Abstract:
A microfluidic device includes at least two layers arranged one above the other, a membrane which is arranged between the at least two layers, a cavity in one of the at least two layers, and a channel in the other of the at least two layers. The membrane is arranged so as to be expandable between the cavity and the channel. The membrane is expandable into at least one specified displacement volume.

Description:
This application is a 35 U.S.C. §371 National Stage Application of PCT/EP2012/059417, filed on May 22, 2012, which claims the benefit of priority to Ser. No. DE 10 2011 078 976.6, filed on Jul. 11, 2011 in Germany, the disclosures of which are incorporated herein by reference in their entirety. 
     BACKGROUND 
     The disclosure relates to a microfluidic device, to a method for producing a microfluidic device and to the use of a microfluidic device. 
     Microfluidic devices are employed, for example, as lab-on-a-chip systems within the framework of molecular-diagnostic laboratory applications. The use of microfluidic devices of this type not only makes a diagnosis possible in a large laboratory or a medical practice, but also, for example, a patient can himself or herself carry out at home appropriate checks, for example of markers or of the blood sugar level, with the aid of the microfluidic device. 
     Microfluidic devices of this type are produced, for example, from polymer plates with integrated ducts and/or cavities in order to transport and/or filter liquids and the like. So that the microfluidic device can be acted upon with liquids or compressed air, it can be connected to a fluid-providing device via hoses. Via the hoses, the fluid-providing device can act with pressure in a directed manner upon the ducts and/or the cavities and consequently move liquids. Furthermore, pneumatic control of microfluidic pumps and/or valves is also possible. So that individual functions of the microfluidic device can be performed in a directed manner, different pressures or pressure levels are required. These are generated outside the microfluidic device by a pneumatic device and are provided to the microfluidic device via additional connections. 
     A microfluidic stop valve for a microfluidic device became known from WO 2007109375 A2. The microfluidic stop valve in this case comprises an inlet, at least three diaphragm valves comprising valve inlets, valve outlets, valve controls and elastomeric diaphragms. When a valve control is acted upon with pressure or a vacuum, the elastomeric diaphragm is deflected in order to modulate a flow of a liquid. Two of the valves are connected to a third valve in such a way that a sufficiently high vacuum at an inlet of the microfluidic stop valve causes the third valve to be opened and sufficient pressure at the inlet of the microfluidic stop valve to be provided so that the third valve is closed. 
     US 200770166199 A1 has disclosed a microfluidic system, comprising a pneumatic multiple distributor with orifices and a chip distributor with ducts, in order to send pneumatic signals from the corresponding orifices to pressure-actuable diaphragms in a microfluidic chip. The ducts in this case transport the pneumatic signals according to a fixed configuration of the pressure-actuable diaphragms in the microfluidic chip. The microfluidic chip likewise comprises reagent reservoirs in order to store fluidic reagents and outlet stores for storage of reaction products of the fluidic reagents. 
     SUMMARY 
     The description below defines a microfluidic device, comprising at least two layers arranged one above the other, an elastic diaphragm which is arranged between the two layers, a cavity which is arranged in one of the two layers, and at least one duct in the other of the at least two layers for acting upon the diaphragm with pressure, the diaphragm being arranged so as to be expandable into at least one stipulated displacement volume. 
     The description below defines a method for producing a microfluidic device as described herein, at least the cavity and/or the duct being produced by means of milling, injection molding and/or hot pressing. 
     The description below defines the use of a microfluidic device as described herein as a lab-on-a-chip system. 
     The description below defines a microfluidic system having a plurality of microfluidic devices as described herein. 
     Different pressure levels of cavities within a microfluidic system having a plurality of microfluidic devices can be made available in a simple way by the stipulated displacement volumes, only a single pressure level having to be made available from outside for the microfluidic system or the microfluidic devices. 
