DE102012011411B3 - Test system for portioning, mixing and distribution of biological sample liquids - Google Patents

Abstract

The invention relates to a test system (10) for biological fluids with a tube (14) as a reaction tube, wherein the tube (14) accommodates a sliding piston (20) which seals the tube (14) and thus a cylindrical reaction chamber (16) open on one side ) for receiving sample liquids (12), wherein the tube (14) has one or more in the Tubuswand embedded, in particular 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) into a test zone (32).

Description

The invention relates to a test system for portioning and sometimes mixing, topping up and diluting and / or distributing small or very small volumes of biological sample liquids, in particular sub-milliliter volumes of such sample liquids, sometimes also referred to as apparatus 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 measurement, rapid analysis is becoming 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" measuring systems. Simplest designs, such as B. Pregnancy or fertility tests have been recognized diagnostic tools for normal consumers for decades. In addition, test systems with widespread use are glucose analyzers based on blood, as used by diabetics worldwide and daily.

For about twenty years, portable drug testing systems have been in use for saliva, using as much as possible the technology of immunochromatographic test strips. 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 solved either manually or device-technically.

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, in the US 6,565,808 B2 describes a test device consisting of a sample receiving chamber and a combined test platform, wherein the sample receiving chamber is removable and releases the sample liquid into the test chamber during the removal. In the US 6,413,784 B1 a hollow cylinder is described which accommodates on the one hand 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 disruptive, the mixture of analyte and reagent reaches a sensor membrane located behind the compartments.

The US Pat. No. 7,225,689 B2 describes a sample testing device that, 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 into each other in a form-fitting manner and allow the passage of a sample, the contact with a buffer liquid and finally the enrichment and contacting of the sample with a test strip.

The US 7,507,374 B2 describes a system of associated cylindrical chambers that allows complete sample evaluation from the ingestion of a body fluid via its mixing with a liberated reagent fluid from another chamber by means of a rotatable mixing chamber to fluid transfer of the mixture to an immunochromatographic test strip via the displacement of said mixing chamber , In the WO 2005/045408 A1 there is described an immunoassay device comprising a housing for at least one test strip, a sample collector receptacle and a first chamber having a sample preparation reagent, and a second chamber for a second reagent. In addition, the device comprises instruments for contacting and incubating the sample and reagent and for mixing them, and finally instruments allowing contact of the mixture with a test strip.

In the WO 2005/068967 A1 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 realizes a fluidic bridge between the sample and the measuring chamber via an axially movable slide valve, in which a capillary, which initially removes 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.

GB 2483077 A describes a device by means of which one or more analytes can be detected in a sample. This device has a housing with a receptacle for a sampling device. In addition, the device has a capsule which is closed with a lid and contains a liquid buffer. The capsule is connected to the housing such that the lid is opened by inserting the sampling device into the receptacle, whereby the buffer is discharged into the receptacle.

US 2010/0274155 A1 also discloses an analysis and sampling device in which a biological sample is picked up by means of a swab. Subsequently, the swab is inserted into the analyzer, where the sample is then analyzed. To address the problem of spurious measurements that may be caused by contamination of the outer surface of the analyzer US 2010/0274155 A1 in that the analysis device has a receptacle for the swab, which has a sealable closure.

Also US 2003/0022392 A1 discloses a test device useful in the detection of various analytes in a body fluid. US 2003/0022392 A1 suggests that a sample collection device comprises a chamber, a reservoir and a valve, wherein the valve between the chamber and the reservoir is arranged. The majority of the sample taken - for example, a urine sample - is initially in the chamber. The required for the analysis smaller amount of this sample can then be transferred by means of the valve in the reservoir.

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 configured as a capillary-active gap, the transfer bag serving as the starting point for the forwarding of the sample liquid, ie, 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 is suitable as a compact detection system with means for integrated sampling and automated processing, which realizes a practical interface between minifluidischen and microfluidic system components with low operating costs.

Advantageous embodiments of the invention are the subject of the dependent 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 with 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 expands the optimal application position 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 therefore simultaneously effective with regard to the desired capillary activity as well as for receiving one end of a test strip or several test strips, thus, for example, for receiving two or three longitudinally juxtaposed test strips.

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 acts as a combined sample preparation and test system for biological fluids by 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 may be provided which, when using the test system, chemically binds to a drug substance to be detected.

