DE102013203293B4 - Apparatus and method for conducting a liquid through a first or second outlet channel - Google Patents

Abstract

Fluidic device rotatable about a center of rotation (114, 216) for directing a fluid through first or second outlet channels, comprising: a compression chamber (104; 204); an inlet channel (108; 202) fluidly coupled to the compression chamber (104; 204); the first outlet channel (110; 206) fluidly coupled to the compression chamber (104; 204) and having a first flow resistance; and the second outlet channel (112; 208) fluidly coupled to the compression chamber (104; 204) and having a second flow resistance, the first outlet channel (110; 206) and the second outlet channel (112; 114, 216) have radially rising portions, wherein the compression chamber (104; 204) and the first and second outlet channels (110, 112; 206, 208) are designed such that upon partial filling of the compression chamber (104; 204) with a Liquid is compressed via the inlet channel (108; 202) and a rotation of the fluidic device at an increased rotational frequency a gas trapped by the liquid in the compression chamber (104; 204) is compressed by a centrifugal pressure passing through the liquid in the inlet channel (108; 202). and the first and second exhaust ports, wherein the first exhaust port (110; 206) has at least a portion extending radially inward extends as a radially innermost portion of the second outlet channel (112; 208), and wherein the first and second exhaust passages (110, 112, 206, 208) are designed such that when the compressed gas expands at a first rate of expansion, the fluid is conductive via the first exhaust passage (110, 206); upon expansion of the compressed gas at a second rate of expansion that is less than the first rate of expansion, the fluid is conductive via the second outlet channel (112; 208).

Description

The present invention relates to apparatus and methods for passing a liquid through a first or second outlet channel, and more particularly to apparatus and methods suitable for switching liquids in a centrifugal microfluidic system.

Centrifugal microfluidics has received much attention over the last decade for its potential for integration and automation of analysis and diagnostic tasks, with regard to centrifugal microfluidic platforms to J. Ducree et al. a., "The centrifugal microfluidic bio-disk platform," J. Micromech. Microeng., Vol. 7, pp. 103-115, July 2007, can be referenced. Economically very interesting is the automation of routine tasks in cheap test carriers on affordable processing equipment. A good candidate for very cheap and widely available processing equipment are laboratory centrifuges. These are part of the standard equipment of laboratories anyway and are relatively cheap due to the large quantities.

In particular, there is a need for a structure that facilitates the sequential separation (switching) of liquids from a common inlet chamber at e.g. B. allows two different outlet chambers, for example, for a DNA purification. For typical laboratory tasks, both aqueous solutions and highly moisturizing liquids must be reliably switched. With respect to aqueous solutions, the surface tension of water is about 73 mN / m at 20 ° C. With regard to highly wetting liquids, the surface tension of ethanol is about 23 mN / m at 20 ° C.

Centrifugal microfluidic structures for switching liquids are known from the prior art.

A published method for switching fluids is based on the Coriolis force. This allows the switching of liquids by reversing the direction of rotation, as described by S. Haeberle et al., "Automation of nucleid acid extraction by a coriolis force actuated droplet router," Paris, France, 2007, pp. 1231-1233; JV Zoval et al., "Flow Switching to a Multi-Structured Microfluidic Cd (Compact Disc) Using Coriolis Force" and the US 2008/190503 A1 is described. This is obviously not a suitable option on a laboratory centrifuge with only one possible direction of rotation, since switching the direction of rotation is required. In addition, for a reliable function, a local modification of the contact angle on the lid is necessary, which makes the manufacturing process more expensive.

Another published switching technique uses the pressure of a preceding liquid column on an enclosed air bubble to force a subsequent liquid into another outlet chamber. Such an approach is in J. Kim u. a., "Passive flow switching valves on a centrifugal microfluidic platform", Sens. Actuators B Chem., Vol. 2, p. 613-621, Jan. 2008. In this system, an inlet chamber is connected to a first chamber via a fluid channel. From the fluid channel branches off a second fluid channel, which is fluidically connected to a second chamber. The operating principle of the switch is based on a liquid column and a trapped air bubble, with a first liquid from the inlet chamber via the fluid channel into the first chamber. A second liquid is introduced, the resulting liquid column exerting pressure on the air bubble trapped between the first liquid and the second liquid, which forces the subsequent liquid to flow into a second chamber. This solution entails a great limitation in the geometry of the microfluidic system and the quantities of liquid that can be used. In the case of a fixed geometry, switching is only possible from predetermined, precisely metered quantities of liquid. In addition, a large distance between the location where the second fluid channel branches off and the level of the first fluid in the fluid channel is necessary to prevent the air bubble from being forced into the first chamber, which would negate the switching effect. So much is lost on a disk of very limited space.

Another known solution for switching liquids is based on two outlet channels that branch off from a common inlet chamber, wherein one of the channels, due to a local, water-repellent (hydrophobic) coating, offers greater resistance to the liquid flow. Depending on the rotational frequency of the microfluidic system, this resistance is either overcome or the liquid forced into the alternative channel. This solution has the disadvantage that the very precisely applied local hydrophobic coating is costly and loses effectiveness in highly moisturizing liquids, since the stopping effect of the hydrophobic coating depends on the surface tension of the liquid.

