EP1419818A1 - Device for sequential transport of liquids by capillary forces - Google Patents

Abstract

The apparatus (10) to move fluid samples in steps, using capillary forces, has a capillary channel (14) for the interconnected reaction chambers. At least two closed ventilation openings (38,40,42) are located at intervals along the channel, with channel connections (22,24,26) for fluid flows, and which divide the capillary channel into sections (44,46,48). The apparatus (10) to move fluid samples in steps, using capillary forces, has a capillary channel (14) for the interconnected reaction chambers. At least two closed ventilation openings (38,40,42) are located at intervals along the channel, with channel connections (22,24,26) for fluid flows, and which divide the capillary channel into sections (44,46,48). The ventilation openings are opened separately, to give flows between the channel sections. Each channel section has at least one chamber (50,52,54) in front of the ventilation connection, in the flow direction.

Description

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

In the most diverse application areas of analytics and diagnostics it is necessary to examine sample liquids. They are used Occasionally, assays require that the sample fluid be sequential be contacted with different reagents. With regard the automation of such assays is beneficial if one is able to to gradually transport the sample fluid to be examined.

In the prior art, it is basically known the transport of liquid through a channel or to fill a chamber, that the channel or the chamber is vented, creating a liquid flow arises. Examples of such selective fluid flow mechanisms WO-A-99/46045, WO-A-01/64344, US-A-4,849,340, US-A-5,230,866, US-A-5,242,606 and US-A-5,478,751.

Furthermore, in US-A-3,799,742 a fluid system is described in which taking advantage of gravity and selective venting of individual serial and parallel chambers a liquid flow from a reservoir is caused in the individual chambers. In this known device extends from a reservoir from a fluid channel. Along this Fluid channels branch off several branch channels, which in two consecutive connected chambers end. In the amount of the junction points of the branch channels into the chambers branch off from these vent lines, the are all closed and can be opened selectively. That before described channel system leaves a liquid transport exclusively taking advantage of gravity too. As long as all the vents are closed, the liquid transport is prevented from the reservoir, by retaining the liquid by the gas back pressure. Is now arranged in the flow direction of the first two per branch channel Chambers vented, so may in this chamber liquid from the Pour in reservoir. The leakage of liquid from the vent line this chamber becomes hydrophobic by incorporating one for the liquid Filter excluded, which is gas permeable. The transfer to the downstream second chamber is prevented by this chamber is not vented. Only when this chamber is vented, passes Liquid also in the second chamber. This known system requires essentially the vertical orientation of the substrate in which the Channel system is formed. This limits the application of the system insofar one, as it is in the horizontal state of the substrate not to a liquid transport can come because the liquid flow initiating Gravity component is missing.

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

• mindestens einem Kanal, durch den Flüssigkeit auf Grund von Kapillarkräften transportierbar ist, und
• mindestens zwei verschlossenen Entlüftungsöffnungen, die an längs des Kanals voneinander beabstandeten Verbindungsstellen in Fluidverbindung mit dem Kanal stehen,
• wobei die Verbindungsstellen den Kanal in mehrere Kanalabschnitte unterteilen,
• wobei die Fluidverbindungen zwischen jeweils einem Kanalabschnitt und der diesem zugeordneten Entlüftungsöffnungen einzeln geöffnet werden können und
• wobei in den Kanalabschnitten den Verbindungsstellen in Strömungsrichtung betrachtet jeweils vorgelagert mindestens eine Kammer angeordnet ist.

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

• at least one channel through which liquid is transportable due to capillary forces, and
• at least two sealed vents in fluid communication with the channel at junctions spaced from each other along the channel,
• wherein the junctions divide the channel into a plurality of channel sections,
• wherein the fluid connections between each one channel portion and its associated vents can be opened individually and
• wherein, viewed in the flow direction, at least one chamber is arranged in each case upstream of the connection points in the channel sections.

According to the invention for the gradual transport of liquids Capillary forces exploited. For this purpose, the channel of the device through which Liquid to be transported, designed accordingly. This applies with regard to the cross sectional areas, cross sectional area configurations and Surface textures of the channel. The channel is at least two Vent holes in fluid communication, which closed in their initial state are. The fluid connection of the vents to the channel occurs at spaced along the channel joints. The vents can directly form the joints, ie directly in the channel wall or a substrate in which the channel is formed is, be arranged. Alternatively, from the connection points Degass bleed ducts that end in the vents. The Venting channels can be used for liquid transport by means of capillary forces be designed. However, this is not mandatory as the vent lines primarily serve the vent.

