Patent Application
20160214104
The present invention relates to a fluidic module, a device for aliquoting a liquid and a method of aliquoting a liquid. Embodiments relate to parallel-pneumatic metering and aliquoting.
In centrifugal microfluidics, rotors are used for processing liquids. Corresponding rotors contain chambers for collecting liquid and channels for directing fluid. While the rotor is being subjected to centripetal acceleration, the liquid is pressed radially outward and can thus arrive at a radially outward position by directing fluid correspondingly. Centrifugal microfluidics is employed, for example, in the field of life sciences, in particular in laboratory analytics. Centrifugal microfluidics serves to automate process flows while replacing operations such as pipetting, mixing, metering, aliquoting and centrifuging.
Aliquoting of liquids may be performed in particular at the beginning, during or at the end of a process chain so as to perform several mutually independent detection reactions (verification reactions) with one sample. For parallelizing laboratory processes within a centrifugal-microfluidic rotor in a fully automated manner, aliquoting processes are therefore indispensable. In this context, certain analysis methods involve not only aliquoting of an individual liquid volume into several aliquots, but also aliquoting of several different liquid volumes, the aliquots of which in turn need to be further processed—e.g., mixed with one another. Quantitatively meaningful analysis processes can be performed only if the aliquots comprise volumes defined as accurately as possible. For this reason, each aliquoting step should also be combined with a metering step. This also applies in case different aliquoting steps take place in parallel within a centrifugal-microfluidic rotor.
Godino et al. [Lab Chip, 2013, 13, 685-69, FIG. 1] describes a metering structure containing a single compression chamber comprising an inlet channel and an outlet channel. The compression chamber consists of two sections extending radially outward (on the left and on the right) and a section extending radially inward. In this context, a defined partial volume can be collected by the left-hand section. Any excess liquid volume exceeding the volume of the left-hand section does not remain within the left-hand section and therefore cannot be separated off either.
However, one possibility of aliquoting defined amounts of liquid is not shown. Moreover, the metering structure taken from Godino et al. is workable only for liquid volumes that have strict upper limits since the overflow structure is contained within the compression chamber. Metering will therefore only work when the overflow chamber is not full. Moreover, said structure allows no aliquoting, as was already mentioned. In addition, the metering structure contains very broad inflow channels, as a result of which the metered volume will highly depend on the input volume.
What is also known is utilizing a compression chamber in combination with fluid channels exhibiting different hydraulic resistances. For example, Zehnle et al. (Lab Chip, 2012, 12, 5142-5145, FIG. 2) shows pumping of liquid within a centrifuge rotor from a radially outward point to a radially inward point without using any external auxiliary devices. However, the fluid structure described there enables neither metering nor aliquoting.
U.S. Pat. No. 5,409,665 describes how end cavities within a centrifugal-microfluidic rotor can be filled, via a supply channel extending radially outward, with ends extending radially inward. In this context, the end cavities are vented, so that air can escape from the end cavities during the filling process. Subsequently, the supernatant liquid above the end cavities is discharged via the supply channel and a siphon.
DE 10 2008 003 979 B3 describes how metering channels within a centrifugal-microfluidic rotor can be filled via a supply channel extending radially inward. The ends of the metering channels have end cavities located thereat. Since the end cavities are not vented, the air which flows from the metering channels into the end cavities while the metering channels are being filled cannot escape and is compressed. While the corresponding pneumatic pressure counteracts the centrifugal pressure of the liquid within the metering channels, the supernatant present will be discharged in the supply channel. By subsequently increasing the rotary frequency of the rotor, the liquid/gas interface between the liquid contained within the metering channels and the air contained within the end cavities becomes unstable, so that the compressed gas will escape from the end cavity through the liquid phase within the metering channel, and so that said liquid phase can be transferred to the end cavity.
In U.S. Pat. No. 5,409,665 and DE 102008003979 B3, aliquots are generated within end cavities. Further fluidic processing of the aliquots is not possible, however.
According to an embodiment, a fluidic module may have: a first measuring chamber and a second measuring chamber; a first fluid inlet channel connected to the first measuring chamber and a second fluid inlet channel connected to the second measuring chamber; and a first fluid outlet channel connected to the first measuring chamber and a second fluid outlet channel connected to the second measuring chamber; the fluidic module being configured such that upon rotation of the fluidic module, a liquid is centrifugally driven into the first measuring chamber via the first fluid inlet channel and into the second measuring chamber via the second fluid inlet channel so that a compressible medium previously present within the first measuring chamber and within the second measuring chamber is compressed by the liquid driven into the first measuring chamber and into the second measuring chamber; the fluidic module being configured such that upon a reduction of the rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, the liquid present within the first measuring chamber is driven out of the first measuring chamber via the first fluid outlet channel, and the liquid present within the second measuring chamber is driven out of the second measuring chamber via the second fluid outlet channel; the fluidic module having a fluid manifold, the first fluid inlet channel and the second fluid inlet channel being connected to the fluid manifold.
According to another embodiment, a device for aliquoting a liquid may have: a fluidic module, which may have: a first measuring chamber and a second measuring chamber; a first fluid inlet channel connected to the first measuring chamber and a second fluid inlet channel connected to the second measuring chamber; and a first fluid outlet channel connected to the first measuring chamber and a second fluid outlet channel connected to the second measuring chamber; the fluidic module being configured such that upon rotation of the fluidic module, a liquid is centrifugally driven into the first measuring chamber via the first fluid inlet channel and into the second measuring chamber via the second fluid inlet channel so that a compressible medium previously present within the first measuring chamber and within the second measuring chamber is compressed by the liquid driven into the first measuring chamber and into the second measuring chamber; the fluidic module being configured such that upon a reduction of the rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, the liquid present within the first measuring chamber is driven out of the first measuring chamber via the first fluid outlet channel, and the liquid present within the second measuring chamber is driven out of the second measuring chamber via the second fluid outlet channel; the fluidic module having a fluid manifold, the first fluid inlet channel and the second fluid inlet channel being connected to the fluid manifold; and a drive; the drive being configured to subject, in a first phase, the fluidic module to such a rotational frequency that liquid is centrifugally driven into the first measuring chamber via the first fluid inlet channel and into the second measuring chamber via the second fluid inlet channel, so that a compressible medium previously present within the first measuring chamber and within the second measuring chamber is compressed by the liquid driven into the first measuring chamber and into the second measuring chamber; and the drive being configured to reduce, in a second phase, the rotational frequency to which the fluidic module is subjected to such an extent that due to the reduction of the rotational frequency and to the expansion, resulting therefrom, of the compressible medium, the liquid present within the first measuring chamber is driven out of the first measuring chamber via the first fluid outlet channel, and the liquid present within the second measuring chamber is driven out of the second measuring chamber via the second fluid outlet channel.