Another known structure for switching liquids is based on the selective opening of ventilation holes in chambers and is in the US 2008/0110500 A1 described. The switching effect is based on the fact that liquid under certain conditions does not flow into an unvented chamber, because the air pressure prevents the liquid from penetrating. A plurality of radially outer chambers is always provided with a closable vent opening. By selectively opening one of these vents, liquid flows with rotation of the test carrier preferably in the vented chamber. The vents can be closed by an adhesive film or a septum. To open either a laser, a suitable for piercing device or a tool can be used. The opening is thus achieved either with a manual operation or by a complicated mechanical or laser-based additional structure.

In other known methods, switching is effected by external pressurized air, such an air pressure based solution permitting the switching of liquids on a T-shaped channel. As with Matthew C. R. Kong u. a., "Pneumatic Flow Switching on Centrifugal Microfluidic Platforms in Motion", Anal. Chem., 2011, 83, pp. 1148-1151, compressed air is actively introduced into a centrifugal platform. Depending on the channel in which the compressed air is passed, the liquid is switched into one of the channels. The disadvantage of this solution is that compressed air must be externally upstream and the circuit can not only be done by changing the rotational frequency.

Further, for example, from the DE 10 2008 003 979 B3 and the DE 10 2009 050 979 A1 Method for centrifugo-pneumatic switching known. In a centrifugal-pneumatic switching, a centrifugable structured substrate is provided with one or more radially inner chambers. These are connected to channels with radially outer chambers, of which at least one has no ventilation other than the connecting channel to the other chambers. The geometry of the channels creates a preferential flow of liquid from the radially inner chamber into this chamber, separating the chamber from the outside air during this process. If now, regardless of the direction of rotation, a high centrifugal force exerted on a liquid in the radially inner chamber by a fast rotation of the substrate about an axis of rotation, this flows through a phase change in the unvented chamber. If another liquid in the radially inner chamber is subjected to a slower rotational frequency, which is not sufficient for a phase change, it is forced by the back pressure of the air in the unaerated chamber in the channel to a ventilated chamber. This allows the switching of liquids with a simple structure without local coatings on a laboratory centrifuge. The switching function of the air backpressure is significantly more stable than liquids with low surface tensions such as hydrophobic valves.

As further in the DE 10 2009 050 979 A1 In another implementation, liquid is also switched from one or more inlet chambers located radially further inward between a plurality of outlet chambers. The chambers are connected by a channel system. In this case, the flow of the liquid through the channel system is preferably directed into a chamber which has a vent whose access is closed by a liquid under certain conditions. For example, the access to the vent at high centrifugal forces can be opened by switching liquid, which previously blocked the access, is pressed into a closed switching chamber, thus allowing the venting. At low centrifugal forces, this switching fluid is forced back into the path of venting by the air pressure in the closed switching chamber, forcing fluid flow into the ventilated chamber.

Finally, Steffen Zehnle u. a, Centrifugo-dynamic inward pumping of liquids on a centrifugal microfluidic platform ", Lab Chip, 2012, 12, 5142-5145, the use of a volume of gas compressed in a compression chamber to pump fluid radially inwardly on a microfluidic centrifugal platform. Liquid is introduced into a compression chamber at a high rotational frequency, thereby compressing a volume of gas trapped in the compression chamber. Rapid deceleration of the platform leads to a rapid expansion of the compressed gas volume, so that the fluid escapes through an outlet channel from the compression chamber, wherein the outlet channel has a smaller flow resistance than an inlet channel, through which the liquid was introduced into the compression chamber.

The known techniques described are disadvantageous in that they do not permit highly-wettable liquids to be centrifuged on a laboratory centrifuge which permits rotation in only one direction of rotation, in a convenient microfluidic test carrier, e.g. B. without local surface modifications from a common input reservoir into different output reservoirs flexible, z. Without strict geometric constraints on the design. Thus, the described techniques have weaknesses, for example when used for DNA extraction on a laboratory centrifuge.

From the US 2003/0207457 A1 For example, there is known a centrifuge rotor having a siphon structure disposed between a first fluid chamber and a second fluid chamber. An inlet of the siphon into the first chamber is disposed radially farther out than an outlet of the siphon into the second Chamber, so that the first chamber is emptied to a level corresponding to the radial position of the outlet.

In the US 2012/0295781 A1 a microfluidic blood separation device is described, which has a sedimentation chamber into which an inlet channel opens. A siphon channel connects the sedimentation chamber to a collection chamber provided with a vent.

The US 201 0/01 35859 A1 describes a microfluidic device having a plurality of starter reservoirs and an output chamber provided with a vent opening.

The US 2009/0111190 A1 discloses a microfluidic device with a microchannel structure and the US 2012/0039769 A1 discloses a disc-based fluid separation system having at least two channel patterns formed on a side surface of the disc.

The object underlying the present invention is to provide a device and a method which make it possible to reliably and flexibly switch a fluid through a first or a second outlet channel.

This object is achieved by a fluidic device according to claim 1 and a method according to claim 15.

Embodiments of the invention provide a fluidic device which is rotatable about a center of rotation for directing a liquid through a first or a second outlet channel, having the following features:
a compression chamber;
an inlet channel fluidly coupled to the compression chamber;
the first exhaust passage fluidly coupled to the compression chamber and having a first flow resistance; and
the second exhaust passage fluidly coupled to the compression chamber and having a second flow resistance,
wherein the first exhaust passage and the second exhaust passage have radially rising portions with respect to the rotation center, wherein the compression chamber and the first and second exhaust passages are configured to increase in a partial filling of the compression chamber with a liquid via the inlet passage and a rotation of the fluidic device with one Rotation frequency, a gas trapped by the liquid in the compression chamber is compressed by a centrifugal pressure generated by the liquid in the inlet channel and the first and second outlet channels,
wherein the first outlet channel has at least a portion that extends radially inward than a radially innermost portion of the second outlet channel, and wherein the first and second flow channels are configured such that upon expansion of the compressed gas at a first expansion rate, the liquid can be conducted via the first outlet channel and that when the compressed gas expands at a second expansion rate which is smaller than the first expansion rate, the liquid can be conducted via the second outlet channel.

