EP1419818B1 - Device for sequential transport of liquids by capillary forces - Google Patents

Description

The invention relates to a device for the stepwise transport of liquid through a plurality of fluidically arranged in series reaction chambers taking advantage of capillary forces, wherein it is preferably to be examined sample liquids in the liquids.

It is necessary to examine sample liquids in a wide variety of analytical and diagnostic applications. The assays used sometimes require that the sample liquid be sequentially contacted with different reagents. With regard to the automation of such assays, it is advantageous to be able to gradually transport the sample liquid to be examined.

In the prior art it is generally known to initiate the transport of liquid through a channel or for filling a chamber in that the channel or the chamber is vented, whereby a liquid flow is formed. Examples of such selective fluid flow mechanisms are in WO-A-99/46045 . WO-A-01/64344 . US-A-5,230,866 . US-A-5,242,606 and US-A-5,478,751 described.

Furthermore, in US-A-3,799,742 describes a fluid system in which, by utilizing gravity and selective venting of individual chambers connected in series and in parallel, a liquid flow from a reservoir into the individual chambers is produced. In this known device, a liquid channel extends from a reservoir. Along this fluid channel branch off several branch channels, which terminate in two chambers connected in series. At the junction of the branch channels in the chambers branch off from these vent lines, the are all closed and can be opened selectively. The channel system described above allows a liquid transport exclusively by utilizing gravity. As long as all vents are closed, liquid transport from the reservoir is prevented by retaining the liquid by the gas back pressure. If, in the direction of flow, the first of the two chambers arranged per branch channel is vented, liquid can flow into the chamber from the reservoir. The leakage of the liquid from the vent line of this chamber is precluded by the incorporation of a liquid hydrophobic filter which is gas permeable. The passage into the downstream second chamber is prevented by the fact that this chamber is not vented. Only when this chamber is vented, liquid also enters the second chamber. This known system essentially requires the vertical orientation of the substrate in which the channel system is formed. This limits the application of the system in that it can not come to a liquid transport in the horizontal state of the substrate, since the fluid flow initiating gravity component is missing.

Out US-A-4,849,340 For example, a fluid system is known in which two fluids flowing through different conduits enter a common chamber. The transport of each liquid through each line and both liquids in the common chamber is carried out selectively, namely by opening vent holes, on the one hand upstream of the common chamber and in fluid communication with the lines and on the other hand downstream of the common chamber and in fluid communication therewith are. Through the openings, various sections of the fluid system can be selectively vented, which allows selective transport of the fluids. Liquid that flows through a portion of the fluid system after opening a vent hole flows through the port in question to a line adjacent to the port.

An object of the invention is to provide a device for the stepwise transport of liquid, in particular to be examined sample liquid, which has a fairly simple structure and is convenient and easy to handle and reliable.

To solve this problem, the invention proposes a device for the stepwise transport of liquid, in particular sample liquid to be examined, by means of a plurality of fluidically arranged reaction chambers in series utilizing capillary forces, which is provided with the features of claim 1.

According to the invention, capillary forces are utilized for the stepwise transport of liquids. For this purpose, the channel of the device is to be transported through the liquid, designed accordingly. This applies with regard to the cross-sectional areas, cross-sectional area configurations and surface characteristics of the channel. The channel is in fluid communication with at least two vents which are closed in their initial state. The fluid connection of the vents to the channel is made at spaced along the channel connecting points. The venting channels are designed for liquid transport by means of capillary forces.

Now, if liquid in the channel, for example, by the channel extends from a sample receiving chamber, the transport of liquid through the channel is prevented as long as the channel (at its end) and the vents are closed. If now the first vent opening in the flow direction of the channel, so liquid reaches up to the open vent hole in fluid communication Connection point of the channel and thereby filling the upstream of this junction chamber; the further transport of the liquid through the channel beyond this connection point is not possible because the adjoining part of the channel is closed to the outside. Only when the vent opening which is next in the direction of flow is opened does the channel section fill between the aforementioned connection point and the connection point associated with the next vent opening, and the liquid chamber arranged in this channel section fills. The chambers may be empty or equipped with substances, inserts (porous bodies or the like) or capillary-generating devices, such as surface textures.

By the concept described above, it is possible in a very simple way, namely only by opening vents, selectively and gradually transport a liquid through a channel with chambers arranged one behind the other. Thus, if reagent substances or reagents are arranged in the individual channel sections or chambers, it is possible to expose the liquid to a previously defined sequence of reactions. Finally, by opening the last vent opening, the sample liquid could enter an examination chamber or the like. Reservoir be initiated in the then in various ways an investigation (for example, lighting inspection) of the sample liquid can be done. But it is also possible that (intermediate) investigations are already carried out in the other reaction chambers. Studies are generally done e.g. optical (optical), in particular by determining the transmission or discoloration of the sample liquid, or microscopically.

