Centrifugo-pneumatic switching of liquid
11141728 · 2021-10-12
Assignee
Inventors
- Ingmar Schwarz (Freiburg, DE)
- Nils PAUST (Freiburg im Breisgau, DE)
- Steffen Zehnle (Merzhausen, DE)
- Mark Keller (Freiburg, DE)
- Tobias Hutzenlaub (Herbolzheim, DE)
- Frank Schwemmer (Freiburg, DE)
Cpc classification
B01L2200/0684
PERFORMING OPERATIONS; TRANSPORTING
B01L2300/0806
PERFORMING OPERATIONS; TRANSPORTING
B01L2400/0487
PERFORMING OPERATIONS; TRANSPORTING
B01L2300/087
PERFORMING OPERATIONS; TRANSPORTING
International classification
Abstract
A fluidic module for switching liquid from a liquid retaining area into which liquid can be introduced into downstream fluidic structures includes at least two fluid paths fluidically connecting the liquid retaining area to the downstream fluidic structures. One of the two fluid paths includes a siphon channel. The downstream fluidic structures are not vented or only vented via a vent delay resistor, such that when the liquid is introduced into the liquid retaining area, an enclosed gas volume results in the downstream fluidic structures. By adjusting the ratio of a centrifugal pressure effected by a rotation of the fluidic module and a pneumatic pressure prevailing in the gas volume, the liquid can be retained in the liquid retaining area or can be transferred into the downstream fluidic structures via the siphon channel wherein venting takes place via the other one of the fluid paths.
Claims
1. Method for switching liquid from a liquid retaining area into downstream fluidic structures by using a fluidic module, the module comprising: a liquid retaining area into which liquid can be introduced, at least two fluid paths fluidically connecting the liquid retaining area to downstream fluidic structures, wherein at least a first fluid path of the at least two fluid paths comprises a syphon channel, wherein a syphon crest of the syphon channel is located radially inside of a radial outermost position of the liquid retaining area, wherein the syphon crest is an area of the syphon channel with minimum distance to the center of rotation, wherein the downstream fluidic structures are at most vented via a vent delay resistor when the liquid is introduced into the liquid retaining area, such that an enclosed gas volume or a gas volume merely vented via the vent delay resistor results in the downstream fluidic structures when the liquid is introduced into the liquid retaining area, and a ratio of a centrifugal pressure effected by a rotation of the fluidic module to a pneumatic pressure prevailing in the gas volume at least temporarily prevents the liquid from reaching the downstream fluidic structures through the at least two fluid paths, wherein transfer of at least part of the liquid to the downstream fluidic structures through the first fluid path and venting of at least part of the gas volume into the liquid retaining area through a second fluid path of the at least two fluid paths is effected by changing the ratio of the centrifugal pressure to the pneumatic pressure, the method comprising: introducing at least one liquid into the liquid retaining area and retaining the liquid in the liquid retaining area by rotating the fluidic module, such that the liquid is retained in the liquid retaining area in a quasi-stationary equilibrium dominated by the centrifugal pressure and the pneumatic pressure; and changing the ratio of the centrifugal pressure to the pneumatic pressure in order to transfer the liquid at least partly through the first fluid path into the downstream fluidic structures and to vent the gas volume at least partly into the liquid retaining area through the second fluid path of the two at least fluid paths, wherein a) retaining the liquid in the liquid retaining area comprises generating a pneumatic overpressure in the downstream fluidic structures prior to initiating the transfer, and changing the ratio of the centrifugal pressure to the pneumatic pressure comprises increasing the rotational speed of the fluidic module, increasing the hydrostatic height of the liquid and/or reducing the pneumatic pressure, or b) retaining the liquid in the liquid retaining area comprises generating a negative pressure in the downstream fluidic structures in order to adjust and retain menisci in the liquid retaining area and the first and second fluid paths without transferring the liquid into the downstream fluidic structures through the first fluid path, and wherein changing the ratio of the centrifugal pressure to the pneumatic pressure comprises reducing the rotational speed of the fluidic module and/or reducing the pneumatic pressure in the downstream fluidic structures.
2. Method according to claim 1, wherein changing the ratio comprises reducing the pneumatic pressure by reducing the temperature in the downstream fluidic structures, increasing the volume of the downstream fluidic structures and/or reducing the amount of gas in the downstream fluidic structures.
3. Method according to claim 1, wherein the second fluid path is not completely filled with liquid during the transfer of the liquid through the first fluid path.
4. Method according to claim 1, wherein the amount of the gas in the downstream fluidic structures is not changed while the liquid is retained in the liquid retaining area.
5. Method according to claim 1, wherein the second fluid path of the at least two fluid paths is a venting channel for the downstream fluidic structures closed from the liquid when the liquid is introduced into the liquid retaining area.
6. Method according to claim 1, wherein the first fluid path leads into the liquid retaining area in a radial outer area or at a radial outer end, wherein the liquid retaining area is emptied via the first fluid path, at least up to the area where the first fluid path leads into the liquid retaining area.
7. Method according to claim 1, wherein the liquid retaining area comprises a first fluid chamber, wherein the first fluid path leads into the first fluid chamber in a radial outer area of the first fluid chamber or at a radial outer end of the first fluid chamber.