According to another embodiment, a method of aliquoting a liquid by means of a fluidic module, which fluidic module may have: a first measuring chamber and a second measuring chamber; a first fluid inlet channel connected to the first measuring chamber and a second fluid inlet channel connected to the second measuring chamber; and a first fluid outlet channel connected to the first measuring chamber and a second fluid outlet channel connected to the second measuring chamber; the fluidic module being configured such that upon rotation of the fluidic module, a liquid is centrifugally driven into the first measuring chamber via the first fluid inlet channel and into the second measuring chamber via the second fluid inlet channel so that a compressible medium previously present within the first measuring chamber and within the second measuring chamber is compressed by the liquid driven into the first measuring chamber and into the second measuring chamber; the fluidic module being configured such that upon a reduction of the rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, the liquid present within the first measuring chamber is driven out of the first measuring chamber via the first fluid outlet channel, and the liquid present within the second measuring chamber is driven out of the second measuring chamber via the second fluid outlet channel; the fluidic module having a fluid manifold, the first fluid inlet channel and the second fluid inlet channel being connected to the fluid manifold, may have the steps of: subjecting the fluidic module to a rotational frequency, so that a liquid is centrifugally driven into the first measuring chamber via the first fluid inlet channel and into the second measuring chamber via the second fluid inlet channel so that a compressible medium previously present within the first measuring chamber and within the second measuring chamber is compressed by the liquid driven into the first measuring chamber and into the second measuring chamber; and reducing the rotational frequency to which the fluidic module is subjected, so that due to the reduction of the rotational frequency and to the expansion, resulting therefrom, of the compressible medium, the liquid present within the first measuring chamber is driven out of the first measuring chamber via the first fluid outlet channel, and the liquid present within the second measuring chamber is driven out of the second measuring chamber via the second fluid outlet channel.
Embodiments of the present invention provide a fluidic module comprising a first measuring chamber, a second measuring chamber, a first fluid inlet channel connected to the first measuring chamber and a second fluid inlet channel connected to the second measuring chamber, a first fluid outlet channel connected to the first measuring chamber and a second fluid outlet channel connected to the second measuring chamber. The fluidic module is configured such that upon rotation of the fluidic module about a center of rotation, a liquid is centrifugally driven into the first measuring chamber via the first fluid inlet channel and into the second measuring chamber via the second fluid inlet channel so that a compressible medium previously present within the first measuring chamber and within the second measuring chamber is compressed by the liquid driven into the first measuring chamber and into the second measuring chamber. The fluidic module is further configured such that upon a reduction of the rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the first measuring chamber is driven out of the first measuring chamber via the first fluid outlet channel, and a large part of the liquid present within the second measuring chamber is driven out of the second measuring chamber via the second fluid outlet channel.
Further embodiments provide a device for aliquoting a liquid. The device comprises the above-described fluidic module and a drive. The drive is configured configured to subject, in a first phase, the fluidic module to such a rotational frequency that liquid is centrifugally driven into the first measuring chamber via the first fluid inlet channel and into the second measuring chamber via the second fluid inlet channel, so that a compressible medium previously present within the first measuring chamber and within the second measuring chamber is compressed by the liquid driven into the first measuring chamber and into the second measuring chamber. The drive is further configured to reduce, in a second phase, the rotational frequency to which the fluidic module is subjected to such an extent that due to the reduction of the rotational frequency and to the expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the first measuring chamber is driven out of the first measuring chamber via the first fluid outlet channel, and a large part of the liquid present within the second measuring chamber is driven out of the second measuring chamber via the second fluid outlet channel.
Further embodiments provide a method of aliquoting a liquid by means of the above-described fluidic module. The method includes subjecting the fluidic module to such a rotational frequency that a liquid is centrifugally driven into the first measuring chamber via the first fluid inlet channel and into the second measuring chamber via the second fluid inlet channel so that a compressible medium previously present within the first measuring chamber and within the second measuring chamber is compressed by the liquid driven into the first measuring chamber and into the second measuring chamber. The method further includes reducing the rotational frequency to which the fluidic module is subjected, so that due to the reduction of the rotational frequency and to the expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the first measuring chamber is driven out of the first measuring chamber via the first fluid outlet channel, and a large part of the liquid present within the second measuring chamber is driven out of the second measuring chamber via the second fluid outlet channel.
Further embodiments of the present invention provide a fluidic module. The fluidic module comprises a measuring chamber, a compression chamber connected to the measuring chamber via a fluid overflow, a fluid inlet channel connected to the measuring chamber, and a fluid outlet channel connected to the measuring chamber. The fluidic module is configured such that upon a rotation of the fluidic module about a center of rotation, a liquid is centrifugally driven into the measuring chamber via the fluid inlet channel until liquid gets into the compression chamber from the measuring chamber via the fluid overflow and until a compression, caused by the liquid driven into the measuring chamber, of a compressible medium previously present within the measuring chamber, within the compression chamber and within the fluid overflow is sufficiently large so that upon a reduction of a rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the measuring chamber is driven out of the measuring chamber via the fluid outlet channel. Moreover, the fluidic module is configured such that upon a reduction of the rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the measuring chamber is driven out of the measuring chamber via the fluid outlet channel.