A (re) closure of the vents, after the liquid front has passed through the associated joints of the channel, is not mandatory, but can certainly be made. An advantage of the invention is that the liquid does not matter the vent can escape. This is inventively achieved with mechanisms that exploit capillary forces to transport the liquid. The transport through a venting channel leading from a connection point to the vent opening also takes place by utilizing capillary forces. The vent is preceded by a capillary stop. This is designed as a hydrophobic part surface of the vent channel.

In an advantageous embodiment of the invention, it is provided that reagents, preferably immobilized, are arranged within the chambers located in the individual channel sections. Contact with the liquid causes the reagents to mobilize and react with the liquid. The vents can be arranged in the simplest case directly in the wall of the channel. The joints then coincide with the vents. Alternatively, it is also possible that branch off from the connection points venting channels that end in the vents.

The opening of the vents is advantageously carried out selectively by means of individual cover elements or a common cover element with which the vents can be selectively exposed according to their arrangement along the channel. In the simplest case, the lid member is an adhesive tape which is glued over one or more vents. For opening a vent opening, the cover element may be removable or puncturable, for example. Alternatively, it is also possible that the lid member is melted or dissolved by the initiation of a reaction or permeable to air. In the simplest case, it is the lid member to an adhesive strip over the Vents of a substrate or the like. Carrier is laid in which the channel system according to the invention is formed. For melting the cover elements, it is for example advantageous if these cover elements are thermally coupled with one or more heating elements. By controlling the heating elements thus selectively cover elements are melted and thus vent openings exposed.

The initiation of a reaction that dissolves a cover element can take place by contacting the cover element with a reaction agent from the outside. It should be formed only for the sample liquid inert reaction mixtures. For example, For example, as the lid member, a hydrophilic material (e.g., gel such as agarose, sucrose or the like, polysaccharides) is used. After dissolution of the cover element by application from the outside, the sample liquid reaches into the next channel section. The cover elements are therefore arranged in this case in the flow direction immediately behind a vent opening or a connection point, so that a released from a dissolved cover element channel section can be vented via this associated vent opening.

The device according to the invention can be used, for example, for a blood test, in which the blood to be examined reacts in a first reaction chamber with a first antibody or a conjugate and subsequently bind second antibodies in a second chamber to the bound first antibodies. Starting from a blood sampling chamber or the like. Task for the blood to be examined then passes this after exposure of the first vent the up to the associated junction extending channel portion of the channel in which the first reaction chamber is arranged with the first antibody or the conjugate. After a certain residence time, the blood sample to be examined with the partially bound antibodies is then transferred by exposing the next venting vent in the direction of flow into a second channel section in which the second reaction chamber with the second antibodies is arranged. Subsequently, by exposing a further vent opening or by exposing the end of the channel, the sample liquid in this further transported or transported out of this.

The device according to the invention can advantageously also have several of the previously described (sample liquid transport) channels with ventilation openings. All of these channels are fluidically parallel to each other, extending from a sample receiving arrangement with a common sample receiving chamber or a plurality of individual, the channels respectively associated sample receiving chambers and preferably have mutually equal length channel sections between the individual connection points. The connection points respectively associated ventilation openings are arranged directly adjacent to each other and can be advantageously exposed with one and the same lid member. This allows a parallel stepwise transport of liquid through the individual channels.

Fig. 1

ein erstes Ausführungsbeispiel für eine Kanalstruktur zum schrittweisen Transport von Flüssigkeit unter Ausnutzung von Kapillarkräften,

Fign. 2 bis 4

die einzelnen Phasen, in denen die Kanalstruktur gemäß Fig. 1 nach sukzessivem Öffnen der einzelnen längs des Kanals angeordneten Entlüftungsöffnungen dargestellt ist,

Fig. 5

ein zweites Ausführungsbeispiel einer Kanalstruktur,

Fign. 6 und 7

die einzelnen Phasen, in denen die Kanalstruktur gemäß Fig. 5 nach sukzessivem Öffnen der einzelnen längs des Kanals angeordneten Entlüftungsöffnungen dargestellt ist, und

Fig. 8

ein drittes Ausführungsbeispiel einer Kanalstruktur zum sukzessiven parallelen Transport von Flüssigkeiten durch mehrere Kanäle.

Several embodiments will be explained in more detail with reference to the drawing, which are not according to the invention insofar as the liquid flows in the vent lines in each case to the vent openings. In detail show:

Fig. 1

a first exemplary embodiment of a channel structure for the stepwise transport of liquid using capillary forces,

FIGS. 2 to 4

the individual phases in which the channel structure according to Fig. 1 is shown after successive opening of the individual vents arranged along the channel,

Fig. 5

A second embodiment of a channel structure,

FIGS. 6 and 7

the individual phases in which the channel structure according to Fig. 5 is shown after successive opening of the individual arranged along the channel vents, and

Fig. 8

a third embodiment of a channel structure for the successive parallel transport of liquids through a plurality of channels.