     The fundamental idea of the present disclosure is, therefore, that, to limit the variation in pressure in the cavity in spite of a higher or lower pressure provided from outside or in spite of action upon the diaphragm with this pressure, the diaphragm admittedly expands and thus varies the pressure in the cavity, but does not do so beyond a predetermined value. As a result of the expansion of the diaphragm, the overall volume of the cavity decreases, and because of this the pressure in the cavity rises. The pressure in the cavity reached when the maximum expansion of the diaphragm is reached is in this case independent of the external pressure provided, as long as the pressure level of the external pressure is sufficiently high to deflect the diaphragm completely into a stipulated displacement volume. The pressure in the cavity upon complete expansion of the diaphragm is then constant even when the externally applied pressure fluctuates above the minimum pressure for a complete expansion of the diaphragm, for example because an external pressure generator is unstable. Thus, on the one hand, reliability in providing the pressure by the diaphragm in the cavity is increased and, on the other hand, more beneficial pressure generators for providing the external pressure for the microfluidic device are therefore also possible. 
     The disclosure likewise affords the advantage that an external pressure generator for providing different pressures can be dispensed with for a microfluidic system, since reduced pressures within the microfluidic system can be generated by means of the diaphragm and the cavity and by limiting means. An extremely cost-effective control of the microfluidic system and of the microfluidic device is thereby possible. The fluid-providing device can also be made substantially more compact: if a highly accurate stipulation of a specific pressure is necessary in a microfluidic system, complicated and therefore cost-intensive external pressure generators are usually required so that this accurate pressure can be provided. Owing to the limiting means, a desired pressure in the cavity can be stipulated extremely accurately, in particular via a stipulated size of the displacement volume of the diaphragm. 
     Furthermore, the disclosure also affords the advantage that even very low overpressures are possible simply and reliably. By a configuration of the limiting means, in particular by the limiting means making an appropriately low displacement volume available for the diaphragm, even the least possible overpressures can be provided simply and reliably. Finally, the disclosure also affords the advantage that the number of interfaces between external pressure generators and the microfluidic system can be reduced. This leads not only to a reduction in production costs, but also to a lower susceptibility to faults and to lower maintenance costs. 
     Further advantageous embodiments and features of the disclosure are described herein. 
     According to an advantageous development of the disclosure, a limiting means is arranged, which is configured to restrict the at least one displacement volume. It consequently becomes possible to define the displacement volume in a simple and reliable way. 
     According to a further advantageous development, the limiting means is configured to limit an expansion of the diaphragm. This ensures that a stipulated pressure level is reached simply and reliably. Thus, for example, the limiting means may be configured such as to provide as small an area as possible between the cavity and duct in the event of maximum expansion of the diaphragm. This avoids the situation where, for example because of a higher pressure, the diaphragm expands further and the pressure level in the cavity is thus increased. 
     According to a further advantageous development, the limiting means is configured as a clearance, in particular as a stop, in at least one of the two layers. Simple and cost-effective production of the microfluidic device and of the limiting means is thereby possible. 
     According to a further advantageous development, the limiting means is formed by extending the fixing of the diaphragm on at least one of the at least two layers. The advantage thus achieved is that the displacement volume can therefore be varied or adapted to current boundary conditions even during the production of the microfluidic device. Extremely flexible production of the microfluidic device is consequently made possible. 
     According to a further advantageous development, a connecting duct is arranged between the cavity and at least one displacement volume. When the diaphragm, which is fixed essentially to at least one of the two layers, is acted upon with pressure, it expands into the predetermined displacement volume. In this case, it is possible that the fixing is subjected to high stress as a result of multiple deflection of the diaphragm and therefore the diaphragm comes loose at least partially from the at least one layer. The arrangement of a duct appreciably increases the reliability of the fixing of the diaphragm, since the connecting duct provides a contraction which counteracts the possibility of the diaphragm coming loose from the at least one layer. 
     According to a further advantageous development of the disclosure, the connecting duct is formed by at least one web. The advantage thereby achieved is that the risk of the diaphragm coming loose or lifting off is consequently reduced considerably. This increases the service life of the microfluidic device. In addition, a connecting duct can also be provided cost-effectively by means of the web. 
