WO2019219108A1

WO2019219108A1 - Cover to be arranged on a microtiter plate, and kit comprising cover and microtiter plate

Info

Publication number: WO2019219108A1
Application number: PCT/DE2019/000145
Authority: WO
Inventors: Franziska Huschmann; Dirk WALLCHER; Manfred Weiss; Gerd KLEBE
Original assignee: Helmholtz-Zentrum Berlin Für Materialien Und Energie Gmbh; Philipps-Universität Marburg
Priority date: 2018-05-14
Filing date: 2019-05-13
Publication date: 2019-11-21
Also published as: DE102018111478A1

Abstract

The invention relates to a cover (1) to be arranged on a microtiter plate (40), and to a kit having a microtiter plate and such a cover. It is provided that the cover has multiple tiles (20) that correspond to the cavities (41) of the microtiter plate (40) and are arranged on a plate (10), which tiles can be displaced with respect to one another on the plate (10), either directly or indirectly.

Description

Cover for placement on a microtiter plate, and kit comprising cover and

microtiter plate

The invention relates to a cover for placement on a microtiter plate and a kit which comprises such a cover and a microtiter plate corresponding thereto.

Knowledge of the three-dimensional structure of biological macromolecules has dramatic implications for both the development of modern biotechnology and the therapeutic treatment of disease. So z. B. determining the three-dimensional structure of a protein target crucial information for the

Identification and development of new drugs that interact with the respective protein target. The elucidation of three-dimensional structures of biological macromolecules is done most accurately by X-ray structure analysis. The prerequisite for structure elucidation is that the macromolecules, such as proteins or their complexes, are available as single crystals.

Furthermore, crystallization methods can contribute to the derivation and generation of crystalline formulations of recombinant drugs, whereby the crystal morphology can have a not inconsiderable influence on the pharmacokinetic properties of a formulation. The polymorphism study of low molecular weight compounds of synthetic or natural origin can be realized by crystallization experiments. Another field of application of crystallization lies in its property as

Purification method for biological macromolecules as well as of low molecular weight

Links.

Crystallization methods can be carried out both on a small scale and on a large scale. Usually, it is attempted to recover crystals from saturated solutions of highly purified proteins in the presence of a concentrated solution of corresponding salts or polymers (polyethylene glycols, etc.). In this case, the protein solutions for the solubility water in a certain time is more or less withdrawn (or in the case of hydrophobic protein and vice versa), so that by a fluctuation of the protein molecules associates of different sizes can arise. The emergence of nucleation germs is the prerequisite for the formation of crystals. These processes are usually empirically tested by selecting different protein concentrations, different salts in varying ionic strength conditions, pHs, buffers,

Polymers, organic solvents, temperatures, etc., with a multi-parameter problem. (McPherson, A., et al., Introduction to Protein Crystallization, Acta Crystallographica Section F: Structural Biology Communications, 70, 2014, 2-20).

There are various crystallization methods available. In so-called batch processes, the protein to be crystallized is added in a suitable sample carrier as a concentrated solution to a previously deposited aqueous solution or vice versa (Chayen, NE, Stewart, PDS, Maeder, D. L. Blow, DM, J. Appl. 1990, 23, 297-302, Chayen, NE, J. Crystal Growth, 1999, 196, 434-41). As with this system no

Enrichment of the precipitation reagents takes place over a longer period of time, but the final concentrations in the application of the protein solution is set directly, it is called a "batch process".

This method does not allow continuous entry into the metastable region of a phase diagram. Thus, the great advantage of classical crystallization processes is lost.

A modified method for the batch process consists in replacing, instead of pure paraffin oil, e.g. to use poly (dimethylsiloxane) (DMS) added paraffin oil so that continuous water diffusion from the solution takes place (D'Arcy A., Elmore, C., Stihle, M., Johnston, JE, J. Crystal, Growth, 1996, Vol 168, pp. 175-80). However, the method does not allow the setting of an endpoint because it is not a closed system. The big disadvantage is that the protein solution dries out completely over a certain period of time. It is therefore only conditionally usable for crystallogenesis. In contrast, in classical methods based on vapor diffusion (hanging or sitting drops) usually a drop of a protein solution (mixed with reservoir solution) in one

closed vessel with a reservoir of aqueous solution of a predetermined higher concentration incubated with exclusion of air. Over time, water evaporates from the drop, increasing the protein concentration continuously. An endpoint is reached when the drop is in equilibrium with the reservoir. The endpoint can thus be set via the concentration of the excess reservoir. However, the provision of crystals suitable for structure elucidation often involves great difficulties or is not possible at all according to known methods. Often it happens that an ordered crystallization fails for unknown reasons. The interplay of physico-chemical processes that take place during the

Crystallogenesis play, is still not clearly described, since crystallization so far eluded a consistent analysis. When crystals are obtained, they are often not of sufficient size or quality.

