EP1405056A1 - Body for flow-through cells and the use thereof - Google Patents

Body for flow-through cells and the use thereof

Info

Publication number
EP1405056A1
EP1405056A1 EP20020732307 EP02732307A EP1405056A1 EP 1405056 A1 EP1405056 A1 EP 1405056A1 EP 20020732307 EP20020732307 EP 20020732307 EP 02732307 A EP02732307 A EP 02732307A EP 1405056 A1 EP1405056 A1 EP 1405056A1
Authority
EP
Grant status
Application
Patent type
Prior art keywords
body
according
flow
base plate
characterized
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP20020732307
Other languages
German (de)
French (fr)
Inventor
Martin A. Bopp
Heinrich Büttgen
Tilo Callenbach
Yves Marmier
Werner Schoch
André Marcel WICKY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Technology Services GmbH
Original Assignee
Zeptosens AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/01Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03Cuvette constructions
    • G01N21/05Flow-through cuvettes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5025Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50855Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates using modular assemblies of strips or of individual wells
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02Adapting objects or devices to another
    • B01L2200/025Align devices or objects to ensure defined positions relative to each other
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02Adapting objects or devices to another
    • B01L2200/026Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0861Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877Flow chambers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00Supporting devices; Holding devices
    • B01L9/52Supports for flat sample carrier, e.g. used for plates, slides, chips
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/01Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03Cuvette constructions
    • G01N2021/0346Capillary cells; Microcells
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/14Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333Saccharide [e.g., DNA, etc.]

Abstract

The invention relates to a system of flow-through cells that is obtained by assembling a body (11) with a base plate. The body (11) comprises the following elements which are adapted for the exact positioning of the body in the receiving openings of a support in three directions (X, Y, Z direction): (a) a first spring element and a first stop, disposed on opposite end sections of the body (11), (b) at least one second spring element and a corresponding second stop, disposed on opposite faces of the body (11), and (c) at least one support element and at least one retaining element.

Description

Body for Durchflusskuvetten and their use

The invention relates to a body for forming an arrangement of flow-through according to the preamble of claim 1, or third

The invention further relates to a carrier according to the preamble of claim 9 and the arrangement of flow-through.

An arrangement of flow-through of the type mentioned above is described in International Patent Application PCT / EP 00/12668.

Figures 24-28 illustrate embodiments, which are described in International Patent Application PCT / EP 00/12668.

Figure 24 is the Figure 1 of the patent application PCT / EP

00/12668 identical and shows a partial cross-sectional view of a first Durchflusskuvettenanordnung. From this figure, the feed 1 and the flow 2 of a single flow cell, as well as parts of the adjacent flow cells are visible.

The Durchflusskuvettenanordnung shown in FIG. 24 comprises a base plate 4 and a body combined therewith 6. The body 6 has a recess 3, which forms a spatial recess for producing a flow cell with an inlet 1 and outlet 2 after assembling the body 6 with the base plate 4. The recess 3 may have any surface area; for example it may be rectangular. Preferably, corners are each rounded. The sequence 2 or the inlet 1 of the adjacent in the cross-sectional direction of flow-through cells are also shown. Preferably, the inlet and the outlet of a flow cuvette at opposite end points of the base surfaces of the recess in case of a substantially rectangular base, arranged for example at the end points of the diagonals.

Figure 25 is identical to that of Figure 2 of the patent application PCT / EP 00/12668 and shows a partial cross-sectional view of another embodiment of the Durchflusskuvettenanordnung according to Fig. 24. In the embodiment shown in Fig. 25, the reservoir 5 as a recess in the outer wall formed of matched with the base plate 4 body. 6 This embodiment makes it possible that while exiting liquid entering from the flow cell into the reservoir 5, but can zurückfHessen in the flow cell does not again as long as the reservoir is not up to the top edge of the boundary on the

Liquid outlet side is filled.

Figure 26 is identical to Figure 3 of the patent application PCT / EP 00/12668 and shows a partial cross-sectional view of another embodiment of the

Durchflusskuvettenanordnung according to Fig. 24. In the embodiment shown in Fig. 26, the reservoir 5 is closed at the top. This embodiment has the consequence that also from the reservoir 5, no liquid can escape through evaporation.

The body 6 can be made in all the above mentioned embodiments of one part or of several parts which are joined together preferably irreversibly into a unit.

Figure 27 is identical to that of Figure 4 of the patent application PCT / EP 00/12668 and exhibits a substantially confined to the base plate partial cross-sectional view of an embodiment with an optical waveguide layer as a base plate. In the embodiment according to FIG. 27, the base plate as an optical film waveguide with immobilized thereon a biological or biochemical or synthetic recognition elements is formed. As shown in FIG. 27 includes this layer waveguide layers a, b and b '. By the reference numeral 27 designates g are the boundaries of a flow cell in Fig., Which is generated by bringing the base plate with a body 6. Therefore, the reference numerals g corresponds to the reference numeral 6 in the figures 24 to 26.

B transparent on an at least in part of the visible or near infrared spectrum layer is initially a thin intermediate layer b 1 and then a layer of a deposited whose refractive index is greater than the refractive indices of the layers b and b '. Also, the layers a and b 'are optically transparent at least in a part of the visible or near infrared spectrum. In the layer lattice structures b c and c 'are formed as a relief grating which is transmitted in the application of the layers located above it into this. an adhesion-promoting layer (f) is applied to the layer A then, which can improve the adhesion to be immobilized biological or biochemical or synthetic recognition elements. orm In this execution, these recognition elements are immobilized in discrete measurement areas d, which are arranged in this embodiment both on and between the grating structures C and C. In the embodiment according to FIG. 27, the base plate with the body will be brought together exhaustive g, which corresponds to the body 6 in the figures 24 to 26.

