WO2013182491A1

WO2013182491A1 - Testing system for portioning, mixing, and distributing biological liquid samples

Info

Publication number: WO2013182491A1
Application number: PCT/EP2013/061294
Authority: WO
Inventors: Thomas Wuske; Jessika Mahn; Rainer Polzius
Original assignee: Dräger Safety AG & Co. KGaA
Priority date: 2012-06-08
Filing date: 2013-05-31
Publication date: 2013-12-12
Also published as: DE102012011411B3

Abstract

The invention relates to a testing system (10) for biological liquids, comprising a tube (14) as a reaction tube. The tube (14) houses a sliding plunger (20) which seals the tube (14) and thus defines a cylindrical reaction chamber (16) that is open on one side for receiving liquid samples (12). The tube (14) has one or more transfer channels (28) which are let into the tube wall, which are vertically offset relative to one another in the axial direction in particular, and which allow the respective liquid sample (12) to penetrate a test zone (32) and at least indirectly allow the liquid sample (12) to advance into the test zone.

Description

DESCRIPTION

Test system for portioning, mixing and distribution of biological

sample liquids

The invention relates to a test system for portioning and optionally mixing, adding and diluting and / or distributing small or very small volumes of biological sample liquids, in particular submilliters volumes of such sample liquids, sometimes also referred to below as a device or test system for biological liquids.

Such devices are known per se.

In the age of mobility, simple measuring methods, which can also be carried out by the layman and can be evaluated quickly, play an increasing role. When it comes to deriving specific diagnoses at any location of measurement results, reliable rapid tests with high ease of use and high functional integration are indispensable. Apart from the precision and accuracy of a measured value, rapid analysis is increasingly important in terms of cost and time-saving diagnostic processes.

In the medical-clinical environment immediately available measurement results allow appropriate measures even in the case of a possibly critical situation of a patient. In addition, the increasing competence and independence of the average consumer also in medical matters beyond clinics and practices evokes a need for measuring in the domestic environment. Vital parameters can be generated there, possibly only prophylactically, more cheaply and as needed and directly. The described measurement requirements are met by so-called "point of care or point of collection" measurement systems.

Pregnancy or fertility tests have been recognized diagnostic tools for normal consumers for decades. Test systems with considerable dissemination are also Glucose analyzers based on blood, as they are used worldwide and daily by diabetics.

For about twenty years, portable drug testing systems for saliva, using as much as possible the technology of immunochromatographic test strips, are in use. There are both visually readable test strips and methods that allow an objectification of the evaluation via reflectometric methods in an analyzer. The fluid management of a sample, optionally its dilution, the reagent uptake and the mixture transfer into the analysis zone is achieved either manually or by device technology.

The necessary accuracy in sample preparation requires sophisticated systems, some of which are based on automated fluid management. The processing of smallest sample volumes enables the use of microfluidic components in sample preparation and analysis.

Multi-chamber rapid assay systems are known for the collection and combined analysis of biological fluids. In this respect, US Pat. No. 6,565,808 B describes a test device which consists of a sample receiving chamber and a combined test platform, wherein the sample receiving chamber can be removed and releases the sample liquid into the test chamber in the course of removal. No. 6,413,784 B describes a hollow cylinder which, on the one hand, accommodates several closed compartments and, on the other hand, carries an integrated sensor membrane. Via a supplied hollow needle, which supplies the analyte on the one hand and, on the other hand, releases reagents from the compartments sequentially disruptively, the mixture of analyte and reagent reaches a sensor membrane located behind the compartments.

US Pat. No. 7,225,689 B describes a sample testing device which, composed of numerous components for sample preparation and analysis, completes a cooperative assembly. A buffer vessel, a cutting facial expressions, a funnel-shaped sample preparation mimic, a sample collector and a test strip in a test strip housing are inserted in a form-fitting manner and make possible the flow of a sample, the contact with a buffer liquid and finally the enrichment and contacting of the sample with a test strip.

US Pat. No. 7,507,374 B describes a system of associated cylindrical chambers, which comprises receiving a body fluid by mixing it with a released reagent fluid from a further chamber with the aid of a rotatable mixing chamber and transferring the fluid to an immunochromatographic test strip via the Shift the said mixing chamber allows a complete sample evaluation. In WO 2005/045408 an immuno-test strip device is described which comprises a housing for at least one test strip, a receptacle for a sample collector and a first chamber with a sample preparation reagent and a second chamber for a second reagent. In addition, the device has instruments for contacting and incubating the sample and reagent and for mixing them, and finally for instruments which allow the mixture to come into contact with a test strip.