In embodiments, the fluidic module may be configured such that upon a rotation of the fluidic module about a center of rotation, the liquid is driven into the measuring chamber via the fluid inlet channel by a centrifugal pressure caused by the rotation and acting upon the liquid, until liquid from the measuring chamber gets into the compression chamber via the fluid overflow and until a counter pressure resulting from a compression, caused by the liquid driven into the measuring chamber, of a compressible medium previously present within the measuring chamber, within the compression chamber and within the fluid overflow becomes sufficiently large so that upon a reduction of a rotational frequency and upon a reduction, resulting therefrom, of the centrifugal pressure, the compressible medium expands and drives a large part of the liquid present within the measuring chamber out of the measuring chamber via the fluid outlet channel. Moreover, the fluidic module may be configured such that upon the reduction of the rotational frequency and the reduction, caused thereby, of the centrifugal pressure, the compressible medium expands and drives a large part of the liquid present within the measuring chamber out of the measuring chamber via the fluid outlet channel.
Further embodiments provide a device for aliquoting a liquid. The device comprises the above-described fluidic module and a drive. The drive is configured to subject, in a first phase, the fluidic module to such a rotational frequency that the liquid is centrifugally driven into the measuring chamber via the fluid inlet channel until liquid from the measuring chamber gets into the compression chamber via the fluid overflow and until a compression, caused by the liquid driven into the measuring chamber, of a compressible medium previously present within the measuring chamber, within the compression chamber and within the fluid overflow becomes sufficiently large so that upon a reduction of the rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the measuring chamber is driven out of the measuring chamber via the fluid outlet channel. Moreover, the drive is configured to reduce, in a second phase, the rotational frequency to which the fluidic module is subjected in such a manner that a large part of the liquid present within the measuring chamber is driven out of the measuring chamber via the outlet channel by the expansion of the compressible medium, which expansion results from the reduction of the rotational frequency.
Further embodiments provide a method of aliquoting a liquid by means of the above-described fluidic module. The method includes subjecting the fluidic module to such a rotational frequency that the liquid is centrifugally driven into the measuring chamber via the fluid inlet channel until liquid from the measuring chamber gets into the compression chamber via the fluid overflow and until a compression, caused by the liquid driven into the measuring chamber, of a compressible medium previously present within the measuring chamber, within the compression chamber and within the fluid overflow becomes sufficiently large so that upon a reduction of the rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the measuring chamber is driven out of the measuring chamber via the fluid outlet channel. Moreover, the method includes reducing the rotational frequency to which the fluidic module is subjected, so that a large part of the liquid present within the measuring chamber is driven out of the measuring chamber via the outlet channel by the expansion of the compressible medium, which expansion results from the reduction of the rotational frequency.
Embodiments of the present invention will be detailed subsequently referring to the appended drawings, in which:
In the subsequent description of the embodiments of the invention, elements which are identical or have identical actions will be provided with identical reference numerals in the figures, so that their descriptions in the various embodiments are mutually exchangeable.
Before embodiments of the invention will be explained in more detail, it shall initially be pointed out that embodiments of the present invention are employed, in particular, in the field of centrifugal microfluidics, which is about processing of liquids within the nanoliter to milliliter ranges. Accordingly, the fluidic structures may comprise suitable dimensions within the micrometer range for handling corresponding volumes of liquid. The fluidic structures (geometric structures) as well as the pertinent methods are suitable for metering and/or aliquoting liquid within centrifuge rotors.
When the expression radial is used herein, what is meant in each case is radial in relation to the center of rotation about which the fluidic module and/or the rotor is rotatable. Within the centrifugal field, therefore, a radial direction away from the center of rotation is radially falling, and a radial direction toward the center of rotation is radially rising. A fluid channel whose beginning is closer to the center of rotation than is its end, is thus radially falling, whereas a fluid channel whose beginning is further away from the center of rotation than is its end, is radially rising.
Before an embodiment of a fluidic module having corresponding fluidic structures will be addressed in more detail with reference to
The body of rotation 10 comprises the fluidic structures that may be used. The fluidic structures that may be used may be formed by cavities and channels within the cover 14, the substrate 12 or within the substrate 12 and the cover 14. In embodiments, for example, fluidic structures may be formed within the substrate 12, whereas filler openings and venting openings are formed in the cover 14.
In an alternative embodiment shown in
In embodiments of the invention, the fluidic module and/or the body of rotation which comprises the fluidic structures may be formed of any suitable material, for example a plastic such as PMMA (polymethyl methacrylate, polycarbonate, PVC, polyvinylchloride) or PDMS (polydimethylsiloxane), glass or the like. The body of rotation 10 may be considered as being a centrifugal-microfluidic platform.
The fluidic structures of the fluidic module 50 may comprise a measuring chamber 60, a compression chamber 66 connected to the measuring chamber 60 via a fluid overflow 68, a fluid inlet channel 70 connected to the measuring chamber 60, and a fluid outlet channel 72 connected to the measuring chamber 60.
The fluidic module 50 may be configured such that upon a rotation of the fluidic module 50 about the center of rotation 52, a liquid is centrifugally driven into the measuring chamber 60 via the fluid inlet channel 70 until liquid from the measuring chamber 60 gets into the compression chamber 66 via the fluid overflow 68 and until a compression, caused by the liquid driven into the measuring chamber 60, of a compressible medium previously present within the measuring chamber 60, within the compression chamber 66 and within the fluid overflow 68 is sufficiently large so that upon a reduction of a rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the measuring chamber 60 is driven out of the measuring chamber 60 via the fluid outlet channel 72. In this context, the fluidic module 50 may be configured such that upon a reduction of the rotational frequency and upon the expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the measuring chamber 60 is driven out of the measuring chamber 60 via the fluid outlet channel 72.