Figure 28 is identical to that of Figure 5 of the patent application PCT / EP 00/12668 and shows an arrangement of Durchflussküvettenanordnungen, in the column-shaped arrangements of base plates 4 and the respective combined therewith bodies 6 along Einsatzblδcke 7 form, which engage in corresponding Aufnahmeδffnungen a common carrier 8 (meta-) are inserted. In this way an arrangement of a total of 6 columns generated by each flow-6. In the embodiment shown in Fig. 28, the support has the basic dimensions of a standard microtiter plate. The inlet openings 9 to feeds 1 (not visible in this figure) are positioned so that they are connected to the grid of a standard 96-well microtiter plate mpatibel k, that is, they are in

Intervals of an integer multiple of 9 mm positioned (for example, distance of the feeds within a column: 9 mm; distance between adjacent columns of the feeds: 18 mm). With a corresponding translation of the carrier with the insert blocks the reservoir 5 with that of a standard 96-well microtiter plate compatible screens are appropriately. In the embodiment according to FIG. 28 of the carrier 8 is so designed that it can accommodate up to 6 Einsatzblδcke. However, it can also use spaces for blocks remain unfilled.

A very accurate positioning of the

Durchflusskuvettenanordnung in a carrier is indispensable to ensure the reliability and accuracy of the measurements, for example optical, electro-optical or electrical measurements.

The invention is therefore based on the object to provide a Durchflusskuvettenanordnung of the aforementioned type is available, which is designed such that it can be positioned with high precision in a carrier which is inputted into an analyzer and there is a high-precision positioned in turn and automatically processed is, the processing to carry out measurements, for example optical, electro-optical or electrical measurements on a relatively large number of very small measurement ranges which are close to each other, comprising.

The invention further has for its object to provide a body to form an arrangement of flow-through, who has - the use of standard, commercially available

pipette tips allows for the supply of samples or reagents to the cuvette, and - small volumes of samples and reagents required.

According to a first aspect of the invention, the first object is achieved with a body according to Claim. 1

According to a second aspect of the invention, the first object is achieved with a Durchflusskuvettenanordnung according to claim. 6 According to a third aspect of the invention, the first object is achieved with a carrier claim 9.

According to a fourth aspect of the invention, the first object is achieved with a Durchflusskuvettenanordnung according to claim. 11

According to a fifth aspect of the invention, the first object is achieved with a Durchflusskuvettenanordnung according to claim 12th

According to a sixth aspect of the invention, the second-mentioned object is achieved by a body according to claim. 3

The further claims indicate preferred embodiments and to the use of a body according to any one of claims 1-5, an arrangement of flow-through according to any one of claims 6-8, 11-14 or of a carrier according to claim 9 or 10 degrees.

The inventive embodiment or arrangement enables high-precision positioning of an arrangement of flow-through of the type mentioned by using a mechanical positioning, wherein the achievable accuracy of positioning is of the order of 50 microns, and, surprisingly, no adjustments need to be made.

The preferred field of application of the inventive Durchflusskuvettenanordnung is the simultaneous (parallel) determining a plurality of analytes in one or more samples. This can be done in that the sample containers to the base plate in one embodiment, as a sensor platform, each so-called "microarray" are housed.

The inventive Durchflusskuvettenanordnung is usable in all the analytical measurement methods described in the above mentioned patent application PCT / EP 00/12668 or mentioned.

Other advantages of the invention will become apparent from the following description of the preferred embodiments.

Figures 1 to 7 show various views of an embodiment of an inventive body to form a linear series - that is, a one-dimensional array - of flow-through.

Fig. 1 shows a perspective view of the body from the top, F Fiigg .. 2 2 shows the front view of FIG. 1,

FIG. 3 1 shows the view from the back to FIG.

FIG. 1 4 shows the view from the left side according to Fig.

FIG. 5 1 shows the view from the right side according to Fig.

FIG. 6 shows the top view of FIG. 1, F Fiigg 7 .. 7 shows the bottom view of FIG. 1.

Figures 8 to 15 show various views of an embodiment of an inventive Durchflusskuvettenanordnung, which is formed by joining a body according to Figures 1 to 7 and a base plate.

Fig. 8 shows a perspective view of Durchflusskuvettenanordnung from above, Fig. 9 shows a perspective view of Durchflusskuvettenanordnung from below,

Fig. 10 shows the front view of FIG. 8,

Fig. 11 shows the rear view of Fig. 8, Fig. 12 shows the view from the left side of Fig. 8,

Fig. 13 shows the view from the right side of Fig. 8,

Fig. 14 shows the top view of FIG. 8,

Fig. 14a showing a partial cross section through the plane II in Fig. 14

Fig. 14b shows an enlargement of the circled in Fig. 14 part

Fig. 15 shows the view from below according to Fig. 8.

Figures 16 to 23 show various views of an embodiment of an inventive carrier for receiving a Durchflusskuvettenanordnung or more Durchflussküvettenanordnungen according to figures 8-15.

Fig. 16 shows a perspective view of the carrier from above,

Fig. 17 shows a perspective view of the carrier from below,

Fig. 18 shows the front view of Fig. 16, Fig. 19 shows the rear view of FIG. 16,

Fig. 20 shows the view from the left side of FIG.

16

Fig. 21 shows the view from the right side of Fig. 16, Fig. 22 shows the top view of FIG. 16,

Fig. 23 shows the view from below according to Fig. 16. Figures 24-28 show embodiments which are described in International Patent Application PCT / EP 00/12668 and incorporated therein as figures 1-5.