In WO 2005/068967 A a device for the examination of biological fluids is described in which a fluid transfer of a sample applied undiluted by means of a metering capillary, which is integrated in a slide valve, is realized. The device implements a fluidic bridge between the sample and the measuring chamber via an axially movable slide valve, in which a capillary, which initially takes a suitable liquid portion in the starting position, is moved to a second position in order to establish contact with a measuring chamber. The device shows a solution for portioning and venting a sample for a test strip. The concept is not suitable for the distribution of a sample liquid on multiple channels, nor for the integration of sampling and sample preparation processes. It is an object of the invention, starting from this prior art, to provide a further embodiment of a device for portioning, mixing, replenishing and diluting and distributing volumes of biological sample liquids, which in particular is easy and intuitive to use. This object is achieved with a device of the type mentioned above with the features of claim 1. Given in such a test system for biological fluids with a tube as a reaction tube, the tube accommodates a sliding piston with valve character, which seals the tube and thus defines a unilaterally open cylindrical reaction space for receiving sample liquids, provided that the tube at least one in has the tube wall inserted transfer channel, which opens at least indirectly in a respective test zone. The transfer channel opens into a transfer pocket designed as a capillary-active gap, the transfer window serving as a starting point for the forwarding of the sample liquid, that is to say, for example, in the direction of a test zone. Since the transfer zone is configured as a capillary-active gap, it is ensured that a sufficient amount of sample liquid is available for this purpose. The advantage of the invention is that the device as a compact detection system with means for the integrated sampling and automatable processing, which at low operating costs, a practical

Interface between minifluidischen and microfluidic system components realized, is suitable.

Advantageous embodiments of the invention are the subject of the dependent claims. This used backlinks point to the further development of the subject matter of the main claim by the features of the respective subclaim; they should not be construed as a waiver of obtaining independent, objective protection for the feature combinations of the dependent claims. Furthermore, with a view to an interpretation of the claims in a closer specification of a feature in a subordinate claim, it is to be assumed that such a restriction does not exist in the respective preceding claims.

In one embodiment of the test system, it is provided that the tube has a plurality of transfer channels, which are embedded in the tube wall and offset axially relative to one another, which open at least indirectly into a respective test zone. Then, with the test system, a multiple examination of the same sample liquid can be carried out quickly and easily in each case in a test zone.

If the at least one transfer channel, individual transfer channels or a plurality of the transfer channels, in particular all transfer channels, have or have a capillary-active geometry, the recording of the respective sample liquid is facilitated in each such transfer channel. This allows easy and simple application of the device even when aligning outside an optimal application position, with an optimal application position of the device is given in an upright or inclined by a few degrees tube. In a device with capillary-active transfer channels, the optimal application position extends up to inclination angles of the tube in the order of 30 °. In one embodiment of the test system, it is provided that the or each transfer bag is provided and designed to accommodate at least one test strip. The transfer bag designed as a capillary-active gap is at least open on one side for this purpose and allows an introduction of at least one test strip on the open side. The gap shape of the transfer bag is thus simultaneously effective with regard to the desired capillary activity as well as for accommodating one end of a test strip or several test strips, that is, for example, for receiving two or three test strips arranged side by side in the longitudinal direction. In a particular embodiment of the test system, it is provided that a test strip which can be used together with the test system has a capillary-active bridge component, that is to say, for example, a fleece acting as a bridge component or the like. The respective bridge component is effective in order to forward sample liquid, which has penetrated into the transfer pocket, like a wick into the test zone. At the same time, the capillary-active bridge component brings about a limitation of the forwarded quantity of the sample liquid, so that in the case of a forwarding to the sensor, this or the test zone is not flooded with sample liquid. If, in a test system of the type described here and below, an overflow chamber is located between the transfer bag and the test zone or respectively a transfer bag and a test zone, the overflow chamber avoids a possible flooding of the test zone by transferring excess sample liquid only into the overflow chamber, but from there did not get to the test zone. The or each transfer bag thus empties into a non-capillary active overflow chamber. By the overflow chamber can be bridged with a test strip inserted into the transfer bag, the accessibility of the test zone remains guaranteed. In one embodiment of the test system, a sensor located in the test zone is characterized by high capillarity, so that it receives sufficient quantities of sample liquid in the test zone adjacent to the overflow chamber. This is favorable if one or more bridge components with in particular average capillarity, for example as an element of a test strip, on the one hand contact the transfer bag and on the other hand the capillary-active sensor and thus bridge the overflow chamber.

A particular embodiment of the test system described here and below functions as a combined sample preparation and test system for biological fluids in that a dry reagent depot, in particular a reaction module in the form of a dry reagent depot, is arranged in the reaction space above the piston. In the dry reagent depot, for example, an oxidizing chemical can be provided which, when the test system is used, forms a chemical compound with a drug substance to be detected.

