EP2598242B1 - Apparatus for separating components of a sample liquid - Google Patents

Description

The present invention relates to a device for the treatment and preferably examination of sample liquid, in particular blood, according to the preamble of claim 1 and such a method.

The present invention is particularly concerned with microfluidic systems and devices. The following explanations therefore relate in particular to devices in which capillary forces act and, in particular, are decisive for the function.

Devices are known in which blood is filtered as sample liquid by means of a flat separating device. The filtrate or the permeate is taken up in a chamber which adjoins the separator on the flat side and is discharged laterally via a connecting channel. Usually, the channel has a relation to the chamber substantially smaller cross-section. It is also known to provide the chamber under the separator with fluidic structures, such as columns or the like, in order to achieve the most uniform distribution and accordingly good discharge or discharge via the channel. However, such fluidic structures are disadvantageous in terms of a much larger dead volume.

Similar devices for blood separation are for example from WO 2005/119211 A1 and the WO 2009/106331 A2 known. According to the WO 2009/106331 A2 it is also possible that the flat, thin separating device can be slightly deformed transversely to its surface extension, in particular in the adjoining the separator downstream chamber.

The US5135719 A discloses a method of separating plasma and red blood cells wherein a low pressure filter (specifically, a microfiber glass filter) is disposed in a flow path between an inlet and a reaction area. Under the filter, the plasma collects in a collecting area and flows through capillary forces driven solely by capillary forces to the reaction area. At the reaction area a vent is connected.

The EP 1500937 A1 discloses an instrument for analyzing fluidic samples wherein a separation sheet separates solid components from the fluid and the filtered liquid distributes from an underlying reservoir into radially outgoing channels. Each of these channels has a branch connected to a vent and an expanded reaction area containing a solid, liquid-soluble reagent.

Experiments have shown that even if the channel extends to the middle of the chamber or under the separator, at the lowest possible chamber height, ie the smallest possible distance to the separator and correspondingly low dead volume is not very uniform discharge from the chamber under the separator , Rather, essentially only in the region of the channel, the pores of the separation device are filled with blood cells or other components filtered out. Accordingly, an optimal throughput, especially in capillary force driven operations is not achieved.

The present patent application is based on the object of specifying a device and a method for the treatment and preferably examination of sample liquid, in particular blood, wherein an optimization of the fluidic throughput is made possible in a simple manner and / or while avoiding an excessively increased dead volume.

The above object is achieved by a device according to claim 1. Advantageous developments are the subject of the dependent claims.

A basic idea of the present invention is that the sample liquid from the downstream of the separator - especially directly and / or flat - subsequent chamber not only one, but at least two channels and accordingly not only one, but at least two lateral Derive drainage areas. Thus, in a simple manner and / or with a minimal increase in the dead volume, a significantly higher throughput or a significantly larger amount be derived on sample liquid. This can be explained in particular by the fact that a better discharge from different areas of the substantially flat or planar chamber and thus also from different areas of the areal separator takes place. Accordingly, the permeability of the sample liquid separator is better utilized over a wider range than is otherwise the case with only a small channel channel.

The sample liquid derived from the two channels, that is to say the sample liquid filtered by the separating device, such as blood plasma or blood serum, can then be supplied, for example, to a common examination area or alternatively to two separate examination areas. In the former case, the channels are preferably brought together in a connecting chamber or connecting line, which is particularly preferably vented in order to avoid undesired gas or air influences, in particular in the case of channels filling at different rates.

Fig. 1

einen schematischen Schnitt einer vorschlagsgemäßen Vorrichtung;

Fig. 2

eine schematische Draufsicht eines Trägers der vorschlagsgemäßen Vorrichtung gemäß einer ersten Ausführungsform; und

Fig. 3

eine schematische Draufsicht eines Trägers der vorschlagsgemäßen Vorrichtung gemäß einer zweiten Ausführungsform.

Further advantages, features, characteristics and aspects of the present invention will become apparent from the claims and the following description of preferred embodiments with reference to the drawing. It shows:

Fig. 1

a schematic section of a proposed device;

Fig. 2

a schematic plan view of a carrier of the proposed device according to a first embodiment; and

Fig. 3

a schematic plan view of a carrier of the proposed device according to a second embodiment.

In the figures, the same reference numerals are used for the same or similar parts, and corresponding or comparable properties and advantages are achieved, even if a repeated description is omitted.

Fig. 1 shows in a schematic section a proposed device 1 for the treatment and preferably examination of sample liquid 2, in particular blood or other human or animal body fluid.

The apparatus 1 has a planar separating device 3 for treating the sample liquid 2, in particular for separating off constituents, such as particles or cells, from the sample liquid 2. In particular, the separator 3 is used for filtering. It preferably has a filter element, a membrane or the like. on. The separator 3 may be constructed one or more layers. It is preferably flat or flat.