Fig. 1 13 shows the basic structure of a capillary channel system 10. The capillary channel system 10 is formed in a substrate 12 (plastic body or the like) and has a channel 14 which includes an inlet port 16 (in fluid communication with a reservoir, not shown) and an outlet port 18 , Liquid located in the channel 14 is transported in the channel by utilizing capillary forces.

The channel 14 has a plurality of (four in the embodiment) connection points 20,22,24 and 26, from which branch off vent lines 28,30,32,34, which end in vents 36,38,40,42. The channel 14 is divided by the connection points 20,22,24,26 into individual channel sections 44,46,48; in each channel section 44, 46, 48 there is a reaction chamber 50, 52, 54.

This in Fig. 1 shown capillary channel system 10 can be selectively filled with liquid as follows.

In the initial state all vents 36,38,40,42 and the outlet 18 of the channel 14 are closed. If now the first vent opening 36 is opened in the flow direction 56 (see arrow), then sample liquid, which is present at the inlet 16 of the channel 14, to the junction 20 and into the vent channel 28 to the vent opening 36. By shortening the vent channels 28, the dead volume of the capillary channel system 10 are minimized. The vent openings 36 may also be formed directly in the wall of the channel 14. After the opening 36 exposed has been, the liquid front within the channel 14 thus migrates to the junction 20; In any case, (still) no liquid enters the channel section 44.

If, on the other hand, the next venting opening 38 in the direction of flow is subsequently uncovered, liquid passes into the second passage section 44 and fills it, which means that the reaction chamber 50 is also filled with liquid to be examined. The advancing liquid front comes to a standstill in the channel at the connection point 22, the liquid only flowing from there into the venting channel 30 as far as the venting opening 38. This condition is in Fig. 2 played.

If now the next vent opening 40 is opened, then the procedure described above for the further channel section 46 is repeated, so that finally the situation according to Fig. 3 established. By exposing the next vent opening 42, finally, the next channel section 48 is filled with liquid, which in Fig. 4 is shown. When subsequently opening the outlet 18 of the channel 14, the liquid passes out of the channel 14 in a (not shown) collecting container or a collecting chamber.

The capillary channel system 10 described above may still have so-called capillary stops, which are overcome only after impressing a pressure pulse on the liquid, wherein subsequently the further transport of the liquid is again induced by capillary forces. Such capillary stops could for example be formed or arranged at the outlets of the reaction chambers 50, 52, 54. The selective transport of the liquid through the Kapillarkanalsystem 10 is carried out in such a case so alternately by exposing vents and impressing a pressure pulse.

It should be noted that it is not mandatory according to the invention that before the first reaction chamber 50 has a vent opening 36 is arranged. This could be omitted together with the vent line 28, as shown in the FIGS. 5 to 7 is shown.

In the FIGS. 5 to 7 A second embodiment of a capillary channel system 10 'is shown. The basic structure of the capillary channel system 10 'of FIGS. 5 to 7 is identical to the one according to the FIGS. 1 to 4 , One difference is the way in which the vents are exposed. These were in the embodiment according to the FIGS. 1 to 4 for example, exposed by individual cover elements 58, while in the embodiment according to the FIGS. 5 to 7 a continuous cover strip 60 is provided as a cover member which is more or less withdrawn and thus gradually exposing the vents 36,38,40,42. The cover strip 60 may be formed as an adhesive strip having individual sections 64, 66, 68 connected by perforation lines or other types of predetermined breaking lines 62. The predetermined breaking lines 62 are located between each two adjacent vent openings 38,40 and 40,42 and preferably approximately in the middle between these openings. At least on the side of a predetermined breaking line 62 facing the downstream vent opening, the adhesive side of the cover strip is free of adhesive in a region 70 adjacent to the predetermined breaking line 62. After detachment of the first section 64, which has at its free end a non-adhesive region 72, which serves as a handle, this section 64 can be torn off at the predetermined breaking line 62. The area 70 of the next section 66 then again serves as a grasping to facilitate the detachment of the portion 66 for the purpose of exposing the next vent opening 40th

Fig. 8 Finally, another embodiment of a capillary channel system 10 ", which has a plurality of (in this embodiment, two) channels 14, each of which, as described in connection with the preceding embodiments, procured and configured, that is several (in this embodiment, two) fluidically has reaction chambers 50, 52 connected in series from each channel 14 So branch off a plurality of vent lines 28,30,32 with vents 36,38,40 at their ends. The first vent openings 36 of all the channels 14 in the flow direction are closed in groups or all by a plurality or a common cover element 74. The same constellation results for the next in the flow direction vents 38,40, which are closed by a cover member 76 and 78, respectively. This system of common cover elements 74, 76, 78 is the same across the entire capillary channel system 10. The channels 14 branch off from a reservoir 80 which is filled with the liquid to be passed into and through the reaction chambers 50, 52 is or is.