In view of the great advances that have been made in recent years in the elucidation / identification of gene and protein sequences by new and automated methods, it is desirable to systematically examine the numerous novel proteins that can now be expressed by automated methods , Also, some areas of X-ray structure analysis have experienced huge increases in efficiency in recent years. Among other things, the provision of X-ray sources of high brilliance contributed to this

(Synchrotrons), as well as providing efficient hardware and software for the

Data interpretation at. The known methods for the crystallization of biological

However, macromolecules have so far not been satisfactorily as

automated high throughput processes are carried out (Chayen, N.E. and Saridakis, E., Acta Cryst., 2002, Vol. D58, 921-27). There is therefore a strong need for methods for the crystallization of proteins that can be easily automated, thus enabling screening of now available proteins and the systematic generation of crystals. A recent state of automation can also be found in the article by S. Shaw and J. Mueller Dieckmann (Automation in biological crystallization, Acta Crystallographica Section F: Structural Biology Communications 70, 2014, 686-696).

In automated diffusion experiments using the hanging-drop or seat-drop method, closed systems are closed, for example, by siliconized glass covers or with self-adhesive transparent films. In the case of the hanging drop method, one drop must be pipetted onto the underside of each lid, the lid turned over and placed over a liquid reservoir without affecting the drop. This must be hermetically sealed. For a robot this is associated with relatively many complex steps. Such automated methods are not attractive in terms of cost, speed and reproducibility and are difficult to implement with very small sample volumes (see also Chayen and Saridakis, 2002). In particular, when using the smallest sample volumes is important to ensure that the solution is protected from evaporation, as long as the systems do not z. B. by application of self-adhesive films or by cover, ie mechanically, are closed.

A variety of different devices for the crystallization of biological

Macromolecules exist. Thus, e.g. U.S. Patent 5,096,676 discloses a device for crystallization in sitting drops, e.g. B. can be closed by means of a self-adhesive film. Other devices are disclosed in U.S. Patents 5,130,105; 5,221, 410; 5,400,741; 5,419,278; 6,039,804 and in applications US-2002/0141905; US-2003/0010278, WO / 00/60345, WO / 01/88231 and WO / 02/102503. All devices allow classical vapor diffusion crystallization experiments and must be mechanically closed, eg. B. by means of a self-adhesive film.

A disadvantage of the known systems is in particular that the covers for the microtiter plate, or for the individual cavities of these plates, are not reversible to open, or the opening of a cavity can not separately, ie detached from the other cavity, but instead rather a cover from the microtiter plate complete

is removed and thus all cavities are exposed. This is especially problematical when crystalization experiments have to be manipulated, for example with regard to ligand or anti-freeze tracer experiments or when the crystals have to be fished out of their growth solution for a diffraction measurement.

Particularly in the case of shallow cavities, such as those used in protein crystallization, this leads to an accelerated evaporation of solvent due to the surface / volume ratio. This in turn can lead to a dramatic deterioration of the crystal quality up to a complete loss of the crystal

Scattering properties of the crystals lead.

The invention is based on the object of providing a cover for a microtiter plate in which the problems of the prior art are eliminated or at least reduced. In particular, a cover should be provided for as far as possible any type of microtiter plate, which allows a separate and reversible opening and closing of individual wells of a microtiter plate.

This object is achieved by a cover for placement on a microtiter plate, as well as a microtiter plate and a kit comprising such a cover and a microtiter plate having the features of the independent claims. Thus, a first aspect of the invention relates a cover for placement on a microtiter plate comprising a rectangular plate for mounting on a microtiter plate. On this plate rectangular tiles are arranged in the form of a grid. Adjacent tiles adjoin each other directly or indirectly. The plate also has passage openings, which are arranged corresponding to the tiles. The position and size of the passage openings in turn correspond to cavities of a microtiter plate to which the cover according to the invention is arranged in the intended use. The grid of tiles is framed by at least three arranged on the plate boundary elements, which serve as stops for the tiles and thus can position them. According to the invention, it is provided that adjacent tiles on the plate are mutually displaceable.