Hereinafter, preferred reference to the figures 1-23

described embodiments of the invention. They are the result of a further development of the embodiments are described in outline in International Patent Application PCT / EP 00/12668. The contents of this patent application is therefore hereby incorporated by reference in full as part of the description below.

As described in more detail below, a one or two-dimensional arrangement of flow-through is used as part of an array of sample containers, said arrangement comprising a base plate and a combined therewith cap body is formed, which is an array of spatial recesses has, corresponding to the arrangement of the sample containers, wherein at least one inlet and outlet is present for each sample container, and wherein the base plate may for example be a glass slide, waveguide chips or a sensor platform.

The single- or two-dimensional arrangement of flow-through makes it possible in a preferred embodiment, even very small sample or of reagents forwarded to the sample containers, which may be arranged in a high number on a small footprint, and / or remove from them, wherein, for each sample compartment at least one reservoir for receiving the sample container be dissipated fluid and a peripheral system of liquid feed and -abführungen is integrated into the assembly.

1) First Embodiment A BODY TO FORM AN DURCHFLUSSKUVETTENANORDNUNG

A body according to the invention for forming a linear array - that is, a one-dimensional array - of flow-through is shown in Figures 1-7. Such an arrangement of flow-through (shown in Figures 8-15) 31 (not shown in the figures 1-7) is formed by assembly of the body 11 with a base plate carrying such as biological or biochemical or synthetic recognition elements. These detection elements are used for binding and detection of the analyte to be determined in the supplied sample.

The body 11 has an outer shape (shown in Figures 16-23) into a receiving opening 42 of a carrier 41 fits, that the body has an outer shape that makes it possible to use it in a receiving opening of the carrier.

The body 11 has the following elements which serve for accurately positioning the body in the receiving opening of the carrier:

(A) a spring 51 and a stop 52 which serve for accurately positioning the body in the X direction and are disposed at opposite end portions of the body 11,

(B) two springs 53, 55 and two these corresponding stops 54, 56 which serve for accurately positioning the body 11 in the Y direction and are disposed on opposite sides of the body 11, wherein the Y-direction is perpendicular to the X direction .

(C) three support points 57, 58, 59, and two snap-action hooks 61, 62, said supporting points and snap fit together serve for accurate positioning of the body in the Z direction.

The Z-direction is perpendicular to the plane which is spanned by two axes, namely an axis in the X direction and an axis in Y-direction.

The spring 51 is located approximately opposite the stop 52nd

The spring 53 (or 55) is located approximately opposite the stop 54 (or 56), but slightly offset such that the outer edge of the stopper 53 (or 55) is located in parallel to the ZY plane of symmetry plane of the spring.

allow the above mentioned positioning elements of the body 11 the body 11 and thus the thus formed assembly of flow-through, without any alignment with an accuracy of +/- 50 microns in each of the three mutually perpendicular directions X Y and Z in a receiving opening of a wearer 41 to position according to figures 16-23.

The snap hooks 61, 62 permit insertion of the assembly in the support by a slight pressure in the Z direction and secure the assembly against falling out of the carrier. The arrangement is designed by its outer shape such that an improper insertion is mechanically impossible. To remove the assembly from the carrier, a slight back pressure in the Z direction, through which the snap-action hooks are pressed slightly inwards 61.62 sufficient. Alternatively, the snap fit can be released by pressure from below by means of a correspondingly shaped tool.

Asymmetrically applied mechanical locators in the form of recesses and tabs of the body 11 and the carrier 41 as well as additional circular recesses on one half of the lugs of the body 11 and the carrier 41 serve as optical positioning and permit an unambiguous positioning of each Durchflusskuvettenanordnung in the carrier. An incorrect positioning of the assemblies in the carrier is excluded.

As the raster of the visible from outside the reservoir 15 with the associated Einlassδffnungen 14 relative to the grid of the flow-through cells 18 is offset in such a way that the inlet openings are located 14 to the flow-through in each case in one of the outer corners of the Fig. 6 and 7.

To facilitate the filling of each flow cell 18 may include a wholly or partially circumferential groove having a cross section with typical dimensions of 50 x 50 microns and 500 x 500 microns have for each flow cell 21, the outer surface of the body. 11 are located in two mutually diagonally opposite corners of this groove 21, the inlet port 14 and the outlet port 17 to each flow cell 18. This groove 21 allows a bubble-free filling of the flow cell. the formation of air bubbles provided during the filling process or during carried out in the flow-through method for the detection of analytes can not be avoided in principle, a groove 21 can thereby be advantageous by resultant air bubbles escape from the interior 13 of the flow cell and in the collecting groove 21st In a preferred embodiment, this property is additionally ensured by a chemical surface treatment of the inner surface of the groove 21 or the entire inner surface of the flow cell, including said groove. This treatment serves to provide a hydrophilic, so better wettable surface.

The body 11 preferably has stops 22, 23, 24 which for accurately positioning the base plate 31 (see Figures 8-15) in relation to the body 11 before the assembly thereof, for example, are used by gluing. There is no mechanical coupling between the stops 22, 23, 24 and the above-mentioned attacks that are used for precise positioning of the body 11 and the arrangement of flow-through in a receiving opening 42 of the carrier 41 formed therewith.

The body 11 preferably has protectors 25, 26, 27 which protects the base plate 31 against tearing or damage from the carrier 41 could occur otherwise in particular during insertion of the Durchflusskuvettenanordnung in ".

In a preferred embodiment, a circumferential web 29 is provided on top of each of the flow cells on which a film can be welded. This film prevents the one hand, "cross-contamination" between the cells; on the other hand prevents liquid losses which might otherwise occur in particular in nucleic acid hybridization assays with process steps at elevated temperatures for example up to about 80 ° C. The following materials are suitable for the manufacture of the body 11:

- moldable, sprayable or millable plastics, thermoplastics (preferred production means "Injection Molding"), metals, silicates, such as glass, quartz or ceramics.