     According to a further advantageous development, at least one of the displacement volumes is configured as a duct. Especially simple manufacture of the microfluidic device is consequently possible, since only a single region has to be provided for the duct and displacement volume in the at least one layer. 
     According to a further advantageous development of the disclosure, the clearance comprises rounded edges. This ensures that, on the one hand, the elastic diaphragm can displace the entire displacement volume, defined by the limiting means, and at the same time the risk of damage to the diaphragm during its repeated actuation is correspondingly reduced. 
     According to a further advantageous development, a further layer is formed as a covering layer at least for the cavity. The cavity can thus be produced especially simply by removing the second layer for the cavity. The covering layer then makes it possible to cover the cavity, so that the latter is closed, pressure-tight, by the covering layer. 
     According to a further advantageous development of the disclosure, at least one of the layers is produced from a polymer, in particular a thermoplastic, and/or the diaphragm is produced from a thermoplastic elastomer and/or a thermoplastic. The advantage achieved thereby is that it becomes possible to have simple and cost-effective production of the microfluidic device and a sufficient service life of the diaphragm with, at the same time, cost-effective production. In particular thermoplastics, for example PC, PT, PE, PMMA, COP, COC and the like, may be used as polymer. 
     According to a further advantageous development of the method for producing a microfluidic device as described herein, the at least two layers are firmly connected to one another by means of laser irradiation welding, ultrasonic welding and/or by means of an adhesive method. Joining together the layer set-up of the microfluidic device can thus take place reliably and cost-effectively. 
     Further, by means of the microfluidic device, it is also possible to provide vacuums in the cavity. In this case, the displacement volume, in particular the limiting means for limiting the expansion of the diaphragm, is provided on that side of the diaphragm which faces away from the cavity, for example on the side of the duct. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Further features and advantages of the disclosure may be gathered from the following description of exemplary embodiments with reference to the drawings in diagrammatic form in which: 
         FIG. 1   a  shows a microfluidic device according to a first embodiment of the present disclosure in a top view; 
         FIG. 1   b  shows a microfluidic device according to the first embodiment in cross section; 
         FIG. 2   a  shows a microfluidic device according to a second embodiment; 
         FIG. 2   b  shows a microfluidic device according to the second embodiment with the action of pressure upon the diaphragm; 
         FIG. 3  shows a microfluidic device according to a third embodiment; 
         FIG. 4   a  shows a microfluidic device according to a fourth embodiment of the present disclosure in a top view; 
         FIG. 4   b  shows the microfluidic device according to the fourth embodiment in cross section; 
         FIG. 5  shows a microfluidic device according to a fifth embodiment; 
         FIG. 6  shows a microfluidic device according to a sixth embodiment; and 
         FIG. 7  shows a microfluidic device according to a seventh embodiment. 
     
    
    
     DETAILED DESCRIPTION 
       FIG. 1  shows a microfluidic device according to a first embodiment in a top view and in cross section. 
     In  FIGS. 1   a  and  1   b , reference M denotes a microfluidic device. The microfluidic device M in this case comprises as the uppermost layer, according to  FIGS. 1   a  and  1   b , an upper polymer layer  1  and also a lower polymer layer  3  (not shown in  FIG. 1   a ). Elements in the lower polymer layer  3  are indicated in  FIG. 1   a  by dashes. In the lower polymer layer  3 , a duct  4   a  is arranged, which is connected pneumatically to a lower displacement volume  7   b , likewise formed in the lower polymer layer  3 . The lower displacement volume  7   b  is pneumatically connected, further, to a diaphragm  2  which is arranged between the two polymer layers  1 ,  3 . The diaphragm  2  in this case forms essentially the second layer of the microfluidic device M. The diaphragm  2  can in this case expand essentially completely into the lower displacement volume  7   b . Further, in the upper polymer layer  1 , a cavity  6  is arranged, which is connected pneumatically to an upper displacement volume  7   a . The upper displacement volume  7   a  is in this case formed as a clearance  5   a  in the upper polymer layer  1 . The diaphragm  2  is in this case arranged between the two polymer layers  1 ,  3  such that the diaphragm  2  can expand into the upper displacement volume  7   a  or into the lower displacement volume  7   b , depending on the action of pressure upon the duct  4   a . When the diaphragm  2  expands into the lower displacement volume  7   b  arranged in the lower polymer layer  3 , the pressure in the cavity  6  is reduced. When the diaphragm  2  expands into the upper displacement volume  7   a  of the upper polymer layer  3 , the pressure in the cavity  6  is increased. 