If such a combined sample preparation and test system has an upwardly directed ventilation channel formed above the transfer channel or a first transfer channel and ending in a ventilation opening outside the tube, such a ventilation channel, for example inserted into the tube wall, fulfills the function of a riser-compensated pressure equalization channel , When using the combined sample preparation and test system, an exemption of the ventilation channel by the plunger of the piston causes pressure equalization in the reaction space 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 in a movement of the piston follows the piston and at one in the course of a movement the release of the transfer channel or the successive release of individual transfer channels into the transfer channel or the respective transfer channel occurs, there penetrates each to the capillary transfer bag located at the end of the respective transfer channel, 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 dry reagent depot is characterized in that a dry reagent of the dry reagent depot is released by a pressure change in the tube, in particular a piston position-dependent pressure change, namely triggered by several strokes of the piston, before release with a movement of the piston one of the transfer channels takes place. 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.

In a test system having at least one vent channel, when the dry reagent depot is dry reagent prior to movement of the plunger to release one of the transfer channels through a plurality; In each case at least the ventilation channel releasing strokes of the piston is released, can be achieved due to the pressure equalization effected via the ventilation channel a particularly homogeneous 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 attachment of a sample collector, it is contemplated that a microporous sample collector with sample liquid bound therein is introduced into the upper open end of the tube. 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.

Show it:

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

2 an enlarged view of one of the analysis units,

3 . 4 and 5 Illustrations illustrating the use of the sample receiving and analysis system 1 .

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

7 a specific embodiment and use of the sample receiving and analyzing system.

1 shows in a sectional view here and hereinafter often only briefly as a device 10 or test system called Probenaufnahme- and analysis system, the or the metered transfer of a hereinafter also as fluid 12 designated liquid sample 12 into individual integrated compartments.

The device comprises a tube 14 , whose internal volume as the reaction space 16 acts and in which one in the 1 sample liquid not shown (sample) 12 with one on a piston rod 18 located piston 20 is axially positionable. The piston 20 seals the tube 14 from one side to the ground. In a lower area of the tube 14 is a plurality of the same or similar executed and as analysis units 22 . 24 . 26 functioning compartments. In the illustrated configuration, the device includes 10 three such analysis units 22 - 26 ,

For a better overview, see 2 as a section of the device 10 according to 1 an enlarged view of one of the analysis units 22 - 26 shown.

Each analysis unit 22 - 26 has one to the inner volume of the tube 14 open transfer channel 28 (Sample reception channel 28 ) on. Everyone transfer channel 28 is also on the tube 14 facing away from the side, so that the designation as a ventilated transfer channel 28 justifies. Beyond the ventilated transfer channel 28 there is a to the respective transfer channel 28 subsequent transfer bag 30 , which is designed as a capillary-active gap. Between the transfer bag 30 and a test zone 32 there is an overflow chamber 34 , Each transfer bag 30 acts as a receptacle for at least one test strip 36 or similar. The test strip 36 includes at least one capillary-active bridge component, which is sometimes referred to below as a bridge component, so for example, a capillary-active nonwoven. At the top of each analysis unit 22 - 26 So with an attached test strip 36 at the end, there is the test zone 32 as a place for a capillary-active sensor 38 , Usually, such a capillary-active sensor forms 38 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 axial direction of the tube 14 measured dimension of the individual analysis units 22 - 26 ,

A fluid transfer when using the device 10 follows first the fluidic principle of the communicating chambers. The driving force is gravity and negative pressure in response to a vertical or angular orientation of the device 10 and a position of the piston 20 in the tube 14 , At the in 1 situation shown may be in the reaction space 16 So above the piston 20 , a sample fluid 12 are located. When operating the piston rod 18 , so when pulling out the piston 20 from the tube 14 , results in an axial positioning of the piston 20 and thus also above the piston 20 located sample liquid 12 , The sample liquid 12 follows the piston position, provided the orientation of the device 10 a wetting of the piston 20 in ideal vertical orientation or tilted up to 30 °. Once the sample liquid 12 in this way in the area of one of the analysis units 22 - 26 , specifically in the area of the respective transfer channel 28 passes, pass parts of the sample liquid 12 in the transfer bag 30 one. Even at this position, the fluid transfer takes place against gravity by means of capillary force and a wick-like supply of the sensor 38 by adding the sample liquid 12 in the transfer channel 28 rises and there the possibly present at the end bridge component of a test strip 36 wetted, which due to their capillary activity, the sample liquid 12 to the test zone 32 and to the sensor located there 38 forwards.