The cover of the invention solves the object of the invention by each one tile serves as a cover for each passage opening and thus ever a cavity. To open the cavity, the corresponding tile on the plate is moved so that the opening of the cavity is released. Depending on the position of the cavity to be opened adjacent tiles are also moved, with the sliding process no further cavity must be opened. Since the tiles directly or indirectly adjoin one another, when moving adjacent tiles, a cavity which is not to be opened is covered by an adjacent tile by being pushed over the adjacent cavity, while the cavity originally closing the opening is shifted by one position in the grid. To create an opening, a cavity which is arranged at the edge of the grid, that is, in an outer row or column of the grid, is moved out of the grid on the plate. Advantageously, it is thus ensured that the opening of a cavity does not necessarily necessitate the opening of further cavities. Moreover, the process of opening a cavity is reversible, i. H. After final preparation, the cavity can be reversibly closed again by repositioning one or more tiles. Thus, an uncontrolled loss of solvent from the cavities or contamination of the preparations is prevented.

Under raster in the present case is a regular arrangement of rectangular points or

Objects (in this case tiles) to understand. The grid extends in two dimensions, rows and columns. Preferably, adjacent rows have the same number of columns and adjacent columns have the same number of rows. Each position of a tile can be clearly defined by assigning a row and a column number. In other words, the tiles are arranged like a grid or the abutting edges of all tiles result in a grid-like structure. The limiting elements are stops which protrude beyond the surface of the plate on which the tiles are arranged, that is to say on the side of the plate which, when used as intended, is remote from the microtiter plate. They are for example designed as separate elements which extend along a row or a column of the grid or formed as elevations on the plate. Alternatively or additionally, the

Limiting elements indirectly formed by a recess in the region of the grid, such that the tiles are arranged in a recess of the disk surface or a return on the disk surface.

In a preferred embodiment of the invention, it is provided that the grid of the tiles in outer shape and size is adapted to a microtiter plate that each cavity of the microtiter plate can be covered by one tile each with the cover to a microtiter plate. In other words, the number of tiles also corresponds to the number of wells of the microtiter plate. The diameter or the length and / or width of a tile then preferably corresponds to the spacing of adjacent cavities, wherein distance relates to the length between the centers of adjacent cavities. That Depending on the configuration, the cover is adapted to a 6, 12, 24, 48, 96, 384 or 1536-well microtiter plate. In addition to the adaptation of the tile positions and tile sizes to the position of the cavities of the respective microtiter plate, the external shape and size are also adapted to the external shape and size of the microtiter plate. In other words, the cover has at least the size of the cavity of the surface of the microtiter plate.

Particularly preferably, the cover is designed to at least partially enclose the microtiter plate. This allows a kind of locking, so stabilizing the position of the cover on the microtiter plate. In other words, the dimensions of the grid and in particular the outer shape of the cover from the dimensions of the microtiter plate on which the cover is to be placed under normal use.

For this purpose, the cover on the side facing away from the tiles side

Stabilizing element, which preferably as a frame, as a stop or as

Clamp or spring element is formed. In embodiments using stops, the stops are preferably used, in particular adjacent to one another, which are arranged on opposite and / or adjacent edges of the cover. In the present case, a frame is to be understood as four frame elements which are arranged circumferentially around the cover and are interconnected perpendicularly, at least one of the frame elements being detachable with the adjacent frame elements connected is. This allows insertion of a microtiter plate under the plate. In addition, the frame, which preferably has a clear height that the height of a

Microtiter plate corresponds, have a closed base, which is arranged on the opposite side of the plate of the frame. When pushing the

Microtiter plate under the plate, the microtiter plate comes to rest on the base, so that advantageously the cover can be transported in order to the microtiter plate without causing slippage or displacement of the plate against the surface of the microtiter plate.

In a further preferred embodiment it is provided that further on the plate

Dodge position, in particular in the form of a recess in a limiting element, is arranged. This recess corresponds to the grid in such a way that a tile on the plate is displaceable into the evading position. This embodiment has the advantage that exactly one tile can be pushed out of the grid and thus exactly one position of the grid and consequently exactly one cavity is opened. Advantageously, the cover comprises a blocking element, which is cohesively introduced into the avoidance position and blocks this position with respect to an adjacent tile. This prevents accidental movement of a tile in the avoidance position and thus provides the tightness of the

Cover safe.