According to embodiments of the present invention, a method for passing a liquid through the first outlet channel or the second outlet channel of a corresponding fluidic device comprises the following steps:
Pressurizing the compression chamber, the intake passage and the first and second exhaust passage at the increased rotational frequency, and
from the rotation at the increased rotational frequency, causing the compressed gas to expand at the first rate of expansion to direct the fluid through the first exhaust port, or causing the compressed gas to expand at the second rate of expansion to pass the fluid to guide the second outlet channel.

Embodiments of the invention are based on the recognition that at least two outlet channels can be designed such that it is possible to empty liquid introduced via an inlet channel into a compression chamber, depending on the rate of expansion of the compressed gas in the compression chamber through one of the outlet channels , The smaller expansion rate may be such that the liquid level in the inlet channel and the first and second outlet channel slowly increases, so that the flow rate is so low that frictional forces in the fluid have virtually no influence on the fluid dynamics. Consequently, the levels in the three parallel fluid paths remain the same, so that the fluid is discharged exclusively via the second outlet channel, since the first outlet channel has a portion that extends radially inward than a radially innermost portion of the second outlet channel. In other words, the liquid flows exclusively via the second outlet channel, since it has the lowest, that is, the radially outermost, vertex. The greater rate of expansion may be such that the liquid levels in the inlet channel, the first outlet channel and the second outlet channel increase rapidly, so that the flow rate is relatively high and frictional forces affect the fluid dynamics. In particular, high frictional forces in the second outlet channel can Limit flow rate so that the first outlet channel filled first and thus the compression chamber is emptied via the first outlet channel. Thus, depending on the expansion rate of the compressed gas, it is possible to switch the fluid through either the first outlet passage or the second outlet passage.

In embodiments of the invention, the second flow resistance is greater than the first flow resistance, such that upon expansion of the compressed gas at a first expansion rate, the liquid is conductive via the first outlet channel and that upon expansion of the compressed gas at a second expansion rate less than the first rate of expansion is that liquid is conductive via the second outlet channel.

In alternative embodiments, the second outlet channel includes a volume buffer configured to receive liquid and prevent liquid from reaching a radially innermost portion of the second outlet channel when the liquid expands upon expansion of the compressed gas at the first rate of expansion through the first outlet channel is directed. In such embodiments, the second flow resistance may be equal to or even less than the first flow resistance.

In embodiments, the second outlet channel has a siphon, wherein a radially inner vertex of the siphon is disposed radially farther out than a radially inner portion of the first outlet channel. For example, this radially inner portion of the first outlet channel may be a siphon of the first outlet channel. Thus, it is reliably possible to empty the liquid through the second outlet channel when expansion of the compressed gas at the first, low expansion rate is effected.

In embodiments of the invention, the second flow resistance is greater than the first flow resistance, the second outlet channel having a volume buffer configured to receive liquid and prevent liquid from reaching the radially innermost portion of the second outlet channel when the liquid expands of the compressed gas at the greater rate of expansion is directed through the first exhaust passage. Thus it can be reliably ensured that liquid is emptied exclusively through the first outlet channel of the compression chamber.

In embodiments of the invention, the inlet channel and the first and second outlet channels are fluidly coupled to a fluid channel which opens into the compression chamber, for example into a radially outer end of the compression chamber. Such an arrangement allows complete emptying of the compression chamber.

In embodiments, the inlet channel and the first and second outlet channels open into a radially inner side of the fluid channel, wherein a radially outer side of the fluid channel has a bulge. This advantageously makes it possible to form a sedimentation chamber on the radially outer side of the fluid channel, into which the inlet channel and the outlet channels open.

In embodiments, a first end of the first outlet channel opens into a position in an outlet chamber located radially inward than an outlet of the compression chamber fluidly coupled to a second end of the first outlet channel. In such embodiments, the expansion of the compressed gas may additionally be used to implement a radially inward pumping of the liquid.

In embodiments, a first end of the first outlet channel is fluidly coupled to an analysis chamber, a first end of the second outlet channel is fluidly coupled to a waste chamber, and second ends of the first and second outlet channels are fluidically coupled to the compression chamber. Thus, embodiments of the present invention are particularly suitable for purifying nucleic acid on a rotating platform.

In embodiments, the fluidic structures, which comprise the compression chamber, the inlet channel, the first outlet channel and the second outlet channel, are formed in a substrate, wherein the substrate may be formed as a rotational body, for example as a disc, or as a fluidic module, which can be inserted into a rotational body is.

Embodiments of a fluidic device are thus directed to a rotary body or a fluidic module with corresponding fluidic structures. Alternative embodiments of a fluidic device further include means for causing the compressed gas to expand at the first rate of expansion or the second rate of expansion. This means for causing the compressed gas to expand accordingly may include, for example, a driving device configured to apply different rotational speeds to the compression chamber, the inlet port, and the first and second exhaust ports, a heater configured to rotate therethrough Gas in the compression chamber with different Apply temperature gradient, or have means for generating a chemical reaction in the compression chamber. Furthermore, combinations of such devices are possible.

