Reagent cartridge with reagent containers for reagents containing particles for their non-invasive homogenization

The invention relates to a to a reagent cassette with a reagent for particle-containing reagent, which is particularly suitable for non-invasive Homogenization of coated and sedimenting particles and a magazine.

State of the art

Diagnostic assay systems include in many cases the use of particles in a liquid for the sequence of reactions. This is to process the Detecting chemical binding reactions, for example in connection with Antigens or antibodies. For the correct processing of assays on these Systems, it is usually required that the particles in their containers at the time of removal have a homogeneous distribution. A homogeneous particle distribution avoids for example by sedimentation occurring concentration differences between successive withdrawals from the containers.

In the area of ​​clinical diagnostic analysis systems for homogenization of particles such as magnetic particles with particle-containing reagent containers are connected subsequent processes already known. There rotating paddles are used. Such rotatably received paddles are known from EP 0745855, and from US 6,772,962. Furthermore, intermittently coming rotating round plastic bottles for use, which are fitted with radial inner fins, such as, for example, US 5,637,275, US 5,795,784 or US 5,856,194 may be removed. In addition, Ultrasonic methods are known in which a stimulated by ultrasound dosing in the liquid is immersed and this mixed. Such solutions may, for example, US 5,658,799, EP 0580483 or US 5,985,672 are removed. Further, it is known to immerse a glass ball in a round, eccentrically rotating glass bottle, to the contents of the glass bottle to impose a mixing motion. such a A method is known for example from US 5,183,638. From the state of the art further reagent cartridges are known which have a rotatably mounted container is driven by a friction wheel drive, so, for example, US No. 5,580,524 or from EP 0435481.

Known from the prior art process for the homogenization of particle-containing reagent, for example in analysis systems, the external actuators, such as use as paddles, adhere to a number of disadvantages. In such a A process for homogenisation of particle-containing reagent is a invasive mixing methods. This means that in principle the risk of Over between different particle-charged reagent is produced. Around the risk of spread counteract in such analysis systems are in these systems special wash stations and washing liquids used with which the risk of spread is to be counteracted. However, this requires a much higher expenditure on equipment in such analysis systems. at Analysis systems of external actuators such as paddle for homogenization use particle-containing reagents, a plurality of reagent can only sequentially be processed. This in turn attracts long preparation times for a run by itself, also have limitations in the design of the machine cycle, the time Access given to other reagent and the device cycle time. According to this Procedures homogenized particle-containing reagents also occurs with decreasing Liquid volume to an increasing foaming, which relatively high Reagenzdruckvolumina entails.

Invasive working ultrasonic systems, when certain types of particles to unauthorized changes in the particle coating. The same occurs with invasive Absence of assistants, as they represent about glass beads on. In systems in which used for homogenization of particle-containing reagents inner radial fins be a strong foaming occurs during mixing certain liquids; also splashed the liquid, which is highly unsatisfactory.

In the prior art according to US 5,788,928 or EP 0,757,253 known systems with pivoting cassettes at predetermined reagent usually a significantly larger tank volume is required, which to a larger Space requirements for such systems leads.

known from the prior art Given the above outlined disadvantages A process for the homogenization of particle-containing reagents is the present Invention, the object of a homogenization of particle-laden Reagents noninvasively provide by rotating a container.

According to the invention this object is achieved by the features of claims 1 and 5 dissolved.

The advantages of the inventively proposed solution are that by the proposed noninvasive homogenization of particle-laden liquid which Carryover risk can be definitely ruled out. It requires no Washing stations. Further, no washing fluid is required and finally there is no Liquid waste that must be disposed of in compliance with legal regulations. In addition, an extremely low dead volume can be achieved, whereby the reagent better can be exploited as a foam, as the prior art known methods outlined below will remain. The inventively proposed solution also allows greater degrees of freedom when designing the system and offers the possibility parallelization of accesses in the reagent, as reagents to several containers filled with a container unit can be accessed. The parallelization also enables significantly shorter process times for homogenization compared with sequential processing.

Furthermore, can be explained by the inventively proposed solution parallelization reach the Ersthomogenisierung for reagent cartridges; because of possible Particle sedimentation can be particularly time consuming just the Ersthomogenisierung. Before Ersthomogenisierung no liquid-level-detection is required because for a Mix by rotation bottles of liquid level inside the reagent cartridges does not have to be known. In contrast, this is when mixing processes using Rührpaddeln required because only insufficient immersion of the agitator paddles may contributes to foaming and produces unwanted splashes.