Now liquid enters the channel by the channel, for example, from extends from a sample receiving chamber, so is the transport of liquid through the channel as long as the channel (at its end) and the vents are closed. Will now be in the flow direction opened channel of the first vent, so passes liquid to be in fluid communication with the open vent Junction of the channel and thereby fills this junction upstream chamber; the further transport of the liquid through the channel beyond this junction is not possible because of the adjoining Part of the channel is closed to the outside. Only when the in Flow direction is opened next vent, fills the Channel section between the aforementioned junction and the next vent associated connection point as well as in this Channel section disposed chamber with liquid. The chambers can empty or with substances, inserts (porous bodies or the like) or capillary forces generating devices, such as e.g. Surface finishes, be equipped.

The concept described above makes it extremely easy to namely only by opening vents possible, selective and gradually a liquid through a channel arranged one behind the other To transport chambers. So if in the individual channel sections or chambers reagent substances or reagents are arranged so is It is possible to apply the fluid to a previously defined sequence of reactions suspend. Finally, by opening the last vent could the sample liquid or the like in an examination chamber. Reservoir initiated in which then in the most different ways an investigation (For example, photometric examination) of the sample liquid done can. But it is also possible that (intermediate) investigations already be carried out in the other reaction chambers. investigations are generally done e.g. photometric (optical), in particular by determination the transmission or discoloration of the sample fluid, or microscopic.

In an advantageous embodiment of the invention, it is provided that within the In the individual channel sections chambers located reagents, preferably immobilized, are arranged. By contact with the liquid the reagents are mobilized and can react with the fluid.

The vents can in the simplest case directly in the wall be arranged of the channel. The joints then fall so with the Vents together. Alternatively, it is also possible that of the Branching off connection points from venting ducts in the vents end up.

A (re-) closure of the vents after the liquid front the assigned junctions of the channel has passed is not mandatory, but it can be done. Appropriately It is however, if it succeeds, that the liquid maximally up to the vent opening flows and ensures that the liquid does not escape Vent can emerge. This is with mechanisms leading to Transport of the liquid Take advantage of capillary forces, easily possible, Appropriately in this regard, it is when the vents are dimensioned accordingly, so that due to surface tensions the liquid is an outlet of the same from the openings omitted. The transport through one of a connection point to the vent leading venting channel also takes place expediently taking advantage of capillary forces. Alternatively or additionally the vent also be preceded by a capillary stop. This is e.g. as hydrophobic (partial) surface of the venting channel or as hydrophobic Vent or formed as a gradual expansion of the channel system.

The opening of the vents is advantageously carried out selectively by means individual cover elements or a common cover element, with the vent openings according to their arrangement along the Selective release of channels. In the simplest case, it is the Cover element around an adhesive strip, the one or more vents is glued. To open a vent, the Cover element, for example, be peelable or punctiform. Alternatively it is also possible that the lid member meltable or by initiation a reaction is dissolved or permeable to air. In the simplest case it is the lid member is an adhesive strip over the Vents of a substrate or the like. Carrier is placed, in which the inventive Channel system is formed. For melting the lid elements it is for example advantageous; if these cover elements with a or more heating elements are thermally coupled. By control the heating elements are thus selectively melted and lid elements thus exposing vents.

The initiation of a lid element dissolving reaction can by Contacting the lid member with a reactant made from the outside. It should be only for the sample liquid inert reaction mixtures arise. For example, For example, as a lid member, a hydrophilic material (e.g., gel, such as agarose, sucrose or the like. Polysaccharides). After Dissolution of the cover element by application from the outside passes the sample liquid into the next channel section. The cover elements are therefore in this case in the flow direction immediately behind a vent or a junction arranged so that one of a dissolved lid member shared channel section on this associated Vent can be vented.

The device according to the invention can be used, for example, for a blood test be in which the blood to be examined in a first reaction chamber react with a first antibody or conjugate and then in a second chamber on the bound first antibodies bind second antibody. Starting from a blood sampling chamber or the like. Task for the blood to be examined then happens after that Exposing the first vent to the associated junction extending channel portion of the channel in which the first Reaction chamber with the first antibody or the conjugate arranged is. After a certain residence time then the blood sample to be examined with the partially bound antibodies by exposing the flow direction next vent in a second channel section transferred, 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 above described (sample liquid transport) channels with vents respectively. All of these channels are fluidically parallel to each other, extend from a sample receiving arrangement with a common Sample receiving chamber or more individual, the channels respectively assigned sample receiving chambers and preferably have mutually equal length channel sections between the individual connection points on. The connecting points respectively associated vents are arranged immediately adjacent to each other and can be advantageously exposed with one and the same lid member. As a result, a parallel stepwise transport of liquid through the allows individual channels.