If such a combined sample preparation and test system has an upwardly directed ventilation channel which forms a ventilation opening outside the tube, such a ventilation channel, for example inserted into the tube wall, fulfills the function of a pressure equalization channel with riser. When using the combined sample preparation and test system causes an exemption of the ventilation duct by the plunger of the piston, the pressure equalization in the reaction chamber and thus facilitates the hydrostatically caused drainage of the sample liquid via the transfer channel or Transfer channels into the transfer bags. Instead of just one ventilation / pressure equalization channel, the test system can also have several such channels, optionally additionally axially offset. A particular embodiment of the combined sample preparation and test system allows the mounting of a sample collector at an upper open end of the tube, in particular the attachment of such a sample collector in a press fit. In use, such a sample preparation and test system is accordingly characterized by a sample collector fitted in an open end of the tube and being able to be moved in an interference fit in the tube. The sample collector comes as a means for supplying a concentrated sample into consideration and the respective sample liquid can be extracted under pressure control of the sample collector with a movement of the piston. If a liquid reagent cartridge is attachable or attached between a piston and a sample collector in a sample preparation and test system, the liquid reagent may be used as a solvent to aid in the extraction of sample liquid from the sample collector. In a method for using a test system as described herein, it is provided that a biological fluid is given as a sample (sample liquid) in an upper, open end of the tube in an application position, namely upright or inclined up to 30 °, and that the sample during a movement of the piston follows the piston and occurs at a successful in the course of a movement of the piston release of the transfer channel or the successive release of individual transfer channels in the transfer channel or the respective transfer channel, there each up to the located at the end of each transfer channel , capillary-active transfer pocket, wets a test strip with a capillary-active bridge component and so finally penetrates to a test zone beyond the overflow chamber adjoining the transfer bag. In this way, the supply of volume fractions of the sample liquid into the transfer channel or individual transfer channels can be controlled selectively via the piston position in the tube. The hydrostatic pressure of the sample and the increased capillarity in the transfer channel trigger the fluid transfer from the tube.

A method for using a test system with a Trockenreagenzde- pot is characterized in that a dry reagent of the dry reagent depot is solved by a pressure change in the tube, in particular a piston position-dependent pressure change, namely triggered by several strokes of the piston, and before with a movement the piston is released one of the transfer channels. The dissolution of the dry reagent represents a sample preparation. With the subsequent release of the transfer channels, the examination of the sample liquid is initiated.

If, in a test system with at least one ventilation channel, the dry reagent of the dry reagent depot is released before a movement of the piston to release one of the transfer channels by a plurality of at least the ventilation channel releasing strokes of the piston, can be due to the over the ventilation channel caused pressure equalization a particularly homogeneous Achieve mixture of sample liquid and dry reagent. A particular embodiment of the method is that a movement with respect to any incubation or reaction times automatically and time-controlled and accordingly by the movement of the piston, the release of the transfer channel or a successive release of individual transfer channels automatically and at predetermined or predeterminable times.

In a method of using a test system that allows the mounting of a sample collector, it is provided that in the upper open end of the tube, a microporous sample collector is introduced with a sample liquid bound therein. The sample collector can be located in a suitable sleeve or tube. In one embodiment of the method, a reagent liquid is displaced from the sample collector via a piston position-dependent pressure change in the tube and finally mixed with the sample liquid. An embodiment of the invention will be explained in more detail with reference to the drawing. Corresponding objects or elements are provided in all figures with the same reference numerals. The or each embodiment is not to be understood as limiting the invention. Rather, in the context of the present disclosure, modifications and modifications are possible, in particular those variants and combinations, for example, by combination or modification of individual in combination with the described in the general or specific description part and in the claims and / or the drawing features or Elements or process steps for the expert in terms of solving the problem can be removed and lead by combinable features to a new subject or to new process steps or process steps, even if they concern testing and working procedures.

Show it:

1 shows a sample receiving and analysis system for metered transfer of a liquid sample into individual integrated analysis units,

2 shows an enlarged view of one of the analysis units,

3,

4 and

5 shows illustrations for illustrating the use of the sample receiving and analyzing system of FIG. 1,

6 shows a specific embodiment and use of the sample receiving and analyzing system of FIG. 1,

7 shows a specific embodiment and use of the sample receiving and analyzing system. FIG. 1 shows a sectional illustration of a sample receiving and analyzing system, here and hereinafter often referred to only briefly as a device 10 or test system, which enables the metered transfer of a liquid sample 12, also referred to below as fluid 12, into individual integrated compartments.

The device comprises a tube 14 whose internal volume acts as a reaction space 16 and in which a sample liquid (sample) 12, not shown in FIG. 1, can be axially positioned with a piston 20 located on a piston rod 18. The piston 20 seals the tube 14 on one side to the ground. In a lower region of the tube 14, there are a plurality of compartments which are identical or identical and act as analysis units 22, 24, 26. In the illustrated configuration, the device 10 includes three such analysis units 22-26.