In embodiments, the measuring chamber 60, the compression chamber 66 and the fluid overflow 68 may be configured such that upon the rotation of the fluidic module 50 about the center of rotation 52, the liquid is centrifugally driven into the measuring chamber 60 via the fluid inlet channel 70 until liquid from the measuring chamber 60 gets into a portion (e.g., collection area) 67 of the compression chamber 66 via the fluid overflow 68, in which portion the liquid which has got into the portion of the compression chamber 66 is fluidically separate from the liquid present within the measuring chamber 60.
To this end, the fluid overflow 68 may be arranged radially further inward than a radially outward end of the measuring chamber 60. For example, the fluid overflow 68 may be arranged, as can be seen in
Moreover, a radially outward end of the compression chamber 66 may be arranged radially further outward than a radially outward end of the measuring chamber 60.
The fluidic module 50 may be configured such that upon the rotation of the fluidic module 50 about the center of rotation 52, the liquid centrifugally driven into the measuring chamber 60 encompasses the compressible medium present within the measuring chamber 60, the compression chamber 66 and the fluid overflow 68.
Prior to filling, i.e., before the liquid is centrifugally driven into the measuring chamber 60, the measuring chamber may also contain (dry or liquid) reagents in addition to the compressible medium. In other words, the measuring chamber 60 may also have (dry or liquid) reagents stored therein.
In embodiments, the measuring chamber 60 may comprise a fluid inlet 62 and a fluid outlet 64, the fluid inlet channel 70 being connected to the measuring chamber 60 via the fluid inlet 62 and the fluid outlet channel 72 being connected to the measuring chamber 60 via the fluid outlet 64. Of course, the measuring chamber 60 may also comprise a combined fluid inlet/fluid outlet 62,64, the fluid inlet channel 70 and the fluid outlet channel 72 being connected to the measuring chamber 60 via the combined fluid inlet/fluid outlet 62,64.
In this context, the fluid outlet 64 of the measuring chamber 60 may be arranged such that the fluid outlet 64 of the measuring chamber 60 is sealed off by the liquid centrifugally driven into the measuring chamber 60. For example, the fluid outlet 64 of the measuring chamber 60 may be arranged at a radially outward end of the measuring chamber 60 (bottom), as is shown in
In the embodiment shown in
The fluidic module 50 may further be configured such that upon the rotation of the fluidic module 50 about the center of rotation 52, the amount of liquid centrifugally driven into the measuring chamber 60 is larger than that which can be accommodated by the measuring chamber 60, so that fluid from the measuring chamber 60 gets into the compression chamber 66 via the fluid overflow 68.
For example, the fluid inlet channel 70 may be connected to an inlet area of the fluidic module 50. The inlet area of the fluidic module 50 may be configured such that the former can accommodate a larger volume of the liquid (liquid volume) than the measuring chamber 60.
Of course, the inlet area of the fluidic module 50 may also be configured such that a larger volume of liquid may be introduced into the inlet area of the fluidic module 50 than the measuring chamber 60 can accommodate. For example, the inlet area of the fluidic module 50 may be connected to a liquid chamber, so that prior to and/or upon the rotation of the fluidic module 50 about the center of rotation 52, liquid from the liquid chamber gets into the inlet area of the fluidic module 50. Moreover, the inlet area of the fluidic module 50 may be configured as a liquid reception or be connected to a liquid reception, so that prior to and/or upon the rotation of the fluidic module 50 about the center of rotation 52, liquid may be introduced into the liquid reception.
The measuring chamber 60 may be configured to meter a defined volume of the liquid (liquid volume). The measuring chamber 60 thus may be configured such that it may accommodate a defined and reproducible liquid volume which may subsequently be driven, e.g. via the fluid outlet channel 72, into a chamber connected to the fluid outlet channel 72.
The measuring chamber 60, the compression chamber 66 and the fluid overflow 68 may be configured such that liquid from the measuring chamber 60 does not get into the portion 67 of the compression chamber 66 via the fluid overflow 68 before the measuring chamber 60 has received the volume of the liquid that is to be metered (e.g., before the measuring chamber 60 has been (completely) filled). Any liquid that continues to be centrifugally driven into the measuring chamber 60 thus flows—once the measuring chamber 60 has received the volume of the liquid that is to be metered—from the measuring chamber 60 into the portion 67 of the compression chamber 66 via the fluid overflow 68, so that the filling level within the measuring chamber 60 will not change.
The volume of the liquid (liquid volume) metered by the measuring chamber 60 may be defined by a point of overflow located between the measuring chamber 60 and the compression chamber 66. The point of overflow may be defined, for example, by a mouth of the fluid overflow 68 that opens into the measuring chamber 60, or by a geometric shape of the fluid overflow 68. For example, the fluid overflow 68 may be configured such that same comprises at least one area (point of overflow) located between the measuring chamber 60 and the compression chamber which is arranged radially further inward (i.e., has a smaller distance from the center of rotation) than are the mouths of the fluid overflow 68 that open into the measuring chamber 60 and the compression chamber 66.
By means of the measuring chamber 60, a defined and reproducible liquid volume may thus be metered. Therefore, liquid may be aliquoted by means of the measuring chamber, or, in other words, at least an aliquot part (sub-portion) of the liquid may be metered and subsequently be driven, via the fluid outlet channel 72, into a chamber connected to the fluid outlet channel 72 by means of the expansion of the compressible medium.
However, it shall be pointed out that a quotient of the liquid volume metered by the measuring chamber 60 and of the volume of the liquid (to be metered and/or aliquoted) contained within the inlet area of the fluidic module 50 or introduced into the inlet area of the fluidic module 50 may be integer or non-integer.
