WO1999001209A1 - Switchable dynamic micromixer with minimum dead volume - Google Patents

Abstract

The invention relates to a switchable dynamic micromixer with minimum dead volume used for cyclic or continuous mixing of small fluids ranging from 1 nl to 10 mu l. The invention provides for a micromixer which is brought into contact on one side with at least two feed ducts (21, 22) and which has at least one discharge duct (26) opposite the feed ducts (21, 22). The micromixer also has a mixing chamber (23) with several magnetizable pearls (4) which are covered on one side by a lid (30) and which can move freely. The entire length of the pearls arranged in an adjacent line is slightly lower than the smallest lateral dimension of the mixing chamber. A magnetic system (5) can be set into rotation and assigned and switched in such a way that it enables an adjacent linear arrangement of the magnetizable pearls (4) in addition to joint rotation of the linear pearl structure.

Description

Switchable dynamic micromixer with minimal dead volume

The invention relates to a switchable dynamic micromixer with a minimal dead volume, which is used for the cyclical or continuous mixing of the smallest amounts of liquid in the order of 1 nl to 10 μl. The micromixer is used with particular preference, in particular in connection with several micromixers with one another, in biotechnology, medical diagnostics, for pharmaceutical screening or DNA computing.

Devices for homogenizing liquids in the form of dynamic and static micromixers are known from the prior art.

Static micromixers, as described for example in MST-news 19/97 p. 30 - 31 (ISSN 09483128), use diffusion to homogenize solutions when using long contact paths and small channel diameters. The disadvantages of this mixing variant consist, due to the necessarily long flow channels, in the resulting pressure losses in the flow system, the low efficiency of the mixing process, the relatively large dead volume and the relatively long mixing times. In DE 195 11 603 AI an arrangement for static mixing is described, which achieves a shortening of the diffusion paths by dividing two or more liquids several times and moving them layer by layer. This also enables mixing of insoluble fluids. Here, too, the dead volume of the mixing device is very large, due to repeated rerouting and layering of the liquids, and the mixing times are also very long. Another static micro-mixer is described in DE 44 16 343 C2. According to this proposal, the mixing of several solutions also takes place difiusively, the fluids to be mixed in front of the mixing chamber being composed of plate-like, layered elements which are crossed by channels which run obliquely to the longitudinal axis of the micro-mixer, and the channels of adjacent elements cross without contact and in the Mix chamber open. Since the mixing effect is brought about by diffusion, a disadvantage of this arrangement is the long mixing time for complete homogenization.

Dynamic mixers use rotating mixing tools that bring the mixing energy into the mix to homogenize the components to be mixed. Because of the design-related, relatively large-volume design of these mixers, they are not suitable for mixing the smallest amounts of liquid which, on the one hand, are not required for the intended use of the present invention or, e.g. cannot be provided due to cost reasons. A microflow processor closest to the invention is described in EP 0495 255 AI. The aim of this microflow processor is to mix small amounts of samples with the smallest possible dead volume, whereby it can be operated with flow rates in the range from ml / min to μl / min. A component of this microflow processor is a micromixer which, due to its miniaturization, which cannot be further increased, can have a volume of 0.1 μl.

The invention has for its object to provide a micromixer that mixes two or more liquids that are present in very small volumes, preferably in a range below 100 nl, in a very short time, with low dead volume and high efficiency, if necessary the mixing can be designed to be interruptible and which allows the integration of several micromixers within a basic body.

The object is achieved by the characterizing features of the first claim. Advantageous configurations are covered by the subordinate claims.

The invention will be explained in more detail below with the aid of schematic exemplary embodiments. Show it: 1 a shows a first possible embodiment of a micromixer in the assembled state without infestation of the media to be mixed, FIG. 1b shows a micromixer according to FIG. 1 with filling of the media to be mixed,

2a shows a second embodiment of a micromixer in the assembled state without filling the media to be mixed, FIG. 2b shows a micromixer according to FIG. 2 with filling the media to be mixed,

3 a shows a third possible embodiment of a micromixer in the assembled state with filling of the mixture to be mixed

3b, the micromixer according to FIG. 3a, through which two laminar flowing media flow when the mixing element is at rest, FIG. 4 an interconnection of three micromixers according to FIG. 1 and FIG. 5, a preferred embodiment of one per se a Misclü ^ ammer subsequent discharge channel.