For a better overview, an enlarged representation of one of the analysis units 22-26 is shown in FIG. 2 as a section of the device 10 according to FIG.

Each analysis unit 22-26 has a transfer channel 28 (sample receiving channel 28) open to the inner volume of the tube 14. Each transfer channel 28 is also open on the side facing away from the tube 14, so that the designation as a ventilated transfer channel 28 justifies itself. On the other side of the ventilated transfer channel 28 there is a transfer pocket 30 which adjoins the respective transfer channel 28 and which is designed as a capillary-active gap. Between the transfer pocket 30 and a test zone 32 is an overflow chamber 34. Each transfer pocket 30 acts as a receptacle for at least one test strip 36 or the like. The test strip 36 comprises at least one capillary-active bridge component, which is sometimes referred to below as a bridge component, that is, for example, a capillary-active nonwoven. At an upper end of each analysis unit 22-26, that is to say with an attached test strip 36 at its end, the test zone 32 is located as the location for a capillary-active sensor 38. Usually, such a capillary-active sensor 38 forms the end of the test stiffener 36. The transfer channels 28 are radially oriented in the tube wall and axially offset from each other. The offset corresponds at least to the length of the piston 20. In the illustrated embodiment, the offset corresponds to the dimension measured in the axial direction of the tube 14 of the individual analysis units 22-26.

A fluid transfer when using the device 10 initially follows the fluidic principle of the communicating chambers. The driving force is

Gravity and negative pressure as a function of a vertical or angular orientation of the device 10 and a position of the piston 20 in the tube 14. In the situation illustrated in FIG. 1, a sample liquid 12 may be located in the reaction space 16, ie above the piston 20. When the piston rod 18 is actuated, ie when the piston 20 is withdrawn from the tube 14, an axial positioning of the piston 20 and thus also the sample liquid 12 located above the piston 20 results. The sample liquid 12 follows the piston position, provided that the alignment of the device 10 wetting of the piston 20 in an ideal vertical orientation or an inclination of up to 30 ° allowed. As soon as the sample liquid 12 reaches the region of one of the analysis units 22-26, specifically into the area of the respective transfer channel 28, parts of the sample liquid 12 enter the transfer pocket 30. Already at this position, the fluid transfer takes place against gravity with the help of capillary force and a wick-like supply of the sensor 38 by the sample liquid 12 rises in the transfer channel 28 and there wets the possibly present at the end bridge component of a test strip 36, which due to their capillary activity the Sample liquid 12 passes into the test zone 32 and the sensor 38 located there.

The rising of the respective sample liquid 12 in the transfer channel 28 can also be understood as a sample / fluid inclusion so that the transfer channel 28, even if it sometimes acts as a drain channel, can also be referred to as a sample collection channel. The transfer channel 28 may optionally have a capillary-active geometry to actively support the uptake of the respective sample liquid 12. Between the transfer channel 28 as the location of the sample receiving and the test zone 32 is the overflow chamber 34. This keeps excess liquid from the sensor 38 far. With regard to the bridge Component of a test strip 36 is a fleece or the like into consideration and the bridge component causes the fluid transport out of the transfer bag 30 and the sensor 38. The sensor 38 is therefore on the capillary active transfer material of the bridge component of the test strip 36 with the Transferta- see 30 in contact and in turn openly accessible, for example, for visual inspection.

The device 10 shown in FIG. 1 can be present in multiple numbers in a test system. The piston 20 can be moved axially or manually by means of an external actuator.

A method for using the device 10 according to FIG. 1 represents a sample processing scheme and can be described as follows: The sliding piston 20 assumes a valve function by releasing a transfer region formed by the transfer channel 28 and the subsequent transfer pocket 30 position-dependent with respect to the reaction space 16 or shielded. A sample liquid 12, which is located above the piston 20, follows the piston 20 when its axial position is changed. An outlet of sample liquid 12 in selectively controlled transfer channels 28 is controlled with their exposure by the sliding piston 20. When the piston 20 reaches one of the transfer channels 28, the sample liquid 12 passes through the respective transfer channel 28, mediated by hydrostatic pressure and low capillary forces, into the transfer pocket 30 and possibly the overflow chamber 34. Only the test zone 32 adjoining this position is supplied with sample liquid 12. For portioning the sample liquid 12, the piston 20 can selectively underflow the respective transfer channel 28 in order to prevent a partial volume of the available liquid from flowing out and to reserve this subset for subsequent processes in subsequent analysis units 22-26. The design of the transfer bag 30 as a gap with low capillarity against a hydrophilic liquid favors by the gap width and the contact angle of the liquid that the inflowing liquid distributed in the entire transfer bag 30 against the flow direction or against gravity and is held there position independent, if fluid contact to the tube 14 is. The gap also forms the receptacle for one or more partially enclosed test strips 36 with bridging components of medium capillarity. This ensures fluid contact with all bridge components. The dimensions of the transfer pockets 30 and the dimensions of the test strips 36 that can be used in each case are matched to one another. Exceeding excess sample liquid 12 passes beyond the transfer bag 30 also only into the overflow chamber 34, to prevent the test zone 32 is flooded. Since the bridge component of the test strip 36 has a greater capillarity with respect to the sample liquid than the gap of the transfer bag 30, it sucks the necessary volume fractions of the sample liquid autonomously from the transfer bag 30 to the capillary-active sensor 38, which in turn opposes the further flow of the sample liquid 12 via increased capillarity maintains the bridge component upright. The sensor 38 is freely accessible for the purpose of optical or visual evaluation and lateral roof-like shutdowns in the analysis unit 22-26 act as a mechanical protection and as protection against contact. Further transfer channels 28 can be actuated piston-position-dependent in order to supply other sensors 38 with sample liquid 12. Excess liquid from leading overflow chambers 34 is available for further analysis units 22-26.