So that upon the reduction of the rotational frequency and upon the expansion, resulting therefrom, of the compressible medium, the liquid present within the measuring chamber 60 is (at least largely or predominantly) driven out of the measuring chamber 60 via the fluid outlet channel 72, the fluidic module 50 may be configured such that a fluidic resistance of the fluid inlet channel 70 is larger than a fluidic resistance of the fluid outlet channel 72. Of course, the fluidic module 50 may also be configured such that a fluidic resistance of the fluid inlet 62 of the measuring chamber 60 is larger than a fluidic resistance of the fluid outlet 64 of the measuring chamber 60.
Moreover, the fluidic module 50 may be configured such that upon the reduction of the rotational frequency and upon the expansion, resulting therefrom, of the compressible medium, the liquid present within the measuring chamber 60 is (almost) completely driven out of the measuring chamber 60.
In this context it shall be noted that even following complete expansion of the compressible medium, a (negligible) portion of the liquid may remain, or linger, within the measuring chamber 60, so that the liquid is not completely, but almost completely driven out of the measuring chamber 60, e.g., in an amount of at least 90% (or 80%, 85%, 95%, 99%).
Moreover, it shall be noted that a (negligible) portion of the liquid may also be driven out of the measuring chamber 60 via the fluid inlet channel 70. In this context, the fluidic module 50 may be configured such that the liquid is largely, e.g., in an amount of at least 90% (or 80%, 85%, 95%, 99%), driven out of the measuring chamber 60 via the fluid outlet channel 72.
For example, the fluidic module 50 may be configured such that upon the reduction of the rotational frequency, the liquid that has got into the compression chamber 66 remains within the compression chamber 66, so that upon the reduction of the rotational frequency and upon the expansion, resulting therefrom, of the compressible medium, the liquid present within the measuring chamber 60 is (almost) completely driven out of the measuring chamber 60. The liquid remaining within the compression chamber 66 thus takes up a part of the volume of the compression chamber 66. Upon the reduction of the rotational frequency and upon the expansion, resulting therefrom, of the compressible medium, the compressible medium thus will have less volume within the compression chamber 66 available to it than it did before, whereby an excess volume fraction, resulting from the liquid remaining within the compression chamber 66, of the compressible medium exits the measuring chamber 60 via the fluid outlet channel 72 while being able to not only drive the liquid out of the measuring chamber 60 (almost) completely, but being able to (almost) completely drive the liquid, via the fluid outlet channel 72 (if a length of the fluid outlet channel 72 is dimensioned accordingly), into a chamber connected to the fluid outlet channel 72.
As can be seen in
As was already described with reference to
As can additionally be seen in
Generally, the fluidic module 50 may comprise at least one further measuring chamber 602 to 60n having a fluid inlet and a fluid outlet, at least a further compression chamber 662 to 66n connected to the at least one further measuring chamber 602 to 60n via at least one further fluid overflow 682 to 68n, at least one further fluid inlet channel 702 to 70n connected to the fluid inlet of the at least one further measuring chamber 602 to 60n, and at least one further fluid outlet channel 722 to 72n connected to the fluid outlet of the at least one further measuring chamber 602 to 60n.
The fluidic module 50 shown in
In accordance with the mode of operation already described with reference to
In embodiments, the fluidic module 50 may comprise a fluid manifold 80, the fluid inlet channel 701 and the at least one further fluid inlet channel 702 to 70n (n=2) being connected to the fluid manifold 80. The fluid inlet channel 701 and the at least one further fluid inlet channel 702 to 70n may comprise fluidic resistances higher than those of the fluid manifold 801 to 802.
For example, the fluid inlet channel 701 and the at least one further fluid inlet channel 702 to 70n each may comprise a fluidic resistance that is higher by at least a factor of 5 (or 10, 15, 20 or more) than that of the fluid manifold 80.
Moreover, the fluidic module 50 may comprise a fluid inlet connected to the fluid manifold 80 via a fluid channel 82. The fluid channel 82 may comprise a fluidic resistance higher than that of the fluid manifold 80.
For example, the fluid channel 82 may have a fluidic resistance that is higher by at least a factor of 5 (or 10, 15, 20 or more) than that of the fluid manifold 80.
In other words, the filling channels (fluid inlet channels 701 to 70n and manifold 80) may be subdivided into areas having low and high fluidic resistances. In this manner, uniform filling of the measuring chambers (measuring cavities) 601 to 60n (n=2) as well as fluidic decoupling of the measuring chambers (measuring cavities) 601 to 60n (n=2) upon emptying by the fluid outlet channels 721 to 72n (n=2) can be ensured. By the areas having low fluidic resistances it may be ensured that the measuring chamber 60n contains a volume similar to that of the measuring chamber 601.
As can be seen in
As can be seen in
In contrast to this, the measuring chamber 602 comprises a combined fluid inlet/fluid outlet 622,642, the fluid inlet channel 70 and the fluid outlet channel 72 being connected to the measuring chamber 602 via the combined fluid inlet/fluid outlet 622,642.
In this context, the fluid inlet channel 70 and the fluid outlet channel 72 may be directly connected to the combined fluid inlet/fluid outlet 62,64, i.e., in each case directly open into the measuring chamber 60 via the combined fluid inlet/fluid outlet 62,64. Of course, the fluid inlet channel 70 and the fluid outlet channel 72 may also be joined upstream from the combined fluid inlet/fluid outlet 62,64.
For example, the fluid inlet channel 70 and the fluid outlet channel 72 may be joined by means of a fluid channel piece (e.g., T-piece or Y-piece), the fluid channel piece being directly connected to the combined fluid inlet/fluid outlet 62,64.
Moreover, the fluid inlet channel 70 may be directly connected to the combined fluid inlet/fluid outlet 62,64, while the fluid outlet channel 72 is connected to the combined fluid inlet/fluid outlet 62,64 via the fluid inlet channel 70, i.e., the fluid outlet channel 72 initially opens into the fluid inlet channel 70.