     The diaphragm  2  according to  FIGS. 1   a  and  1   b  is connected to the lower polymer layer  1  and the upper polymer layer  3  via a weld seam or adhesive bond  2 ′. In this case, the weld seam or adhesive bond  2 ′ is arranged in the region of the duct  4   a  on the upper polymer layer  1  and in the region of the cavity  6  on the lower polymer layer  3 . The upper displacement volume  7   a  is in this case determined, on the one hand, by the clearance  5   a  and, on the other hand, also by the extent of the weld seam or adhesive bond  2 ′ on the lower polymer layer  3 . The cavity  6  is thus formed by that part of the clearance  5   a  according to  FIG. 1   b  into which the diaphragm  2  cannot expand because of the fixing to the lower polymer layer  3 . The diaphragm  2  can expand completely into the lower displacement volume  7   b , formed by the clearance  5   b , as a result of the generation of a vacuum in the duct  4   a . A further duct  4   b  formed in the upper polymer layer  3  is arranged at the cavity  6  and serves for connection to pneumatically actuable structural elements, such as microfluidic pumps, valves, filters, reservoirs, chambers, mixers and the like. 
     In general, the duct  4   a  is provided with pressure, by means of which the elastically formed diaphragm  2  can then expand into the upper or lower displacement volume  7   a ,  7   b . The following then applies, according to the Boyle-Marriote Law, to the pressure in the cavity  6 : 
               p   2     =       (         V   V     +     V   K     +     V   R           V   K     +     V   R         )     ⁢     p   1             
p 2  describing the pressure after actuation of the diaphragm  2 , p 1  normal pressure, that is to say a pressure at which the diaphragm  2  is not expanded and/or compressed, V v  the displacement volume  7   a ,  7   b , V K  the volume of the cavity  6  and V R  all the remaining volumes which are connected to the cavity  6 , for example the ducts  4   b  or the like.
 
       FIGS. 2   a  and  2   b  show a microfluidic device according to a second embodiment without and with the action of pressure upon the diaphragm. 
       FIGS. 2   a  and  2   b  show essentially a similar set-up of the microfluidic device M according to  FIG. 1 . In contrast to  FIG. 1 , the lower displacement volume  7   b  is again formed as a clearance  5   b , but as a duct portion of the duct  4   a . The lower polymer layer  3  can thus be structured or produced more simply, and furthermore a space saving for the microfluidic device M is achieved, since the thickness of the lower polymer layer  3  is smaller.  FIG. 2   a  shows the diaphragm  2  in the nonloaded state, that is to say the pressure in the duct  4   a  and that in the cavity  6  are essentially equal. Dashes indicate the limit between the cavity  6 , into which the diaphragm  2  cannot expand, and the upper displacement volume  7   a , into which the diaphragm  2  can expand when the supply duct  4   a  is acted upon with pressure. In the region of the cavity  6 , the diaphragm  2  is fixed to the lower polymer layer  3  by means of a weld seam or adhesive bond  2 ′, whereas, in the nonloaded state, the diaphragm  2  merely bears against the lower polymer layer  3  in the region without a weld seam or adhesive bond  2 ′, that is to say in the region of the upper displacement volume  7   a.    
       FIG. 3  shows a microfluidic device according to a third embodiment. 