In embodiments, the means for causing the compressed gas to expand at a corresponding rate of expansion includes a drive configured to urge the compression chamber, the inlet port and the first and second exhaust ports to rotate at the constant rotational frequency, and to decrease the rotational frequency either at a first rotational frequency reduction rate from the constant rotational frequency rotation to cause the compressed gas to expand at the first rate of expansion and to direct the fluid through the first exhaust port, or at a second rotational frequency reduction rate; which is less than the first rotational frequency reduction rate to cause the compressed gas to expand at the second expansion rate and to direct the fluid through the second exhaust port.

Embodiments of the present invention will be explained below with reference to the accompanying drawings. Show it:

1 a schematic plan view of a fluidic device according to an embodiment of the invention;

2 a schematic representation of different rotational frequency protocols;

3 schematic representations of different phases of a method for conducting liquids through a first or second outlet channel;

4 a schematic plan view of a fluidic device according to an alternative embodiment;

5 schematic representations of an alternative embodiment of a fluidic device during different phases when passing a liquid through a first or second outlet channel;

6 and 7 schematic side views for explaining embodiments of fluidic devices.

Before specific embodiments of the invention are explained in more detail, it should first be pointed out that examples of the invention can be used in particular in the field of centrifugal microfluidics, which involves the processing of liquids in the nanoliter to milliliter range. Accordingly, the fluidic devices may have suitable dimensions in the micrometer range for handling corresponding volumes of fluid. In particular, embodiments of the invention can be applied to centrifugal microfluidic systems, as known for example under the name "Lab-on-a-Disk". An application focus of embodiments of the invention may be in the field of DNA extraction / purification. In this case, lysate and wash buffer are passed through a solid phase and then switched into a waste chamber. Next, an elution buffer is passed through the solid phase and switched to a separate outlet chamber and therefrom either processed or withdrawn. However, the invention is not limited to this field of application and may be used in other contexts requiring microfluidic switching of liquids.

As used herein, the term radial is meant to be radial with respect to the center of rotation about which the fluidic module or rotor is rotatable. Thus, in the centrifugal field, a radial direction is radially sloping away from the center of rotation and a radial direction toward the center of rotation is radially increasing. A fluid channel, the beginning of which is closer to the center of rotation than the end, is thus radially sloping, while a fluid channel, the beginning of which is farther from the center of rotation than its end, is radially increasing. A channel which has a radially rising section thus has directional components which rise radially or extend radially inwards. It is clear that such a channel does not have to run exactly along a radial line, but can run at an angle to the radial line.

According to the invention, the switching through one of at least two outlet channels depends on the rate of expansion of the gas compressed in the compression chamber. The expansion rates do not have to be constant. Only in a limited time period does the first expansion rate have to be greater than the second expansion rate.

In embodiments of the invention, upon rotation at the increased rotational frequency, rotation may occur at a constant rotational frequency such that a balance of forces is created between pressure generated by the gas trapped and compressed in the compression chamber by the fluid and counteracting centrifugal pressure is generated by the liquid in the inlet channel and the first and second outlet channel arises.

Referring to the 6 and 7 First examples of centrifugal microfluidic systems are described, in which the invention can be used.

6 shows a device with a fluidic module 10 in the form of a body of revolution, which is a substrate 12 and a lid 14 having. The substrate 12 and the lid 14 may be circular in plan view, with a central opening through which the body of revolution 10 via a conventional fastening device 16 on a rotating part 18 a drive device 20 can be appropriate. The rotating part 18 is rotatable on a stationary part 22 the drive device 20 stored. In the drive device 20 For example, it can be a conventional adjustable-speed centrifuge or a CD or DVD drive. A control device 24 may be provided, which is designed to drive the drive 20 to control the rotational body 10 to act on rotations with different rotational frequencies. The control device 24 As can be appreciated by those skilled in the art, for example, it may be implemented by a suitably programmed computing device or user-specific integrated circuit. The control device 24 may be further configured to respond to manual inputs by a user, the drive device 20 to control to cause the required rotations of the rotating body. In any case, the control device 24 be configured to the drive device 20 to control the rotational body with the required rotational frequencies to implement embodiments of the invention as described herein. As a drive device 20 a conventional centrifuge with only one direction of rotation can be used.

The rotation body 10 has the required fluidic structures. The required fluidic structures may be through cavities and channels in the lid 14 , the substrate 12 or in the substrate 12 and the lid 14 be formed. In embodiments, for example, fluidic structures in the substrate 12 be pictured while filling openings and vents in the lid 14 are formed. In embodiments, the patterned substrate (including fill openings and vents) is located at the top and the lid is located at the bottom.

For an alternative in 7 shown embodiment are fluidic modules 32 in a rotor 30 inserted and form together with the rotor 30 the rotation body 10 , The fluidic modules 32 can each have a substrate and a lid, in which in turn corresponding fluidic structures can be formed. The one by the rotor 30 and the fluidic modules 32 formed rotational body 10 is in turn by a drive device 20 by the control device 24 is controlled, acted upon with a rotation.

In embodiments of the invention, the fluidic module or body having the fluidic structures may be formed of any suitable material, for example a plastic such as PMMA (polymethyl methacrylate), PC (polycarbonate), PVC (polyvinylchloride) or PDMS (Polydimethylsiloxane), glass or the like. The rotation body 10 can be considered as a centrifugal microfluidic platform.

