DE102016226194A1 - Microfluidic device, process for its production and injection-compression molding device - Google Patents

Abstract

A microfluidic device (400) comprises at least one structured carrier plate (100) and at least one cover plate (300), wherein a functional elastic intermediate layer (200) is arranged between the at least one carrier plate (100) and the at least one cover plate (300). The intermediate layer (200) is made on the basis of liquid silicone rubber (LSR).

Description

The present invention relates to a microfluidic device, for example a microfluidic chip, to a method for the production thereof, and to an injection-compression-molding device which is set up to produce the microfluidic device.

State of the art

For various applications, microfluidic devices, such as microfluidic chips, are used. Such, typically made of plastic, fluidic devices can be used for example for analytical, preparative or diagnostic applications in medicine. The microfluidic devices can be used for example in the form of a so-called lab-on-chip system, wherein the functionalities of a laboratory are effectively combined in credit card format. In general, such microfluidic devices consist of a structured plastic carrier plate, which integrates the various required reaction chambers, channels and other functional elements. Furthermore, an intermediate plate or optionally a plurality of intermediate plates may be provided. In general, a cover plate is further provided to seal the microfluidic device. In this way, various analysis components, pumps, heat sources, sensors and others can be integrated to run complex biochemical processes or the like in the fluidic device. Such systems are particularly suitable for automated applications, so that they can be used, for example, for a timely diagnosis in medical practices or hospitals.

The production is usually carried out by a separate production of the individual plastic plates in special injection molding or embossing tools or hot stamping systems. After the manufacture of the individual elements, the microfluidic device is assembled and sealed by means of complicated bonding or welding processes. Especially for medical products, the sterility of the device is very important. Furthermore, no impurities may enter the device in order not to falsify, for example, later analysis results. In general, therefore, all components of such a system are manufactured under clean room conditions, assembled and packaged.

The German patent application DE 10 2010 041 287 A1 describes, for example, a method for producing a microfluidic device in which a structured carrier plate and a cover plate are formed separately. Between these plates, a functional element, for example an intermediate plate, is arranged. Subsequently, the arrangement is covered with a cover plate and sealed airtight. The functional element may be a pumping membrane formed of thermoplastic elastomer (TPE) or the like. External air valves allow this membrane to perform a pump function.

Disclosure of the invention

Advantages of the invention

The invention provides a microfluidic device comprising at least one structured support plate and at least one cover plate. Furthermore, a functional elastic intermediate layer is provided in the microfluidic device according to the invention, which is arranged between the at least one support plate and the at least one cover plate. The functional elastic intermediate layer is produced according to the invention on the basis of liquid silicone rubber (LSR). In contrast to elastic intermediate layers or membranes, which are known in such devices from the prior art, the elastic intermediate layer of the microfluidic device according to the invention is an elastomer layer which is crosslinked. As a result, this intermediate layer is much less sensitive to various conditions, for example to elevated temperatures. The intermediate layer is also much more resistant to media compared to conventional intermediate layers. The invention thus provides a microfluidic device with integrated reaction chambers, channels, and functional elements (eg, pump functions, etc.) that is highly media-resistant, robust, and therefore suitable for a variety of applications. For example, the device can be used as a versatile adaptive microfluidic analysis chip. In addition, the fluid channels are permanently sealed by the inventive elastic intermediate layer based on LSR, for example, even at elevated temperatures and in a variety of different media. Thus, even under conditions in which conventional microfluidic devices can no longer be used, a system is provided by the microfluidic device which ensures the pumping and / or sealing function between individual fluid channels through the elastic intermediate layer, for example, even at elevated reaction temperatures and completely different media.

For example, conventionally used thermoplastic elastomer is very sensitive to elevated temperatures. For example, the use of a heat source in the System may be critical, as it can quickly exceed a critical limit for the stability and strength of the elastomeric membrane. Furthermore, with the use of thermoplastic elastomer membranes sterilization, which is usually carried out at high temperatures, not possible. All these disadvantages do not occur in the LSR intermediate layer according to the invention.

In a particularly preferred embodiment of the microfluidic device according to the invention, the elastic intermediate layer is optically transparent. The optical transparency of LSR is a particularly advantageous property in this context. An optically transparent elastic intermediate layer has the particular advantage that optical elements can be integrated directly into the intermediate layer, for example magnifying optics and / or monitoring windows. In this context, it may be preferred if the other components of the microfluidic device, ie in particular the carrier plate and / or the cover plate, are at least partially transparent. Preferably, the entire device is completely transparent. In this embodiment, on the one hand, an evaluation of the processes running can be carried out by optical methods, without having to remove samples from the device. On the other hand, the current processes in the fluid channels can be monitored very well.