Particularly preferably, the separating device 3 by a membrane, as in the WO 2009/106331 A2 described, formed or provided with it.

The device 1 has a chamber 4 for receiving sample liquid 2 that has flowed through the separating device 3. In particular, the chamber 4 thus receives sample fluid 2 treated or filtered by the separating device 3, such as blood plasma or blood serum.

The chamber 4 preferably connects flat side and directly to the separator 3 downstream. In particular, the chamber 4 is arranged below the separating device 3. In the illustrated example, the separating device 3 is larger in area than the chamber 4 is formed. In particular, the separating device 3 protrudes laterally beyond the chamber 4, in the illustrated embodiment particularly preferably on all sides.

Particularly preferably, the sample liquid 2 is guided free of side walls in the chamber 4. This is achieved in the illustrated example, in particular, that adjoins a bottom 5 of the chamber 4 laterally a capillary stop, which is particularly preferably formed by a circumferential or laterally adjoining trench 6. However, other constructive solutions are possible.

In the illustrated example, the chamber 4 in particular between the bottom 5 of the chamber 4 on the one hand and the opposite region of Separator 3 formed. Due to the small distance between these two opposite surfaces, the sample liquid 2 is preferably kept free of side walls in the chamber 4 by capillary forces. The capillary forces or prevent the capillary stop that the sample liquid 2 flows into the trench 6 laterally adjoining in the representation example. In particular, the trench 6 forms by its abrupt cross-sectional enlargement - ie its greater depth relative to the chamber height (distance of the bottom 5 of the separator 3) - the capillary stop.

In the exemplary embodiment, the device 1 preferably has a carrier 7, an associated cover 8 and / or a receiving element 9.

The carrier 7 is preferably plate-like and / or rigid.

The carrier 7 is preferably made of plastic and / or by injection molding. The carrier 7 preferably has microfluidic structures for the sample liquid 2 and / or deaeration structures or the like. on, which will be discussed later. These structures are preferably - at least partially - covered by the cover 8.

The cover 8 is preferably made of plastic and / or designed as a film. The cover 8 is preferably laminated to the carrier 7 or glued or otherwise connected thereto.

The cover 8 preferably extends at least substantially over the entire surface or continuously over the carrier 7.

The receiving element 9 preferably serves to hold the separating device 3 and / or to receive the sample liquid 2, such as a blood drop, as in FIG Fig. 1 indicated. The receiving element 9 has for this purpose, for example, a receiving area 10, such as an opening, opening or the like., On.

The separator 3 may, for example, in an annular shoulder or the like. be held on the receiving element 9.

The separating device 3 is connected, for example, by gluing, clamping and / or welding or in any other suitable manner with the receiving element 9 and / or the carrier 7 or the cover 8 or held thereof.

In the illustrated example, the receiving element 9 is arranged on the cover 8 or connected thereto. However, the receiving element 9 can also be directly connected to the carrier 7 and / or be formed by this.

In order to achieve a lateral venting of the chamber 4, the trench 6 is connected via a vent channel 11 to the environment. The vent channel 11 is formed in the carrier 7.

In the present description, the sample liquid 2 that has passed through the separator 3 is also referred to as the sample liquid 2. In Fig. 1 is merely indicated schematically that the sample liquid 2 upstream of the separator 3 may include, for example, schematically indicated larger components that are no longer contained in the sample liquid 2 after flowing through the separator 3 - ie in the chamber 4. It is in particular in the chamber 4 and further downstream then to the treated or filtered sample liquid 2 or its permeate. The further description is to be understood in particular in this sense.
Fig. 2 shows a schematic plan view of a preferred fluidic structure for the discharge of the sample liquid 2 from the chamber 4 of the proposed device 1 according to a first embodiment. In particular, the shows Fig. 2 in a schematic plan view of the carrier 7 without cover 8, receiving element 9, separator 3, sample liquid. 2

The device 1 has a first channel 12, which laterally adjoins the chamber 4 in a first outflow region 13. The device 1 further has at least one second channel 14, which laterally adjoins the chamber 4 in a second discharge region 15.

The device 1 thus has a plurality of channels 12, 14 and discharge regions 13, 15 for the discharge of sample liquid 2 from the chamber 4.

The channels 12, 14 have a relation to the chamber 4 a substantially smaller cross-section. The channels 12, 14 preferably each have a minimum or average cross section or a cross section in the region of the respective outflow region 13/15, which is less than 20%, preferably less than 15%, in particular less than 10%, particularly preferably less than 5 % of the maximum cross section of the chamber 4 is. Maximum cross-section of the chamber 4 is to be understood here in particular as a product of chamber height with the average or maximum diameter of the bottom 5.