Examples of the materials for making the body 11 are, in particular

- Polycarbonate (PC), for example. B. unfilled, colored black

- polybutylene terephthalate (PBT), for example. B., glass sphere filled with black colored

- "ABS" (acrylonitrile / butadiene / styrene graft copolymer).

To reduce reflections, it is advantageous when the body 11 of the Durchflusskuvettenanordnung is colored black, except under the to be passed into the base plate 31 (when configured as a waveguide) led light, the base plate directly contacting walls of the body. 11

2) Second Embodiment A BODY TO FORM AN DURCHFLUSSKUVETTENANORDNUNG

This embodiment is an inventive body to form a two-dimensional matrix-like arrangement of flow-through, which comprises a plurality of Küvettenreihen with the structure of the body 11 described above, and contains all the elements or elements with an equivalent function as described above. The features of such a body therefore seen substantially from the figures 1-7.

A body according to this second embodiment is also suitable, by joining with a base plate carrying such as biological or biochemical or synthetic recognition elements, to form a Durchflusskuvettenanordnung. This body, for example, even already have the external dimensions and external features of a standard microtiter plate by SBS standard.

This body may also have such an outer shape that in a receiving opening of a correspondingly shaped carrier fits (z. B. with external dimensions to SBS standards).

Also in this embodiment, the body may have the following elements which serve for accurately positioning the body in the receiving opening of the carrier:

(A) a spring and a stopper, which serve for accurately positioning the body in the X direction and are disposed at opposite end portions of the body,

(B) two springs and two these corresponding stops which serve direction for exact positioning of the body in the Y and are arranged at opposite sides of the body, wherein the second direction is perpendicular to the first direction,

(C) three support points and two snap hooks, which supporting points and snap fit together serve for accurate positioning of the body in the Z direction.

the same materials usable for the production of the body, indicated in 1) above. 3) first embodiment of a DURCHFLUSSKÜVETTENANORDNUNG

A first inventive arrangement of

Flow-through, which a straight series - that is, a one-dimensional array - comprises of flow-through, is shown in Figures 8-15. Such an arrangement of flow-through is formed by assembly of the body 11 described above with reference to Figures 1-7, with a base plate 31 which carries as biological recognition elements. The base plate 31 and the body 11 are joined together for example by gluing or cliffs.

In a preferred embodiment, the base plate 31 is adapted to serve as a waveguide.

The following advantageous features are of the embodiment of Figures 14, 14a, and particularly in FIG. 14b of the

Body 11 can be seen according to the figures 1-7 and figures 8-15:

Quite unlike in the embodiment according to Fig. 25 (embodiment according to Fig. 2 of PCT / EP 00/12668), the inlet 12 in the body according to the invention and in the thus formed Durchflusskuvettenanordnung as a feed at a low level the three dimensional structure of the body 11 arranged, and this inlet 12 has only a low, a funnel-shaped inlet border, so that now the exterior inlet to the recess 13 without an intervening, relatively long channel (see Fig. 25 of FIG. 2 corresponds to PCT / EP 00/12668 ) merges into the inner inlet 14 of the flow cell. This version of the inlet 12 has the following advantages:

a) The flow-through can be more easily and filled with pipette tips of larger diameter than in the previous version according to FIG. 25 (embodiment according to Fig. 2 of PCT / EP 00/12668). It can be used in particular regular, commercially available tips according to industry standard.

b) The required filling volumes and volumes of sample for filling can be significantly reduced.

As, inter alia, Fig. 6 can be seen, the body has a boundary wall 16 for defining the

Reservoir 15 serves the Einlassδffnung each cuvette 14 and is disposed around this Einlassδffnung.

The materials for the base plate, the body combined therewith and an additional cover plate, if used, must satisfy the requirements for the particular intended use of the assembly. Depending on the specific application, these requirements are related to chemical and physical resistance, for example against acidic or basic

Media, salts, alcohols or detergents as constituents of aqueous solutions, or formamide,

Temperature resistance (for example, between -30 ° C and 100 ° C), similar as possible thermal expansion coefficients of the base plate and thus zusammengebrachtem body, optical properties (eg. As relative fluorescence freedom, reflectivity), mechanical workability, etc. It is preferred that the material of the selected matched to the base plate body of the group, sprayable or millable plastics by moldable, thermoplastic plastics, metals, silicates, such as glass, quartz or ceramics, is formed. Also, the material of the additional continuous cover plate may be selected from the group, sprayable or millable by moldable plastics, metals, silicates, such as glass, quartz or ceramics, is formed. Also with respect to the base plate is preferable that the materials of the base plate comprises materials from the group, sprayable or millable plastics by moldable, thermoplastic plastics, metals, silicates, such as glass, quartz or ceramics, is formed. Thereby the mentioned components (the base plate so that of joined body, cover plate) or in each case consist of a uniform material also comprise a mixture or in layers or lateral joining of different materials, the materials may replace each other.

The surfaces of the body 11 which form the 'lid' and the side walls of the sample containers should be as little as possible reflective to keep disturbing influence from there reflected excitation light as low as possible.

In the intended use of the arrangement (for both possible refractive measurements as well as for fluorescence measurements) the excitation light ia is always irradiated through the base plate and the measurement light (at the excitation wavelength and / or

Fluorescence or luminescence) captured on the same side from which the light irradiation was carried out. Therefore, the material of the base plate is preferably selected so that it is transparent at least in the one or more excitation wavelengths used and optionally also with the corresponding luminescence wavelengths.