The proposed inventions, joinable cartridge further provides Advantage that lid opening and lid closing sequences during homogenization now can be dispensed with. The proposed inventions, more reagents receiving reagent cartridge is provided with a slide fastener, the extra cycles such as opening or closing, and thus avoids the throughput times reduced.

The proposed inventions joinable reagent cartridge also provides a cost-effective, in high volume manufacturable represents plastic component, which a simple Cartridge assembly allows. Thus, for a cartridge assembly be achieved if two Klipsteile provided with buckles of including Container containing particle-loaded reagents are simply plugged together can. There are large and flat surfaces on the plug-together Klipsteilen, which greatly simplify the labeling. The individual Klipsteile as well as the container, which receives the particle-loaded liquid, can temporally independent be filled from each other.

drawings

Reference to the drawing, the invention is hereinafter described in more detail.

It shows:<dl tsize="17"><dt>figure 1</dt><dd>an assembled reagent cartridge, two cartridge parts comprising, between which a further container is fixed,</dd><dt>figure 2</dt><dd>one of the two Klipsteile the reagent cartridge in a perspective view,</dd><dt>figure 3</dt><dd>the Klipsteil the reagent cartridge of Figure 2 in half-section,</dd><dt>Figure 4.1 to 4.3</dt><dd>Representations of a particle-loaded reagents containing vessel with spiral structure,</dd><dt>figure 5</dt><dd>an assembled reagent cartridge, between which the Klipsteilen Container is fixed according to the figures 4.1 to 4.3,</dd><dt>figure 6</dt><dd>a section through the assembled reagent cartridge according to the Representation in Figure 5, </dd><dt>figure 7</dt><dd>the items that make up the proposed inventions Reagent cartridge is assembled,</dd><dt>figure 8</dt><dd>the assembled from the individual parts according to figure 7 reagent cartridge,</dd><dt>figure 9</dt><dd>a connection piece via which an integrated in the reagent cartridge, a particle-laden liquid accommodating container in rotation can be set,</dd><dt>figure 10</dt><dd>a mixed magazine with a magazine plate, on top of which the inventively proposed reagent cartridges are included and</dd><dt>figure 11</dt><dd>a perspective view of the apparatus of Figure 10, partially cut.</dd></dl>

variants

The illustration shown in Figure 1 is a made-up, on its upper side still open Reagent cartridge be taken according to the present invention.

A reagent cartridge 1 is a first, forming a container cassette part 2 and a second, also forming a container cassette part 3 is formed. The Container forming cartridge parts 2, 3 are provided at their mutually facing sides, respectively provided with a buckle. 5 Between the bulges 5 of the cassette parts 2, 3 a container 20 (Beadflasche). The container 20 has on its upper side a as Welding surface formed on annular surface 24, as well as forming the container Cassette parts 2, 3 have on their upper side a welding surface 9th The container 20 is used for receiving a particle-charged reagent, while in the cavities 4 of the container forming cartridge parts 2, 3 are filled as a liquid crafted reagents can. At their designed as welding surfaces tops 9, 24, the Cassette parts 2, 3, respectively, designed as a container 20 having a Beadflasche Film are welded to the contents of the container 20 and the container forming cartridge parts 2, 3 to protect against contamination.

As is apparent from the illustration in Figure 1, are the forming the container Cassette parts 2, 3 along a butt joint 13 to each other. The joining of the container forming cassette parts 2, 3 takes place at the butt joint 13 via detent openings 6, in which Detents 7 engage. illustrated the assembled in Figure 1 in the state Reagent cartridge 1 includes a large side wall 11 and an end wall 12, which offer large flat surfaces for applying a label. The containers forming cartridge parts 2, 3 are preferably made as injection-molded parts, to which in one operation to the respective cassette parts 2, 3, both the latching noses 7 and the locking openings 9 and the bulges 5 can be formed.

The illustration shown in Figure 2 is one of the two together fügbaren cartridge parts of the reagent can be seen.