Embodiments of fluidic structures for implementing fluidic devices according to the present invention will be described below with reference to FIGS 1 to 5 explained in more detail. Such fluidic structures enable fluid to be switched from an inlet reservoir in one centrifuge rotor into one of two or more different subsequent outlet channels depending on the frequency protocol. In which of the outlet channels the liquid is switched depends on the frequency protocol used. In this case, fluid can first be pumped through one or more inlet channels radially outward into a compression chamber at high rotational frequency, in which a compressible medium is enclosed and compressed. At the same time, two or more outlet passages connected to the compression chamber are partially filled. For example, by braking the rotor to a low rotational frequency, the compressible medium expands again. Depending on the predefined hydraulic resistances and the height of respective siphon structures of the outlet channels, the liquid now completely fills one or more of the siphon structures. The deceleration rate determines which of the exhaust ports are completely filled. Alternatively, the emptying process (pumping operation) can take place without deceleration exclusively by expansion of the compressible medium in the compression chamber. Such expansion can be thermally induced or triggered by gas evolution due to chemical reactions. Combinations of the described effects are also possible. After the complete filling of one or more outlet channels, the liquid to be switched is then transferred completely or partially into the corresponding outlet channel or the corresponding outlet channels.

1 schematically shows a plan view of an embodiment of a fluidic device in the form of a centrifugal disc. Fluidic structures in the centrifugal disc 100 are formed, for example, for an automated Bacterial DNA extraction from whole blood suitable. The fluidic structures have an inlet reservoir 102 , a compression chamber 104 , a sedimentation chamber 106 , an inlet channel 108 that the inlet reservoir 102 with the sedimentation chamber 106 fluidly connects, a first outlet channel 110 and a second outlet channel 112 on. The fluidic device 100 is a rotation center 114 rotatable. Multiple fluid inlets 116a to 116c for the inlet reservoir 102 are provided. A first, radially inner end of the inlet channel 108 opens into a radially outer portion of the inlet reservoir 102 and a second, radially outer end of the inlet channel 108 opens into a radially inner portion of the sedimentation chamber 106 ,

The first outlet channel 110 and the second exhaust duct 112 each have a siphon structure. First ends 120 and 122 of the first outlet channel 110 and the second outlet channel 112 are disposed at a position that is radially outward than the compression chamber 104 and the sedimentation chamber 106 so that the outlet channels 110 and 112 are suitable to completely empty these chambers. A second end of the first and second outlet channels 110 and 112 opens into a radially inner region of the sedimentation chamber 106 ,

The second outlet channel 112 has a higher flow resistance than the first outlet channel 110 on. In general, in embodiments of the invention, different flow resistances (hydraulic resistances) of respective fluid channels can be achieved via different flow cross sections. Thus, the second outlet channel may be implemented with a smaller flow area than the first outlet channel and thus be referred to as a narrow fluid channel.

By compression chamber is meant herein a chamber that allows the compression of a compressible medium. In embodiments of the present invention, this is a non-vented chamber. In embodiments, with the exception of the fluid inlet and the two or more fluid outlets, the compression chamber has no further fluid openings. In alternative embodiments, the compression chamber may be provided via an optional additional channel 124 coupled with additional compression volume. In yet alternative embodiments, the compression chamber may include a vent opening which is closable to allow compression of a compressible medium in the compression chamber.

About the fluid inlets 116a to 116c For example, liquid reagents that may be upstream may enter the inlet reservoir 102 be initiated. From there, the liquids can be centrifuged through the inlet channel 108 over the sedimentation chamber 106 in the compression chamber 104 be pumped. In this case, in the compression chamber, a gas volume 130 enclosed and compressed. At the same time it is building in the inlet channel 108 and the outlet channels 110 and 112 a centrifugal back pressure on. At a (generally constant) rotational frequency of the fluidic device 100 (the centrifugal disc), which is suitable to that in the compression chamber 104 To compress enclosed gas volumes (usually air), a balance of forces between the air pressure of the gas volume and the counteracting centrifugal pressure of the liquids in the inlet channel 108 , the first outlet channel 110 and the second outlet channel 112 one. A suitable rotational frequency may be, for example, in the range of 30 to 120 Hz, for example of the order of 75 Hz. Such a rotational frequency may be referred to as a high rotational frequency. The resulting equilibrium state is in 3A shown, being in the compression chamber 104 a compressed gas volume 130 located. The associated high rotation frequency is further in the frequency log in FIG 2 to recognize under A.

Starting from the in 3A Now, the liquid can pass through either the first outlet channel 110 or the second outlet channel 112 depending on the rate at which the rotation frequency is reduced. 3B shows the case where slow deceleration takes place while in 3C the case is shown in which a rapid reduction of the rotational frequency takes place.

In other words, in a subsequent reduction of the rotational frequency to a low rotational frequency, for example 15 Hz, the speed at which the rotational frequency is reduced decides through which outlet channel, ie siphon, the processed fluid expires. With a slow reduction of the rotational frequency, for example at a rate of less than 5 Hz / s, the gas volume expands slowly and the liquid is slowly displaced from the compression chamber. This increases the liquid level in the first outlet channel 110 , in the second outlet channel 112 and slowly in the inlet channel, so that the flow rate is approximately zero. Thus, frictional forces in the fluid have virtually no influence on the fluid dynamics and the levels in the three parallel fluid paths remain substantially the same. There is thus a quasi-static case. Because the vertex of the second exhaust duct 112 radially further out than the vertex of the first exhaust duct 110 , the liquid thus flows exclusively through the second outlet channel 112 since it has the lowest, ie radially outermost, vertex. This case is in 3B shown. The correspondingly slow rotation frequency reduction is also in the frequency protocol of 2 under B to recognize.