Figure 1 shows a first embodiment of a micromixer 1 according to the present invention. In the example, the micromixer 1 is formed from a first base plate 20, into which a mixing chamber 23 and two feed channels 21 and 22 adjoining the mixing chamber 23 are introduced. On the side opposite the supply ducts 21, 22, the misclic chamber 23 is followed by comb-shaped capillary paths 24 which open into a trench 25 to which a discharge duct 26 is connected. A plurality of magnetizable beads 4, in particular made of a ferromagnetic material, are also introduced into the mixing chamber 23. The diameter of these beads 4 is such that it lies somewhat below the clear chamber height, which is limited by a cover plate 30 at the top. A magnet 5 which can be set in rotation (cf. FIG. 1b) is provided below the base plate 20. If its magnetic polarization is determined accordingly, this magnet 5 effects a linear and adjacent one Alignment of the beads 4, which undergo a rotation within the mixing chamber 23 following the magnetic rotation. Depending on the predetermined volume of the mixing chamber 23, the diameter of the pearls can be between 1 μm and 100 μm. Their total number is then further determined so that the length of the linearly oriented pearl structure is below the smallest lateral extent of the mixing chamber 23.

The mixing chamber 23, the feed channels 21, 22, the discharge channel 26, the comb-like capillary paths 24 and the trench 25 are introduced into the base body 20 with the aid of microstriction technologies. Both wet chemical or physical etching techniques for the structuring of silicon or photostructurable glass, laser cutting processes or molding techniques for polymers can be used to produce the structures. The basic body 20, which carries the structures made in this way, is sealed with a cover plate 30, consisting of a glass or a transparent polymer. This means that the mixing result in the mixing chamber or in the subsequent channels can be detected at any time. The beads 4 can be introduced before the base body 20 is sealed to the cover plate 30 or at a later point in time when the beads 4 are pumped into the mixing chamber 23 together with a liquid, with the feed channels 21, 22 appropriately designed . A return transport of the beads 4 from the mixing chamber 23 is prevented by a flow flow maintained in the micromixer. If the beads 4 are finally brought into the mixing chamber 23, they are demagnetized before being transported into the mixing chamber 23 in order to avoid clogging due to a plurality of beads 4 being connected. When an external magnetic field is switched on for the first time, the beads 4 are magnetized and only then exhibit a ferromagnetic behavior. This leads to the fact that, owing to the ferromagnetic material of the pearls 4, several pearls 4 always come together and join together to form a ketter-shaped structure, and then rotate together when a positionally changing magnetic field is supplied. This requires a stirring effect with a high degree of mixing, as indicated in Fig. 1b. There are two fluids Media A and B are fed through the feed channels 21, 22 into the mixing chamber 23, in which, in the illustration, an optimal mixing has already taken place due to the rotation of the linearly oriented pearl structure. The mixed medium C can then be discharged via the comb-shaped capillary paths 24, the trench 25 and the discharge channel 26. The design of the capillary paths 24, which adjoin the mixing chamber 23, each with an opening cross-section that is smaller than the diameter of the beads 4 used, represents an effective retention means for the beads 4. It is within the scope of the invention, to provide further discharge channels 26 on the trench 25 in order to derive the identical mixing result C. In the embodiment of the micromixer 1 according to FIGS. 1a, 1b, the fluids A, B to be mixed are permanently mixed with one another. The discharge channel can additionally be used as a detection channel, for which purpose a particularly preferred embodiment is described in FIG. 5. For conventional uses of the micromixer 1, such as in molecular biology, the mixing chamber 23 is given a volume of 1 nl to 10 μl.

Figures 2a and 2b basically describe a design identical to Figures la and lb; Identical functional elements are provided with the same reference symbols. The only difference is that here the retaining means for the beads 4 is formed by an overflow channel 24 '. In its width dimension b, this overflow channel 24 'extends essentially over the width of the mixing chamber 23 to which it is attached. The gap-shaped vertical extension of the overflow channel 24 ', which is bounded at the top by the cover plate 30 which is then attached, is dimensioned in comparison with the bead diameters used so that the beads 4 cannot get into the overflow channel 24'.

The micromixers 1 designed according to FIGS. 1 a, 1 b, 2 a, 2 b are designed for purely dynamic operation, that is to say for the constant mixing of fluids. These designs of the micromixers 1 have a plurality, at least two, of the inputs 21 and 22, which in this operating mode are not necessarily in one plane with the others Components such as 23 and the following need to be maintained, via which the solutions A and B can be fed to the mixing chamber 23, are mixed there by means of the beads 4 in the manner described, so that a mixture C can be removed from the discharge channel 26.

The micromixer 1 undergoes a certain modification for further uses, as is indicated in FIGS. 3a and 3b. These designs represent a switchable micromixer. If the micromixer 1 according to FIGS. 1 a, 1 b, 2 a, 2 b each contains only one discharge channel 26, three discharge channels 26, 27, 28 are provided in an embodiment according to FIG 2a are designed analogously to the height dimensioning of the overflow channel 24 ', as a result of which the channel edge designs 261, 271, 281 simultaneously assume the function of the overflow channel 24'.