The illustration shown in Figure 2 can be seen that the forming a container Cassette part 2 on the side of the buckle 5 is a semicircular enclosure 29 and having a positioning 10th The positioning aid 10 is in the representation semicircular as shown in FIG. 2 In the area of ​​the side wall 11 are the lugs 6, while on the opposite side wall of the locking lugs 7 are formed. The cavity 4 of the cassette part 2 is enclosing at the top of forming a container cassette part 2 a welding surface 9 is formed.

The diagram in Figure 3 is shown in Figure 2, forming a container Cassette part reproduced in section.

From the view in Figure 3 shows that the cavity 4 of a container forming cassette part 2 is bounded by a raised access floor 8, the terms the dead volume is optimized. Under dead volume is in the present context understood the reagent, which from the cavity 4 of the cassette part 2 no longer is removable.

The welding surface 9 at the top of a container forming part of the cassette 2 for designed a double sealing, ie the welding surface 9 may be stepped design, so that a welding multiple superposed films for closure (Double sealing) of the cavity 4 of a container forming cassette part 2 is possible. The enclosure shown as a quarter circle in the illustration shown in Figure 3 29 and the positioning aid 10 is also shown as a quarter circle are the rotary Storage of a container 20, not shown in Figure 3, in which a particulate-containing Reagent is added. On the rear side wall 11 of a container forming Cassette part 2 projecting detents 7 are molded, which of the paths Plastic injection molding in a single operation during manufacture of the Containers constructed cassette part 2 can be molded.

Figure 4.1 shows a designed as a container for receiving a Beadflasche particle-containing reagent.

The container 20 comprises at its upper side an annular surface 24, on which a foil is aufschweißbar to after filling the container 20 with a particle-charged reagent to protect the interior against contamination. At the top of the Beadflasche formed container 20 is designed, in particular a positioning ring 22 that with of which is arranged on the container designed as a cassette parts 2, 3 facing 29 cooperates. At the bottom of the container 20, a slotted plastic ring 21 is molded. Also of the particle-containing reagent receiving container 20 (Beadflasche) may, by means of plastic injection molding inexpensively in one operation getting produced.

From the view in Figure 4.2, the container 20 is shown in section.

Below the at the top of the container 20 (Beadflasche) formed annular surface is the positioning ring 22. In the lower area of ​​the container 20 is at this its inside provided with a spiral structure 23 in helix form. the Helical shape Performing spiral structure 23 generated during intermittent turning a vertical flow in the cylindrical wall portion of the container 20 and a running counter to vertical flow in the center of the container 20. To compensate arises bottom of the bottle, a defined, extending in radial direction of flow, is very suitable, the sedimented in the bottom region of the container 20 particles resuspend. The flat angle of the spiral structure 23, based on the Liquid surface, enables gentle flow generation without Cavitation and definitely prevents foaming inside the Container 20 and damage of particles optionally with a coating can be provided.

The container 20 is limited by a cylinder bottom 30th Below the Bottle bottom is molded onto the container 20 (Beadflasche) a slotted ring 21st The slotted ring includes slots through separate straps 34, the spring are formed and which are not a coupling connection with a in Figure 4.2 Coupler represented 31 allow.

From Figure 4.3, shown in perspective shows that the spiral Structure 23 in spiral form along the lower two-thirds of the container 20 (Beadflasche) extends. The bottle bottom 30 is frustoconical. Below the bottom of the bottle 30 is attached to the container 20 for receiving a particle-containing reagent a slotted ring 21 is molded, the individual by Slots separate tabs 34 are formed resiliently apart to a simple to enable coupling with a coupling piece to a magazine.

Figure 5 shows an assembled reagent cartridge, two containers forming cartridge parts and a recorded between these, a particle-containing reagent receiving Container 20 comprising.