       FIG. 3  shows a microfluidic device M, the set-up of which corresponds essentially to the set-up of the microfluidic device of  FIGS. 2   a  and  2   b . In contrast to  FIGS. 2   a  and  2   b , the height of the displacement volume  7   a , said height being defined as the distance between the diaphragm  2  in the nonloaded state and the top edge of the clearance  5   a  of the displacement volume, is lower than the height of the cavity  6 , which height is defined as the maximum distance between the welded-on or bonded-on diaphragm  2  and the upper polymer layer  1 . It is thus possible for overpressure in the cavity  6  to be capable of being selected in a more flexible way. 
       FIG. 4   a  and  FIG. 4   b  show a microfluidic device according to a fourth embodiment in a top view and in cross section. 
       FIGS. 4   a  and  4   b  show a microfluidic device M, the set-up of which is similar to the set-up of the microfluidic device M of  FIG. 3 . In contrast to  FIG. 3 , a connecting duct  10  is formed in the region between the clearance  5   a  of the upper displacement volume  7   a  and the cavity  6 . The connecting duct  10  connects the upper displacement volume  7   a  pneumatically to the cavity  6 . The connecting duct  10  may in this case be formed by a horizontally wide web  8  which is arranged so as to project vertically downward out of the upper polymer layer  3 . Loosening of the diaphragm  2  from the lower polymer layer  3  upon the repeated actuation of the diaphragm  2  is thereby reduced. The service life of the microfluidic device M is increased. 
       FIG. 5  shows a microfluidic device according to a fifth embodiment of the present disclosure. 
       FIG. 5  shows essentially a microfluidic device M set up in a similar way to  FIG. 4 . In contrast to  FIG. 4 , in  FIG. 5  a covering layer  9  is arranged on the top side of the upper polymer layer  1 . Further, in contrast to  FIG. 4   a  and  FIG. 4   b , the web  8  is of L-shaped form and extends vertically upward from the welded-on diaphragm  2  on the lower polymer layer  1 . The shorter edge of the “L” extends to the left. The height of the web  8  between the third layer  9  and the lower polymer layer  3  is lower than the height of the upper polymer layer  1 , so that a connecting duct  10  is formed between the top edge of the web  8  and the third layer  9 . Furthermore, the shorter leg of the “L” of the web  8  does not extend horizontally completely as far as the upper polymer layer  1 , so that the connecting duct  10  is consequently formed completely between the upper displacement volume  7   a  and the cavity  6 . The upper displacement volume  7   a  is formed, on the one hand, by a clearance  5   a  in the upper polymer layer  1  and, on the other hand, by the web  8 . As a result, overall, the probability of a possible loosening of the diaphragm  2  from the lower polymer layer  2  is reduced even further. 
       FIG. 6  shows a microfluidic device according to a sixth embodiment of the present disclosure. 
       FIG. 6  shows essentially a microfluidic device M according to  FIGS. 2   a  and  2   b . In contrast to  FIG. 2   a  and  2   b , the lower displacement volume  7   b  is in this case formed correspondingly to the upper displacement volume  7   a  of the microfluidic device M according to  FIG. 2   b . The upper displacement volume  7   a  is formed as a clearance  5   a , but as a duct portion of a duct in the upper polymer layer  1 . The upper polymer layer  1  can thus be structured or produced more simply.  FIG. 6  shows the diaphragm  2  in the nonloaded state, that is to say the pressure in the duct  4 a and that in the cavity  6  are essentially equal. Dashes indicate the limit between the lower displacement volume  7   b , into which the diaphragm  2  can expand, and a lower volume  6 ′, into which the diaphragm  2  cannot expand when the supply duct  4   a  is acted upon with pressure, and which is therefore configured essentially as a subduct of the supply duct  4   a . In the region  6 ′, the diaphragm  2  is fixed to the upper polymer layer  1  by means of a weld seam or adhesive bond  2 ′, whereas, in the nonloaded state, the diaphragm  2  merely bears against the upper polymer layer  1  in the region without a weld seam or adhesive bond  2 ′, that is to say the region of the lower displacement volume  7   b . The microfluidic device is therefore suitable particularly for generating a vacuum in the cavity  6 . 