For applications with luminescence detection, the base plate should be as free of self-luminescence. The base plate may consist of a uniform material (eg. B. as a platelet of glass or transparent plastic in accordance) and are thereby, for example, in a classic reflected light arrangement irradiated with excitation light. It can also be a multilayer system to be (for

Example formed as a thin-film waveguide). The light may also take place in the just-described conventional arrangement. It is preferred that the base plate a (thin-) film waveguide is, with the process described in PCT / EP 00/12668 characteristics and embodiments.

The following materials are suitable for example for the production of the base plate 31: moldable, sprayable or millable plastics, thermoplastics (preferred

Production by means of "Injection Molding"), metals, silicates, such as glass, quartz or ceramics.

For all applications in which an excitation light is irradiated through the base plate 31 therethrough in the direction of detected thereon molecules, the material of the base plate is selected such that the base plate is substantially transparent at least at the wavelength of said excitation light.

In an embodiment in which the base plate 31 serves as an optical film waveguide, the base plate, for example, has the structure according to Fig. 27 showing a substantially confined to the base cross-sectional view. In the embodiment according to FIG. 27, the base plate as an optical film waveguide with immobilized thereon a biological or biochemical or synthetic recognition elements is formed. As shown in FIG. 27 comprises the

Layer waveguide layers (a), (b) and (b 1). With the reference numeral (g) 27 refers to the limitations of a flow cell in Fig., Which is generated by bringing the base plate with a body. The reference numeral (g) therefore corresponds to the reference numeral 11 in Figures 1 to 15 °.

On a transparent at least in a part of the visible or near infrared spectrum layer (b) is initially a thin intermediate layer (b 1) and then a

Layer (a) is applied having a refractive index greater than the refractive indices of the layers (b) and (b 1). Also, the layers (a) and (b ') are optically transparent at least in a part of the visible or near infrared spectrum. In the layer (b) grating structures (c) and (c ') are formed as a relief grating which is transmitted in the application of the layers located above it into this. is applied to the layer (a) then a adhesion-promoting layer applied (f), which can improve the adhesion to be immobilized biological or biochemical or synthetic recognition elements. In this embodiment, these detection elements (d) in laterally separated measurement areas immobilized, which are arranged in this embodiment both on and between the grating structures (c) and (C). In the embodiment according to FIG. 27, the base plate with the body (g) is matched conclusively that corresponds to the body 11 in Figures 1 to 15. The layer (a) of the base plate is for example a high-index metal oxide layer on the layer (b).

Examples of materials for the second optically transparent layer b:

- Silicates such. As glass or quartz, or

- a transparent thermoplastic or injectable plastics material, preferably from the group that is formed of polycarbonate, polyimide, polymethyl methacrylate or polystyrene.

4) SECOND EMBODIMENT OF A DURCHFLUSSKUVETTENANORDNUNG

This second inventive arrangement of flow-through is formed by assembly of a body which is suitable according to the above-described under 2) second embodiment of one of the two embodiments of such a body to form a matrix-like arrangement of flow-through described there, and a base plate, for example, biological recognition elements contributes. The base plate and the body are joined together for example by gluing or cliffs. The Durchflusskuvettenanordnung thus formed can in an analysis system either as an independent unit, ie without using a carrier or with a carrier be used which has at least one recess for receiving the Durchflusskuvettenanordnung.

Also in this embodiment, the base plate 31 is preferably adapted to serve as a waveguide. For the production of the components of

Durchflusskuvettenanordnung be used the same materials listed above under 3).

5) first exemplary embodiment of A SUPPORT FOR A

BODY TO FORM AN DURCHFLUSSKUVETTENANORDNUNG

An inventive support 41 for a body 11 to form a linear array - that is, a one-dimensional array - of flow-through is shown in Figures 16-23. The carrier 41 has a plurality of recesses 42, whose shape and dimensions is adapted to the outer shape of the body 11 so that a precise positioning of the body 11 is made possible in the recess 42nd

The outer dimensions of the carrier is preferably in accordance with the SBS standard. Therefore, the carrier has the dimensions of a standard microtiter plate, that is about 85 mm x 128 mm.

The carrier may be designed for single use or as a reusable component from which the Durchflusskuvettenanordnungen inserted therein S can be solved by compressing the snap hook. Alternatively, the snap fit can be released by pressure from below by means of a correspondingly shaped tool.

The carrier may for example contain up to 5 Durchflusskuvettenanordnungen that each contain for example 6 flow-through cells.

On the upper side of the carrier 41 are located in the outer corners 3 same type (square) protrusions 43, 44, 45 and another of which several protrusion 46 (see FIG. 16) to which corresponding recesses 63, 64, 65, 66 in the bottom of the beam 41 meet (see Fig. 17). These projections and recesses allow to stack a plurality of carriers over each other and simultaneously to keep the lower surfaces of the einzuklebenden in the body 11 base plates 31 (glass flakes, waveguide chips or sensor platforms) without contact from the support, so that contamination of the underside of the base plates is avoided.

there are two recesses of different size, which prevent incorrect insertion of the carrier into the input device of an automated analysis system on the long sides of the carrier 41st

After loading of the carrier 41 in the input device, a receiving web traveling at complementary to the two recesses surveys of the carrier, and then slightly raise it. Parallel to the longitudinal sides of the support extending in the input device comprises two light barriers. When the carrier is inserted with a incorrect orientation in the input device whose side is raised too much with the smaller lateral recess. This is accomplished by a corresponding

detected light barrier, which results in a denial of receiving the support in the automatic analysis system result.