With particular advantage, the at least one support plate and the at least one cover plate of the microfluidic device are positively connected to each other and in particular also media-tight. By a positive connection, which can be realized in particular in the course of the assembly injection molding method to be explained in more detail below, the individual components can be connected to each other directly in the formation of the individual elements and encapsulated as it were. This eliminates subsequent elaborate welding or adhesive processes. Due to the positive connection, the various plates can be connected and encapsulated media-tight in one production step, whereby the production is considerably simplified and, above all, also shortened. In the case of the microfluidic device, it can further be provided that feed and discharge openings for media or, in general, for the fluids which are guided through the microfluidic device are integrated directly into the cover plate.

The invention further comprises a method for producing a microfluidic device which comprises at least one structured carrier plate and at least one cover plate as well as a functional elastic intermediate layer between the carrier plate and the cover plate. In the production, the functional elastic intermediate layer is manufactured according to the invention using LSR, the advantages of which have already been explained above. The inventive production of the microfluidic device is preferably carried out in a mounting injection molding, in which the carrier plate and the cover plate and the elastic intermediate layer are produced and connected to each other media-tight during the manufacturing process. There are no additional process steps, such. As laser welding or gluing or another connection of the individual components required during assembly. The openings required for media or fluid guidance to the outside can be integrated directly into the device during the manufacturing process. With this method, manufacturing times can be shortened, since, for example, transports of the individual components between different production locations are eliminated and the device can be manufactured in a single manufacturing process. Furthermore, additional tools, machines and thus various sources of error can be saved or avoided. If the manufacturing process is carried out in a special clean room and the components used are handled cleanly and sterile, no germs or impurities enter the system, so that microfluidic devices produced in this way are particularly suitable for, for example, medical applications. By reducing the process steps, the microfluidic device can be produced in a short cycle time and very cost-effectively with little waste, since sources of error in the production process are avoided.

In the production of the structured carrier plate is preferably first formed from a thermoplastic material with corresponding channels, reaction chambers, etc. In the formation of the support plate elements may further be provided, which realize a fixing frame for the subsequent alignment and merging of the different plastic layers. The elastic intermediate layer is produced separately on the basis of LSR. The material for this is provided in particular in the form of two components which are brought together and then react or crosslink with one another. The crosslinking is preferably carried out at an elevated temperature. In order to avoid premature crosslinking, it is advantageous if the corresponding tool is first tempered to a lower temperature. Subsequently, the tool can be heated, so that the crosslinking of the LSR can be done very quickly at the elevated temperature. For example, a temperature between 140 ° C and 180 ° C may be provided for the crosslinking, depending on the specific mixture of the LSR. Especially suitable for the elastic intermediate layer is an LSR with a Shore A hardness between 40 and 80. For example, the product Silopren ^® from Momentive with the product designations 740 to 780 is suitable for this purpose.

Preferably, functional elements are integrated in the production of the elastic intermediate layer, for example functional pump membranes and / or optical elements. For example, a region of the elastic intermediate layer may be formed in the form of a lens, so that this region has corresponding optical properties. Furthermore, in the manufacture of the elastic intermediate layer, elastic connecting stubs can be formed, which can later be connected directly to the hoses of the fluidic system, for example for a sample feed.

After the production of the elastic intermediate layer, the intermediate layer is assembled with the shaped structured support plate. In a corresponding injection compression tool, the cover plate is formed from thermoplastic material. In the production of the carrier plate and / or the cover plate preferably positive-locking elements for a connection of the cover plate are formed with the carrier plate. For example, grooves may be provided in the support plate, ie recesses in the support plate, which are poured in the later production of the cover plate with the plastic melt for the cover, so that a positive connection of the individual plates of the device and simultaneously a media-tight encapsulation of the microfluidic device is achieved , For this purpose, the positive elements in the device are expediently in the outer edge region of the device.

Depending on the intended use of the microfluidic device, biocompatibility of the individual elements of the device may be required. Therefore, biocompatible plastic components are preferably used for the backing plate and the cover plate, for example cyclo-olefin polymer (COP), cyclo-olefin copolymer (COC), polycarbonate (PC) or polymethyl methacrylate (PMMA).