The illustrations in FIGS. 3, 4 and 5 show a use of the device 10 according to FIG. 1 as a rapid drug tester for undiluted or prepared diluted sample liquids 12. The device 10 comprises a housing 40 which is produced from injection-moldable polypropylene. In the housing 40 of the tube 14, a plurality of transfer channels 28, the first open transfer bags 30 (transfer bag profiles), overflow chambers 34 and test zones 32 are molded. The liquid-tight analysis units 22-26 are formed by complementary injection-molded parts which form a sealing connection with the housing 40 via a snap-fit or via a weld seam. The capillary gap of the transfer pockets 30 has, for example, a width of 0.8 mm and a length of 6 mm. The ends of immunochromatographic test strips 36 function as capillary-active sensors 38. Capillary-active glass fiber or polyester nonwovens having sufficient rigidity form part of these test strips 36 as bridge components. The nonwoven is coated, for example, with a gold reagent. This is it colloidal gold conjugates coupled with monoclonal antibodies that bind specifically to the drug substances amphetamine and tetrahydrocannabinol carboxylate. On the immunochromatographic test strip 36 is a capture line in the form of a nitrocellulose membrane immobilized protein-drug conjugate and a control line with an immobilized anti-Host antibody. The sample liquid 12 is urine, which is filled into the reaction space 16 via a dropper bottle, a commercially available pasteur pipette or the like. The illustrations in FIG. 4 and FIG. 5 show that the sample liquid, via the change in the piston position, reaches a respectively released transfer channel 28 and, initiated by the produced fluid contact, continues to run into the transfer pocket 30 and the overflow chamber 34. According to the principle of the communicating chambers, the liquid level between the reaction chamber 16 and the overflow chamber 34 equalizes according to the position of the device 10. In the position shown here, the sample liquid 12 is passed through the tilt angle (about 30 °) of the device 10 into a lower part of the overflow chamber 34. The surplus sample liquid 12 derived therefrom can no longer flood the test tire 36. Otherwise, the sample liquid 12 passes via the capillary-active glass fiber fleece of the test strip 36 acting as a bridging component onto a nitrocellulose membrane of the test strip 36. As the glass fiber fleece passes, gold conjugate is taken up and dissolved in the sample liquid 12 as it flows through the glass fiber fleece. The dissolved conjugate forms a complex with the dissolved drug substance, thereby preventing binding of the conjugates in a capture zone of the nitrocellulose. In the absence of the drug substance, no complex formation takes place in the glass fiber fleece. The gold conjugates can thus be bound alternatively in the capture zone. An intense color line indicates the drug-free nature of the sample. FIG. 5 finally shows that upon further axial lowering of the piston 20, the excess sample liquid 12 flows back into the tube from the overflow chamber, while a remainder remains in the transfer pocket 30 of the first analysis unit 22 in order to supply the sensor with the necessary sample liquid. The excess sample liquid passes again from the tube via the Excess sample liquid flows into the overflow chamber 34, while the sensor 38 of the test strip 36 is supplied from the transfer bag 30 via its capillary-active bridge component 35 with sample liquid 12 in the test strip 36 with the sensor 38 at the end thereof is, for example, a test strip for tetrahydrocannabinol carboxylate (THC acid).