Alternatively, starting from the in 3A a rapid reduction in the rotational frequency, for example at a rate of more than 10 Hz / s, the gas volume is caused to expand rapidly and the liquid to displace rapidly. Thus, the liquid levels in the inlet channel, the first outlet channel and the second outlet channel increase rapidly, so that the flow rate is relatively high and frictional forces affect the fluid dynamics. Since a dynamic process thus takes place, different fill levels in the three parallel fluid paths can be achieved so that liquid can be derived, ie switched, exclusively via the first outlet channel. In particular, the high frictional forces in the second outlet channel limit 112 the flow rate therethrough such that the first exhaust passage 110 is filled first. Depending on the geometric design of the outlet channels, ie the siphons, it can be accomplished that the liquid is the vertex of the second outlet channel 112 not reached, so that only the siphon of the first outlet channel switched and the liquid is discharged exclusively through this outlet channel. For this purpose, as in 1 is shown, the second outlet channel 112 a volume buffer 140 which can receive a certain volume of liquid, so that it can be ensured that the liquid is the vertex of the second outlet channel 112 not reached. The corresponding state is in 3C shown. The corresponding fast speed reduction from the high rotational frequency is in the frequency protocol of 2 shown under C.

After in the illustrated embodiment, liquid only through the second outlet channel 112 is passed, if after a reduction in the rotational frequency, a high volume of liquid was pumped back into the inlet reservoir, this outlet channel is in 2 referred to as a volume siphon, while the first outlet channel 110 , is discharged through the liquid due to a dynamic process, is referred to as a dynamic siphon.

In the described embodiment, the sedimentation chamber 106 a bulge at a radially outer portion thereof. Further, the sedimentation chamber 106 with a radially outer portion of the compression chamber 104 coupled with the same. Thus, higher density materials in the liquid at high rotational frequency can be deposited in the bulge. Thus, in addition to switching a further functionality, namely a sedimentation can be achieved. The derived liquids can then each be appropriately processed liquids.

As described above, the second exhaust passage 112 a volume buffer 140 exhibit. The volume buffer 140 may be of any shape as long as it is capable of receiving a volume of liquid to ensure that the liquid does not reach the vertex of the bulk siphon before draining via the first outlet channel.

An alternative embodiment of a volume buffer is shown in FIG 4 shown. In this alternative embodiment, the second outlet channel 112 a volume buffer 142 on, which is designed as a curved channel. This allows that when emptying through the second exhaust duct 112 takes place, ie the volume siphon is switched, the liquid to be processed completely from the. Volume siphon is discharged. In contrast, in the case of 1 illustrated embodiment residual liquid in the volume buffer 140 remain.

An alternative embodiment of a fluidic device suitable for nucleic acid purification with one-step purification will now be referred to 5 described, in 5 different phases of the device are shown during a corresponding process.

As in 5 1, the fluidic structures of a corresponding fluidic device have an inlet chamber 200 , an inlet channel 202 containing the inlet chamber with a compression chamber 204 fluidly connects, a first outlet channel 206 , a second outlet channel 208 , a rubbish bin 210 and an outlet chamber 212 on. The corresponding fluidic structures are in a rotational body 214 formed around a rotation center 216 is rotatable. Another fluid channel 218 can with the outlet chamber 212 be fluidly coupled, for example, can establish a fluidic connection to other processing stages.

In the inlet chamber 200 can be arranged in this embodiment, a particularly coated sorbent (Nexttec clean column).

For the purification of nucleic acid in the so-called one-step method (one-step method), the sorbent is first mixed with a buffer 220 wetted. The buffer 220 is in 5 represented by an oblique hatching. Under centrifugation at a high rotational speed after wetting excess liquid is removed from the sorbent and transferred to the compression chamber. As a result, a gas bubble is trapped and compressed in the compression chamber. The equilibrium state resulting from the corresponding pressure p is in 5B shown. From this condition, by slowly reducing the speed of centrifugation, the liquid wets the volume siphon, ie the second outlet channel 208 and is transferred to the waste reservoir by centrifugal juices 210 transferred. The resulting state is in 5C shown.

In the next step, the sorbent (the column) is passed through the actual sample liquid 222 wetted in 5C represented by a cross-hatching. The thus purified sample is again transferred by centrifugation at a high rotational frequency in the compression chamber. By rapidly reducing the rotational frequency, there is a rapid expansion of the air volume trapped in the compression chamber, so that the liquid now mainly through the first outlet channel 206 (dynamic outlet), which has a lower hydraulic resistance than the second outlet channel, is pumped, as in 5D is shown. As a result, the purified sample liquid enters the discharge chamber, which constitutes an analysis chamber. As in 5 is shown, the analysis chamber 212 radially inward than the compression chamber 204 so that radial inward pumping is implemented in addition to switching.

In embodiments, the inlet channel may have a higher or lower flow resistance than the outlet channels.

Exemplary embodiments of the present invention are suitable for bacterial DNA extraction from whole blood, see, for example, that in US Pat 1 shown embodiment, or for nucleic acid purification with a one-step purification, see the in 5 shown embodiment.

Embodiments of the invention provide a centrifugal-dynamic switch that extends the spectrum of centrifugal switches by, for example, selectively utilizing variable speed reduction rates. Thus, embodiments of the invention are particularly suitable for complex fluidic processes. For sepsis diagnostics, which enables the detection of bacterial infections in the blood (blood poisoning), complex process sequences with a multitude of individual steps are necessary. Thus, the highly sensitive pathogen diagnostics requires individual steps for mixing liquids, sedimenting bacteria, removing the supernatant into a drainage chamber or on a silica column and resuspending the sediment. Embodiments of the present invention are suitable for automating such processes on a centrifugal microfluidic platform, which may require fluidic switches that can selectively divert liquid from an inlet channel into two or more different outlet channels.