Finally, the invention comprises an injection-compression molding device for producing the described microfluidic device. The injection-compression molding device comprises a two-cavity injection-compression molding tool with corresponding stamping dies for shaping the support plate and for forming the cover plate, as well as an injection mold for producing the elastic intermediate layer. For the formation of the structured carrier plate, a first injection molding unit for a thermoplastic material is preferably provided, with which the carrier plate is formed. Furthermore, a second injection molding unit is preferably provided, with which the LSR for the elastic intermediate layer is introduced into the corresponding injection molding tool. Since the LSR material is preferably a two-component mixture, this requires a mixing and metering system with which the material provided as separate mixtures can be conveyed separately and mixed in a suitable ratio. For this metering device, a temperature control can be provided to prevent premature crosslinking. The injection mold for producing the elastic intermediate layer is preferably heated to an elevated temperature in order to facilitate rapid and targeted crosslinking of the plastic. Furthermore, a third injection molding unit for the thermoplastic material, from which the cover plate is formed, is provided. This third injection molding unit is comparable to the first injection molding unit.

The two-cavity injection-compression molding tool is equipped with suitable stamping dies for shaping the carrier plate and for forming the cover plate. Here, the structuring of the carrier plate are predetermined by the first die. In addition to various channels that can be formed in this case, various depressions are generally provided here, which are provided for example as reaction chambers or reagent or buffer chambers (reagent bar). In addition, further inserts may be provided in the first die, with which further functional structures are realized on the carrier plate. For example, the embossing stamp may have a Teflon insert, with the aid of which, for example, a composite foil can be introduced as a reagent chamber foil into a depression of the carrier plate. With the aid of this composite foil, for example, a reagent chamber can be welded media-tight after demoulding the cooled carrier plate, after this reagent chamber has been filled with appropriate media.

The injection-compression molding device is preferably set up to carry out the described production process. With regard to further elements of the injection-compression molding device, reference is therefore made to the above description. In general, the injection-compression molding device according to the invention and its individual elements, for example the configuration of the cavities and the stamping die, can be adapted to the intended design of the microfluidic device. By an appropriate design of the injection-compression molding device, the optical elements, for example, the lenses of the elastic intermediate layer and the various chambers of the support plate can be designed so that For example, an external evaluation device always has an optimal focus.

In a preferred embodiment of the injection-compression molding device, elements are provided for the molding step of the cover plate in the injection-compression molding tool, which allow delimitation of functional elements of the elastic intermediate layer during the step of manufacturing the support plate. Preferably, these are hollow ejector elements (eg hollow pins) that are placed on the corresponding areas of the functional elements of the intermediate layer, so that during the injection of the plastic melt for the cover plate these areas are recessed and not covered by the plastic melt. In these areas, the cover plate so to speak recesses, so that the functional elements of the elastic intermediate layer, such as pump diaphragms or optical elements, remain accessible from the outside. With the ejector elements, a slight contact pressure can additionally be exerted after the injection-compression tool is closed, so that the layer package formed by the structured carrier plate and the elastic intermediate layer arranged thereon is additionally fixed during injection-compression of the cover plate.

Due to the specific design of the injection-compression molding device, the various functional elements of the microfluidic device to be produced can be precisely adjusted and adapted to the intended applications. For example, with the dimensions of the pump diaphragms and with an integrated film stamp, it is possible to set exactly the quantity of air and reagent required for the evaluation of defined sample quantities. When using the microfluidic device, so when performing analyzes or the like, the system remains completely closed to the outside (with the exception of the connecting piece) after opening the welded reagent chambers, which takes place by means of the integrated film stamp.

Further features and advantages of the invention will become apparent from the following description of exemplary embodiments in conjunction with the drawings. In this case, the individual features can be implemented individually or in combination with each other.

list of figures

• 1 Schematic diagram of an injection-compression tool of the injection-compression molding device according to the invention in section for producing a structured support plate;
• 2 Schematic diagram of an injection mold of the injection-compression molding device according to the invention in section for the production of the elastic intermediate layer;
• 3 Schematic diagram of an injection-compression tool of the injection-compression molding device in section for producing the cover plate and for encapsulating the microfluidic device;
• 4 schematic plan view of a microfluidic device according to the invention and
• 5 schematic sectional view of a microfluidic device according to the invention.