8. Method according to claim 7, wherein the first fluid chamber is at most vented via an additional vent delay resistor or the vent delay resistor when the liquid is introduced into the liquid retaining area, such that a gas volume enclosed in the first fluid chamber and the downstream fluidic structures or a gas volume merely vented via the vent delay resistor results when the liquid is introduced into the liquid retaining area.
9. Method according to claim 7, wherein the liquid retaining area further comprises a second fluid chamber into which liquid is introduced by a centrifugal pressure effected by the rotation of the fluidic module, wherein the first fluid path leads into the first fluid chamber and the second fluid path leads into the second fluid chamber, and wherein the second fluid path is closed by liquid introduced into the second fluid chamber.
10. Method according to claim 9, wherein the first fluid chamber and the second fluid chamber are fluidically connected via a connecting channel whose orifice into the first fluid chamber is located radially further inside than a radial outer end of the first fluid chamber, such that liquid from the first fluid chamber flows over into the second fluid chamber when the filling level of the liquid in the first fluid chamber reaches the orifice and closes the second fluid path leading into the second fluid chamber.
11. Method according to claim 1, wherein the second fluid path comprises a siphon channel.
12. Method according to claim 11, wherein the second fluid path leads into the liquid retaining area in a radial outer area of the liquid retaining area.
13. Method according to claim 12, wherein a crest of the siphon channel of the second fluid path is located radially further inside than a crest of the siphon channel of the first fluid path.
14. Method according to claim 12, wherein a fluid intermediate chamber is arranged in the second fluid path between the crest of the siphon channel of the second fluid path and an orifice of the second fluid path into the liquid retaining area, wherein the fluid intermediate chamber is at least partly filled with the liquid when the liquid is introduced into the liquid retaining area.
15. Method according to claim 1, wherein the downstream fluidic structures comprise at least one downstream fluid chamber into which the first fluid path leads.
16. Method according to claim 15, wherein the first fluid path leads into the at least one downstream fluid chamber radially further outside than the second fluid path.
17. Method according to claim 15, wherein the at least one downstream fluid chamber is a first downstream fluid chamber and the downstream fluidic structures comprise a second downstream fluid chamber fluidically connected to the first downstream fluid chamber via at least a third fluid path.
18. Method according to claim 17, wherein the first downstream fluid chamber is fluidically connected to the second downstream fluid chamber via a third fluid path and a fourth fluid path, wherein at least the third fluid path comprises a siphon channel, wherein the third fluid path and the fourth fluid path are closed by the liquid when the liquid reaches the first downstream fluid chamber of the downstream fluidic structures through the first fluid path due to a change of the ratio of the centrifugal pressure to the pneumatic pressure, wherein an enclosed gas volume or a gas volume vented merely via an additional vent delay resistor or the vent delay resistor results in the second downstream fluid chamber and a ratio of the centrifugal pressure to the pneumatic pressure prevailing in the gas volume in the second downstream fluid chamber at least temporarily prevents the liquid from reaching the second downstream fluid chamber through the fluid paths, wherein it can be effected by changing the ratio of the centrifugal pressure to the pneumatic pressure in the second downstream fluid chamber that the liquid at least partly reaches the second downstream fluid chamber through the third fluid path and the gas volume is vented from the second downstream fluid chamber at least partly into the liquid retaining area through the fourth fluid path.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1) Embodiments of the present invention will be detailed subsequently referring to the appended drawings, in which:
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DETAILED DESCRIPTION OF THE INVENTION
(15) Embodiments of the invention relate to microfluidic structures for centrifuge-pneumatic switching and methods for centrifuge-pneumatic switching, in particular for centrifugo-pneumatic switching of liquids from a liquid retaining area that can comprise a first chamber to subsequent or downstream fluidic structures. Here, downstream or subsequent (wherein these expressions are used interchangeably herein) fluidic structures mean fluidic structures such as channels or chambers which liquid reaches from a preceding or upstream (wherein these expressions are used interchangeably herein) fluidic structures during handling the same. Here, the microfluidic structures can comprise a first chamber connected to the subsequent fluidic structures via at least two fluid paths, wherein at least the fluid path through which the liquid is transferred into the subsequent fluidic structures during switching is configured in the shape of a siphon. The structures and the method can be configured such that the significant pressures in the direction of or against the filling of the path for the transfer of liquid are given by centrifugal pressures or pneumatic pressures.
(16) Switching where centrifugal pressures and pneumatic pressure dominate other pressures can be referred to as centrifugo-pneumatic switching.
(17) In embodiments, pneumatic overpressures and/or negative pressures can be used.
(18) In the case of using overpressures, when filling the first chamber with a liquid, gas is displaced into the subsequent fluidic structures whereby pneumatic overpressure results in the same. By suitable design within broad limits, this pneumatic overpressure can be selected and determines significantly, with otherwise unamended processing conditions, the rotational frequency (switching frequency) needed for switching the liquid. In this case, prior to the switching process, the centrifugally induced pressure in the first chamber is lower than the pressure needed to wet the crest of the siphon-shaped channel against the pneumatic overpressure in the subsequent fluidic structures, by which the liquid is transferred into the subsequent fluidic structures during the switching process. This represents a (quasi-static) equilibrium state. By increasing the rotational frequency of the cartridge via the switching frequency, the centrifugal pressure can be increased above the switching pressure, whereby the siphon is wetted and transfer of the liquid into the subsequent fluidic structures is initiated. Alternatively or in combination, the hydrostatic height of the liquid can be increased in order to initiate the transfer of liquid, for example by adding additional liquid into the liquid retaining area via upstream fluidic structures.