From the view in Figure 5 shows that the the particle-containing reagent receiving container 20 rotatably forming between each container cassette parts 2 is mounted and third The container 20 (Beadflasche) on the one hand by the semi-circular positioning 10 the container serving as the cassette parts 2, 3 fixed above the split ring 21, and on the other hand by the above Positioning ring 22 abutting semicircular mounts 29. In the illustration according to Figure 5 is formed between the container cartridge parts 2, 3, a container 20 stored, which is constructed as Beadflasche. The container shown in Figure 5 20 comprises a spiral-shaped structure in helix form 23, extending above the Bottle bottom 30 extends. From in Figure 5 in the assembled state 26 illustrated reagent cartridge 1 shows that in the assembled state, having reagent cassette 3 separate container. These are the cavities 4 of the cassette part 2 and the cassette part 3 and the cavity of the container 20 to the Receiving the particle-charged reagent. The cavities 4 of the cassette parts 2 and 3 and the cavity of the container 20 to be optimized in each case by a dead volume Floor 8 and bounded by a frustoconical bottom 30th

From the view in Figure 5 shows that both of forming a container Cassette part 2 and the forming a container cassette part 3 each have a exhibit floor space. The on the container 20 for receiving the particle-charged Reagent formed slotted ring 21 also represents a level surface. In made-up state 26 form the standing surfaces of the cartridge parts 2, 3 or the container 20 for receiving the particle-charged reagent a plane Bottom 28 of the reagent 1 in the assembled state 26 At the top of the Reagent cartridge 1 in the assembled state 26 are serving as welding surfaces Faces 9 formed; at the top of the container 20 for receiving the particle-containing reagent is the also serves as a welding surface Ring face 24th

From the view in Figure 5 is also removed, the split ring 21 more separate from each other by slots resilient tabs 34 has. With Numeral 5, the curved surfaces of the container forming cartridge parts 2, 3 identified that a cavity between the locators 10 and the Positioning ring 22 form when the container forming cartridge parts 2, 3 fitted together, that are plugged together.

From the view in Figure 6 is a sectional view of the in Figure 5 Reagent cartridge shown forth in the assembled state.

The forming between the container cartridge parts 2, 3 rotatably mounted trough 20 Receiving a particle-charged reagent is 20 by the mounts 29 and the , Stored positioning ring 22 which is molded onto the container 20 in the upper region, while the rotatable mounting of the container 20 (Beadflasche) in the lower region by the semicircular positioning aids 10 occurs, the the at the bottom curved surfaces 5 of the cassette parts 2, 3 are molded. forming each of the containers Cassette parts 2, 3 comprises a dead space optimized floor 8 (see FIG. Representation according to Figure 3).

The diagram in Figure 6 is formed between the container cartridge parts 2, 3 a container 20 inserted, a spiral structure 23 in spiral shape on its having inside. Upon rotation of the container 20 containing via the tabs 34 split ring 21 by the spiral structure 23 in spiral form on the Inside of the container 20 includes a homogenization of the particle-containing reagent in the Case 20 (Beadflasche) achieved, which occurred by sedimentation Concentration differences can be compensated for in the particle-charged reagent, ie achieved a uniform distribution of particles within the particle-containing reagent can be.

The end walls 12 of the reagent 1 in the assembled state 26 can for Applying labels to be used. The same applies to between the end walls 12 side wall 11 of the reagent 1 in the assembled state 26 along the butt joint 13 are the container-forming cartridge parts 2, 3 to each other; out Reasons of graphic representations are cooperating with each other Detent openings 6 and locking lugs 7 along the butt joint 13 in Figures 5 6 and is not shown.

Figure 7, the individual containers from which the proposed inventions is joined reagent cartridge to remove.

The cassette parts shown respectively in section 2, 3 and the containers 20 are in Direction of the arrows joined together. When joining, ie succession moved toward the Container forming cartridge parts 2, 3 engage the locking lugs 7 of a container forming Cassette part 2 forming in the catch openings 6 of the other, a container Cassette part 3 a. During the joining of the container 20 (Beadflasche) is to to be joined receiving a particle-charged reagent so between each other Cassette parts 2, 3 are aligned, that the positioning ring 22 beneath the enclosures 29 comes on top of the two cassette parts 2 to the plant. The two at the lower Region of the container forming cartridge parts 2, 3 arranged positioning 10 enclose the container 20 above the slotted ring 21, of sprung design Tabs 34 has. This is a rotatable mounting of a particle-containing Reagent receiving container 20 (Beadflasche) in one illustrated in Figure 8 Reagent cartridge reaches the assembled state 26th Due to the formation of Footprint of a container forming cassette part 2 and the other, a Container forming cassette part 3 and the geometry of the split ring 21 is in the made-up state 26 of the reagent cartridge 1 will receive a flat underside 28th Due to the availability of the individual containers, ie, the cassette parts 2 and 3 and the Container 20 (Beadflasche), a filling of reagents and consequently carried cassette assembly time independently. As from the representations according to FIGS 7 and 8 shows a joining of the following inventively proposed reagent cartridge 1 by simply plugging together the components 2, 3 and 20, without any additional parts such as cover or neck-shaped joining elements would be required.