FIG. 3 a shows the FaU that the micromixer works in dynamic operation, analogously to the previous figures, and thus the Hquid media A and B supplied via the feed channels 21, 22 are mixed. In this mode of operation, an identical mixed solution C can be taken from all discharge channels 26, 27, 28.

Provided that laminar flow conditions exist in the mixing chamber 23, which can be achieved by adhering to Reynold numbers <1, the discharge channels 26, 27, 28 are assigned with the proviso that the two discharge channels 21, 22 provided in the example are the three discharge channels 26, 27, 28 are assigned at the other end of the mixing chamber in such a way that the first feed channel 21, and thus the first medium A that can be fed through it, a first discharge channel 27, the second feed channel 22, and thus the second medium B that can be fed through this a second discharge channel 28 and a third discharge channel 26, the contents of which are discarded, are assigned to a common flow zone formed by media A and B. If the micromixer in the example according to FIG. 3b works in static operation, ie the beads 4 are not exposed to the rotating magnetic field, and a laminar flow through the mixing chamber 23 is ensured, forms a relatively sharp interface emerges between the two media streams A and B. This interface zone S and its closely adjacent areas are taken up by the discharge channel 26, as a result of which contamination of the individual components A and B is avoided, and the pure media stream of component A reaches the discharge channel 27 and that of component B in the discharge channels 28. The mixed Media stream W is usually discarded in the further process. A micromixer manufactured according to FIGS. 3 a and 3 b can be expanded within the scope of the invention to a plurality of feed and discharge channels, the above requirements in each case being observed and a further channel for a partially mixed component W of the respective border zone area being to be provided between two channels that discharge pure components . It is possible to switch alternately between the operating states according to FIGS. 3a and 3b, which is advantageous, for example, for combinatorial processing of a large number of components and, for example, requires synthesis in the flow.

The micromixers described in FIGS. 1 a to 3 b can be connected in series in any number, as a result of which entire networks of mixing agents are possible. Such a design is shown in FIG. 4 using three micromixers 1a, 1b, 1c designed according to FIG. Each of these micromixers contains a mixing chamber 23a, 23b, 23c. In this example it is also possible, depending on the desired process sequence, to block one or more feed channels as required, so that only one or no components of a micromixer get into the other micromixers. When using the above-mentioned staging procedures for the production of the micromixers, several micromixers can be accommodated in one piece in a base body 20 and covered by a common cover plate 30. In a practical implementation variant, for example, if necessary, up to 90,000 individual mixing chambers 23 and the associated feed and discharge channels can be introduced into a 4 "silicon wafer if the mixing chambers 23 comprise a cavity of 100-100-50 μm ³ . Finally, FIG. 5 shows a special design of a discharge channel 26, in particular for the last-mentioned, but not limited to, the integrated embodiment variant. This discharge channel, like the one shown in FIGS. 1 a to 3 b, presses against the mixing chamber or subordinate assemblies on the one hand and is meandered several times over a length adapted to the mixing chamber volume. The volume of the channel 26 should in this case be dimensioned such that it takes up at least three times the volume of the mixing chamber volume. This meandering design of the discharge channel favors the use of commercially available detection units, for example optical spectroscopes, with the aid of which a relatively large sample volume and thus increased signals are available when imaged by a transparent cover plate 30, since several meandering channel sections can be detected at the same time.

The embodiments described have an extremely low dead volume, since practically the entire mixing chamber volume can be used for further uses.

For all of the exemplary embodiments described, it is expressly within the scope of the invention that the structures introduced into the base body 20 are also mirror-image inserted identically into the cover plate 30. Such training opens e.g. based on the figures la and lb with appropriate material selection for the base body and the cover plate, for example pyrex glass, a circular cross-sectional design of the capiaries 24, which then symmetrical to the mixing chamber 23, with the provision of further, not shown magnet systems, the positioning of individual beads 4 in individual or Allow a switchable closure of the discharge path on the capillary mouth areas.