(19) In the case of using negative pressure for the switching principle, in embodiments, first, the subsequent fluidic structures can be heated such that a gas contained therein expands and part of this gas can escape. When liquid is subsequently transferred into the liquid retaining area and the rotational frequency is increased, the liquid in the fluid connecting path can approximately be at the same radial height as in the liquid retaining area. When reducing the temperature and the subsequent fluidic structures, a negative pressure results which acts in the direction of the subsequent fluidic structures. However, since the connecting paths are configured in a siphon shape, this increases the hydrostatic height in the connecting paths, such that, in this case, the centrifugal force counteracts further filling of the connecting path. This is the (quasi-static) equilibrium state under negative pressure conditions. Then, by increasing the negative pressure further and/or by reducing the centrifugal pressure, a switching process can be initiated.
(20) Embodiments present methods for retaining liquids and initiating the switching process by other changes of the processing conditions together with the associated structures. All structures and methods have in common that the second fluid connection between liquid retaining area and downstream fluidic structures can be used during the transfer to let gas escape from the downstream fluidic structures into the liquid retaining area or a fluid chamber of the liquid retaining area or to let it flow in, whereby the pneumatic pressure difference to the downstream fluidic structures can be reduced.
(21) In the following, some definitions for terms used herein will be specified.
(22) Hydrostatic height means the radial distance between two points in a centrifugal cartridge, if liquid of a continuous amount of liquid is located at both points. Hydrostatic pressure means the pressure difference between two points induced by a centrifugal force due to the hydrostatic height between the same. The effective fluidic resistance of a microfluidic structure is the quotient of the pressure driving a fluid through a microfluidic structure and resulting liquid flow through the microfluidic structure. Aliquoting means dividing a liquid volume into several separate individual volumes, so-called aliquots.
(23) Metering means measuring a defined liquid volume out of a greater liquid volume. Switching frequency is the rotational frequency of a microfluidic cartridge, wherein, when exceeding the same, a transfer process of liquid from a first structure to a second structure starts. A siphon channel is a microfluidic channel or a portion of a microfluidic channel in the centrifugal microfluidic cartridge, where an entrance and exit of the channel have a greater distance from the center of rotation than an intermediate area of the channel. Siphon crest means the area of a siphon channel in a microfluidic cartridge with minimum distance from the center of rotation.
(24) A vent delay resistor is the fluidic resistor by which a fluidic structure in which a pneumatic differential pressure to the ambient pressure prevails is vented. Here, the fluidic resistance is at least so high that reducing the differential pressure by half takes at least 0.5 seconds by merely considering venting by the fluidic resistor. This applies to any point in time during venting.
(25) When a vent delay resistor for the downstream fluidic structures is provided in embodiments, the time course of the pressure drop in these fluidic structures can be determined, for example, in that the liquid retaining area is filled with liquid at constant temperature during centrifugation and the hydrostatic height between an upstream chamber and a fluid chamber in which the liquid is retained the liquid retaining structures is captured in the quasi-stationary equilibrium by a suitable camera system (e.g., by stroboscope exposure). From the rotational frequency and the hydrostatic height the pneumatic overpressure existing in the subsequent structures results. Thus, the degradation rate of the overpressure can also be determined from this image information which results in the magnitude of the vent delay resistor. In other embodiments, such as during switching at negative pressure, the method can be used analogously in that liquid is filled in at a specific frequency and start temperature and subsequently, defined fast cooling is generated. From the developing hydrostatic height in the connecting paths and their degradation rate, again, the magnitude of the vent delay resistor results.
(26) All liquids that are in a quasi-static fluid state change their position within the cartridge where they are located in direct dependency on the processing conditions. This means all fluid transport processes between fluidic structures running at constant processing conditions are self-contained. Further, liquid transport processes that are a sequence of changes of processing conditions decrease, during the change of the processing conditions within at most 1s, by their respective half as soon as the change of the processing conditions is abruptly stopped.
(27) A liquid supply path is a microfluidic structure through which liquid from the liquid retaining area flows into one or several subsequent fluidic structures while the inventive method is performed. A gas supply path is a microfluidic structure through which gas exchange between the subsequent fluidic structures and the liquid retaining area takes place while the inventive method is performed. A liquid receiving volume is a microfluidic structure providing a volume into which the liquid is transferred after triggering the inventive switching process.
(28) Here, a microfluidic cartridge is an apparatus, such as a fluidic module comprising microfluidic structures allowing liquid handling as described herein. A centrifugal microfluidic cartridge is a respective cartridge that can be subjected to rotation, for example in the form of a fluidic module insertable into a rotation body or a rotation body.
(29) If a fluid channel is mentioned herein, this is a structure whose longitudinal dimension from a fluid inlet to a fluid outlet is, for example, by more than 5 times or more than 10 times greater than the dimension(s) defining the flow cross-section. Thus, a fluid channel has a flow resistance for the flow through the same from the fluid inlet to the fluid outlet. On the other hand, a fluid chamber is a chamber having such dimension that during a flow through the chamber, a flow resistance neglectable compared to connected channels occurs, which can be, for example 1/100 or 1/1000 of the flow resistance of the channel structure with smallest flow resistance connected to the chamber.