Furthermore, the fluid outlet channel 72 may be directly connected to the combined fluid inlet/fluid outlet 62,64, while the fluid inlet channel 70 is connected to the combined fluid inlet/fluid outlet 62,64 via the fluid outlet channel, i.e., the fluid inlet channel 70 initially opens into the fluid outlet channel 72.
The fluidic module 50 may be configured such that upon a rotation of the fluidic module 50 about the center of rotation 52, a liquid is centrifugally driven into the measuring chamber 601 via the fluid inlet channel 701 and into the at least one further measuring chamber 60n (n=2) via the at least one further fluid inlet channel 70n (n=2), so that a compressible medium previously present within the measuring chamber 601 and within the at least one further measuring chamber 60n (n=2) is compressed by the liquid driven into the measuring chamber 601 and into the at least one further measuring chamber 60n (n=2). The fluidic module 50 may further be configured such that upon a reduction of the rotational frequency and upon an expansion, resulting therefrom, of the compressible medium, a large part of the liquid present within the measuring chamber 601 is driven out of the measuring chamber 601 via the fluid outlet channel 721 and a large part of the liquid present within the at least one further measuring chamber 60n (n=2) is driven out of the at least one further measuring chamber 60n (n=2) via the at least one further fluid outlet channel 72n (n=2).
The mode of operation of the fluidic module 50 shown in
The fluidic module 50 shown in
To this end, liquid is transferred from an inlet area of the fluidic module 50 into different measuring chambers (measuring cavities or metering cavities) 601 to 60n (n=2) under centrifugation. Each measuring chamber 601 to 60n (n=2) is configured such that when being filled with liquid under centrifugation, a volume of a compressible medium (e.g., air volume) will be trapped and compressed. The liquid therefore can flow in for such time until a pneumatic counter-pressure equivalent to the centrifugal pressure has been built up. The measuring chamber 601 to 60n (n=2) may be configured such that normally, the amount of liquid flowing in is larger than that to be metered. Any excess liquid flows from the measuring chamber 601 to 60n (n=2) via a point of overflow and remains within the compression chamber 661 to 66n (n=2), which forms a separate collection area.
Different output volumes generate different counter-pressures due to different levels of compression of the compressible medium (e.g., air). This results in that the filling levels within the fluid inlet channels (filling channels) 701 to 70n (n=2) and the fluid outlet channels (channels to subsequent cavities) 721 to 72n (n=2) depend on the input volume. In order to achieve as high a level of measurement accuracy as possible it is therefore useful to generate as small interfaces 76 as possible in fluid inlet channels 701 to 70n (n=2) and fluid outlet channels 721 to 72n (n=2) that are narrowed accordingly (see
If the rotational frequency (or centrifugation speed) is reduced, the centrifugal pressure will decrease. Due to the lower pressure, the compressed volume of the compressible medium (e.g., air volume) expands, and the metered liquid is forwarded from the measuring chambers 601 to 60n (n=2) into subsequent chambers via channels 701 to 70n (n=2). The aliquots thus forwarded will then be defined in terms of their volumes and can be used for further processes.
Since liquid will remain within the compression chamber (collection area) 661 to 66n (n=2), the volume of liquid that is pumped on during this metering process is smaller than that of compressible medium (e.g., air) which has been compressed. Moreover, the geometric configuration of the measuring chamber 601 to 60n (n=2) and of the fluid inlet channels (filling channels) 701 to 70n (n=2) 70 may be selected such that the compressible medium (e.g., air) escapes advantageously through the fluid outlet channel 721 to 72n (n=2). Consequently, the measuring chamber 601 to 60n (n=2) may thus be completely emptied even if the fluid outlet channel 721 to 72n (n=2) points radially inward.
Thus, the interplay with any further aliquoting structure results in the possibility of aliquoting several liquids into split end cavities in parallel without involving several fluidic layers. In known aliquoting principles, this is possible only to a very limited extent because of channel crossings.
When manufacturing a physical fluid structure, the various channels for forwarding will not be exactly identical. As a result, the fluidic resistances of the fluid inlet channels 701 to 70n (n=2) and of the fluid outlet channels 721 to 72n (n=2) will vary, and there will be inaccuracies regarding emptying. To minimize said inaccuracies it is useful to reduce or even minimize fluidic communication between the measuring chambers 601 to 60n (n=2). This may be effected, for example, in that the fluid inlet channel (filling channel) 701 to 70n (n=2) has a fluidic resistance substantially higher than that of the fluid outlet channels 721 to 72n (n=2) for forwarding the liquid/directing the liquid onward.
In the following, the mode of operation of the fluidic module 50 shall be described in more detail with reference to
The fluidic module 50 shall be subjected, for example by the drive 20 described with reference to
In this process, as can be seen in
As compared to
In other words, due to the liquid volume remaining within the compression chambers 661 to 66n (n=2), the liquid volume metered within the measuring chambers 601 to 60n (n=2) may be (almost) completely driven, due to the expansion of the compressible medium, into downstream chambers connected to the fluid outlet channels 721 to 72n (n=2).
Thus, the fluidic module 50 as shown in
The eight measuring chambers 601 to 60, (n=8) are subdivided into a first half of measuring chambers 601 to 604 and a second half of measuring chambers 605 to 608, the first half of measuring chambers 601 to 604 being arranged radially further inward than the second half of measuring chambers 605 to 608.
The fluid inlet channels 701 to 704 of the first half of measuring chambers 601 to 604 are connected to a first inlet area 841 of the fluidic module 50 via a first manifold 801 and a first radially extending channel 821, while the fluid inlet channels 705 to 708 of the second half of measuring chambers 605 to 608 are connected to a second inlet area 842 of the fluidic module 50 via a second manifold 802 and a second radially extending channel 822.
The fluid outlet channels 701 to 704 of the first half of measuring chambers 601 to 604 and the fluid outlet channels 705 to 708 of the second half of measuring chambers 605 to 608 are connected in pairs, respectively, to a (downstream) chamber 861 to 864.