Description of exemplary embodiments

The 1 to 3 illustrate the tools that can be used to fabricate a microfluidic device according to the invention in the assembly injection molding process. The injection molding apparatus according to the invention comprises a two-cavity injection molding tool 10 ( 1 and 3 ) and an injection mold 20 ( 2 ). In a first cavity of the two-cavity injection-compression mold 10 First, the structured carrier plate 100 shaped as it is in 1 is illustrated. The injection compression tool 10 includes a floor element 11 and a lid member 12 passing through a parting plane 13 are separated from each other. The bottom element 11 and the cover element 12 form a cavity in which the carrier plate 100 is formed. For structuring the surface of the carrier plate 100 is a correspondingly structured die 14 with hydraulic cylinders 19 intended. With the stamp 14 become depressions 101 . 102 and here unspecified channel structures in the carrier plate 100 educated. For the production of the carrier plate 100 is a plastic melt via a first injection molding unit, not shown here 30 in the tool 10 brought in. In the heated to 80 ° C to 140 ° C injection mold 10 becomes the carrier plate 100 shaped. In the stamp 16 can be a teflon insert 17 be provided to a preformed composite film 103 in the die 16 appeal. This composite foil 103 forms a Reagenzkammerfolie for a design of the recess 101 , The composite foil 103 is formed by the expansion of the Teflon insert 17 fixed at the appropriate mold temperature and in the course of the injection-compression process of the plastic melt, so the preferably optical thermoplastic material, back-injected. After over the injection unit 30 the plastic component (eg COP, COC, PC, PMMA) into the cavity of the injection mold 10 was injected, is the carrier plate with the structured die 16 100 low-distortion shaped in their shape. The floor element 11 and the lid member 12 are designed so that during injection molding of the carrier plate 100 outside the actual structures (channels and Depressions or chambers 101 . 102 ) Grooves 104 and a fixation frame 105 be formed, which are used for later alignment and merging of the various components of the microfluidic device.

After demolding the cooled support plate 100 can the depression 101 be filled as reagent chambers with appropriate solutions or media and the composite film 103 can be used as cover layer of the reagent chamber 101 sealed media-tight.

The production of the elastic intermediate layer, which takes place in a separate manufacturing step, is based on the 2 illustrated. For this purpose, the injection mold 20 used that a floor element 21 and a lid member 22 coming from a dividing plane 23 be separated. For the formation of functional elements in the intermediate layer, the cover element 22 a lens mold insert 24 and a mold insert 25 for a pump diaphragm. These inserts 24 . 25 can also be present in majority. The floor element 21 has a corresponding mold insert 26 for forming the pump diaphragm 204 on, wherein the pump diaphragm 204 represents a bulge of the elastic intermediate layer. With the help of the mold insert 26 can still a foil stamp 201 in the elastic intermediate layer 200 in the area of the pump membrane 204 to get integrated. For the production of the elastic intermediate layer LSR is used as a two-component mixture via the second injection molding unit, not shown 40 into the cavity of the injection mold 20 injected. Preferably, optical LSR used (eg. As Silopren LSR ^® 7060 ), with which also optical functionalities of the elastic intermediate layer can be realized. With the help of the lens mold insert 24 can be a lenticular widening 202 as an optical element in the elastic intermediate layer 200 will be realized. Before shooting the injection mold 20 become the stable film stamps 201 made of thermoplastic used in the tool. With the help of these film stamps 201 can later use the reagent chamber slides 103 be torn up. When injecting the crosslinking at appropriate temperature plastic (LSR) in the cavity of the injection mold 20 then becomes the elastic intermediate layer with the functional elements 201 . 202 and the pump diaphragms 204 as well as with a fixation frame 205 formed. By appropriate molding of the injection mold 20 In addition, elastic connecting pieces 203 be generated for the tubes of the later sample and fluid guide. Subsequently, the LSR is chemically crosslinked at a mold temperature between 140 ° C and 180 ° C, so that the resulting elastic intermediate layer 200 is very temperature and media resistant.