(30) Before embodiments of the invention will be discussed in more detail, it should be noted that examples of the invention can be applied in particular in the field of centrifugal microfluidics that deals with processing liquids in the picoliter to milliliter range. Accordingly, the fluidic structures can have suitable dimensions in the micrometer range for handling respective liquid volumes. In particular, embodiments of the invention can be applied in centrifugal microfluidic systems such as known, for example, by the term “lab-on-a-disk”.
(31) If the term radial is used herein, it means radial with respect to the center of rotation around which the fluidic module or the rotation body can be rotated. Thus, in the centrifugal field, a radial direction away from the center of rotation is radially declining and a radial direction towards the center of rotation is radially rising. Thus, a fluid channel whose beginning is closer to the center of rotation than its end is radially declining while a fluid channel whose beginning is further apart from the center of rotation than its end is radially rising. Thus, a channel comprising a radially rising portion comprises directional components that radially rise or run radially towards the inside. It is obvious that such a channel does not have to run exactly along a radial line but can also run at an angle to the radial line or in a curved manner.
(32) With reference to
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(34) The rotational body 10 comprises the fluidic structures described herein. Respective fluidic structures are indicated merely schematically in
(35) In an alternative embodiment shown in
(36) In
(37) In embodiments of the invention, the fluidic module or the rotational body comprising the fluidic structures can be formed of any suitable material, such as plastic like PMMA (polymethylmethacrylate), PC (polycarbonate), PVC (polyvinyl chloride) or PDMS (polydimethylsiloxane), glass or the same. The rotational body 10 can be considered as a centrifugal microfluidic platform.
(38) As will be discussed below, in embodiments, the control means 24 is, an actuator that can adjust the rotational speed of the driving means in order to initiate the transfer of liquid, i.e., to effect the change of the ratio of the centrifugal pressure to the pneumatic pressure that effects switching of the liquid. In embodiments of the invention, the actuator can additionally comprise one or several heating means and/or cooling means for controlling the temperature of the fluidic structures to initiate the transfer of liquid. For example, one or several temperature control elements 40 (heating element and/or cooling element) can be integrated in the rotational body as show in
(39) With reference to
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(41) Further, the fluidic module 50 comprises subsequent fluidic structures comprising a fluid chamber 58 as a fluid receiving volume and two fluid paths 60, 62 fluidically connecting the first chamber 52 to the fluid chamber 58. The fluid path 62 comprises a siphon channel whose siphon crest 64 is located radially inside the radial outermost position of the first chamber 52. The subsequent fluidic structures in the form of the fluid chamber 58 are either not vented or can be vented via a vent delay resistor 66 satisfying the above definition. Such a vent delay resistor 66 can optionally be provided in all embodiments described herein without being specifically mentioned.
(42) In the shown embodiment, the first fluid path 60 between the first chamber and the subsequent fluidic structure 58 consist of a channel leading from a radial inner area of the first chamber 52, for example the radial innermost point 68 of the first chamber 52 to a radial inner area of the subsequent fluid chamber 58, for example to the radial innermost point 70 of the subsequent fluid chamber 58. The second fluid path 62 between the first chamber 52 and the subsequent fluid chamber 58 is connected in a radial outer area, for example at the radial outermost point 72 of the first chamber 52, to the same and leads to a radial outer area, for example the radial outermost point 74 of the subsequent fluid chamber 58 via the siphon crest 64.
(43) A radial slope is located between the respective orifice of the two fluid paths 60 and 62 into the first fluid chamber 52 and the respective orifice into the subsequent fluid chamber 58.
(44) Embodiments of an inventive method include introducing at least one liquid into a first chamber of the liquid retaining area. This introducing can take place by a centrifugally induced transfer of liquid into the first chamber 52. Subsequently, centrifuge-pneumatically induced retaining of the liquid in the liquid retaining area, for example the first chamber 52, can take place. Subsequently, switching the liquid into the subsequent fluidic structures, for example the subsequent fluid chamber 58 can take place. During the switching process, at least part of the liquid is transferred through at least one fluid path (e.g., fluid path 62) from the liquid retaining area (e.g., first chamber 52) into the subsequent fluidic structures (e.g., fluid chamber 58). Fluid paths through which liquid is transferred during a switching process will be referred to below as liquid guidance paths. During the switching process, gas (normally air) can be transferred from the subsequent fluid structures back to the liquid retaining area through at least one further fluid path (e.g., fluid path 62) between the liquid retaining area (e.g., first chamber 52) and the subsequent fluid structures (e.g., fluid chamber 58). Fluid paths allowing this will be referred to below as gas guidance path.
(45) In the following, an embodiment of such a method will be described based on the operation of the fluidic module 50 shown in
(46) In a first state shown in
(47) As shown in
(48) The pneumatic overpressure Δp building up in the first chamber 52 and the subsequent fluidic structures 58 counteracts the centrifugally induced filling of the first chamber 52 as well as the filling of fluid guidance channel 62, such that the siphon crest 64 in the fluid guidance channel 62 is not wetted and the liquid within the first chamber 42 as well as in the chamber 54 upstream of the first chamber 52 is retained. Thus, these fluidic structures represent a liquid retaining area.
