one of the foregoing claims, wherein - at least one of the substrate body (10) and the at least one insert module (20) is made of an elastically deformable material .
5. Fluidic microsystem according to claim 4, wherein
- the substrate body (10) is made of a stiff polymer material and the at least one insert module (20) is made of an elastically deformable polymer material.
6. Fluidic microsystem according to one of the foregoing claims, wherein
- the at least one insert module (20) is separably coupled with the substrate body (10).
7. Fluidic microsystem according to one of the foregoing claims, wherein
- the at least one module receptacle (12) and the at least one insert module (20) have inner and outer shapes, resp., which are matched to each other.
8. Fluidic microsystem according to claim 7, wherein
- the inner and outer shapes have an elliptic, a polygonal or a circular cross-sectional contour.
9. Fluidic microsystem according to one of the foregoing claims, wherein
- at least three fluid conduits (11) open into the at least one module receptacle (12),
- two of the at least three fluid conduits (11) are connected through the conduit section (21) of the at least one insert module (20) arranged in the at least one module receptacle (12), and - one of the at least three fluid conduits (11) is closed by the at least one insert module (20) arranged in the at least one module receptacle (12).
10. Fluidic microsystem according to one of the foregoing claims, wherein
- the at least one insert module (20) includes at least one functional element (22) including at least one of an electrode, a pump, a tube connector, a container, an injector, an outlet, linkers, a T-junction, a flow-focussing junction, a nozzle, and an incubation line.
11. Fluidic microsystem according to one of the foregoing claims, wherein
- the fluid conduits (11) in the substrate body (10) have a transverse arrangement including a first group of fluid conduits (11) extending along a first direction and a second group of fluid conduits (11) extending along a second direction,
- multiple module receptacles (12) are arranged at intersections points of the first group and second groups of fluid conduits (11), resp..
12. Method of manufacturing a fluidic microsystem, including a step of providing a substrate body (10) with fluid conduits
(11) embedded therein,
characterized by the steps of
- forming at least one module receptacle (12) extending in a thickness direction of the substrate body (10) and being ar- ranged such that at least one of the fluid conduits (11) opens into the at least one module receptacle (12), and
- arranging at least one insert module (20) with at least one conduit section (21) in the module receptacle (12), resp., wherein - the at least one insert module (20) is press-fitted in the at least one module receptacle (12) and the at least one conduit section (21) is aligned with the at least one of the fluid conduits (11) of the substrate body (10) .
13. Method according to claim 12, including a step of
- forming the at least one module receptacle (12) and the at least one insert module (20) such that the at least one module receptacle (12) has an inner size which is smaller than an outer size of the at least one insert module (20) to be arranged in the at least one module receptacle (12) .
14. Method according to one of the claims 12 to 13, wherein
- multiple module receptacles (12) are formed in the sub- strate body (10), and
- one insert module (20) is arranged in each of the multiple module receptacles (12) .
15. Method according to one of the claims 12 to 14, includ- ing a step of
- forming at least one of the substrate body (10) and the at least one insert module (20) of an elastically deformable material .
16. Method according to claim 15, wherein
- the substrate body (10) is made of a stiff polymer material and the at least one insert module (20) is made of an elastically deformable polymer material.
17. Method according to one of the claims 12 to 16, including a step of
- forming the at least one module receptacle (12) and the at least one insert module (20) with inner and outer shapes, resp., which are matched to each other.
18. Method microsystem according to claim 17, wherein
- the inner and outer shapes have a circular or a polygonal cross-sectional contour.
19. Method according to one of the claims 12 to 18, including a step of
- integrating at least one functional element to the at least one insert module (20) , said at least one functional element including at least one of an electrode, a pump, a tube connector, a container, an injector, an outlet, linkers, a T- junction, a flow-focussing junction, a nozzle, and an incubation line.
20. Method according to one of the claims 12 to 19, wherein
- the fluid conduits (11) in the substrate body (10) have a transverse arrangement including a first group of fluid conduits (11) extending along a first direction and a second group of fluid conduits (11) extending along a second direc- tion,
- the multiple module receptacles (12) are formed at intersections points of the first group and second groups of fluid conduits (11) , resp..
21. Method according to one of the claims 12 to 20, comprising the steps of
- providing a substrate cover plate (15) and a substrate con¬ duit plate (16), wherein the substrate cover plate (15) is formed with a plane surface and the substrate conduit plate (16) is formed with a structured surface including recesses (17) ,
- forming the substrate body (10) by bonding the substrate cover plate (16) with the substrate conduit plate (16), wherein the fluid conduits (11) are formed by closing the re- cesses (17) in the substrate conduit plate (16) by the substrate cover plate (15), and
- forming the at least one module receptacle (12) by drilling into the substrate body (10) .
22. Method according to one of the claims 12 to 21, comprising the steps of
- providing a module conduit slab (27) and a module cover slab (29), wherein the module conduit slab (27) is formed with a structured surface including recesses (28) and the module cover slab (29) is formed with a plane surface,
- bonding the module cover slab (29) with the module conduit slab (27), wherein conduit sections (21) are formed by closing the recesses (28) in the module conduit slab (27) by the module base slab (29) , and
- forming the at least one insert module (20) by punching at least one portion from the bonded slabs including at least one conduit section (21) .
23. Method according to claim 22, wherein
- the module conduit slab (27) is formed by soft lithography.
PCT/EP2013/003834 2013-12-18 2013-12-18 Fluidic microsystem and method of manufacturing thereof WO2015090339A1 (en)

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CN114055772A (en) * 2021-09-29 2022-02-18 福建医科大学 Manufacturing method of 3D printing assembling paper-based micro-fluidic chip
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