Alternatively, the cover has a plurality of escape positions, which are arranged in particular along a row or a column, wherein preferably a number of

Dodge positions corresponds to a number of columns or rows. In this embodiment, a plurality of positions, at most as many as avoidance positions are available to open at the same time, since ever a tile can be moved in each one evasive position.

Advantageously, the plate further comprises at least one guide element, which the

Displaceability of the tiles in the direction of a row and / or a column of the grid limited and / or supported in another direction along the guide member. The guide elements are preferably connected to the plate. A guide element in the sense of this embodiment is a longitudinally along a row or a column of the grid element extended, for example, a rail which is designed to allow a displacement parallel to the guide element, a displacement perpendicular thereto, but preferably in the direction of the guide member preferably to prevent , For this purpose, the guide element preferably has an area in which a region of the tile overlaps with the guide element. Guide elements are preferably on the side facing the tiles of the Plate and / or arranged on the side facing away from the tiles of the plate. In an arrangement on the side facing the tiles, the guide elements are preferably arranged on the boundary elements or part of the boundary elements. Alternatively or additionally, guide elements are arranged between each column or row of the grid. It is either possible that the tiles on the

Resting guide element that two adjacent tiles contact each other and both the contact edge, as well as parts of the two adjacent tiles rest on the guide member. Here, a mobility of the tiles both longitudinally and transversely to the guide element is possible. Alternatively, a guide element between adjacent tiles is arranged so that the tiles have no contact with each other or contact only in a portion of the edge each other and a displacement of the tiles on the plate thus only parallel to the guide element is possible. Here are several

Avoiding positions may be provided, in particular as many alternative positions as the grid has columns, when the guide elements between the tiles along the columns are arranged or as many alternative positions as the grid has rows, when the guide elements between the tiles along the rows of the grid are arranged. The latter embodiment offers the particular advantage of stabilization and tightness of the plate. In addition, only one shift, or sliding movements, is always necessary to open any passage opening of the plate.

The guide elements can each extend over the entire length or width of the grid, which results in a stability advantage of the plate, or be arranged along the abutting edges of adjacent tiles, along the abutting edge of two adjacent rows and / or two adjacent columns more spaced apart

Guide elements are arranged one behind the other. This embodiment is particularly preferred when the guide elements, which are arranged on the plate, direct by the arrangement and height of a mobility of the tiles and in two directions, namely in the column direction and in the row direction limit. In this embodiment, only one alternative position is required, so that it advantageously offers a greater number of degrees of freedom.

With particular advantage, the plate is formed in the region of the grid as a grid, which extends along abutting edges of adjacent tiles. This has the advantage that

largest possible through holes in the plate arise and also have the lattice struts stabilizing effect on the plate and can also serve as a guide element for the tiles. In this case, the lattice struts preferably have a maximum width, which corresponds to the smallest distance between two adjacent cavity edges of a corresponding microtiter plate.

More preferably, the tiles on an overlap region with adjacent tiles and / or with boundary elements. Particularly preferably, the overlapping region is designed as a positive connection, in particular as a tongue and groove connection. This embodiment offers the advantage of stabilizing and fixing the tiles to each other, wherein nevertheless all degrees of freedom with respect to the displacement in the direction of

Raster coordinates exist. In particular, the configuration as a tongue and groove connection allows that even without guide rails or lattice struts above the tiles, ie on the side facing away from the plate side of the tiles, the tiles can not escape laterally to the plate, resulting in increased tightness of the cover and a increased positional stability of the tiles leads.

In order to increase the tightness of the cover and thus to reduce the escape of solvent from the cavities when used as intended, it is preferably provided that the plate, the tiles and / or the guide element or the guide elements have or have a sealing element.

The sealing element is, for example, circumferentially around a passage opening on one

Surface of the plate on the tiles facing and or arranged on the side facing away from the tiles, so that the sealing element fluid-tight contact between the plate and tile, or when used as intended between the plate and

Microtiter plate, training. This embodiment ensures, in particular, that solvents from different cavities which enter the gas phase mix in the gas phase or as condensate and then return to the cavities. Thus, mixing of solvent in different cavities can be effectively prevented. Alternatively or additionally, in each case a sealing element is arranged on a tile, wherein the sealing element is arranged, for example, along a circumferential edge of the tiles and / or on a surface of the tiles facing the tile.