(49) Retaining the liquid in the liquid retaining area is obtained in that 1) the transfer of liquid into the first chamber 52 reduces the hydrostatic height between upstream chamber 52 and first chamber 52, whereby the centrifugal pressure acting in the direction of filling the first chamber 52 is reduced, and 2) the pneumatic overpressure in the subsequent fluidic structures rises simultaneously with progressing filling of the first chamber 52,
such that with suitable rotational frequency of the cartridge an equilibrium results between the pressures acting in the direction of filling the liquid guidance path 62 and the pressures counteracting the filling of the liquid guidance path. The respective suitable rotational frequency can be determined easily in dependence on the used geometries and amounts of liquid.
(50) In all embodiments described herein, when the geometries of the chambers and the fluid guidance channels are suitably selected, it can be obtained that centrifugal pressure and pneumatic overpressure dominate with respect to other pressure sources, such as the capillary pressure taking into account arbitrary liquid characteristics and cartridge material characteristics. This means that these other pressure sources are not able to effect a deviation from the filling state of the liquid guidance path triggering a switching process which results by merely considering the equilibrium of pneumatic overpressure and centrifugal pressure. According to the invention, this equilibrium is also realized if the involved pressures are continuously varied by slight specific variations of the processing conditions, wherein the qualitative state of retaining the liquid in the liquid retaining area (e.g., the first chamber) is maintained. In other words, while retaining the liquid in a quasi-stationary equilibrium, slight variations of the processing conditions can occur without triggering the switching process.
(51) Starting from the equilibrium state shown in
(52) By increasing the centrifugal pressure, further liquid is transferred from the chamber 54 upstream of the first chamber 52 into the first chamber, such that the filling level in the first chamber 52 and the liquid guidance path 62 increases and the siphon crest 54 of the fluid guidance channel 62 is filled, as shown in
(53) Alternatively, the switching process can be obtained by reducing the pneumatic overpressure in the subsequent fluidic structures, such that, with constant rotational frequency, liquid is transferred, pneumatically induced, from the upstream chamber 54 into the first chamber 52 and thereby the siphon crest 64 of the liquid guidance path 62 is filled. Reducing the pneumatic overpressure can be obtained, for example, by reducing the temperature in the subsequent fluidic structures, by increasing the volume of the subsequent fluidic structures or reducing the amount of gas in the subsequent fluidic structures. The latter can take place via a vent delay resistor, for example the vent delay resistor 66 shown in
(54) As a consequence of the described process condition variations that trigger a switching process or a combination of the same, the part of the siphon shaped channel 64 in the liquid guidance path 62 running radially to the outside is filled, which increases the hydrostatic height in this channel. The centrifugal pressure resulting from the hydrostatic height between first chamber 52 and subsequent fluidic structures results in a transfer of liquid from the first chamber 52 into the subsequent fluidic structures as shown in
(55) During the transfer of liquid, gas is transferred from the subsequent fluidic structures via the at least one gas guidance path 60 into the first chamber 52, which counteracts the buildup of additional pneumatic overpressure as a consequence of the transfer of liquid into the subsequent fluidic structures, see
(56) The switching pressure and the associated rotational frequency of the cartridge (switching frequency) can be selected within broad limits by a suitable selection of the positions and geometries of the chambers and the fluid guidance paths.
(57) In the following, further embodiments will be discussed in more detail. Due to the dependencies between structure and method, the specific features and specifics of the method resulting from the features are indicated together for the embodiments. Where parts of the description would be repeated in the description of the different embodiments, the same are partly omitted such that parts of the description can apply across embodiments. Although the described embodiments partly only show one fluid path between preceding fluidic structures and first chamber as well as only one liquid guidance path and one gas guidance path between first chamber and subsequent fluidic structures, this does not limit the number of possible connecting paths between the fluidic structures of the invention and merely serves to simplify the description of the embodiments.
(58)
(59) In the embodiment shown in
(60) In the embodiment shown in
(61) The embodiment of a pneumatic counterpressure siphon valve shown in
(62) During operation, liquid 80 is introduced into the first fluid chamber 52 via the upstream fluidic structures. Here, the fluidic structures are configured such that the first fluid chamber 52 is completely filled with the liquid 80. By the introduced liquid, a gas volume is enclosed in the downstream fluidic structures. In
(63) By the position of the liquid menisci 102, 104 in the fluid connecting path 60, 62, the described structure for dimensioning the amount of liquid in the first chamber 52 and the fluid connecting paths can be used, whereby high accuracy of the measured volume can be obtained.
(64) Starting from the state shown in
(65) In the following, an embodiment wherein a compression chamber volume is provided in the gas guidance path will be described with reference to
(66)
(67) The liquid receiving chamber 58 is connected to the gas guidance path 60 at an orifice point. The orifice point is not located at the radial outermost position of the liquid receiving chamber 58, for example in a radial inner area of the same or at the radial innermost position 70. The liquid receiving chamber 58 is further fluidically connected to the liquid guidance path 62, advantageously radially outside the connecting position 72 between the liquid guidance path 62 and the first fluid chamber 52. The liquid guidance path 62 can lead into the liquid receiving chamber 58 at a radial outer position, for example at the radial outermost position 74.