In the third step, the carrier plate 100 with the sealed reaction chamber (s) 101 together with the elastic intermediate layer 200 directly over the structured surface of the carrier plate 100 in the intended fixing frame 105 . 205 in a second cavity of the injection mold 10 inserted. The tool comes with a second stamp 18 with hydraulic cylinder 19 closed. Then drive hollow ejector elements (pins) 31 . 32 . 33 with slight pressure on the edges of the in the elastic intermediate layer 200 trained functional elements, so over the area of the pump diaphragm 204 with the film temple 201 , the area of the elastic connecting piece 203 and the area of the optical element 202 , As a result, the layer package is additionally fixed. Next, with the injection molding unit 50 injected a melt of a preferably optical thermoplastic material in the slightly open cavity. With the stamp 18 the melt is pressed against the inserted plastic layers (carrier plate 100 and elastic intermediate layer 200 ) pressed and in this way the cover plate 300 with a fixation frame 305 and the bleed 306 formed. In this case, the connecting grooves of the support plate 100 filled with plastic melt, so that a positive connection 304 for the connection and encapsulation of the microfluidic device produced in this way. The set embossing force becomes the elastic intermediate layer 200 slightly compressed and thereby seals the fluid channels of the structured carrier plate 100 against each other. After curing of the plastic, the preferably completely transparent and encapsulated microfluidic device can be removed and packaged in sterile condition.

4 illustrates a microfluidic device 400 in supervision. 5 shows the microfluidic device 400 on average. Visible is the support plate 200 and the cover plate 300 , By structuring the carrier plate 200 become different fluid channels 106 educated. The fluid channels 106 are over the connecting pieces 203 accessible from outside. The flexible connection piece 203 can be used with hoses 501 be connected for the fluid guide.

The fluid is routed via the pump diaphragms 204 which are in the elastic intermediate layer 200 are integrated. The pump diaphragms 204 with the foil stamps 201 are located above the reaction or reagent or buffer chambers 101 , For observation and evaluation of the processes taking place in the microfluidic device, the optical elements 202 of the elastic intermediate layer are 200 accessible from outside or from above.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• DE 102010041287 A1 [0004]

Claims (12)

The microfluidic device (400) having at least one structured support plate (100) and at least one cover plate (300), wherein a functional elastic intermediate layer (200) between the at least one carrier plate (100) and the at least one cover plate (300) is arranged, characterized in that the functional elastic intermediate layer (200) is manufactured on the basis of liquid silicone rubber (LSR). Microfluidic device according to Claim 1 , characterized in that the elastic intermediate layer (200) is optically transparent. Microfluidic device according to Claim 1 or Claim 2 , characterized in that the at least one support plate (100) and the at least one cover plate (300) are positively connected with each other. A method of manufacturing a microfluidic device (400) comprising at least one structured support plate (100) and at least one cover plate (300) and a functional elastic intermediate layer (200), characterized in that the functional elastic intermediate layer (200) is made using Liquid Silicone Rubber (LSR) is manufactured. Method according to Claim 4 , characterized in that the carrier plate (100) and the cover plate (300) are produced with the functional elastic intermediate layer (200) in a mounting injection molding and media-tight. Method according to Claim 4 or Claim 5 , characterized in that the crosslinking of the liquid silicone rubber (LSR) takes place at an elevated temperature. Method according to one of Claims 4 to 6 , characterized in that in the production of the elastic intermediate layer (200) functional pumping membranes (204) and / or optical elements (202) are integrated and / or formed. Method according to one of Claims 4 to 7 , characterized in that in the production of the elastic intermediate layer (200) elastic connecting piece (203) are formed. Method according to one of Claims 4 to 8th , characterized in that in the manufacture of the carrier plate and / or the cover plate form-fitting elements (104, 304) for a media-tight connection of the cover plate (300) with the carrier plate (100) are formed. Injection-stamping device for producing a microfluidic device (400) with at least one structured carrier plate (100) and at least one cover plate (300) and a functional elastic intermediate layer (200), characterized in that the injection-compression device has a two-cavity injection-compression molding tool (10) with embossing dies (16 , 18) for forming the carrier plate (100) and for forming the cover plate (300) and an injection mold (20) for producing the elastic intermediate layer (200) on the basis of liquid silicone rubber (LSR). After injection molding device Claim 10 , characterized in that the injection-compression molding device for carrying out a method according to one of Claims 4 to 9 is set up. After injection molding device Claim 10 or Claim 11 characterized in that the dual cavity injection die (10) comprises hollow ejector elements (31, 32, 33) for defining functional elements (202, 203, 204) of the resilient intermediate layer (200) during the step of forming the cover plate (300) ,

Images