The rising of the respective sample liquid 12 in the transfer channel 28 can also be understood as a sample of the sample / the fluid, so that the transfer channel 28 Even if it sometimes functions as a drainage channel, it can also be called a sample collection channel. The transfer channel 28 Optionally have a capillary-active geometry to the recording of the respective sample liquid 12 actively support. Between the transfer channel 28 as the location of the sample intake and the test zone 32 is the overflow chamber 34 , This keeps excess liquid from the sensor 38 remote. 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 from the transfer bag 30 out and to the sensor 38 , The sensor 38 is therefore about the capillary active transfer material of the bridge component of the test strip 36 with the transfer bag 30 in contact and in turn openly accessible, for example, for a visual inspection.

In the 1 shown device 10 can be present in multiple numbers in a test system. The piston 20 Can be moved axially or manually with an external actuator.

A method of using the device 10 according to 1 represents a sample processing scheme and can be described as follows: The sliding piston 20 assumes a valve function by passing a through the transfer channel 28 and the subsequent transfer bag 30 formed transfer region position-dependent with respect to the reaction space 16 is released or shielded. A sample liquid 12 that is above the piston 20 is located, follows the piston 20 when its axial position is changed. An outlet of sample liquid 12 in targeted controlled transfer channels 28 with their exposure through the sliding piston 20 controlled. Reached the piston 20 one of the transfer channels 28 , sample liquid occurs 12 mediated by hydrostatic pressure and low capillary forces across the respective transfer channel 28 in the transfer bag 30 and optionally the overflow chamber 34 out. Only the test zone following this position 32 is with sample liquid 12 provided. For portioning the sample liquid 12 can the piston 20 the respective transfer channel 28 specifically subverted to prevent a partial volume of the available liquid at the outlet and this subset for subsequent processes in subsequent analysis units 22 - 26 reproach.

The design of the transfer bag 30 as a gap with low capillarity to a hydrophilic liquid favored by the gap width and the contact angle of the liquid, that the inflowing liquid throughout transfer case 30 distributed against the direction of flow or against gravity and is held there position independent, provided fluid contact with the tube 14 consists. The gap also forms the receptacle for one or more partially wrapped test strips 36 with bridge components of medium capillarity. This ensures fluid contact with all bridge components. The dimensions of the transfer bags 30 and the dimensions of the test strips which can be used in each case 36 are geared to each other. Further exiting excess sample liquid 12 passes over the transfer bag 30 only in the overflow chamber 34 to prevent the test zone 32 is flooded. Because the bridge component of the test strip 36 has a greater capillarity 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 on the capillary-active sensor 38 , in turn, the further flow of the sample liquid 12 maintains elevated capillarity to the bridge component. 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 mechanical protection as well as contact protection. Other transfer channels 28 can be controlled piston position dependent to other sensors 38 with sample liquid 12 to supply. Excess liquid from leading overflow chambers 34 stands for further analysis units 22 - 26 to disposal.

The illustrations in 3 . 4 and 5 show a use of the device 10 according to 1 as a drug rapid tester for undiluted or prepared diluted sample fluids 12 , The device 10 includes a housing 40 , which is made of injection-moldable polypropylene. In the case 40 are the tube 14 , several transfer channels 28 , the first open transfer bags 30 (Transfer bag profiles), overflow chambers 34 and test zones 32 shaped. The liquid-tight analysis units 22 - 26 caused by complementary injection-molded parts, which via a snap or via a weld with the housing 40 form a sealing connection. The capillary gap of the transfer bags 30 For example, has a width of 0.8 mm and a length of 6 mm. As capillary-active sensors 38 The ends of immunochromatographic test strips act 36 , Capillary-active glass fiber or polyester nonwovens with sufficient rigidity form part of these test strips as bridge components 36 , The nonwoven is coated, for example, with a gold reagent. These are conjugates of colloidal gold coupled with monoclonal antibodies that bind specifically to the drug substances amphetamine and tetrahydrocannabinol carboxylate. On the immunochromatographic test strip 36 there 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, via a dropper bottle, a commercial pasteur pipette or the like in the reaction space 16 is filled.