The illustration shown in Figure 9 is a coupling piece can be removed, with which the split ring on the underside of the particle-containing reagent receiving container is added.

The coupling member 31 shown in Figure 9 has a disc-shaped Base 32 and a formed on this coupling head 33. When plugging the reagent cartridge 1 engages in the assembled state 26 according to Figure 8 of the slotted Ring, ie the resiliently designed lugs 34 at the coupling head 33 a. The spring trained, separated by slots tabs 34 surround the Coupling head 33 in its entirety. By the split ring 21, formed at the in Rotation want to move containers 20 for receiving a particle-charged reagent, and the coupling piece 31, a clutch connection is made, through which a Rotation in the particle-containing reagent receiving container 20 (Beadflasche) can be initiated. The engagement of the resilient lugs 34 of the split ring 21 also supports the correct positioning of the container 20 within the reagent cartridge 1 and is advantageous for a low-friction rotation of bottles within the reagent cartridge 1 in the assembled state 26. The engagement of split ring 21 on the coupling piece 31 is carried out in manual or automatic Assembling a Reagenzmagazins, as will be described below.

For completeness, it should be mentioned that shown in Figure 7, for example, Detent connection between the detent openings 6 and 7 of the latching lugs to the each other to mating receptacle-forming cartridge parts 2, 3 can also be configured so that non-destructive loosening of the two cartridge parts is not possible from each other.

From the view in Figure 10 is a schematic view of a Reagenzmagazin forth.

The Reagenzmagazin 40 essentially comprises a magazine plate 41, of a central shaft is held 46th The magazine plate 41 rotates in the direction of rotation 42, indicated by identified by reference numeral 42 arrow. Instead of the illustrated in Figure 10 Magazine disc 41, which represents a possible embodiment; can the be Reagenzmagazin 40 formed in matrix arrangement. are in the magazine plate 41 several coupling pieces 31 admitted. The coupling members 31 are in turn of a drive shaft driven 45 into a gear 44 with a drive 43 Connection is. On top of the magazine disc 41 are reagent cartridges 1 in ready-made state 26 is positioned. Due to the newly formed Bottom 28 of the reagent cartridge 1 in the assembled state 26 are this plan to the top of the magazine disc 41 on. The reagent cartridge 1 in the assembled State 26 are positioned on top of the magazine disc 41 that split ring of a container 20 of a reagent cartridge 1 in the assembled state 26, the driven clutch pieces 31 engages the magazine plate 41st This a clutch connection between the rotation in the reagent cartridge 1 in made-up state 26 mounted container 20 for receiving a particle-charged created reagent. The drive 43, the transmission 44 and the drive shaft 45 the coupling piece 31 is the rotatably mounted in the reagent cartridge 1 container 20 offset for receiving a particle-charged reagent in rotation, while the Reagent cartridge 1 in the assembled state 26 in position at the top of Magazine disc 41 remains. This can in a reagent cartridge 1 three reagents be added, one of which is to be homogenized, the since sedimenting particles containing reagent in over the coupling connection 21, 31 driven vessel 20 (Beadflasche) is included. In one operation can thus pro Reagent cartridge 1 to prepare several reagents for further processing. From the Representation according to Figure 10 shows that at the top of the magazine disc 41 according to the number of the driven couplings 31 more Reagent cartridges 1 can be treated in parallel. forming the container Cassette parts 2, 3 are respectively connected via the engagement catches 6, 7, detent openings 6 and Detents 7 comprising releasably interconnected, said clip connection between the vessel-forming cartridge parts 2, 3 can also be designed, that destructive loosening is no longer possible.

From the view in Figure 11 a Reagenzmagazin goes in a schematic view in Array produced.