In detail, the first fluid outlet channel 721 and the fifth fluid outlet channel 725 are connected to the first (downstream) chamber 861, while the second fluid outlet channel 722 and the sixth fluid outlet channel 726 are connected to the second (downstream) chamber 862, while the third fluid outlet channel 723 and the seventh fluid outlet channel 727 are connected to the third (downstream) chamber 863 and while the fourth fluid outlet channel 724 and the eighth fluid outlet channel 728 are connected to the fourth (downstream) chamber 864.
For example, the fluidic module 50 may be used for mixing liquids in that a first liquid is introduced into the first inlet area 841 and a second liquid is introduced into the second inlet area 842, so that upon the reduction of the rotational frequency and the associated expansion of the compressible medium into the (downstream) chambers 861 to 864, an aliquot of the first liquid and a aliquot of the second liquid are centrifugally driven, respectively.
In the following, the mode of operation of the fluidic module 50 shown in
In other words,
The fluid inlet channel 701 to 704 leading to the measuring chamber 601 to 604 may be configured to start at the top end of the measuring chamber 601 to 604 (not mandatory). The fluid outlet channel 721 to 724 is then hermetically sealed by a first portion of the inflowing liquid. Thus, further inflowing liquid will then (at least partly) compress the entrapped compressible medium (e.g., gas volume) within the compression chamber (pressure chamber) 661 to 664 (see
The liquid keeps on flowing until the inlet area 841 has been emptied completely. Each of the measuring chambers 601 to 604 has a compression chamber (pressure chamber) 661 to 664 connected to it wherein a defined volume of the compressible medium (e.g., air volume) is entrapped. Excess liquid keeps flowing into the drain areas of the individual compression chambers (pressure chambers) 661 to 664 until the inlet area 841 has been emptied (not mandatory). Now a balance between the centrifugal force and the pneumatic counter-pressure is achieved.
If the rotary frequency is reduced, the entrapped compressible medium (e.g., air volume) within the compression chamber (pressure chamber 206) will expand under the lower centrifugal pressure. As a result, the liquid column within the radially extending channel 821 and within the fluid outflow channel 721 to 724, which may be configured as a siphon, for example, increases in turn. From a specific fill height, the filling level exceeds the crest of the siphon 721 to 724, and the liquid is transported on. Due to the centrifugal force and excess pressure, the liquid is now completely transferred from the measuring chambers 601 to 604 into the chambers 861 to 864.
Due to the fact that the fluid inlet channel (filling channel) 701 to 704 starts at the top end of the measuring chamber 601 to 604, the liquid remains within the fluid inlet channels 701 to 704 and is not distributed to the measuring chambers 601 to 604.
The accuracy of the aliquoting process will be particularly high when the fluid inlet channels 701 to 704 and the fluid outlet channels 721 to 724 are small as compared to the measuring chamber 601 to 604. Inaccuracies in measurement arise, e.g., due to the fact that different starting conditions such as the input volume, manufacturing tolerances, etc., result in differences in the filling levels during the metering step. As a result, the metering accuracy is directly correlated to the dimensions of the fluid inlet channels 701 to 704 and of the fluid outlet channels 721 to 724. In this context, smaller dimensions will result in more accurate metering.
Further measuring errors arise during emptying of the measuring chambers (measuring cavities) 601 to 604. Since there may be a difference in pressure between the measuring chambers 601 to 604, there may be an exchange of liquid between the measuring chambers 601 to 604. To minimize this, it is possible, on the one hand, for the fluid outlet channel (e.g., siphon) 721 to 724 to have a fluidic resistance much smaller than the sum of resistances of the fluid inlet channels 701 to 704, and it is possible, on the other hand, for the fluid inlet channel (filling channel) 701 to 704 to start at a radially inward point of the measuring chamber 601 to 604. As a result, the measuring chambers 601 to 604 are not in fluidic communication at least during a certain emptying period. During this time, thus, potential pressure differences will not cause any additional errors.
The above-described aliquoting concepts (radially inward aliquoting) may also be used for aliquoting liquids from radially outward to radially further inward by making small changes (radially outward aliquoting). In this context, the siphon 721 to 724 may be replaced by a fluid outlet channel 725 to 728 leading inward (see
By combining the two above-described aliquoting concepts (radially inward aliquoting and radially outward aliquoting), an aliquoting concept may be devised which aliquots two liquids on one fluidic layer. The overall structure may then be configured, e.g., such that an aliquot from a first aliquoting structure (first half of the measuring chambers 601 to 604) and an aliquot from a second aliquoting structure (second half of measuring chambers 605 to 608), respectively are transferred into a shared chamber (cavity) 861 to 864. The subsequent chamber (cavity) 861 to 864 may be a mixing chamber 861 to 864. The entire circumference around the axis of rotation may potentially be used for fluidic structures.
The aliquoting concept presented herein generally is also suited for aliquoting on a disc structured in a multi-layered manner. The disc may be configured such that the liquid for filling may be guided over a fluidic layer A and in the process may potentially be directed past crossing channels. The chamber is now emptied via a channel on the fluidic layer B. This channel may be both a siphon (e.g., 721 to 724) and a different channel leading radially inward, for example (e.g., 725 to 728). Other than that, the aliquoting process takes place as was described with regard to radially inward aliquoting. This is the obvious process to be performed, e.g., when the number of aliquots for the radially inward liquid is high (>10) and, as a result, the adjacently arranged siphon structures (721 to 724) can no longer be introduced in a spatially efficient manner. Moreover, such a configuration is advantageous as soon as more than two liquids are aliquoted into one chamber (cavity) 861 to 864. The fluidic connection may be realized either within the measuring chamber 601 to 608 itself or within a fluidic opening specifically provided for this purpose. It is possible to either provide each measuring chamber 601 to 608 with a fluidic opening of its own or for several measuring chambers 601 to 608 to share one fluidic opening.