All of the features illustrated in the description, the following claims and the drawing can be essential to the invention both individually and in a resolute combination with one another. Reference list

1, la, lb, lc micromixer

20 basic bodies

21, 22 feed channels

23 mixing chamber

24 comb-like capillary ways

24 'overflow channel

25 receiving trench

26, 27, 28 discharge channels

261a, 261b, 261c - discharge / feed channels

30 cover plate

4 magnetizable beads

5 switchable, rotatable magnet system

A, B, C, W fluid media

Claims

claims 1. Switchable dynamic micromixer with minimal dead volume, comprising a mixing chamber (23), which is connected on one side to at least two feed channels (21, 22) and, on the other hand, opposite the feed channels (21, 22), has at least one discharge channel (26) , inside the mixing chamber (23) several magnetizable beads (4) are provided, the diameter of which is somewhat smaller than the high chamber height of the mixing chamber (23) such that these are within the mixing arm walls, which are covered on one side by a cover (30) , can move freely, and the total length of which is fixed in a linear, adjacent row somewhat below the smallest lateral mixing chamber extension, between the mixing chamber outlet and the inlet of the at least one Discharge channel (26) retaining means (24; 24 '; 251-271) are provided which prevent the beads (4) from penetrating into the discharge channel (26) or the discharge channels (251-271) and prevent the mixing chamber (23) from entering Rotation-displaceable magnet system (5) is assigned switchable, which is so designed that it enables a linear adjacent alignment of the magnetizable beads (4) and a common rotation of the linear bead bundle. 2. Switchable dynamic micromixer according to claim 1, characterized in that it consists of a first basic body (20) in which the structures for the mixing chamber (23), the at least two supply channels (21, 22), the at least one discharge channel (26 ) and the . Retaining means (24; 24 '; 251-271) are introduced, which is covered on one side by a second cover plate (30). 3. Switchable dynamic micromixer according to claim 2, characterized in that the same structures (23; 21, 22; 23; 24; 24 ';251-271; 26) of the basic body (20) are introduced in the cover plate (30) in a mirror-image fashion are. 4. Switchable dynamic micromixer according to claim 1 or 2, characterized in that the retaining means are formed by a multiplicity of comb-shaped capillary paths (24) which, on the one hand, connect to the mixing chamber (23), each with an opening cross section which is smaller than the diameter of one Pearl (4) and, on the other hand, open into a receiving trench (25), which is followed by the at least one discharge channel (26). 5. Switchable dynamic micromixer according to claim 1 or 2, characterized in that the retaining means are formed by an overflow channel (24 ') adjoining the mixing chamber (23) in a step-like manner, which on the other hand opens into a receiving trench (25) to which the at least one discharge channel (26) connects. 6. Switchable dynamic micromixer according to claim 5, characterized in that the width (b) of the overflow channel (24 ') corresponds essentially to the adjacent mixing chamber extension. 7. Switchable dynamic micromixer according to claim 1 or 2, characterized in that two respective supply channels (21, 22) are assigned three associated discharge channels (26, 27, 28) in such a way that, with essentially laminar flow through the mixing chamber (23 ), the first feed channel (21), and thus the first medium (A) that can be fed through it, a first discharge channel (27), the second feed channel (22), and thus the second medium (B) that can be fed through this, a second discharge channel (28) and a third discharge channel (26) is associated with a common flow zone (S) that can be formed by the media (A, B). 8. switching baffle dynamic micromixer according to claim 7, characterized in that the discharge channels (26, 27, 28) are formed step-like to the mixing chamber (23) such that their smallest lateral dimensions are defined below the diameter of the beads (4). 9. Switchable dynamic micromixer according to one of the preceding claims, characterized in that a plurality of micromixers (la, lb, lc) are assigned to one another in such a way that at least two discharge channels (261a, 261b), each of which discharge channel (261a, 261b ) belongs to a separate mixing chamber (la, lb), the Feed channels to another mixing chamber (lc). 10. Switchable dynamic micromixer according to claim 9, characterized in that when using a plurality of interconnected micromixers one or more feed or discharge channels can optionally be blocked. 11. Switchable dynamic micromixer according to one of the preceding claims, characterized in that the at least in the Grundköφer (20) made recesses for the individual Functional assemblies (21, 22; 23; 24; 24 ', 26-27) are introduced by wet-chemical etching techniques or physical removal processes or by impression techniques. 12. Switchable dynamic micromixer according to one of the preceding claims, characterized in that the basic body (20) with the structures introduced into it for the individual functional modules (21, 22; 23; 24; 24 ', 26-27) is formed in one piece. 13. Switchable dynamic micromixer according to spoke 12, characterized in that several micromixers (la, lb, lc) are introduced into the integrally molded basic body (20). 14. Switchable dynamic micromixer according to one of the preceding claims, characterized in that at least one discharge channel (26, 27, 28, 261a, 261b) is designed to be multiply meandered over an area of its lateral extent. 15. Switchable dynamic micromixer according to spoke 14, characterized in that the individual paraUel extending meandering sections are introduced as closely as possible to each other in the basic body (20) and / or the cover plate (30). 16. Switchable dynamic micromixer according to spoke 14, characterized in that the multiply meandered discharge duct sections are able to take up a volume which corresponds to at least three times the volume of the volume comprised by the mixing chamber (23).