In the described embodiments, two outlet channels are provided. In alternative embodiments, a larger number of outlet channels may be provided, each of which may have siphon structures whose apex may be located at different radial positions. In the embodiments described, liquid was switched either through the one outlet channel or the other outlet channel. In alternative embodiments, with medium speed reduction, both (or even more) siphons may be filled. In this way, liquid can be distributed in several different paths, so that an aliquot can be achieved.

In embodiments of the invention, channel cross sections of the outlet channels, for. B. the siphons in the range of a few 10 microns to a few 100 microns. In this case, the channel cross sections (for example channel diameter) of the high resistance region (second outlet channel) and the low resistance region (first outlet channel) may differ by only a few 10% or even by several 100%, depending on the design of the structure and on the liquid properties. The exact dimensioning of the channel resistances depends on the liquid properties and other geometrical parameters, for example the length of the respective channels, etc., wherein appropriate dimensioning for achieving the desired effect can be readily implemented by those skilled in the art.

In embodiments of the invention, only one switching operation takes place in each case by one of the outlet channels. However, the switching operations can be repeated as often as desired in all implementations, wherein the order of the switching operations can be selected arbitrarily. Furthermore, in all implementations, one or more outlet channels may be recirculated to a fluid pathway leading to the input channel, thereby allowing recirculation of the processing fluids.

In embodiments, the first flow resistance is less than the second flow resistance, so that the fluid flow through the second outlet channel is greatly limited. In alternative embodiments, the first flow resistance also came to be higher than the second flow resistance when a volume buffer in the bulk siphon is large enough to receive the corresponding volume of liquid.

Embodiments of the present invention thus provide fluidic structures having at least one chamber for confining and compressing a compressible medium and at least one inlet channel and at least two outlet channels, wherein at least one of the outlet channels is filled hydrodynamically, i. H. due to various hydraulic resistances to the inlet channels or other outlet channels. In embodiments of the invention, at least one of the exhaust ports is volume controlled, i. H. the outlet channel (s) are filled by hydrostatic pressure. In embodiments of the invention, the expansion of the compressible medium can be actuated by reducing the rotational frequency of the rotor. In alternative embodiments of the invention, the expansion of the compressible medium may be actuated by thermal expansion. In yet alternative embodiments, the expansion of the compressible medium can be actuated by chemical reactions.

Embodiments of the present invention thus allow for the implementation of centrifugal pneumatic switches that can direct liquids from an inlet channel into one of two outlet channels or into both outlet channels and back into the inlet channel. The switching of the liquid can take place in any order. Furthermore, the switch can be used as often as desired. The switch is largely independent of the user and material properties, in particular independent of surface tension and contact angle. In embodiments, the actuation can be done exclusively by centrifugation.

Embodiments of the invention thus provide a fluidic device having fluidic structures which have at least one chamber for confining and compressing a compressible medium and at least one inlet channel and at least two outlet channels. In this case, at least one of the outlet channels is filled hydrodynamically, d. H. due to various geometric layouts with respect to the inlet duct or ducts.

Embodiments of the invention provide numerous advantages over the prior art. So no change of the direction of rotation for the switching operation is necessary. Furthermore, no exactly defined input liquid volumes are necessary for the switching operation and the geometry can be varied within larger limits. In embodiments, neither local nor large-scale coatings are necessary. Furthermore, no external active components are necessary. The switching is done by the high rotational frequencies largely independent of wetting properties of the liquids and surfaces. The repeated switching of liquids in different chambers is possible, for example switching a first liquid via the first outlet channel in a first chamber, a second liquid via the second outlet channel in a second chamber, and a third liquid via the first outlet channel back into the first Chamber.

Claims (16)