In a further preferred embodiment of the invention it is provided that the tiles on a side facing away from the plate have a recess and / or a survey for the arrangement of a tool or a finger. This allows a safe and accurate displacement of a tile or a row of tiles, in which, for example, a tool is placed in the recesses or on the survey and on the tool targeted pressure in a direction is exerted on the tiles, so that the tiles and possibly the adjacent row are moved. Preferably, the recess is a hole that is less deep than the tiles thick and has a diameter that corresponds, for example, the outer circumference of a ballpoint pen tip or the outer shape of a spatula tip. These are items that are constantly in stock in a laboratory and thus can easily serve as a sliding tool without being made especially for the cover of the invention. In addition, this embodiment allows the application of the cover according to the invention in automation, if, for example, the

Tool is part of a robot.

It is further preferred if the tiles are made of a material which is at least partially transparent and thus allows a view through the through opening. Thus, with proper use of the cover according to the invention, the progress in the respective cavity can be observed without having to open the cavity.

Alternatively or additionally, the tiles also each have a passage opening, which is closed in a fluid-tight and / or gas-tight manner by means of a transparent foil or a septum, in particular. In this embodiment, the film is preferably also made transparent and allows a clear view through the passage opening of the plate. A passage opening in a tile, which is closed in particular with a septum, on the one hand offers the above-described advantages of the cover according to the invention, in particular that each cavity of a microtiter plate can be opened and closed separately and independently of the others. In addition, however, it is also possible, especially several automated

Cavities, especially all cavities to pipette at the same time, without having to move all the tiles or remove the cover of the invention.

The film is preferably a so-called heat-sealing film, which is thermally welded onto the tiles. These have the advantage that an absolute air and moisture tightness can be guaranteed.

The material of the cover and in particular of the tiles essentially comprises the

Properties that have the materials from which conventional microtiter plate are made. Thus, the cover according to the invention and in particular the tiles made of transparent, chemical and / or temperature-resistant, injection-moldable materials. Preference is given to plastics, in particular thermoplastic or

thermosetting plastics such as polyvinyl chloride, polypropylene or polystyrene. Preferably, the plate and the limiting elements arranged thereon and / or the guide elements arranged thereon are produced in one piece, for example by injection molding or by means of printing processes (3D printers).

Another aspect of the invention relates to a kit comprising a microtiter plate and a cover according to the invention in one of the aforementioned embodiments. In addition to the aforementioned advantages, the kit offers the possibility of modular design of the cover and the microtiter plate, wherein in particular the guide elements or additional guide rails for fixing the microtiter plate to the cover are detachably connected or connectable to the cover according to the invention. The kit is preferably arranged in a sterile packaging, in particular for single use.

Further preferred embodiments of the invention will become apparent from the remaining, mentioned in the dependent claims characteristics.

The various embodiments of the invention mentioned in this application are, unless otherwise stated in the individual case, advantageously combinable with each other. Thus, for example, the cover of the invention is preferably also separately, so without arrangement in the kit, modular executable.

The invention is described below in embodiments with reference to the associated

Drawings explained. Show it:

FIG. 1 shows a schematic representation of a microtiter plate cover in a first preferred embodiment of the invention,

FIG. 2 shows a schematic representation of a cover with a microtiter plate in a second preferred embodiment of the invention,

Figure 3 is a schematic representation of a cover in a third preferred

Embodiment of the invention,

Figure 4 is a schematic representation of the operation of the invention

Cover in the second embodiment and Figure 5 is a schematic exploded view of a kit with microtiter plate and

Cover in the first preferred embodiment of the invention.

FIG. 1 shows the cover 1 according to the invention under intended use, arranged on a microtiter plate 40 in a preferred embodiment. Shown is the cover 1 according to the invention in plan view, as well as in an oblique view of two cut edges A-A and B-B.

The cover 1 according to the invention comprises, in the embodiment shown, a plate 10 on which a grid of rows 16a and columns 16b of adjacent tiles 20 is arranged. The grid 16 is framed in the embodiment shown by four limiting elements 1 1, which serve as stops for the tiles 20. In an area adjacent to position 1-1, in the form of an interruption of a first limiting element 11, a

Dodge position 14 arranged. This evasive position 14 has at least the size of a tile 20.

As can be seen in the sectional view, the limiting elements 11 are configured in one piece with the plate 10 in the embodiment shown.