The following materials are suitable for the preparation of the support 41:

- moldable, sprayable or millable plastics, thermoplastics (preferred production means "Injection Molding"), metals, silicates, such as glass, quartz or ceramics,

Examples of the materials for forming the carrier 41 are in particular:

- Polycarbonate (PC), for example. B. unfilled, black in color,

- polybutylene terephthalate (PBT), for example. B., glass sphere filled colored black, - polyphenylene sulfide (PPS), glass / mineral filled, colored black,

- "ABS" (acrylonitrile / butadiene / styrene graft copolymer).

To reduce reflections, it is advantageous when the carrier is colored black.

6) Second Embodiment A TR GERS FOR A BODY TO FORM AN DURCHFLUSSKUVETTENANORDNUNG

This second embodiment of a carrier used for receiving at least one body according to 2) above, that is a body to form a two-dimensional matrix-like arrangement of flow-through. This second embodiment of a carrier includes at least one recess, whose shape and dimensions is adapted to the outer shape of the male body so that it enables a precise positioning of the body in the recess.

the same materials usable for the preparation of the support are indicated above under 6). 7) A first exemplary embodiment FROM A CARRIER BORNE DURCHFLUSSKUVETTENANORDNUNG

This embodiment of a Durchflusskuvettenanordnung contains one or more Durchflusskuvettenanordnungen each inserted into a receiving opening 42 of a support 41 according to figures 16-23 as that described above under 3) on the basis of figures 8-15.

The base plate 31 and the body 11 are joined together for example by gluing. Alternatively, in a variant, the base plate is clamped 31 between the body 11 and the carrier 41, and assembled with the body exclusively by means of a force which is generated by composition of the body 11 and the carrier 41st

In the just-mentioned variant, the base plate is maintained as follows:

On the underside of the carrier 41 are located circumferentially around the receiving openings, thin (z. B. 0.3 mm thick) support webs, so that the provided (at its top) with the biological or biochemical or synthetic recognition elements, base plates (31, for example,

Glass flakes, platelets waveguide, the sensor platforms) can be inserted into the carrier 41 at first. Only then will the body 11, with integrated sealing lips or 0- rings (z. B. made of elastic plastic), which may include the grooves 21 shown in Fig. 7 are inserted into the carrier 41 barb-like with, for example holders such that between the bodies 11 and the base plate 31, a contact pressure of defined thickness is produced, so that a mutual fluid sealing of the flow cell to the base plate 31 together is effected generated.

For this variant suitable body 11, consisting of rigid and elastic plastic parts are preferably made in a 2-component injection molding process. Alternatively, this variant can comprise an appropriately shaped rigid plastic body and einzulegende in corresponding recesses of the body sealing rings. Such an embodiment makes it possible in particular, that the immobilization of the biological or biochemical or synthetic recognition elements is performed (e.g., by "spotting") on the base plates 31 only on site by the customer.

For the case of manufacturing the body 11 by a 2-component injection molding method, the plastic materials for the rigid components are as mentioned above. For the second elastic component which is brought together sealed with the base plate, preferred materials include thermoelastic plastics (TPE), for example

Styrene ethylene butadiene styrene (SEBS), Silicone / silicone, and elastomers (rubber).

8) second exemplary ONE OF A CARRIER BORNE DURCHFLUSSKUVETTENANORDNUNG

This embodiment of a Durchflusskuvettenanordnung contains at least one inserted into a receiving opening of a carrier according to the above 6)

Durchflusskuvettenanordnung as that which is described above under 4). Alternatively, the Durchflusskuvettenanordnung can be shaped so that it forms a self-contained unit that does not require a carrier to be used in an analysis system.

Such Durchflusskuvettenanordnung may comprise, for example, 96 or more flow-through, for example, 384 or 1536 flow-through, which are arranged on the same footprint, or even arrays of any size.

The base plate and the body are joined together for example by gluing or cliffs. Alternatively, in a variant, the base plate between the body 7 and is nipped by the support according to a variant embodiment, and assembled with the body exclusively by means of a force which is generated by composition of the body and the carrier.

9) EXAMPLES OF PROCESS WITH THE ABOVE DURCHFLUSSKÜVETTENANORDNUNGEN PRACTICABLE ARE

For simplicity, the following paragraphs 1 to 18 are numbered and phrases of the type used "process according to N1-N2", of which "A process according to any one of paragraphs Nl N2" is to be understood.

Among other things, the following method with the above-described Durchflusskuvettenanordnungen be carried out:

9.1) A method for detecting one or more analytes in one or more liquid samples by means of a Durchflusskuvettenanordnung, wherein the sample compartments sample and optionally additional reagent liquids are supplied and these may in a with a flow-through fluidly connected reservoir, as a component of said sample containers, emerge.

9.2) A process according to 9.1), wherein biological or biochemical or synthetic recognition elements are immobilized for the detection of one or more analytes on the base plate of said arrangement, is guided excitation light to the measurement areas on said base plate and the light emanating from said measurement areas light is detected with at least one detector ,

9.3) A process according to 9.2), wherein the base plate comprises a continuous or divided into individual regions optical waveguide, excitation light is directed through an optical coupling element in said optical waveguide, and is detected by one or more detectors measurement light from the measurement areas, which with in optical interaction said optical waveguides are.

9.4) A process according to 9.3), where ^ said optical waveguide is formed as an optical film waveguide with a first optically transparent layer (a) on a second optically transparent layer (b) with lower refractive index (as the layer a), wherein furthermore excitation light using one or more grating structures, which in the optically transparent

Layer (a) are pronounced into the optically transparent layer (a) is coupled and located thereon measurement areas (d) is passed as a guided wave, and further wherein the luminescence of the luminescent molecules with one or more detectors generated in the evanescent field of said guided wave detected and the concentration of one or more analytes of the intensity of these luminescence signals is determined.