Fluidic device which is located around a center of rotation ( 114 . 216 ) for directing a liquid through a first or a second outlet channel, comprising: a compression chamber ( 104 ; 204 ); an inlet channel ( 108 ; 202 ) connected to the compression chamber ( 104 ; 204 ) is fluidically coupled; the first outlet channel ( 110 ; 206 ) connected to the compression chamber ( 104 ; 204 ) is fluidically coupled and has a first flow resistance; and the second outlet channel ( 112 ; 208 ) connected to the compression chamber ( 104 ; 204 ) is fluidically coupled and has a second flow resistance, wherein the first outlet channel ( 110 ; 206 ) and the second outlet channel ( 112 ; 208 ) with respect to the center of rotation ( 114 . 216 ) radially increasing portions, wherein the compression chamber ( 104 ; 204 ) and the first and second exhaust ducts ( 110 . 112 ; 206 . 208 ) are designed such that in a partial filling of the compression chamber ( 104 ; 204 ) with a liquid via the inlet channel ( 108 ; 202 ) and a rotation of the fluidic device with an increased rotational frequency by means of the liquid in the compression chamber ( 104 ; 204 ) is compressed by a centrifugal pressure which is due to the liquid in the inlet channel ( 108 ; 202 ) and the first and second outlet channels, the first outlet channel ( 110 ; 206 ) has at least one portion that extends radially further inwards than a radially innermost portion of the second outlet channel (US Pat. 112 ; 208 ), and wherein the first and second exhaust ducts ( 110 . 112 ; 206 . 208 ) are designed in such a way that, when the compressed gas expands at a first expansion rate, the liquid is discharged via the first outlet channel (FIG. 110 ; 206 ) is conductive and that with an expansion of the compressed gas at a second expansion rate, which is smaller than the first expansion rate, the liquid via the second outlet channel ( 112 ; 208 ) is conductive. Fluidic device according to claim 1, wherein the second flow resistance is greater than the first flow resistance, so that upon expansion of the compressed gas at a first expansion rate, the fluid is discharged via the first outlet channel (11). 110 ; 206 ) is conductive and that with an expansion of the compressed gas at a second expansion rate, which is smaller than the first expansion rate, the liquid via the second outlet channel ( 112 ; 208 ) is conductive. Fluidic device according to claim 1 or 2, in which the second outlet channel ( 112 ; 208 ) a volume buffer ( 140 ; 142 ) configured to receive liquid and prevent liquid from entering a radially innermost portion of the second outlet channel (12). 112 ; 208 ) is reached when the liquid is expanded during expansion of the compressed gas at the first expansion rate through the first outlet channel (16). 110 ; 206 ). Fluidic device according to one of claims 1 to 3, wherein the second outlet channel ( 112 ; 208 ) has a siphon, wherein a radially inner vertex of the siphon is arranged radially further outward than a radially inner portion of the first outlet channel ( 110 ; 206 ). Fluidic device according to one of claims 1 to 4, wherein the inlet channel ( 108 ; 202 ) and the first and second exhaust ducts ( 110 . 112 ; 206 . 208 ) with a fluid channel ( 106 ) are fluidically coupled into a compression chamber ( 104 ; 204 ) opens. Fluidic device according to claim 5, wherein the inlet channel ( 108 ; 202 ) and the first and second exhaust ducts ( 110 . 112 ; 206 . 208 ) in a radially inner side of the fluid channel ( 106 ), wherein a radially outer side of the fluid channel ( 106 ) has a bulge. Fluidic device according to one of claims 1 to 6, wherein a first end of the first outlet channel ( 206 ) at a position in an outlet chamber ( 212 ), which lies radially inward than an outlet of the compression chamber ( 104 ; 204 ) connected to a second end of the first outlet channel ( 206 ) is fluidically coupled. Fluidic device according to one of claims 1 to 6, wherein a first end of the first outlet channel ( 206 ) with an analysis chamber ( 212 ) is fluidically coupled, wherein a first end of the second outlet channel ( 208 ) with a waste chamber ( 210 ) is fluidically coupled, and at the second ends of the first and the second outlet channel ( 206 . 208 ) with the compression chamber ( 104 ; 204 ) are fluidically coupled. Fluidic device according to claim 8, wherein a position at which the first end of the first outlet channel ( 206 ) into the analysis chamber ( 212 ) radially further inward than an outlet of the compression chamber ( 104 ; 204 ) connected to the second end of the first outlet channel ( 206 ) is fluidically coupled. Fluidic device according to one of claims 1 to 9, in which the compression chamber ( 104 ; 204 ), the inlet channel ( 108 ; 202 ) and the first and second exhaust ducts ( 110 . 112 ; 206 . 208 ) in a rotating body ( 100 ; 214 ) or are formed in a usable in a rotary body module. Fluidic device according to claim 10, comprising means ( 22 . 24 ) for causing the compressed gas to expand at the first expansion rate or the second expansion rate. Fluidic device according to claim 11, in which the device ( 22 . 24 ) for effecting a drive device which is designed to rotate around the body of revolution ( 110 ; 214 ) to apply at different rotational speeds, a heater which is adapted to the gas in the compression chamber ( 104 ; 204 ) with different temperature gradients, means for generating a chemical reaction in the compression chamber ( 104 ; 204 ) or a combination of such devices. Fluidic device according to claim 10 or 11, comprising a drive device ( 22 . 24 ) which is designed to hold the rotating body ( 100 ; 214 ) to act with different rotational speeds. Fluidic device according to Claim 13, in which the drive device ( 22 . 24 ) is configured to rotate the body ( 110 ; 214 ) to apply a rotation at the increased rotational frequency, and to reduce the rotational frequency either at a first rotational frequency reduction rate, starting from the rotation at the increased rotational frequency, to cause the compressed gas to expand at the first rate of expansion and to move the fluid through the first rotational rate first outlet channel ( 110 ; 206 ), or at a second rate of reduction of the frequency of rotation lower than the first rate of reduction of the frequency of rotation to cause the compressed gas to expand at the second rate of expansion and the fluid to pass through the second outlet channel (12). 112 ; 208 ). Method for passing a liquid through the first outlet channel ( 110 ; 206 ) or the second outlet channel ( 112 ; 208 ) of a fluidic device according to one of claims 1 to 14, comprising the following steps: applying to the compression chamber ( 104 ; 204 ), the inlet channel ( 108 ; 202 ) and the first and second exhaust ports at the increased rotational frequency, and starting from the rotation at the increased rotational frequency, causing the compressed gas to expand at the first rate of expansion to move the fluid through the first exhaust port (12). 110 ; 206 ) or causing the compressed gas to expand at the second rate of expansion to pass the liquid through the second outlet channel (12). 112 ; 208 ). The method of claim 15, wherein causing the compressed gas to expand at the first expansion rate comprises decreasing the rotational frequency at a first rate of rotational rate reduction, and causing the compressed gas to expand at the second rate of expansion the rotational frequency having a second rotational frequency reduction rate.

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