(68) In the embodiment shown in
(69) One embodiment of an inventive method using fluidic structures as shown in
(70) By a suitable selection of the partial compression volume 112 and the volumes of the downstream fluidic structures, the pneumatic overpressure Δp prevailing in the subsequent fluidic structures in the equilibrium can almost be freely selected.
(71) By increasing the rotational frequency, starting from the operating state shown in
(72) With reference to
(73) In embodiments, the connecting position 132 between the preceding fluidic structures (for example the inlet channel 110 and the upstream fluid chamber 54) and the first fluid chamber 52 can be located at a freely selectable positions of the first fluid chamber 52. The same applies to connecting positions 132, 134 of the connecting paths 60, 62 between first fluid chamber 52 and subsequent fluidic structures 58 to the first fluid chamber 52. In the case that a partial compression chamber 112 exists in the gas guidance path 60, the connection points 132 and 180 of the connections between first fluid chamber 52 and partial compression chamber 112 and the connection points 120, 132 between partial compression chamber 112 and the subsequent fluidic structures 58 can also be freely selected. The orifice point 136 of the gas guidance path 60 into the downstream fluid chamber 58, i.e., the liquid target volume, is not located at the radial outermost position of the liquid target volume. Further, the connecting position 138 of the liquid guidance path 62 into the downstream fluid chamber 58 can be freely selected. The connecting position 134 is in a radial outer area of the first fluid chamber 52 since the first fluid chamber 52 can only be emptied up to this connecting position above the liquid guidance path 62.
(74) Based on
(75) As shown in
(76) By respective filling of the liquid retaining area comprising the first chamber 52 and the partial compression chamber 112, an equilibrium state can be obtained where the meniscus 104 of the liquid is located in the area of the siphon-shaped area of the liquid guidance path 60 running radially towards the inside and the pressures acting in the direction of wetting the siphon crest 64 (centrifugal pressure and possibly other pressures, such as the overpressure Δp.sub.1) are in equilibrium with the pressures acting against the wetting (the pneumatic overpressure in the subsequent fluidic structures and possibly other pressures). This operating state is shown in
(77) Starting from the state shown in
(78) Since in the embodiment shown in
(79)
(80) Thus, the fluidic structures shown in
(81) In the method shown with reference to
(82) First, analogously to the above described method, liquid that is centrifugally induced is transferred into the first fluid chamber 52 and the fluid connecting paths 60, 62 and the gas prevailing in the same is displaced into the subsequent fluidic structures whereby a pneumatic overpressure is generated within the same which counteracts further filling and hence wetting of the siphon crest 64 in the liquid guidance channel 62. The downstream fluidic structures comprise the downstream fluid chamber 58, the fluid path 160, 162 and the downstream fluid chamber 158. After the first fluid chamber 52 has been completely filled with liquid, the quasi-static state shown in
(83) During the first transfer process, as described above with reference to
(84) Thus, with reference to
(85) Generally, according to the invention, transfer of liquid is effected by changing the ratio of the centrifugal pressure to the pneumatic pressure. The change of this ratio can take place in different ways. In embodiments, the ratio can be changed by increasing a rotational speed of the fluidic module. For that purpose, for example, a driving means by which the fluidic module is rotated can be controlled accordingly by means of a respective control means.
(86) Alternatively or additionally, it is possible to reduce the pneumatic pressure to change the ratio. For that purpose, a vent delay resistor can be provided which can be considered as actuator that is configured to reduce the pneumatic pressure. Alternatively or in combination, the pneumatic pressure can be reduced by controlling, in particularly reducing, the temperature of the enclosed gas volume. This can take place by controlling either the temperature of the entire fluidic module or at least parts of the fluidic module where the gas volume is enclosed. For that purpose, as described above with reference to
(87) With reference to
(88) As already described, temperature-controlled reduction of the pressure in the subsequent fluidic structures that serves to initiate the transfer of liquid from the first fluid chamber into the liquid target volume can be obtained by reducing the temperature of the gas in the subsequent fluidic structures.
(89) As shown in
(90) The fluidic structures shown in
(91) In a first step, liquid that is centrifugally induced is transferred from upstream fluidic structures (not shown) through the inlet channel 200 into the first fluid chamber 202. Here, liquid is also transferred into the areas of the siphon-shaped connecting paths 206, 208 between the first fluid chamber 202 and the subsequent fluidic structures 210 which run radially towards the inside. From the time of wetting the connection point of the last of the connecting paths 206, 208, the further liquid flowing into the connecting paths displaces the gas contained in the connecting paths into the downstream fluidic structures, which results in an overpressure in the subsequent fluidic structures at constant temperature as shown in
(92) Starting from the operating state shown in
(93) In the embodiment described above, the liquid retaining area comprises a first fluid chamber. In alternative embodiments, the liquid retaining area can comprise several fluid chambers which can be connected via one or several fluid channels or not.