The channels 12, 14 and drainage areas 13, 15 are preferably offset at the edge of the chamber 4 or arranged or connected on opposite sides. Accordingly, the discharge of sample liquid 2 from the chamber 4 from different areas or at different locations, whereby the throughput of the device 1 and the separation or filter performance of the device 1 and the separator 3 can be significantly increased in a surprisingly simple manner, as already explained at the beginning.

Of course, more than two channels and drainage areas for the discharge of sample liquid 2 from the chamber 4 to the chamber 4 may be laterally connected. Thus, the throughput or the discharge of sample liquid 2 can be further increased. For example, a cross-type arrangement of four channels and outflow areas on the chamber 4 is possible.

Fig. 2 It can be seen that the lateral trench 6 is divided by the drainage regions 13, 15 into two trench sections, which surround the chamber 4 or its bottom 5, in particular like an annular segment. The outflow regions 13, 15 form web-like or bridge-like connections via the trench 6 to the chamber 4 or its bottom 5. The channels 12, 14 are preferably formed by groove-like or groove-like depressions, in particular in the carrier 7.

The channels 12, 14 extend over the drainage regions 13, 15, particularly preferably into the chamber 4 or the bottom 5 and / or under the separating device 3. In particular, the channels 12, 14 end open towards the separating device 3 in their respective end region , The cover 8, which otherwise covers the channels 12, 14, may also, as required, extend into or over the drainage regions 13, 15 and / or into the chamber 4 or over the bottom 5, in particular to form tongue-like protuberances 16, as in FIG Fig. 2 indicated by dash-dotted lines.

The channels 12, 14 extend at least substantially to one another in the middle of the chamber 4 or in the bottom 5, as in FIG Fig. 2 indicated by dashed lines.
In the illustrated example, the device 1 has a preferably chamber-like examination area 17 for the examination of sample liquid 2 derived from the chamber 4. For the supply of sample liquid 2 from the chamber 4 into the examination area 17, both the first channel 12 and the second channel 14 are fluidly connected to the examination area 17 in the illustrated example. This can optionally be done directly or optionally via a connecting line 18 and / or a connecting chamber 19, as in Fig. 2 indicated. The connection line 18 and the connecting chamber 19 are thus in particular optional and can also be omitted if necessary.

In the illustrated example, the two channels 12 and 14 initially combine and the sample liquid 2 derived from the chamber 4 is then forwarded to the examination region 17 via the common connection line 18. At the union of the two channels 12 and 14 or at the transition to the connecting line 18, the optional connecting chamber 19 is preferably formed. As I said, but this is only optional and can be omitted if necessary.

Preferably, a vent for the examination area 17 and / or for the connecting line 18 and / or connecting chamber 19 is provided. The venting of connecting line 18 and connecting chamber 19 is preferably carried out in the illustrated embodiment by a vent channel 20, for example, directly or indirectly connected to the environment and / or may be in gas exchange and / or with the examination area 17 and / or trench 6 for venting or can be connected.

The venting provided is preferably designed such that, even with differently fast filling of the channels 12, 14 with sample liquid 2 derived from the chamber 4, no unwanted gas or air inclusion occurs in the examination area 17 or in the sample area 2 supplied to the examination area 17.

The vent is preferably also by groove-like or groove-like depressions and / or openings or the like. formed in the carrier 7 and / or, if necessary, in the cover 8.

The connecting chamber 19 preferably serves primarily only for venting and therefore has a preferably only minimal volume.

The following is based on Fig. 3 a second embodiment of the proposed device 1 or microfluidic structure explained. Here, only essential differences from the first embodiment will be explained. The previous remarks and explanations therefore apply in particular supplementary or corresponding.

Fig. 3 make one Fig. 2 Some aspects, such as the optional venting and the possible protuberances 16 of the cover 8 in the discharge areas 13, 15 and chamber 4, have been omitted, but can be realized accordingly.

In the second embodiment, the two channels 12, 14 are connected to separate examination areas 17 and 21. The device 1 thus has, in addition to the (first) examination area 17, a further or additional examination area 21, which is supplied with sample fluid 2 by the second passage 14.

The two embodiments or individual aspects thereof can also be combined with one another as desired. For example, the connection line 18 or connection chamber 19 may also be connected to a further separate examination area 21 in addition to the examination area 17 in order to separate or divide the sample liquid 2 removed from the chamber 4 again after the channels 12, 14 have been combined.

Alternatively or additionally, it is also possible, for example, for four channels to derive the sample liquid 2 from the chamber 4 and to unite in pairs, in order then to supply the sample liquid 2 to the separate examination regions 17 and 21.

In general, the following should be noted with respect to the present invention and to both embodiments:
The device 1 is in particular a microfluidic device.

The volumes of the device 1 or individual or all microfluidic structures, such as the chamber 4, the channels 12, 14, the connecting line 18, the connecting chamber 19 and / or the examination areas 17, 21 are preferably less than 1 ml, in particular less than 500 .mu.m, more preferably substantially 100 .mu.l or less.