The illustrations in 4 and 5 show that the sample liquid on the change of the piston position in a respective release transfer channel 28 passes and, initiated by the established fluid contact, further into the transfer bag 30 and the overflow chamber 34 running. According to the principle of the communicating chambers, the liquid level is similar between the reaction space 16 and overflow chamber 34 according to the location of the device 10 out. In the position shown here, the sample liquid 12 by the tilt angle (about 30 °) of the device 10 in a lower part of the overflow chamber 34 directed. The surplus sample liquid derived there 12 can the test tire 36 do not flood anymore. Otherwise, the sample liquid passes 12 via the capillary-active glass fiber fleece of the test strip functioning as bridge component 36 on a nitrocellulose membrane of the test strip 36 , When passing the glass fiber fleece, gold conjugate is taken up and in the sample liquid 12 dissolved when flowing 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.

5 finally shows that on further axial lowering of the piston 20 the excess sample liquid 12 from the overflow chamber flows back into the tube, while a remainder in the transfer bag 30 the first analysis unit 22 remains to supply the sensor with the necessary sample liquid. The excess sample liquid passes again from the tube via the next transfer channel 28 and from there into the subsequent transfer bag 30 into the next analysis unit 24 , Excess sample liquid flows into the overflow chamber 34 while the sensor 38 of the test strip 36 from the transfer bag 30 out about his capillary active bridge component 35 with sample liquid 12 is supplied with the test strip 36 with the sensor located at its end 38 For example, it is a test strip for tetrahydrocannabinol carboxylate (THC acid).

The representation in 6 shows an alternative embodiment of the device 10 according to 1 , which is also eligible for a rapid drug test. The device 10 In contrast to the device in 1 a reaction module, in particular a reaction module in the form of a dry reagent depot 42 , The dry reagent depot 42 is above the piston 20 on a porous filter-like reagent carrier 44 applied. The reagent carrier 44 For example, it is made of sintered polyethylene. Further, the device differs 10 in 6 from the device 10 in 1 through a ventilation opening 46 at the end of a ventilation duct 48 in the tube above a first transfer channel 28 going on.

The sample liquid 12 For example, it consists of diluted saliva. The dry reagent depot 42 For example, it contains an oxidizing chemical that forms a chemical compound with the drug substance. Following the filling of the diluted saliva sample, it collects above the dry reagent depot 42 and wet this. The capillary-porous structure of the reagent carrier 44 prevents the gas exchange to the underlying reaction space 16 , Only pulling out the piston 20 creates a negative pressure. Through several strokes of the piston 20 becomes the reagent carrier 44 rinsed several times and the dry reagent 42 finally dissolved and distributed over the resulting convective vortices homogeneously in the diluted saliva sample. Especially this preparation of the sample liquid 12 allows an accurate analysis.

The exemption of the ventilation duct 48 through the piston 20 causes a pressure equalization in the reaction space 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 about one in the transfer bag 30 fixed glass fiber fleece. The immunochromatographic test strips 36 are prepared so 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 fluid 12 This results in more or less colored lines, which can be read visually or by means of an optical device.

7 shows a further embodiment of the device according to 1 , This points as the device in 6 above the piston 20 a on a porous, filter-like reagent carrier 44 Applied dry reagent depot 42 and a ventilation duct 48 on. Unlike the device 10 in 6 allows the device shown here 10 easy integration of sample and sample preparation modules in the cylindrical tube 14 above the sliding piston 20 in the sense of an extension to a complete analysis system.

In this case, a sampling interface and a sample preparation section can be integrated in such a way that controlled fluid transfer of a sample extract generated in the pressure change process from the sampled sampling apparatus via a mixing zone is targeted after pressure equalization via transfer channel 28 and transfer bag 30 into different test zones (diagnosis / analysis areas) 32 he follows. 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 chamber 16 and receiving for an axially sliding piston 20 , the tube 14 Seals on one side to the bottom, as well as optional pick-up for a sample collector 50 and one or more reagent depots.

The tube 14 indicates at certain points below an integrated sample collector 50 radially aligned transfer channels 28 , which are axially offset from each other, and a ventilation duct 48 on. The offset of the transfer channels 28 corresponds at least to the length of the piston 20 , The one in the tube 14 movable and opposite the cylindrical wall sealing piston 20 Can be moved axially or manually via external actuators. The piston top can optionally be used as a receiver for a dry reagent depot 42 serve. The further embodiment of the device 10 corresponds to the embodiments already described above. Accordingly, there are beyond the ventilated transfer channels 28 the transfer bags designed as a capillary gap 30 , Between transfer bag 30 and test zone 32 there is an overflow chamber 34 , In the test zone 32 that attach to a through the overflow chamber 34 formed overflow zone, is in the form of a test strip 36 at least one open-access capillary-active sensor 38 using the capillary-active transfer material of the test strip 36 with the transfer bag 30 is in contact.