The illustration in FIG. 6 shows an alternative embodiment of the device 10 according to FIG. 1, which is also suitable for a rapid drug test. In contrast to the device in FIG. 1, the device 10 comprises a reaction module, in particular a reaction module in the form of a dry reagent depot 42. The dry reagent depot 42 is applied to a porous filter-type reagent carrier 44 above the piston 20. The reagent carrier 44 is made of sintered polyethylene, for example. Furthermore, the device 10 in FIG. 6 differs from the device 10 in FIG. 1 through a ventilation opening 46 at the end of a ventilation channel 48, which branches off in the tube above a first transfer channel 28. The sample liquid 12 is, for example, diluted saliva. The dry reagent depot 42 includes, for example, an oxidizing chemical that forms a chemical compound with the drug substance. Following filling of the diluted saliva sample, it collects above the dry reagent reservoir 42 and wets it. The capillary-porous structure of the reagent carrier 44 prevents gas exchange with the reaction space 16 below. Only pulling out the piston 20 generates a negative pressure. Through several strokes of the piston 20, the reagent carrier 44 is flushed through several times and the dry reagent 42 finally dissolved and distributed over the resulting convective vortex homogeneously in the diluted saliva sample. Specifically, this preparation of the sample liquid 12 allows a detailed analysis.

The release of the ventilation channel 48 by the piston 20 causes a pressure equalization in the reaction chamber 16 and thus facilitates the hydrostatically caused drainage of the sample liquid 12 via the transfer channels 28 in the Transfer bags 30 and allows the recording of the sample liquid 12 from the immunochromatographic test strips 36 via a fixed in the transfer bag 30 glass fiber fleece. The immunochromatographic test strips 36 are prepared in such a way that the antibody-gold conjugates used can specifically bind the chemically modified drug derivatives. Furthermore, the nitrocellulose bound protein-drug conjugates can bind the antibody-gold conjugate. According to the drug concentration in the sample liquid 12 results in more or less colored lines that can be read visually or by means of an optical device.

7 shows a further embodiment of the device according to FIG. 1 This, like the device in FIG. 6, has a dry reagent depot 42 applied to a porous, filter-type reagent carrier 44 above the piston 20 and a ventilation channel 48. In contrast to the device 10 in FIG. 6, the device 10 illustrated here enables the simple integration of sampling and sample preparation modules in the cylindrical tube 14 above the sliding piston 20 in the sense of an expansion into a complete analysis system. In this case, a sampling interface and a sample preparation section can be integrated in such a way that a controlled fluid transfer of a sample extract generated in the pressure change process from the sampled sampling device via a mixing zone targeted after pressure equalization via transfer channel 28 and transfer bag 30 in different test zones (Diagno- / Analysis areas) 32 takes place. The following describes how this is achieved by means of various components and a special arrangement of the components to each other:

One or more connected open cylindrical tubes 14 are reaction chambers 16 and an axially sliding piston 20 receptacle which seals tube 14 to the bottom on one side, and optional receptacles for a sample collector 50 and one or more reagent depots. The tube 14 has at certain points below an integrated sample collector 50 radially aligned transfer channels 28, which are axially offset from each other, and a ventilation channel 48. The offset of the transfer channels 28 corresponds at least to the length of the piston 20. The movable in the tube 14 and sealed against the cylindrical wall piston 20 can be moved axially or manually via external actuators. The piston top may optionally serve as a receiver for a Trockenreagenzdepot 42. The further embodiment of the device 10 corresponds to the embodiments already described above. Accordingly, located beyond the vented transfer channels 28 designed as a capillary gap transfer bags 30. Between transfer bag 30 and test zone 32 is an overflow chamber 34. In the test zone 32, which adjoins a formed by the overflow chamber 34 overflow zone, is in the form of a Test strip 36 at least one open-access capillary-active sensor 38, which is on the capillary-active transfer material of the test strip 36 with the transfer bag 30 in contact.

At the upper end of the cylindrical tube 14 is the acted upon by the respective sample liquid 12, in particular capillary porous sample collector 50. This is either an integral part of the Komplettanalysesystems or is designed so that it is supplied to the tube in the course of an analysis following a sampling can. The sample collector 50 is finally on the outer open part in a press fit in the tube 14 movable and is airtight enclosed by the tube 14 in the fully sucked state. Between sample collector 50 and piston 20 there is a mixing zone 52 with a dry reagent depot 42, which is located on a porous carrier material of the reagent carrier 44. In addition, a cartridge 54 for liquid reagent is located between sample collector 50 and piston 20. The sample collector 50 is characterized by a capillary-porous structure and can be made of sintered polyethylene, for example, or designed in the form of collectors flocked with polyester fibers, for example to receive a saliva sample. The sample collector 50 is provided with a mandrel or the like and, in its rigid design, is capable of perforating surrounding cartridge foils. Possible sample processing in a complete test kit formed by the device 10 according to FIG. 7 proceeds as follows:

The sample collector 50 is wetted by the nature of the sample liquid 12 with aqueous liquid and is initially in the upper part of the tube 14. The so-wetted porous sample collector 50 seals against the tube 14 from. The sample collector 50 can be pushed down with an external slider in the tube, perforating an underlying cartridge 54 containing a reagent depot or dilution buffer. In this way, a downstream piston stroke based extraction or mixing process can be initiated.