The illustration shown in Figure 11 are given reagent cartridges, the first the Container forming part of the cassette 2 (R1-bottle) and the second container forming Cassette part 3 exhibit. The cartridge parts 2 and 3 are separated by a Locking connection, given by the latching opening 6 and is snap latching lug 7 connected with each other. Both in in Figure 11 in a 47 Reagenzmagazin Array recorded reagent cartridges stand with their flat bottoms 28 on a plate 48 of Reagenzmagazins 47 in matrix arrangement. The Reagent cartridges are closed at their upper side and contain 20 individual containers (Beadflaschen). The Beadflaschen 20 are secured by means of positioning rings 22 and coupled in the region of the bottle bottom 30 to the coupling piece 31st The Coupler 31 in turn is driven by a drive shaft 52 with a Pulley or the like is provided and, for example, by a toothed belt 51 can be driven. The toothed belt 51 encloses another drive, which the reagent cassette shown in Figure 11 on the left side of the figure, consisting forming from the first container cassette part 2 and the second container forming part of the cassette 3 is disposed. The toothed belt 51 is a Drive gear 50 of a drive 49 is driven and rotated by means of drive shafts 52, of the coupling pieces 31, which at the bottom by the area of ​​the bottle bottom 30 the coupling piece 31 coupled containers 20 (Beadflaschen) within the Reagent cartridges in rotation.

With the embodiments shown in Figure 11, in one reagent cartridge three reagents in different containers 20 (Beadflaschen) be taken from which the average over the coupling piece 31, the drive shaft 52, the toothed belt 51 and the drive 49 to be homogenized containing reagent reservoir bottle 20 in Rotation can be set. This can be similar to the figure in in one operation 10 illustrated embodiment, each reagent cassette 1 more reagents for prepare further processing. The to be homogenized, as sedimenting particles containing reagent is preferably in over the coupling connection 31, 52 driven vessel included 20 (Beadflasche). According to the size of Plate surface of the plate 48 for the Reagenzmagazin 47 in matrix arrangement and corresponding to the number of the driven via the toothed belt 51 drive shafts 52 a plurality of reagent cassettes 1 in a matrix arrangement in which in Figure 11 illustrated Reagenzmagazin be treated 47 in a matrix arrangement.

LIST OF REFERENCE NUMBERS

<dl tsize="2" compact="compact"><dt>1</dt><dd>reagent cartridge</dd><dt>2</dt><dd>first container forming part of the cassette (R1-bottle)</dd><dt>3</dt><dd>second container forming part of the cassette (R2-bottle)</dd><dt>4</dt><dd>cavity</dd><dt>5</dt><dd>curved side</dd><dt>6</dt><dd>latching opening</dd><dt>7</dt><dd>locking lug</dd><dt>8th</dt><dd>Raised floor</dd><dt>9</dt><dd>welding surface</dd><dt>10</dt><dd>positioning aid</dd><dt>11</dt><dd>Side wall</dd><dt>12</dt><dd>end wall</dd><dt>13</dt><dd>butt joint</dd></dl><dl tsize="2" compact="compact"><dt>20</dt><dd>Container (Beadflasche)</dd><dt>21</dt><dd>slotted ring</dd><dt>22</dt><dd>positioning</dd><dt>23</dt><dd>spiral structure (spiral shape)</dd><dt>24</dt><dd>Annular surface (stepped weld surface)</dd></dl><dl tsize="2" compact="compact"><dt>26</dt><dd>assembled reagent cartridge</dd><dt>27</dt><dd>top reagent cartridge</dd><dt>28</dt><dd>flat lower reagent cartridge</dd><dt>29</dt><dd>mount</dd><dt>30</dt><dd>bottle bottom</dd><dt>31</dt><dd>coupling</dd><dt>32</dt><dd>base</dd><dt>33</dt><dd>coupling head</dd><dt>34</dt><dd>resilient tabs split ring 21</dd></dl><dl tsize="2" compact="compact"><dt>40</dt><dd>Reagenzmagazin</dd><dt>41</dt><dd>magazine plate</dd><dt>42</dt><dd>rotation </dd><dt>43</dt><dd>drive</dd><dt>44</dt><dd>gear</dd><dt>45</dt><dd>Drive shaft for coupling</dd><dt>46</dt><dd>central shaft</dd><dt>47</dt><dd>Reagenzmagazin in array</dd><dt>48</dt><dd>Plates in array</dd><dt>49</dt><dd>drive</dd><dt>50</dt><dd>drive gear</dd><dt>51</dt><dd>Timing</dd><dt>52</dt><dd>drive shaft</dd></dl>