9.5) A process according to 9.4), wherein (1) the isotropically emitted luminescence or (2) (in the optically transparent layer a) coupled by a grating structure (c) is coupled out or luminescence comprising both parts (1) and (2) simultaneously measured become.

9.6) A process according to 9.4) - 9.5), a luminescent dye or luminescent nanoparticle is used as a luminescence label for the generation of luminescence, which can be excited at a wavelength between 300 nm and 1100 nm and emitted.

9.7) A process according to 9.6), wherein the luminescence label to the analyte or, in a competitive assay to an analogue of the analyte, or in a multistage assay to one of the binding partners of the immobilized biological or biochemical or synthetic recognition elements or to the biological or biochemical or synthetic recognition elements bound is.

9.8) A process according to 9.6) - 9.7), wherein a second or further luminescence labels with the same or different excitation wavelength as the first luminescence label and similar or different emission wavelength are used.

9.9) A process according to 9.8), wherein the second or further luminescence labels can be excited at the same wavelength as the first luminescence dye, but emit at other wavelengths.

9.10) A process according to 9.8), the excitation spectra and emission spectra of the luminescent dyes used overlap only slightly or not at all.

9.11) A process according to 9.8), wherein for detecting the analyte charge or optical energy transfer is used by a first luminescent dye acting as a donor to a second luminescent dye acting as an acceptor.

9.12) A process according to 9.4) - 9.11), wherein determined in addition to determining one or more luminescences, changes in the effective refractive index on the measurement areas.

9.13) A process according to 9.4) - 9.12), wherein the one or more luminescences and / or determinations of light signals at the excitation wavelengths are performed polarization-selective.

9.14) A process according to 9.4) - 9.13), wherein the one or more luminescences at a polarization different from that of the excitation light to be measured. 9.15) A process according to 9.4) - 9.14) for the simultaneous or sequential, quantitative or qualitative determination of one or more analytes from the group of antibodies or antigens, receptors or ligands, chelators or "histidine-tag components", oligonucleotides, DNA or RNA - strands, DNA or RNA analogs, enzymes, enzyme cofactors or inhibitors, lectins and carbohydrates.

9.16) A process according to 9.4) - 9.15), wherein the samples to be examined naturally occurring

Kδrperflüssigkeiten such as blood, serum, plasma, lymph or urine or tissue fluids or egg yolk.

9.17) A process according to 9.4) - 9.15), wherein the sample to be examined an optically turbid liquid

is surface water, a soil or plant extract, a bio- or process broth.

9.18) A process according to 9.4) - 9.17), wherein the samples to be examined are taken from biological tissue parts.

10) EXAMPLES OF USES OF THE ABOVE ARRANGEMENTS AND PROCEDURES

The body support arrangements of flow-through cells and methods described above are suitable for the following uses:

Uses quantitative or qualitative analyzes for the determination of chemical, biochemical or biological analytes in screening methods in pharmaceutical research, combinatorial chemistry, clinical and preclinical development, to real-time binding studies and the determination of kinetic parameters in affinity screening and in research, for qualitative and quantitative analyte (in particular for DNA and RNA analysis and the determination of genomic or proteomic differences in the genome, such as single nucleotide polymorphisms, for the measurement of protein-DNA interactions, for the determination of control mechanisms for mRNA expression and for the protein bio ) synthesis, for the generation of toxicity studies and the determination of expression profiles, especially for the determination of biological and chemical marker substances, such as mRNA, proteins, peptides or small-molecular organic (messenger) compounds, and for Proof of

Antibodies, antigens, pathogens or bacteria in pharmaceutical product research and development, human and veterinary diagnostics, agrochemical product research and development, for symptomatic and pre-symptomatic plant diagnostics, for

Patient stratification in pharmaceutical product development and for the therapeutic drug selection, and / or for the detection of pathogens, pollutants and pathogens, especially of salmonella, prions, viruses and bacteria, especially in food and environmental analytics. LIST OF REFERENCE NUMBERS

a layer b layer b 'intermediate layer c lattice structure c' d grating structure measuring range f adhesive layer g boundary of the flow cell (corresponding to reference numeral 6)

1, feed

2 Sequence 3 recess

4 base plate

5 reservoir

6 body

7 Durchflusskuvettenanordnung (insert block) 8 carrier ( "meta-')

9 Einlassδffnungen 10

11 body

12 inlet 13 recess

14 Einlassδf fnung the cutout 13

15 reservoir

16 Establishment wall

17 outlet opening of the recess 13 a flow-through position 18

19 20

21 groove (circumferential groove)

22 Stop Stop

attack

protectors

protectors

protectors

Web (circumferential web)