Embodiments of the present invention enable simultaneous, parallel aliquoting of two liquids on a fluidic layer. Measuring, or metering, of the volumes takes place at high pressures, whereby capillary forces have little influence. Moreover, embodiments enable a potentially high level of accuracy since metering of the liquids takes place at high rotational frequencies. In addition, embodiments can dispense with sharp edges.
Unlike known aliquoting methods, the metering step of embodiments is performed at “high” rotational frequencies (rotary frequencies) and is subsequently switched to low rotational frequencies (rotary frequencies). Unlike known fluidic structures, the fluidic structure described herein is still functional even in the event of heavy overfilling (>50% of the volume measured). Unlike known aliquoting concepts, the aliquoting concept described herein enables aliquoting and connecting two liquids on one fluidic layer. Unlike known fluidic structures, in the fluidic structure described herein, the liquid may be supplied to the measuring chambers from outside and, additionally, the liquid may subsequently be processed further. Unlike known fluidic structures, at least two aliquots may have a waste cavity connected (directly or via a channel) to said metering chamber, which may be exploited, e.g., for performing individual quality control on each single aliquot by reading out the filling level within the waste cavity. Unlike known fluidic structures, in the fluidic structure described herein, the measuring chambers are separated from one another by a fluidic resistance higher than that of the channel used for forwarding the aliquots.
Further embodiments provide a fluidic structure comprising a fluid inlet channel (fluid inlet) having a high fluidic resistance, a fluid outlet channel (fluid outlet) having a low fluidic resistance, a measuring chamber and a compression chamber (pressure chamber), which are separated by a fluid overflow (fluid channel). The fluidic structure is configured such that upon filling of the fluidic structure, a compressible medium (e.g., air volume) is entrapped and that the volume of liquid introduced is larger than that encompassed by the volume of the measuring chamber, whereby excess liquid flows into the compression chamber (pressure chamber) through the fluid overflow and remains there; upon reduction of the rotational frequency (rotary frequency), a defined amount of liquid now directed through the fluid outlet channel (outlet).
Further embodiments provide a fluidic structure and a method of aliquoting several aliquots, the metering step being performed at “high” rotational frequencies (rotary frequencies), and forwarding of the liquids taking place at low rotary frequencies. The fluidic structure may be configured such that upon filling of the measuring chamber, a compressible medium (e.g., air) is compressed within the compression chamber. Moreover, the fluidic structure may be configured such that the fluid inlet of the measuring chamber comprises a fluidic resistance higher than that of the fluid outlet of the measuring chamber. Furthermore, the fluidic structure may be configured such that at least two aliquots comprise a waste cavity connected (directly or via a channel) to said measuring chamber. In addition, the fluidic structure may be configured such that during the volume-determining metering step, the meniscus is present only in such channels which are small as compared to the measuring chamber. Moreover, the fluidic structure may be configured such that the volume-determining measuring chamber is filled to a level of more than 50% (70%, 90%, completely). Furthermore, the fluidic structure may be configured such that during emptying, an interface between the compressible medium and the liquid (e.g., air/water interface) is displaced radially inward. Moreover, the fluidic structure may be configured such that at least one measuring chamber is filled from a radially further inward direction and is emptied in a radially further outward direction.
It shall be noted that the rotational frequency need not be increased in order for the liquid present within the at least one measuring chamber 1041 to 104i to be centrifugally driven out of same. The increase in the rotational frequency results in an increase in the centrifugal pressure, so that the liquid present within the at least one measuring chamber 1041 to 104i can be driven out of same faster.
Moreover, the fluidic module 100 may comprise an inlet area 116 connected to the fluid inlet channel 102.
A first portion 102a of the fluid inlet channel 102 may be connected to the inlet area 116 and may extend from radially further inward to radially further outward. A second portion 102b of the fluid inlet channel 102, to which the at least one measuring chamber 1041 to 104i may be connected, may extend laterally (e.g. have a uniform radial distance from the center of rotation 114). A third portion 102c of the fluid inlet channel 102 may extend from radially further inward to radially further outward and may be connected to the overflow 112.
Moreover, the fluidic module 100 may comprise at least one further chamber 1181 to 1184 connected to an output of the at least one variable fluid resistance element 1101 to 110i, the at least one measuring chamber 1041 to 104i being connected to the at least one variable fluid resistance element 1101 to 110i via an input of the at least one variable fluid resistance element 1101 to 110i.
In other words,
In this context, the flow resistance of the valve 1101 to 110i is sufficiently high so that at a first rotational frequency f1, the velocity at which the liquid fills the measuring chamber 1041 to 104i and at which excess liquid drains into the overflow area 112 from the inlet area 116 via the overflow channel 102 is much higher than that at which liquid is forwarded into a subsequent chamber 1181 to 118, downstream from the valve 1101 to 110i. Typically, the process of dividing the liquid would be at least 10 times (or, better, 100 times) faster than forwarding the liquid. As a result, the volume accuracy of metering is ensured without involving a valve 1101 to 110i which would completely prevent the flow of liquid during the filling process.
Even though some aspects have been described within the context of a device, it is understood that said aspects also represent a description of the corresponding method, so that a block or a structural component of a device is also to be understood as a corresponding method step or as a feature of a method step. By analogy therewith, aspects that have been described in connection with or as a method step also represent a description of a corresponding block or detail or feature of a corresponding device. Some or all of the method steps may be performed by a hardware device (or while using a hardware device), such as a microprocessor, a programmable computer or an electronic circuit. In some embodiments, some or several of the most important method steps may be performed by such a device.
While this invention has been described in terms of several 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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 102013219929.5 | Oct 2013 | DE | national |
This application is a continuation of copending International Application No. PCT/EP2014/070018, filed Sep. 19, 2014, which claims priority from German Application No. 10 2013 219 929.5, filed Oct. 1, 2013, which are each incorporated herein in its entirety by this reference thereto.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/EP2014/070018 | Sep 2014 | US |
| Child | 15089317 | US |