At the upper end of the cylindrical tube 14 is the one with the respective sample liquid 12 acted upon, in particular capillary porous sample collector 50 , This is either an integral part of the Komplettanalysesystems or is designed so that it can be supplied to the tube in the course of an analysis following a sampling. The sample collector 50 is finally located on the outside open part in a press fit in tube 14 movable and becomes airtight from the tube in the fully sucked state 14 edged. Between sample collector 50 and pistons 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 located. In addition, between sample collector 50 and pistons 20 a cartridge 54 localized for liquid reagent. The sample collector 50 is characterized by a capillary porous structure and can be used z. B. made of sintered polyethylene or in the form of flocked with polyester fibers collectors, for example, to receive a saliva sample. The sample collector 50 is provided with a mandrel or the like and in its rigid design suitable to perforate surrounding cartridge films.

One possible sample processing in one by the device 10 according to 7 formed complete test kit is as follows:
The sample collector 50 is due to the nature of the sample fluid 12 wetted with aqueous liquid and is initially in the upper part of the tube 14 , The thus 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, an underlying cartridge 54 perforating 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 is capable of being located below, inside or above the sample collector 50 To move liquid located axially, thus to suck or push away. The pressure-controlled fluid transfer in this way is the driving force for extraction by perfusion in the porous sample collector 50 concentrated sample liquid 12 with a liquid reagent located either on either side of or beyond the sample collector 50 located.

Moves the piston 20 from the sample collector 50 away, the mixture of sample liquid 12 and Flüssigreagenz by a negative pressure on the below deposited dry reagent 42 rinsed. This dissolves the dry reagent 42 in a mixture. The optimum mixing of all reagents is achieved by several piston strokes mediated by convection vortices during pressure change and repeated flow through the dry reagent depot 42 and sample collector 50 ,

The homogeneous reagent-sample mixture takes over by further pulling out of the piston 20 a vent valve function by the ventilation duct 48 is exposed. Thus, the occurring negative pressure is compensated by inflowing air. The escape of liquid is prevented by the ventilation duct 48 is designed in the form of a sufficiently long riser.

The outlet of mixture in the transfer channels 28 with their exposure through the sliding piston 20 controlled. Reached the piston 20 one of the transfer channels 28 , Mixture mediates by hydrostatic pressure and capillary-active transfer to the respective transfer channel 28 subsequent transfer bag 30 out. The transfer bag 30 On the one hand ensures via a capillary gap that a portion of the effluent mixture is held in this zone and on an absorbent microfluidic and acting as a bridge component transfer material of a test strip 36 can be transmitted, which is also positioned on the gap geometry in this zone.

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

Exceeding excess mixture passes through the transfer bag 30 out into an overflow chamber 34 which prevents capillary-active sensors 38 in the adjacent and also acting as an analysis area test zone 32 are positioned to be flooded.

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

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

A bottom transfer bag 30 is designed such that excess, not consumed in the analysis process mixture in one as a reference memory 56 acting absorbent material is physically bound. This can be used to secure sample material for an external reference examination.

One of the devices described here 10 comes as a basis for a hand-held pen-shaped applicator into consideration. Such an applicator is for manual collection and subsequent automated analysis of saliva as sample liquid 12 usable by means of a separate buffer cartridge placed in sealing contact with the applicator. The outside of the tube 14 attached test tires shows dosimetrically drug substances directly after the fluidic processing of the sample liquid 12 at. 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 sample so spiked in a tubular reaction space 16 by means of a sealing piston 20 and the piston stroke dependent hydrostatically initiated transfer of the homogenously conditioned sample fluid 12 in independent associated test zones 32 for the trace detection of a drug analyte in the sample by means of immunochromatographic test strips 36 ,

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

Individual prominent aspects of the description submitted here can thus be briefly summarized as follows: First indicated is a device 10 for portioning, mixing and distributing submillitler volumes of biological sample fluids 12 with the help of a piston-stroke mechanism in several separately accessible, also as analysis units 22 - 26 or analysis chambers conceivable compartments, with capillary active sensors 38 are equipped. Furthermore, a method of using the device 10 specified. The concept is within sample volume and position tolerant and also allows the integration of sampling and sample preparation modules for rapid sequential sample processing consisting of extraction of a biological sample liquid, its dilution with liquid reagent, replenishment with dry reagent 42 their homogeneous mixture and the transfer of the mixture to a sensor 38 ,