baseplate

carrier

Recess / receiving aperture

survey

survey

survey

survey

feather

attack

feather

attack

feather

Stop 57 bearing point

58 support point

59 support point

60

61 snap hooks

62 snap hooks

63 recess

64 recess

65 recess

66 recess 67, 68 69 70

71 72 73 74 75

76 77 78 79

Claims

claims
1. body (11) to form a linear array or a matrix-like arrangement of flow-through assembly of the body (11) having a base plate (31), said body (11) being characterized in that it comprises the following elements, for accurate positioning serve the body in the receiving opening of a support (41): (a) a first spring element (51) and a first
Stop (52) for precise positioning of the body (11) in a first direction (X-direction) are used, and at opposite end portions of the body are arranged (11), (b) at least one second spring element (53, 55) and a to corresponding second stop (54, 56) serving for accurate positioning of the body (11) in a second direction (Y-direction) and on opposite sides of the body (11) are arranged, wherein the second direction (Y-direction) perpendicular to the first direction (X-direction),
(C) at least one support element (57, 58, 59) and at least one retaining element (61, 62), said support element and retaining element (together for exact positioning of the body in a third direction Z
Direction) are used, which is perpendicular to a plane defined by two axes, namely an axis in the first and another axis in said second direction.
2. Body according to claim l, characterized in that it comprises at least one, preferably all of the following features: (i) at least a further second spring element (55) and at least one corresponding thereto further second stop (56);
(Ii) at least two additional support elements;
(Iii) the support elements are support points (57, 58,
59)
(Iv) at least one further holding member;
(V) the holding elements are snap-in hooks (61, 62)
3. body (11) to form an array of
Flow-through is characterized by the joining of the body (11) having a base plate (31), said body (11) characterized in that it comprises at least one Durchflusskuvettenteil (18) having an inlet (12) and an outlet (17), wherein the Durchflusskuvettenteil ( 18) is formed so that an inner space (13) with an inlet opening (14) and with an outlet opening (17) is formed during assembly of the body (11) with the base plate (31) having interior (13) of the inlet (12 combines) and the outlet (17) fluidically, and wherein the inlet (12) is substantially funnel-shaped and near (at the base plate 31) in the inlet opening (14) is such that (when filling the flow cell 11, 31) in particular by means of a Pippette, the tip of the Pippette can be guided close to the base plate (31).
4. Body according to claim 3, characterized in that the Durchflusskuvettenteil (18) has a surface which forms a part of the interior (13) and which is provided with at least one groove (21), (wherein the inlet port (14) and outlet port 17), preferably in the groove (21) lie.
5. Body according to any of claims 1-4, characterized in that it has an outer shape that fits into a receiving opening (42) of the carrier (41).
6. First arrangement of flow-through, which is formed by assembly of a body (11) according to claim 5 and a base plate (31).
7. First arrangement of flow-through according to claim 6, characterized in that the base plate (31) biological and / or biochemical and / or wearing synthetic recognition elements.
8. First arrangement of flow-through according to claim 6 or 7, characterized in that the base plate (31) is adapted to serve as a waveguide.
9. support for receiving (41) of at least a first array of flow-through according to any one of claims 6-8, characterized in that it comprises at least one recess (42), whose shape and dimensions to the external shape of the body (11) adapted to are that a precise positioning of the body (11) in the recess (42) is made possible.
10. carrier (41) according to claim 9, characterized in that it comprises a plurality of recesses (42).
11. Second arrangement of flow-through, characterized in that it comprises a first array of flow-through according to any one of claims 6-8 and a carrier according to claim 9 or 10 degrees.
12 includes third arrangement of flow-through, characterized in that it comprises a body (11) according to one of claims 1-5, a carrier (41) according to claim 9 or 10 and a base plate (31) between the body (11) is clamped and the support (41).
13. Third arrangement of flow-through in accordance with
To claim 12, characterized in that the base plate
(31) is held only by the contact pressure obtained by assembling the body (11) and the carrier
(41) is generated.
14. Third arrangement of flow-through of claim
12 or 13, characterized in that it comprises sealing means for fluidic sealing of the interior (13).
15. Use of a body according to any one of claims 1- 5, an arrangement of flow-through according to any one of claims 6-8, 11-14 or of a carrier according to claim 9 or 10 for detecting one or more analytes in a sample fluid.
quantitative 16. Use of a body according to any one of claims 1- 5, an arrangement of flow-through according to any one of claims 6-8, 11-14 or of a carrier according to claim 9 or 10 or qualitative analyzes for the determination of chemical, biochemical or biological analytes in screening methods in pharmaceutical research, combinatorial chemistry, clinical and preclinical development, for real-time binding studies and the determination of kinetic parameters in affinity screening and in research, for qualitative and quantitative analyte determinations, especially for DNA and RNA analysis and the determination of genomic or proteomic differences in the genome, such as single nucleotide polymorphisms, for the measurement of protein-DNA interactions, for the determination of control mechanisms for the -RNA- expression and for the protein (bio) synthesis, for the generation of toxicity studies for the determination of expression Prof ilen, in particular for the determination of biological and chemical marker substances, such as mRNA, proteins, peptides or small-molecular organic (messenger) compounds, for the detection of antibodies, antigens, pathogens or bacteria in pharmaceutical product research and development, human and veterinary diagnostics, agrochemical product research and development, for symptomatic and pre-symptomatic plant diagnostics, for patient stratification in pharmaceutical product development and for the therapeutic drug selection and / or for the detection of pathogens, pollutants and pathogens, especially of salmonella, prions, viruses and bacteria, especially in the food - and environmental analysis. _ _ _
EP20020732307 2001-06-15 2002-06-10 Body for flow-through cells and the use thereof Withdrawn EP1405056A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CH10892001 2001-06-15
CH108901 2001-06-15
PCT/CH2002/000309 WO2002103331A1 (en) 2001-06-15 2002-06-10 Body for flow-through cells and the use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP20090015283 EP2169383A1 (en) 2001-06-15 2002-06-10 Body for flow through cuvettes and use thereof

Publications (1)

Publication Number Publication Date
EP1405056A1 true true EP1405056A1 (en) 2004-04-07

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EP20090015283 Withdrawn EP2169383A1 (en) 2001-06-15 2002-06-10 Body for flow through cuvettes and use thereof

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Also Published As

Publication number Publication date Type
US7399628B2 (en) 2008-07-15 grant
EP2169383A1 (en) 2010-03-31 application
US20080274451A1 (en) 2008-11-06 application
US20040185576A1 (en) 2004-09-23 application
WO2002103331A1 (en) 2002-12-27 application

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Inventor name: WICKY, ANDRE, MARCEL

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