The delimiting elements 11 can have a guide rail 15 along the abutting edges between the tiles 20 and delimiting element 11, which preferably comprises an area in which parts of a tile 20 overlap with sections of a delimiting element 11. These guide rails 15 may be formed, for example, as a groove 15b spring 15b system.

In addition, also integrally formed with the plate 10, a frame 13 is arranged thereon. The frame 13 comprises at least three frame elements 13 which are arranged on at least three adjacent edges of the plate 10. In the embodiment shown, the frame members 13 form a right angle to the plate 10 and extend from a side facing away from the tiles of the plate 10. In addition, the cover 14 may comprise frame members 13 which in the form of a frame around the plate 10 and the plate 10 are arranged. In the embodiment shown, the frame 13 is designed, when used as intended, to comprise at least part of the microtiter plate 40, in particular to cover the microtiter plate 40 over its entire height.

In addition, a fixing element (not shown) may be provided, such as a clamp or a guide rail formed, for example, in the form of a groove. The Fixing stabilizes the position of the microtiter plate 40 relative to the cover.

Alternatively or additionally, the frame element 13 is designed as a clamp.

The plate 10 has through openings 12 arranged in the form of a grid 16, that is, in positions which can be clearly described by a line number and a column number. The through-openings 12 are arranged congruently with the openings of cavities 41 of the microtiter plate 40 when used as intended. In this case, the size of a passage opening 12 essentially corresponds to the size of an opening of a cavity 41. In the case of conventional, substantially round cavities 41 of the microtiter plate 40, a

Through opening 12 also round, preferably with the same diameter as that of the cavity 41, executed. On the other hand, if the cover is designed for microtiter plates 40, which has irregularly configured cavities 41, as used, for example, for

Protein crystal biography can be used. Thus, the passage opening 12 of the plate 10 describe the entire circumference of the cavity 41, each comprising the individual cavities associated with a cavity 41, or consist of a plurality of through holes, which are arranged corresponding to the individual wells of a cavity 41.

Alternatively, passage openings 12 are formed through gaps of a grid, wherein the grid struts extend along the abutting edges of the tiles 20. In this embodiment, a passage opening 12 has a substantially rectangular, in particular square shape.

The plate 10 optionally has on the side facing the tiles 20 and / or the side facing away from the tiles 20 a sealing element (not shown), which is cohesively arranged on the plate 10 and when used properly, the cavity 41 against the plate 10 and / or the plate 10 seals against a tile 20 disposed thereon.

The tiles 20 are configured substantially plate-shaped and have a passage opening 21 in the embodiment shown. The passage opening 21 is arranged in an exact grid, so over exactly one through hole 12 in the plate 10 overlapping with the through hole 12 so that in view of the plate 10, the view through two corresponding through holes 12 and 21 is free and in arrangement of the tile the passage opening 21 is closed fluid-tight and gas-tight. For this purpose, a film (as shown for example in FIG. 5) is preferably arranged on a surface 20 remote from the plate 10. The film 25 is preferably made transparent and, for example, glued or welded onto the tiles 20. Alternatively, the film 25 can also be used as a septum be configured, ie be designed so that even after a cannula is passed through the film 25 and the septum no gas or liquid exchange takes place through the film 25.

Optionally, the tile 20 on the side facing away from the plate 10, a means 22 which is adapted to arrange a tool or a finger and lock it to some extent, so that the tile 20 can be moved over a means arranged on this means 22 tool , The means 22 is preferably a recess and / or a

Raising, which is adapted in shape and size to the preferred tool, such as the expression of a pen, a spatula edge or a human finger.

Circumferentially along the edges of a tile 20 and / or on the plate 10 facing side of a tile 20, a sealing element (not shown) is optionally arranged, which adjacent tiles 20 and the transition from plate 10 to tile 20 fluidly against each other and / or gas-tight seals. The sealing element is preferably made of an elastic plastic and molded or glued to the tile 20. If a tile 20 has a sealing element on the side facing the plate 10, then no further sealing element is preferably provided on the plate 10 in this area, but rather a sealing element can then be provided

Recess may be provided, which corresponds to the arranged on the tile 20 sealing element.

In the embodiment shown in FIG. 1, the tiles 20 are arranged in two directions so as to be displaceable relative to one another on the board. For better stabilization and guidance, each have two, in particular adjacent edges of each tile 20, a spring 23 and the respective opposite edges of the tile 20 to the springs 23 corresponding groove 24.