(94) An embodiment where the liquid retaining area comprises several fluid chambers and wherein a switching by temperature-controlled pressure reduction can take place will be discussed below with reference to
(95) Again, respective fluidic structures are formed in a fluidic module 50. The fluidic structures comprise upstream fluidic structures, a liquid retaining area and downstream fluidic structures. The liquid retaining area comprises a first fluid chamber 300 and a second fluid chamber 302. The first fluid chamber 300 and the second fluid chamber 302 are fluidically connected via a radially declining connecting channel 304. The upstream fluidic structures comprise an upstream fluid chamber 306 which can comprise, in a radially outer area of the same with respect to a center of rotation R, chamber segments 306a and 306b allowing the measurement of liquid volumes. The chamber segment 306a is fluidically connected to the first fluid chamber 300 via a fluid channel 308 and the chamber segment 306b is fluidically connected to the second fluid chamber 302 via a fluid channel 310. A further inlet channel 312 can be fluidically connected to the first fluid chamber 300. A further inlet channel/vent channel 314 can be fluidically connected to the second fluid chamber 302. A vent opening 316 is shown schematically in
(96) Here, it should be noted that the upstream fluidic structures in the embodiments shown in
(97) As shown in
(98) The liquid guidance path 320 leads into the first fluid chamber 300 in a radial outer area, advantageously at a radial outer end. The gas guidance path 328 leads into the second fluid chamber 302 in a radial outer area, advantageously at a radially outer end. The first fluid chamber 300 can be configured such that when filling the same with first liquid volume, the downstream fluidic structures 322 remains vented to the second fluid chamber 302 via the gas guidance path 324. This operating state where a first liquid volume 380 is introduced in to the first fluid chamber 300 is shown in
(99) If further liquid volume is introduced into the first fluid chamber 300, for example via channels 308 and/or 312, the liquid volume in the first fluid chamber 300 rises until excess volume flows into the second fluid chamber 302 via the connecting channel 304 representing an overflow. For that purpose, the orifice of the connecting channel into the first fluid chamber 300 is located radially further inside than a radial outer end of the first fluid chamber 300. The excess liquid volume 382 flowing over into the second fluid chamber 302 hermetically closes the gas guidance path 324 leading into the second fluid chamber 302 at a radial outer end. Thus, both fluid paths 320 and 324 to the downstream fluidic structures are hermetically closed after the liquid guidance path 322 has already been hermetically closed when introducing the liquid volume 380 into the first fluid chamber 300. This operating state is shown in
(100) Starting from this operating state, as already described above with reference to
(101) At strong negative pressure, the syphon channels of both the liquid guidance path 320 as well as the gas guidance path 324 can be filled with liquid. Thereby, both the liquid in the first fluid chamber 300 and the liquid in the second fluid chamber 302 would be at least partly transferred. By the subsequent transfer of the liquid through the fluid guidance path into the chamber 322, the negative pressure in the chamber 322 can at least be partly compensated. By transferring sufficiently large amounts of liquids, beyond the compensation of the negative pressure, an overpressure can be generated, which results, in one of the syphon channels, in the shown embodiment in the gas guidance channel 324, to a reversal of the flow direction of the liquid, and subsequently to a phase change to gas, whereby gas from the subsequent fluidic structures 322 is vented into the chamber 302.
(102) A configuration as described with reference to
(103) The fluidic structures described with reference to
(104) Here,
(105) As shown in
(106) Fluidic structures as described with reference to
(107) It is obvious for persons skilled in the art that during the described usage of negative pressure, the fluid chamber of the fluid-retaining area can also be divided into three or more chambers. In embodiments, the different chambers of the liquid retaining area do not have to be connected via channels, except the connection via the downstream fluidic structures and the connecting channels connecting the fluid chamber to the downstream fluidic structures.
(108) Generally, in embodiments, the liquid guidance path leads into a liquid receiving chamber of the subsequent fluidic structures located at a position radially outside a position where the liquid guidance path leads into a fluid chamber of the liquid retaining area. In other words, the liquid guidance path generally comprises a radial incline. Thus, it is possible to transfer the liquid from the respective chamber of the liquid retaining area into the subsequent fluidic structures via the liquid guidance path comprising a syphon channel via a syphon crest, which is arranged radially inside the orifice of the liquid guidance path into the fluid chamber of the liquid retaining area.
(109) In embodiments, the downstream fluidic structures can comprise at least one liquid-receiving chamber into which the liquid is transferred. In embodiments, the liquid retaining area can comprise at least one fluid chamber from which liquid is transferred into the downstream fluidic structures.
(110) In embodiments, the fluidic structures are configured such that centrifugal pressures and pneumatic pressure have a superior role while capillary forces can be negligible. In embodiments, the respective fluid paths can be configured as fluid channels, wherein chambers, for example partial compression chambers, can be arranged in the fluid paths.