LIST OF REFERENCE NUMBERS

10

Sample Collection and Analysis System ("Device")

12

Sample / sample liquid

14

tube

16

reaction chamber

18

piston rod

20

piston

22-26

analysis units

28

transfer channel

30

transfer case

32

test zone

34

Overflow chamber

35

Capillary active bridge component

36

test strips

38

sensor

40

casing

42

Trockenreagenzdepot

44

reagent

46

ventilation opening

48

ventilation duct

50

sample collector

52

mixing zone

54

Cartridge (for liquid reagent)

56

reference memory

58

Transferdüse

60

reaction chamber

62

cartridge flange

64

Test Paper

Claims (16)

Test system ( 10 ) for biological fluids with a tube ( 14 ) as a reaction tube, wherein the tube ( 14 ) a sliding piston ( 20 ) housing the tube ( 14 ) and thus a unilaterally open cylindrical reaction space ( 16 ) for receiving sample liquids ( 12 ), characterized in that the tube ( 14 ) at least one embedded in the tube wall transfer channel ( 28 ), which is in a capillary active transfer bag ( 30 ), the penetration of the respective sample liquid ( 12 ) and at least indirectly, a penetration of the sample liquid ( 12 ) into a test zone ( 32 ) allowed. Test system ( 10 ) according to claim 1, wherein the tube ( 14 ) several let into 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 ) into a test zone ( 32 ) allow. Test system ( 10 ) according to claim 1 or 2, wherein the or each transfer channel ( 28 ) has a capillary-active geometry. Test system ( 10 ) according to one of claims 1 to 3, wherein each transfer bag ( 30 ) for receiving at least one test strip ( 36 ) is provided and configured. Test system ( 10 ) according to claim 4, wherein one together with the test system ( 10 ) usable test strip ( 36 ) has a capillary-active bridge component. Test system ( 10 ) according to one of claims 1 to 5, wherein between each one transfer bag ( 30 ) and a test zone ( 32 ) an overflow chamber ( 34 ) and wherein the overflow chamber ( 34 ) with one in the transfer bag ( 30 ) used test strips ( 36 ) is bridgeable. 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 dry reagent depot ( 42 ) is arranged. Test system ( 10 ) according to claim 7, with one above a first transfer channel ( 28 ) formed ventilation channel ( 48 ) outside the tube ( 14 ) in a ventilation opening formed as a riser ( 46 ) ends. Test system ( 10 ) according to claim 7 or 8, with one in an open end of the tube ( 14 ) and in a press fit in the tube ( 14 ) movable sample collector ( 50 ). Test system ( 10 ) according to claim 9, with an intermediate piston ( 20 ) and sample collector ( 50 ) mounted cartridge ( 54 ) for liquid reagent. Method for portioning, mixing, replenishing, diluting and / or distributing biological sample liquids with a test system ( 10 ) according to any one of claims 1 to 10, wherein a biological fluid is used as a sample ( 12 ) in a in an application position upper open end of the tube ( 14 ) and the sample liquid ( 12 ) during a movement of the piston ( 20 ) the piston ( 20 ) and at one in the course of a movement of the piston ( 20 ) release of the transfer channel ( 28 ) or a gradual release of individual transfer channels ( 28 ) in the transfer channel or the respective transfer channel ( 28 ), there until the end of the respective transfer channel ( 28 ), capillary-active transfer bag ( 30 ) penetrates, there a test strip ( 36 ) wetted with a capillary-active bridge component and so finally up to one on the other side of the transfer bag ( 30 ) subsequent overflow chamber ( 34 ) ( 32 ) penetrates. Method according to claim 11 for the use of a test system ( 10 ) according to claim 8 or 9, wherein a dry reagent of the dry reagent depot ( 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. Method according to claim 11 for the use of a test system ( 10 ) according to claim 9, wherein a dry reagent of the dry reagent depot ( 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 strokes of the piston ( 20 ) is solved. Method according to one of claims 11 to 13 for the use of 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 ) is introduced. 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. Method according to one of claims 11 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 ) automatically and at predetermined or predeterminable times.

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