The sliding piston 20 is capable of producing position-dependent pressure gradients and thus capable of axially moving, thus sucking or pushing away a liquid located below, inside or above the sample collector 50. The pressure-controlled fluid transfer in this manner is the driving force for extraction by perfusion of a sample liquid 12 concentrated in the porous sample collector 50 with a liquid reagent located either on either side of or beyond the sample collector 50. If the piston 20 moves away from the sample collector 50, the mixture of sample liquid 12 and liquid reagent is flushed by a negative pressure onto the dry reagent 42 deposited below. As a result, the dry reagent 42 dissolves in the mixture. The optimal mixing of all reagents is carried out by a plurality of piston strokes mediated by Konvektionswirbel the pressure change and the repeated passage of dry reagent storage 42 and sample collector 50th

By further pulling out of the piston 20, the homogeneous reagent-sample mixture adopts a ventilation valve function by exposing the ventilation channel 48. Thus, the occurring negative pressure is compensated by inflowing air. The leakage of liquid is prevented in that the ventilation channel 48 is designed in the form of a sufficiently long riser. The outlet of mixture into the transfer channels 28 is controlled with their exposure by the sliding piston 20. When the piston 20 reaches one of the transfer channels 28, the mixture passes through hydrostatic pressure and capillary-active transfer into the transfer pocket 30 adjoining the respective transfer channel 28. On the one hand, the transfer pocket 30 ensures via a capillary gap that a portion of the effluent mixture is held in this zone and can be transferred to an absorbent microfluidic transfer material of a test strip 36 which acts as a bridge component and which can likewise be positioned via the gap geometry in this zone.

The transfer channels 28 may be selectively released or isolated via the position of the piston 20. The piston 20, namely the piston rod 18, for example, via a rigid connecting element and a coupling mechanism coupled to a liftable actuator, so that the positioning of the piston 20 can also be done automatically, semi-automatically or at least supported by equipment.

Exceeding excess mixture passes through the transfer bag 30 into an overflow chamber 34, which prevents capillary-active sensors 38, which are positioned in the adjacent test zone 32, which also functions as the analysis area, from being flooded.

The bridge component sucks all necessary liquid onto the capillary-active sensor 38, which in turn controls the flow of the mixture through capillary structures. The sensor 38 is freely accessible for the purpose of optical or visual evaluation.

Other transfer channels 28 can be driven to provide other sensors 38 with mixture. The excess liquid from leading overflow chambers 34 can run in the preferred position of the complete test kit (upright or inclined up to 30 °) and is available for further test zones 32.

A lowermost transfer bag 30 is configured such that excess mixture not used up in the analysis process is stored in a reference store 56 acting absorbent material is physically bound. This can be used to secure sample material for an external reference examination.

One of the devices 10 described herein may be considered as the basis for a hand-held pen-shaped applicator. Such an applicator is useful for manual recovery and subsequent automated analysis of saliva as the sample fluid 12 by means of a separate buffer cartridge placed in sealing engagement with the applicator. The test tire resting on the outside of the tube 14 indicates dosimetrically drug substances directly after the fluidic processing of the sample fluid 12. The shape of the pen-like applicator is suitable both for manual handling during sampling and for the direct presentation of test results after the test run as well as a depot for residual amounts of the sample, which were not used in the initial analysis and thus a secondary analysis (B Sample) can be supplied.

The pen applicator optionally integrates a sample collector 50, allows the actuator-based dilution and extraction of the saliva sample, their enrichment with reagent and the homogeneous mixing of the so spiked sample in a tubular reaction chamber 16 by means of a sealing piston 20 and the piston stroke-dependent hydrostatically initiated transfer of the homogeneous conditioned sample liquid 12th into independent associated test zones 32 for trace detection of a drug analyte in the sample by means of immunochromatographic test strips 36.

Each embodiment of the device 10 described here, as well as variants thereof, can be mounted in an analyzer for automatic or semi-automatic processing of the respective sample liquid 12. The piston 20 is combined with an actuator of the analyzer and is one-dimensionally movable relative to the fixed device 10 by means of the actuating element. Depending on the embodiment, an analyzer can accommodate one of the devices 10 described here or at the same time several of the described devices 10. The analyzer comprises a control device which has at least one actuator, for example an electric motor or a pneumatic cylinder. Linder, and thus determines the movement of the actuating element and finally the movement of the piston 20 of the or each device spatially and temporally. This makes automatic or semi-automatic sample processing possible.

Individual foregrounding aspects of the description submitted here can thus be briefly summarized as follows: First, a device 10 for portioning, mixing and distributing submilliliter volumes of biological sample liquids 12 by means of a piston-stroke mechanism into a plurality of separately accessible, also as Analysis units 22-26 or analysis chambers viewable compartments equipped with capillary-active sensors 38. Furthermore, a method for using the device 10 is given. The concept is tolerant to sample volume and sample tolerances and also enables the integration of sampling and sample preparation modules for rapid sequential sample processing consisting of extraction of biological sample liquid, dilution with liquid reagent, addition of dry reagent 42, homogenous mixing and transfer the mixture to a sensor 38.