(111) Thus, embodiments provide fluidic modules, apparatuses and methods wherein two fluid connecting paths are provided between a chamber in which liquid is retained prior to switching and a target structure for the liquid after the switching process. This allows an almost liquid-characteristic independent monolithic realization of a structure for switching liquid while selectively exceeding or falling below a high rotational frequency of the cartridge. Embodiments provide a centrifugo-pneumatic vent syphon valve comprising fluidic structures on a centrifugal test carrier. The fluidic structures can comprise a first number of chambers, subsequent fluidic structures, as well as at least two fluid paths connecting the first number of chambers to the subsequent fluidic structures. At least one of the fluid paths between the first number of chambers and the subsequent fluidic structures includes a syphon channel, wherein the connection via the fluid paths from the first number of chambers to the subsequent fluidic structures is arranged such that when filling the first number of chambers with liquid, a state can be established in which a gas volume enclosed by the liquid results in the subsequent fluidic structures or a quasi-enclosed gas volume results, wherein the subsequent structures comprise venting with a vent delay resistor. In embodiments of such fluidic structures, a syphon channel is provided in at least one of the fluid-connecting paths between the first number of chambers and the subsequent fluidic structures, wherein the syphon crest is located within the radial outermost position of a first chamber into which the syphon channel leads. In embodiments of such fluidic structures, the subsequent fluidic structures are not vented. In embodiments, the number of chambers can include one chamber or more than one chamber.
(112) Embodiments provide a method for retaining and switching liquids by using a respective centrifugo-pneumatic vent syphon valve, wherein one or several liquids are retained in a liquid retaining area (a first number of chambers) in a quasi-static equilibrium dominated by centrifugal pressures and pneumatic pressures, such that subsequent initiation of a transfer of at least one liquid from the liquid retaining area into the subsequent fluidic structures is merely possible by changing the acting centrifugal and/or pneumatic pressures. In embodiments of such a method, during the transfer of liquid from the liquid retaining area into the subsequent fluidic structures, gas is transferred from the subsequent fluidic structures in a direction of the liquid retaining area via at least one fluid path. In embodiments of such a method, during the transfer of liquid from the liquid retaining area into the subsequent fluidic structure, at least one fluid connecting path between the liquid retaining area and the subsequent fluidic structures is not completely filled with liquid. In embodiments of such a method, the amount of gas in the subsequent fluidic structures is not changed by a fluid path connected to the environment, while liquid is retained in the liquid retaining areas. In embodiments of such a method, liquid in the liquid retaining area is retained in the subsequent fluidic structures due to a pneumatic negative pressure in the subsequent fluidic structures prior to initiating the transfer. In embodiments of such a method, liquid is retained in the liquid retaining area due to a pneumatic overpressure in the subsequent fluidic structures prior to initiating the transfer.
(113) Embodiments can comprise any variations and combinations of the shown schematic embodiments and are not limited by the same.
(114) Although features of the embodiment of the invention have been described above based on a method or based on an apparatus, it is obvious that the described apparatus features also represent features of a respective method and the described method features also represent features of a respective apparatus that can be configured to provide respective functionalities.
(115) Thus, embodiments of the invention provide methods and apparatuses for switching liquid by using a centrifugo-pneumatic vent syphon valve comprising fluidic structures as described herein. Contrary to conventional technology, embodiments of the described structure can fulfill, in connection with the described method in the field of centrifugal microfluidics, several requirements for the unity operations of retaining and later specific switching of liquid at the same time. Embodiments allow monolithic realization of the allocated fluidic structures in a centrifugal microfluidic cartridge. Embodiments offer the option of configuring the structure such that the functional principle is almost independent with respect to liquid and cartridge material characteristics. This includes, in particular, the angle of contact between liquid and cartridge material, as well as the viscosity and surface tension of the liquid. Embodiments offer the option of further adaptations of the fluidic structures in order to determine the processing conditions for triggering a switching process within broad limits. The adaptation options can, in particular, relate to the option of free selection of the gas volume transferred into the subsequent fluidic structures and the pneumatic overpressure generated thereby.
(116) Embodiments offer the option of initiating the switching process by using different variations of the processing conditions. This includes, in particular, rotational frequencies, temperatures and waiting times (when using a vent delay resistor) during processing. Embodiments offer the option, by falling back on temperature variations depending on the process control, of switching a liquid when the rotational frequency rises above a threshold frequency or when the same falls below a threshold frequency. Embodiments offer the option of producing the microfluidic structures without sharp edges, i.e. with low demands on the production methods, such as injection molding and injection embossing. Embodiments of the invention allow the avoidance of strongly rising pneumatic pressures in the fluidic target volume during the transfer of liquid after the switching process. Embodiments offer the option of cascading the fluidic structures. Finally, embodiments offer the option of multi-usage of the fluidic structures in order to retain several liquids after one another and to switch the same specifically.
(117) Embodiments of the invention are configured to change the ratio of centrifugal pressure to pneumatic pressure in order to exceed a threshold, wherein a syphon crest of the syphon channel in the first fluid path is overcome, such that transferring the liquid from the liquid retaining area into the subsequent fluidic structures takes place.
(118) Embodiments of the invention describe variations of the fluidic structures and allocated methods showing different options for influencing the equilibrium of the pressures acting in the direction of or against the initiation of the inventive switching process. Embodiments of the invention are further based on the knowledge that the described switching principle can be easily combined with other operations on the same centrifugal microfluidic platform, for example by guiding liquid into an inventive structure after preceding fluidic operations or by cascading the described switching structure.
(119) While this invention has been described in terms of several advantageous embodiments, there are alterations, permutations, and equivalents which fall within the scope of this invention. It should also be noted that there are many alternative ways of implementing the methods and compositions of the present invention. It is therefore intended that the following appended claims be interpreted as including all such alterations, permutations, and equivalents as fall within the true spirit and scope of the present invention.