The volume of the channels 12, 14 is in each case preferably less than 20%, in particular less than 10%, of the volume of the chamber 4.

The preferred derivation of the sample liquid 2 from the chamber 4 on the other hand in cross section small, but several channels 12, 14 has the advantage that even with minimal volume of the chamber 4, in particular minimum chamber height or possibly little or no microstructuring of the chamber 4 or of the chamber bottom 5 for minimizing the dead volume, a good throughput or a high separation efficiency can be achieved. Alternatively or additionally, a treatment and in particular examination of the sample liquid 2 can take place even in the event of failure or obstruction of a channel 12 or 14, when the two channels 12, 14 are fluidically connected to a common examination area. When diverted into separate examination areas 17 and 21, the use of a plurality of channels 12, 14 can also achieve a faster filling of the examination areas 17 and 21 compared to the prior art.

The channels 12 and 14 preferably extend at least substantially in the main extension plane of the chamber 4 or the carrier 7 and / or in a plane parallel thereto.

The device 1 can in particular for examining the sample liquid 2 or for determining an analyte in the sample liquid 2 or the like. be used. For example, the device 1 for realizing a Imuno assay reaction or the like serve. For example, the device 1 can serve for the determination or analysis of specific analytes or other values of the sample liquid 2.

LIST OF REFERENCE NUMBERS

1

contraption

2

sample liquid

3

separator

4

chamber

5

ground

6

dig

7

carrier

8th

cover

9

receiving element

10

reception area

11

vent channel

12

first channel

13

first drainage area

14

second channel

15

second drainage area

16

protuberance

17

study area

18

connecting line

19

connecting chamber

20

vent channel

21

additional examination area

Claims (13)

1. Device (1) for treatment and preferably for examination of liquid samples (2), in particular blood, with a carrier (7)
   with a planar separating device (3),
   with a downstream chamber (4) connected to a planar side of the separating device (3) for receiving the liquid samples (2) flowing through the separating device (3), with the chamber (4) arranged under the separating device (3) and the separating device (3) formed with a larger surface area than the chamber (4),
   with a first channel (12) and a second channel (14) connected to a side of the chamber (4) in a first drainage area (13) and a second drainage area (15) and which feature a smaller cross-section compared with the chamber (4), and
   with an examination area (17) to which the initial channel (12) and/or the second channel (14) is fluidly connected in order to direct liquid samples (2) from the chamber (4) to the examination area (17),
   characterised in that
   a capillary stop in the form of a segment-like surrounding trench (6) is connected laterally to a floor (5) of the chamber (4), with the trench connected to the surrounding area via a venting channel (11) in the carrier (7), and
   the drainage areas (13, 15) form plank-like or bridge-like connections over the trench (6) to the chamber (4) and the channels (12, 14) extend over the drainage areas (13, 15) to the centre of the chamber (4).
2. Device of claim 1 characterised in that the second channel (14) is fluidly connected to the examination area (17) together with the channel (12) in order to direct liquid samples (2) from the chamber (4) to the examination area (17).
3. Device of claim 1 or 2 characterised in that the mechanism features a connection pipe (18) and/or a connection chamber (19) to which both channels (12, 14) are fluidly connected.
4. Device of claim 3 characterised in that the mechanism features ventilation for the connection pipe (18) or connection chamber (19).
5. Device of claim 3 or 4 characterised in that the connection pipe (18) or connection chamber (19) is connected to the examination area (17) for the supply of liquid samples (2).
6. Device of claim 1 characterised in that the second channel (12) is fluidly connected to a separate additional examination area (21) in order to direct liquid samples (2) from the chamber (4) to the additional examination area (21).
7. Device of one of the preceding claims characterised in that both drainage areas (13, 15) are arranged or connected to the chamber (4) offset at the edge.
8. Device of one of the preceding claims characterised in that both drainage areas (13, 15) are arranged or connected to the chamber (4) on opposite sides.
9. Device of one of the preceding claims characterised in that both channels (12, 14) extend under the separating device (3).
10. Device of one of the preceding claims characterised in that both channels (12, 14) are formed with recesses, especially notch-like or groove-like ones, in a floor (5) of the chamber (4) and/or in the drainage areas (13, 15).
11. Device of claim 10 characterised in that a cover (8), especially a tongue-like one, is used to cover the drainage areas (13, 15) and/or extends under the separating device (3) and covers the channels (12, 14) there.
12. Device of one of the preceding claims characterised in that both channels (12, 14) are at least partly formed with recesses, especially notch-like or groove-like ones, in a carrier (7) for the device (1) covered by a cover (8).
13. Device of one of the preceding claims characterised in that both channels (12, 14) are connected to each other under the separating device (3).

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