LIST OF REFERENCE NUMBERS

10 sample receiving and analysis system ("device")

12 sample / sample liquid

14 tube

16 reaction space

18 piston rod

20 pistons

22-26 analysis units

28 transfer channel

30 transfer bag

32 test zone

34 overflow chamber

35 Capillary active bridge component

36 test strips

38 sensor

40 housing

42 dry reagent depot

44 reagent carrier

46 Ventilation opening

48 ventilation duct

50 sample collector

52 mixing zone

54 cartridge (for liquid reagent)

56 reference memory

58 transfer nozzle

60 reaction chamber

62 cartridge flange

64 reagent paper

Claims

1 . Test system (10) for biological fluids with a tube (14) as a reaction tube,

the tube (14) housing a sliding piston (20) which seals the tube (14) and thus defines a cylindrical reaction chamber (16) open on one side for receiving sample liquids (12),

characterized in that

the tube (14) has at least one transfer channel (28) embedded in the tube wall, which opens into a capillary-active transfer pocket (30), which penetrates the respective sample liquid (12) and at least indirectly advances the sample liquid (12) into a test zone (32) allowed.

2. Test system (10) according to claim 1, wherein the tube (14) has a plurality of recessed in the tube wall, axially offset from each other transfer channels (28), the penetration of the respective sample liquid (12) and at least indirectly a penetration of the sample liquid (12). allow in a test zone (32).

The test system (10) of claim 1 or 2, wherein the or each transfer channel (28) has a capillary-active geometry.

4. test system (10) according to any one of claims 1 to 3, wherein each Transferta- see (30) for receiving at least one test strip (36) is provided and configured.

The test system (10) of claim 4, wherein a test strip (36) usable with the test system (10) comprises a capillary-active bridge component.

6. test system (10) according to one of claims 1 to 5, wherein between each one transfer bag (30) and a test zone (32) has an overflow chamber (34) and wherein the overflow chamber (34) can be bridged with a test strip (36) inserted into the transfer pocket (30).

7. A combined sample preparation and test system (10) for biological fluids in the form of a test system (10) according to one of the preceding claims, wherein in the reaction space (16) above the piston (20) a reaction module in the form of a Trockenreagenzdepots (42) is arranged.

8. Combined sample preparation and test system (10) according to claim 7, with a ventilation channel formed above a first transfer channel (28)

(48) terminating outside the tube (14) in a vent opening (46) formed as a riser.

9. A combined sample preparation and test system (10) according to claim 7 or 8, with one in an open end of the tube (14) fitted and in one

Press fit in the tube (14) movable sample collector (50).

A combined sample preparation and testing system (10) according to claim 9, including a liquid reagent cartridge (54) mounted between said piston (20) and sample collector (50).

1 1. A method of using a test system (10) according to any one of claims 1 to 10, wherein a biological fluid is added as sample (12) to an upper open end of the tube (14) in an application position, and wherein the sample fluid (12) a movement of the piston (20) follows the piston (20) and in the course of a movement of the piston (20) takes place releasing the transfer channel (28) or a successively releasing individual transfer channels (28) in the transfer channel or the respective transfer channel (28), where it penetrates to the capillary-active transfer pocket (30) located at the end of the respective transfer channel (28), where it wets a test strip (36) with a capillary-active bridge component and finally finally to one beyond the transfer pocket (30) subsequent overflow chamber (34) located test zone (32) penetrates.

12. The method of claim 1 1 for using a test system (10) according to claim 8 or 9, wherein a dry reagent of the Trockenreagenzdepots (42) before a movement of the piston (20) for releasing one of the transfer channels (28) by a piston position-dependent pressure change in the tube (14) is solved.

13. The method of claim 1 1 for using a test system (10) according to claim 9, wherein a dry reagent of the Trockenreagenzdepots (42) before a movement of the piston (20) for releasing one of the transfer channels (28) by a plurality, in each case at least the ventilation channel ( 48) releasing Hubbewegun- conditions of the piston (20) is released.

14. The method according to any one of claims 1 1 to 13 for using a test system (10) according to claim 10, wherein in the upper open end of the tube (14) a microporous sample collector (50) with a sample liquid bound therein (12) introduced becomes.

15. The method of claim 14, wherein from the sealed sample collector (50) a reagent liquid via a piston position-dependent pressure change in the tube (14) is displaced.

16. The method according to any one of claims 1 1 to 15, wherein by a movement of the piston (20) the release of the transfer channel (28) or a successive release of individual transfer channels (28) takes place automatically and at predetermined or predeterminable times.