Fig. 1

ein erstes Ausführungsbeispiel für eine erfindungsgemäße 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 erfindungsgemäßen 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 erfindungsgemäßen Kanalstruktur zum sukzessiven parallelen Transport von Flüssigkeiten durch mehrere Kanäle.

The invention will be explained in more detail with reference to several embodiments with reference to the drawings. In detail show:

Fig. 1

a first embodiment of a channel structure according to the invention for the stepwise transport of liquid by utilizing 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 vent openings arranged along the channel,

Fig. 5

A second embodiment of a channel structure according to the invention,

FIGS. 6 and 7

the individual phases in which the channel structure of Figure 5 is shown after successive opening of the individual arranged along the channel vents, and

Fig. 8

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

Fig. 1 shows the basic structure of the capillary channel system according to the invention 10. The capillary channel system 10 is in a substrate 12 (Plastic body or the like.) Formed and has a channel 14 which has a (in fluid communication with a reservoir, not shown) inlet opening 16 and an outlet opening 18. Liquid that is in the Channel 14 is in the channel taking advantage of capillary forces transported.

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 through the connection points 20,22,24,26 into individual channel sections 44,46,48 divided; in each channel section 44,46,48 is a reaction chamber 50,52,54.

The capillary channel system 10 shown in FIG. 1 can be selectively entrained as follows Fill the liquid.

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

If, on the other hand, then the next vent in the flow direction 38 exposed, so liquid enters the second channel section 44 and fills this, which means that the reaction chamber 50 to be examined with Liquid is filled. The advancing fluid front comes in the channel at the junction 22 to a standstill, wherein the Liquid from there only in the vent channel 30 to the vent 38 flows. This condition is shown in FIG.

Now, if the next vent opening 40 is opened, it is repeated previously described operation for the further channel section 46, so that Finally, the situation according to FIG. 3 sets. By exposing the next Vent 42 eventually becomes the next channel section 48 with liquid filled, which is shown in Fig. 4. If you then the outlet 18 of the channel 14 opens, 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 can still via so-called Capillary stops have, which only after impressing a pressure pulse on the Be overcome liquid, followed by the further transport of the Liquid in turn is induced by capillary forces. Such capillary stops could, for example, at the outputs of the reaction chambers 50,52,54 be formed or arranged. The selective transport of the liquid through the Kapillarkanalsystem 10 takes place in such a case so alternately by exposing vents and imprints one Pressure pulse.

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

In the Fign. 5 to 7 is a second embodiment of a capillary channel system 10 'shown. The basic structure of the capillary channel system 10 'of FIGS. 5-7 is identical to that shown in FIGS. 1 to 4. One Difference exists in the way of exposing the vents. These were in the embodiment according to FIGS. 1 to 4 for example, exposed by individual cover elements 58, while in the Embodiment according to FIGS. 5 to 7 a continuous cover strip 60 is provided as a cover element, which deducted more or less and thus gradually exposes the vents 36,38,40,42. The cover strip 60 may be formed as an adhesive strip, the individual connected by perforation lines or other types of frangible lines 62 Subsections 64,66,68 has. The predetermined breaking lines 62 are located between each two adjacent vents 38,40 and 40,42 and preferably about midway between these openings. At least up that side of a predetermined breaking line 62 leading to the downstream vent opening has, the adhesive side of the cover strip in one of the Rupture line 62 adjacent area 70 free of adhesive. After replacing the first section 64, which has a non-adhesive at its free end Area 72 has, which serves as a gripping, this subsection 64 demolished at the predetermined breaking line 62. The area 70 of the next Subsection 66 then again serves as a summary to facilitate the Detaching the portion 66 to expose the next vent opening 40th

Finally, FIG. 8 shows a further exemplary embodiment of the invention Capillary channel system 10 ", the more (in this embodiment two) channels 14, each of which, as in connection with the described above, procured and designed is, so several (in this embodiment, two) fluidically in Row has switched reaction chambers 50,52. From each channel 14 So branch several vent lines 28,30,32 with vents 36,38,40 at their ends. The first in the flow direction vents 36 of all channels 14 are in groups or all by several or a common cover element 74 is closed. 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 or groupwise common cover elements 74,76,78 is considered over the entire capillary channel system 10 " equal. The channels 14 branch off from a reservoir 80 which communicates with the in and is filled by the reaction chambers 50,52 to conductive liquid or is.