In particular, the limiting elements 11, the plate 10, the frame 13 and the tiles 20 may also be configured in the embodiments of the further figures 2-5 as described in Figure 1.

Figure 2 shows a further embodiment of the cover 1 according to the invention, also in the perspectives in which the embodiment shown in Figure 1 is already shown. In essence, both embodiments are the same design, with some features that are independent of each other with the features of the shown in Figure 1 and

described embodiment may be combined to those in Figure 1 are different. In particular, the differences between those shown in FIG Embodiment received. In contrast to the embodiment of FIG. 1, the cover 1 of the embodiment of FIG. 2 not only has an alternative position 14, but several lines are along one line (hereby capitalized)

Dodge positions 14 arranged, which corresponds to the number of columns (numbers 1-12).

Between adjacent columns, a guide element 15 is arranged along the abutting edge of adjacent tiles 20, which in particular runs continuously over the length or width of the grid and optionally additionally extends over the deviating positions 14 such that it separates adjacent escape positions 14 from one another. In the embodiment shown, a guide member 15 prevents tiles 20 perpendicular to the

Guide element 15, ie along a line 16a, are mutually displaceable. On the other hand, neighboring tiles of a row 16a are not prevented from being touched. The latter increases in particular the tightness of the cover 1. The guide element 15 has in the embodiment shown on one side a spring 15a and on the other side a groove 15b, with a groove 24 and a spring 23 in the guide element to the 15th adjacent tile 20 corresponds. Since a displacement of the tiles 20 along a line 15a in the embodiment shown is not possible, a groove / spring system along a gap 16b of adjacent tiles 20 has been dispensed with in this embodiment.

In contrast to the embodiment of FIG. 1, the tiles 20 in the embodiment shown in FIG. 2 themselves have no passage opening, but this is only one

Embodiment and is not limited thereto. Thus, it can also be provided that the tiles are equipped with a passage opening 21 and / or a means 22 as described in FIG.

The embodiment of the cover 1 according to the invention shown in FIG. 3 pays special attention to a variant of guide elements 15 which are shown in FIG

Embodiment as guide webs on the plate 10 are arranged. In this case, along the abutting edges of the tiles 20 (not shown here) are each arranged at the intersections of column and row insertion webs, so that in the closed grid four tiles 20 are in contact with a guide web 15. In addition, the serve

Delimiting elements 11 also as guide elements 15 by having a recess in which the tiles overlap with the guide element 1 1, so that the return acts as guide rails. The features mentioned can be combined with each of the features described in FIGS. 1 and 2. This relates in particular to the execution of several alternative positions 14, the configuration of the tiles 20, delimiting 1 1, frame 13 and guide elements 15 and the through holes 12th In Figure 3, the embodiment is shown with only one alternate position adjacent to position 1-1, however, the described guide elements 15 are explicitly preferred with an array of multiple escape positions along a row or column.

The cover 1 shown in Figure 3 shows only a section of the cover, since the tiles 20, which are also part of the cover 1 according to the invention, are not shown. This allows a view of the through openings 12. The embodiment shown is adapted to a microtiter plate 40 for protein crystallography. Therefore, the

Through holes 12 not a round shape but an irregular shape, which transforms the irregular wells of a cavity for protein crystallography.

In FIG. 4, the opening of an arbitrary position (here position 2 - 2) is shown by way of example for the embodiment of a cover 1 according to the invention with an evasive position 14 and takes place correspondingly in any other embodiment. The design of the tiles 20, the delimiting elements 11 and the other features is only the

Illustration and is instead executable in one of the variants described above. In the partial view A of Figure 4, the cover 1 is in the initial state, which means all the positions of the grid 16 and thus all through holes 12 and therefore all

Cavities 41 of the arranged under the cover microtiter plate 40 are closed. To open any cavity 41 is first the tile 20 of the position 1 - 1 in the

Dodge position 14 pushed. This opens the position 1 - 1 of the grid as shown in partial view B. The underlying passage opening 12 in the plate and the cavity 40 arranged underneath are accessible. Based on this, it is now possible to proceed with adjacent positions, that is to say with the position 2 - 1 or 1 - 2, by shifting them to positions 1 - 1, respectively. Alternatively, multiple tiles can be moved simultaneously along a row or column, so that (referring to the example above) each tile 20 of one of the row 1 or each tile of the column 2 by one position in the direction

Badge position 14 is moved. The said steps can also be carried out directly one after the other, so that first of all one or more tiles 20 of a row are displaced in the direction of avoidance position and then one or more tiles 20 of the column in which a passage opening 12 is exposed is displaced in the direction of this free position. The result is the opening of any position shown in partial view C (position 2 - 2 in FIG. 4C). Accordingly, the opening of any position in the embodiment of the cover 1 takes place with a plurality of alternative positions, wherein the opening of any position in each case only the displacement in one direction, namely along a column when the alternative positions 14 are arranged in a row or the displacement along a Line if the

Dodge positions are arranged along a column.