By the cover elements 74,76,78 it is now possible to initiate or carry out the stepwise liquid transport through all the channels 14 at the same time and in parallel. The purpose of the first flow reaction chamber 50 upstream vent openings 36 of the channels 14 becomes clear considering that the channels 14 may be of different lengths in their sections between the reservoir 80 and the first reaction chambers 50 (for example, by design). The connection points 20 of the channels 14, at which the vent lines 28 branch off, are arranged at the same distance along the channel 14 of the first reaction chambers 50. After exposure of the first vent openings 36 is then in each channel 14, the liquid front equidistant from the first reaction chamber 50 at. Thus, the simultaneous filling of the first reaction chambers 50 after exposing the second vent openings 38 is ensured.

Alternatively it can be provided for all vents a common cover member which gradually releases vents (according to the cover member of the embodiment according to FIGS. 5 to 7 ). Furthermore, in the embodiment according to Fig. 8 Alternatively, it may be provided that the venting channels 28, 30, 32 branching off from the sample liquid transport channels 14 are arranged in groups (the first group comprises the first venting channels 28, the second group in the flow direction second venting channels 30, etc.) in a common vent opening 36,38,40 end.

As in connection with the first embodiment according to the FIGS. 1 to 4 also mentioned, the capillary channel systems 10 'and 10 "of the FIGS. 5 to 8 additionally be provided with capillary stops, which, as also mentioned above, for example, at the outlet end of the reaction chambers 50,52 considered with respect to the flow direction are arranged.

The capillary channel system according to the invention is characterized by a precise timing and triggering of the further transport of the liquid. Furthermore, extremely simple opening mechanisms for the vents are described. The system is expediently designed for single use and designed as a disposable item. It requires a minimum of test fluid and no filter / membrane components used. Further, the system allows the completely closed formation on a substrate or the like. Carrier, which is why the risk of contamination is minimized. For triggering the reactions and in particular the transport of the liquid are no centrifugal forces or the like. required. The system according to the invention operates independently of position, since capillary forces are utilized for liquid transport.

Claims (7)

1. A device for the stepwise transport of liquid, particularly of sample liquid to be analyzed, through several reaction chambers located in series in terms of flow while utilizing capillary forces, comprising

   - a channel (14) through which liquid is transportable on the basis of capillary forces, and

   - at least two closed vent holes (38,40,42) which are in fluid communication with the channel (14) at connection sites (22,24,26) spaced from each other along the channel (14), and which are adapted to be opened separately,

   - wherein the connection sites (22,24,26) divide the channel (14) into several channel sections (44,46,48),

   - wherein the fluid connection between a respective channel section (44,46,48) and the closed vent holes (38,40,42) allocated thereto is adapted to be flown through by liquid by being opened separately,

   - wherein at least one chamber (50,52,54) is arranged in the channel sections (44,46,48) upstream of each connection site (22,24,26) in flow direction,

   - wherein capillary vent channels (30,32,34) ending in the vent holes (38,40,42) branch off from the channel (14) at the connection sites (22,24,26) thereof,

   - wherein a capillary stop arranged inside each respective vent channel (30, 32, 34) is provided upstream of each respective vent opening (38, 40, 42), and

   - wherein the capillary stops are each configured as a hydrophobic partial surface of each respective vent channel (30, 32, 34).
2. The device according to claim 1, characterized in that a reagent substance is arranged in at least one chamber (50,52,54).
3. The device according to claim 2, characterized in that the reagent substance is immobilized and adapted to be mobilized when contacting the liquid.
4. The device according to one of claims 1 to 3, characterized in that each vent hole (38,40,42) is closed by a cover element (60,74,76,78) that is adapted to be pulled off, punctured, melted open and/or soluble or air-permeable by initiating a reaction.
5. The device according to claim 4, characterized in that all the vent holes (38,40,42) are covered by a common cover element (60,74,76,78), the cover element (60,74,76,78) being adapted to be selectively pulled off, punctured, melted open and/or soluble or air-permeable by initiating a reaction.
6. The device according to claim 4 or 5, characterized in that one or more heating elements thermally coupled with the cover element (60,74,76,78) are provided for melting open the cover element (60,74,76,78).
7. The device according to one of claims 1 to 6, characterized in that several channels (14) are provided, the first, second and further vent holes (38,40,42) of which, which succeed each other in flow direction, are respectively adapted to be uncovered in common in groups.

Images