By means of the cover elements 74, 76, 78 it is now possible to carry out the stepwise liquid transport through all channels 14 at the same time and in parallel to initiate or perform. The purpose of the first reaction chambers in the flow direction 50 upstream vents 36 of the channels 14 is clearly, taking into account that the channels 14 in their sections between the reservoir 80 and the first reaction chambers 50 (e.g., by design) can be different in length. The connection points 20 the channels 14, at which the vent lines branch off 28, are in the same Distance along the channel 14 from the first reaction chambers 50 arranged. After exposure of the first vents 36 is then in Each channel 14, the liquid front equidistant from the first reaction chamber 50 on. This is the simultaneous filling of the first reaction chambers 50 after exposure of the second vents 38 ensured.

Alternatively, for all vents a common cover element be provided, which gradually releases vents (corresponding to the cover element of the embodiment according to FIGS 7). Furthermore, in the embodiment according to FIG. 8, provision may alternatively be made be that branching off from the sample liquid transport channels 14 Venting channels 28, 30, 32 in groups (the first group comprises while the first in the flow direction venting channels 28, the second Group in the flow direction second venting channels 30 etc.) in one common vent 36,38,40 end.

As in connection with the first embodiment according to FIGS. 1 to 4, the capillary channel systems 10 'and 10 "of FIG 8 are additionally provided with capillary stops which, as also mentioned above, for example, at the outlet end viewed with respect to the flow direction the reaction chambers 50,52 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. Further will be extremely simple opening mechanisms for the vents described. The system is expediently designed for single use and designed as a disposable item. A minimum of test fluid is needed and no filter / membrane components used. Further allowed the system the completely closed training on a substrate or the like. Carrier, which is why the risk of contamination is minimized. For the Trigger the reactions and in particular the transport of the liquid no centrifugal forces or the like. required. The system according to the invention works independent of position, since capillary forces are used for liquid transport become.

Claims (11)

Device for the stepwise transport of liquid, in particular of the sample liquid to be examined, by means of a plurality of reaction chambers lying in series in fluid flow, taking advantage of capillary forces a channel (14) through which liquid is transportable due to capillary forces, and at least two sealed vents (38, 40, 42) in fluid communication with the channel (14) at joints (22, 24, 26) spaced from each other along the channel (14), wherein the connection points (22, 24, 26) subdivide the channel (14) into a plurality of channel sections (44, 46, 48), wherein the fluid connections between each one channel portion (44,46,48) and its associated vent openings (38,40,42) can be opened individually and wherein in the channel sections (44,46,48) the connection points (22,24,26) viewed upstream in the flow direction at least one chamber (50,52,54) is arranged. Apparatus according to claim 1, characterized in that in at least one chamber (50,52,54) is arranged a reagent substance. Apparatus according to claim 2, characterized in that the reagent substance is immobilized and can be mobilized on contact with the liquid. Device according to one of claims 1 to 3, characterized in that branch off at the connecting points (22,24,26) of the channel (14) venting channels (30,32,34) which terminate in the vent openings (38-42). Apparatus according to claim 4, characterized in that with the vent opening open (38,40,42) liquid by capillary action through the vent passage (30,32,34) to the vent opening (38,40,42) is transportable. Device according to one of claims 1 to 5, characterized in that when the vent opening (38,40,42) open, the liquid after opening the vent opening (38,40,42) by the vent opening (38,40,42) in Flow direction seen upstream channel portion (44,46,48) flows until it reaches the vent opening (38,40,42). Device according to one of claims 1 to 6, characterized in that each vent opening (38,40,42) by a cover member (60,74,76,78) is closed, the peelable, puncturable, meltable and / or by initiation of a reaction dissolvable or permeable to air. Apparatus according to claim 7, characterized in that all the vent openings (38,40,42) by a common cover element (60,74,76,78) are covered, wherein the cover element (60,74,76,78) selectively removable, puncturable , is meltable and / or dissolvable by the initiation of a reaction or permeable to air. Apparatus according to claim 7 or 8, characterized in that one or more thermally coupled to the cover element (60,74,76,78) heating elements are provided for melting the lid member (60,74,76,78). Device according to one of claims 1 to 9, characterized in that a plurality of channels (14) are provided, the successive in the flow direction first, second and further ventilation openings (38,40,42) are each group exposed jointly. Device according to one of claims 1 to 10, characterized in that the vent openings (38,40,42) are capillary openings.

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