FIG. 5 shows an exploded view of a kit 100 according to the invention. The embodiment of the microtiter plate 40 and the cover 1 as well as the tiles 20 shown here are only to be understood by way of example and can be used with any of the aforementioned

Embodiments or individual features can be combined. FIG. 5 pays special attention to an optional modular design of the kit 100 according to the invention, in particular the delimiting elements, unlike the embodiments shown above, are not fixedly connected to the plate 10. Rather, the plate 10 holding elements, which correspond in the sense of a key-lock principle with three clip-like designed boundary and frame members 11, 13. The

Delimiting elements 11 are designed in a clip-like manner such that they enclose both the edge of the cover 1 and the edge of the microtiter plate 40 in the intended arrangement, so that the position of the microtiter plate 40 is fixed in relation to the cover 1. An additional limiting element 11 a is arranged parallel to the plurality of alternative positions 14. It is depending on the arrangement of the plate 10 by inserting a fixing rail with the plate 10 positively connected. This detachable connection of the additional limiting element 11 a allows removal of the tiles 20, which in the embodiment shown with each other and with the limiting elements 1 1 are positively connected to each other by a tongue and groove system and thus not in particular solved by vertical lifting of the plate 10 can be.

LIST OF REFERENCE NUMBERS

cover

plate

limiting element

a additional limiting element

Through opening

Frame / frame element

evasive position

guide element

a spring

b groove

grid

a line

b column

c open position

tile

Through opening

Means (recesses and / or survey)

feather

groove

foil

microtiter plate

Cavity 0 Kit

Claims

claims

1. Cover (1) for placement on a microtiter plate (40), comprising

a rectangular plate (10) for resting on a pine microtiter plate (40)

on the plate (10) in the form of a grid (16) arranged directly or indirectly adjacent rectangular tiles (20),

wherein the plate (10) corresponding to the tiles (20) arranged

Having through openings (12)

- The grid (16) arranged by at least three on the plate (10)

Limiting elements (11) is framed, and

wherein adjacent tiles (20) on the plate (10) are mutually displaceable.

2. Cover (1) according to claim 1, characterized in that the grid (16) of the tiles (20) in outer shape and size is adapted to a microtiter plate (40) that when the cover (1) to a microtiter plate (40) each cavity (41) of the microtiter plate (40) can be covered by a respective tile (41).

3. Cover (1) according to any one of the preceding claims, characterized in that on the plate (10) further comprises a deflection position (14), in particular in the form of a recess in a limiting element (1 1), arranged with the grid ( 16) corresponds such that a tile (20) on the plate (10) in the

Dodge position (14) is displaceable.

4. Cover (1) according to any one of the preceding claims, characterized in that the plate (10) further comprises at least one guide element (15) which the displaceability of the tiles (20) in the direction of a line (16 a) and / or a column (16b) of the grid (16) limited.

5. Cover (1) according to one of the preceding claims, characterized in that the plate (10) in the region of the grid (16) is formed as a grid which extends along abutting edges of adjacent tiles (20).

6. Cover (1) according to one of the preceding claims, characterized in that the tiles (20) form-fitting connection with each other and / or with the Have limiting elements (11), which is designed in particular as a tongue and groove connection.

7. Cover (1) according to one of the preceding claims, characterized in that the plate (10), a tile (20) and / or a guide element (15) a

Has sealing element.

8. Cover (1) according to one of the preceding claims, characterized in that a tile (20) on one of the plate (10) facing away from a recess (22) and / or a survey (42) for the arrangement of a tool or a finger respectively.

9. Cover (1) according to one of the preceding claims, characterized in that a tile (20) has a passage opening (21) which is closed with a particular transparent film (25) or a septum fluid and / or gas-tight.

A kit (100) comprising a microtiter plate (40) and a cover (1) for the

Microtiter plate (40) according to one of the preceding claims.