       FIG. 7  shows a microfluidic device according to a seventh embodiment of the present disclosure. 
       FIG. 7  shows a microfluidic device essentially according to  FIG. 6 . In contrast to  FIG. 6 , the device is suitable especially preferably for generating a vacuum in the cavity  6 . Instead of the upper displacement volume  7   a , the cavity  6  is in this case arranged directly above the diaphragm  2  which is arranged so as also to be expandable into the cavity  6 . As in  FIG. 6 , too, a lower displacement volume  7   b  is arranged below the diaphragm  2  as a result of the formation of a clearance  5   b  in the lower polymer layer  3 . The displacement volume  7   b  is connected to a supply duct  4   a  for vacuum generation, the duct  4   b  being provided for the connection of further pneumatic or microfluidic elements to the cavity  6 . Since the microfluidic device according to  FIG. 7  is suitable particularly for vacuum generation, there is no provision for expansion of the diaphragm  2  into the cavity  6 , but instead only into the lower displacement volume  7   b . It thereby becomes possible to have a smaller base area, that is to say a horizontal extent of smaller cross section of the microfluidic device M. 
     In general, further pneumatically actuable elements can be connected to the cavity  6  via the duct  4   b  which is connected pneumatically to the cavity  6 . By the action of pressure upon the duct  4   a  and consequently upon the elastic diaphragm  2  and by the expansion of the latter, a corresponding pressure rise takes place in the cavity  6 , and it becomes possible to actuate the pneumatically actuable elements which require a correspondingly adapted pressure level, for example a displacement chamber of a diaphragm pump or diaphragm valves. 
     It is likewise possible to actuate a duct network connected to the cavity, in that a defined volume is displaced within the duct network which can be separated from the cavity  6  by means of a valve. The cavity  6  can thus be “charged” in a similar way to an electrical capacitor and, after the opening of the valve, the duct network can be acted upon with a defined liquid volume. If, for example, a pneumatic resistance of such a duct network is defined as R and the pneumatic capacity of the cavity as C, the time pressure profile of the pressure within the cavity can be described approximately by the formula
 
 p   2 ( t )= p   2 ( t= 0) e   −t/τ 
 
with the characteristic time constant τ=RC. On account of the strong dependence of the above-defined pneumatic resistance R, for example, upon a radius of the corresponding duct, which is proportional to 1/r 4  according to Hagen-Poiseuille, the characteristic time constant τ can be stipulated or adapted over a wide range. Thus, for example for air and typical duct diameters of between 30 μm and 500 μm, values for the characteristic time constant of one second to 10 5  seconds are possible.
 
     The thickness of a polymer layer of a microfluidic device may in this case amount to between 0.1 mm and 5 mm, in particular to between 0.5 mm and 3 mm. The thickness of an elastic diaphragm may in this case be between 10 μm and 500 μm, in particular between 25 and 300 μm. The volume of a cavity of a microfluidic device may in this case amount to between 1 mm 3  and 10 000 mm 3 , in particular to between 10 mm 3  and 1000 mm 3 , and/or the dimensions of the cavity may in this case amount for the length and/or width of the cavity to between 10 μm and 50 mm, in particular to between 25 μm and 25 mm, and the height of the cavity may in this case amount to between 25 μm and 10 mm, in particular to between 50 μm and 5 mm. The displacement volume  7   a ,  7   b , defined by the limiting means  5   a ,  5   b , may in this case amount to between 0.1 mm 3  and 5000 mm 3 , in particular to between 1 mm 3  and 2000 mm 3 , depending on the desired pressure change. 
     A microfluidic device M particularly according to  FIGS. 1-7  may in this case have lateral dimensions of between 1 mm 2  and 10 6  mm 2 , in particular between 100 mm 2  and 10 4  mm 2 . 
     Although the present disclosure was described above by means of preferred exemplary embodiments, it is not restricted to these, but can be modified in many different ways.