DE102018111478A1 - Cover for placement on a microtiter plate, and kit comprising cover and microtiter plate - Google Patents

Abstract

The invention relates to cover (1) for placement on a microtiter plate (40), as well as a kit with a microtiter plate and such a cover.
It is provided that the cover has a plurality of tiles (20) arranged on a plate (10) corresponding to the cavities (41) of the microtiter plate (40) and which are displaceable directly or indirectly against one another on the plate (10).

Description

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. For example, determining the three-dimensional structure of a protein target can provide crucial information for the identification and development of new drugs that interact with the particular 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 application field of crystallization lies in its property as a purification method for biological macromolecules as well as of low molecular weight compounds.

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 In this case, the protein solutions for the solubility water in a certain time is more or less withdrawn (or in the case of hydrophobic protein and vice versa), so that by a fluctuation of the protein molecules associates of different sizes can arise.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 nuclei 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, pH values, 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 process, 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. Cryst, 1990, 23, 297-302; Chayen, NE; J. Crystal Growth. 1999, 196, 434-41 ). Since this system does not accumulate the precipitating reagents over a longer period of time, but instead sets the final concentrations directly when applying the protein solution, this 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 of using, instead of the pure paraffin oil, for example, a poly-dimethylsiloxane (DMS) added paraffin oil, so that a 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, classical methods based on vapor diffusion (hanging or sitting drops) generally incubate a drop of a protein solution (added with reservoir solution) in a closed vessel with a reservoir of an aqueous solution of a predetermined higher concentration 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 crystallogenesis is still not clearly described, since crystallization has 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 high-brilliance X-ray sources (synchrotrons) and the provision of efficient hardware and software for data interpretation contributed to this. However, the known processes for the crystallization of biological macromolecules have hitherto not been satisfactorily performed as automated high-throughput processes ( Chayen, NE 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 is also the essay by S. Shaw and J. Mueller Dieckmann ( Automation in biological crystallization, Acta Crystallographica Section F: Structural Biology Communications 70, 2014, 686-696 ) refer to.

In automated diffusion experiments by the hanging drop method or the sit-drop method, closed systems are used e.g. closed by siliconized glass lids or with self-adhesive transparent foils. 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, d. H. mechanically, are closed.

A variety of different devices for the crystallization of biological macromolecules exist. For example, this describes U.S. Patent 5,096,676 a device for crystallization in sitting drops, the z. B. can be closed by means of a self-adhesive film. Other devices are in the U.S. Patents 5,130,105 ; 5,221,410 ; 5,400,741 ; 5,419,278 ; 6,039,804 , as well as in the applications US-2002/0141905 ; US-2003/0010278 . WO / 00/60345 . WO / 01/88231 and WO / 02/102503 described. 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 of the microtiter plate is completely removed and thus exposing all cavities. 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 to a complete loss of the scattering properties of the crystals.

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 to 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 arranged by at least three on the plate Framed 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.

In this case, raster is to be understood as a regular arrangement of rectangular points or objects (in the present case tiles). 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 are indirectly formed by a recess in the region of the grid, such that the tiles are arranged in a recess of the plate surface or a recess on the plate 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. Ie. 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 on a stabilizing element, which is preferably designed as a frame, as a stop or as a clamp or spring element. 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, wherein at least one of the frame elements is detachably connected to the adjacent frame elements. This allows insertion of a microtiter plate under the plate. In addition, the frame, which preferably has a clear height which corresponds to the height of a microtiter plate, may have a closed base surface which is arranged on the side of the frame opposite the plate. When pushing the microtiter plate under the plate, the microtiter plate comes to lie on the base, so that advantageously transported the cover in arrangement on the microtiter plate can be without causing slippage or displacement of the plate against the surface of the microtiter plate.

In a further preferred embodiment, provision is made for a deflection position, in particular in the form of a recess in a delimiting element, to be arranged on the plate. 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 displacement of a tile in the avoidance position and thus ensures the tightness of the cover.

Alternatively, the cover has a plurality of avoidance positions, which are arranged in particular along a row or a column, wherein preferably a number of the avoidance 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 limits the displaceability of the tiles in the direction of a row and / or a column of the grid and / or supports it in another direction along the guide element. 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 arranged on the side facing the tiles of the plate and / or 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. In this case, it is either possible for the tiles to rest on the guide element such that two adjacent tiles contact one another and both the contact edge and parts of the two adjacent tiles rest on the guide element. 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. In this case, a plurality of alternative positions must be provided, in particular as many alternative positions as the grid has columns, if the guide elements between the tiles along the columns are arranged or as many alternative positions as the grid lines, if 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 the 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 in the form of a positive connection, in particular as tongue and groove Connection, trained. This embodiment offers the advantage of stabilizing and fixing the tiles to one another, wherein nevertheless all degrees of freedom with respect to the displacement exist in the direction of the grid coordinates. 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 arranged around a passage opening on a surface of the plate on the side facing the tiles and or on the side facing away from the tiles, so that the sealing element forms a fluid-tight contact between plate and tile, or when used as intended between plate and microtiter plate , 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 the tool targeted pressure is exerted in one direction on the tiles, so that the tiles and possibly the be moved adjacent row. 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, for example, if 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, in particular automatically, to pipette several cavities, in particular all cavities, at the same time, without having to displace all the tiles or having to remove the cover according to 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 has substantially the properties that comprise 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, especially 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.

• 1 eine schematische Darstellung einer Abdeckung mit Mikrotiterplatte in einer ersten bevorzugten Ausführungsform der Erfindung,
• 2 eine schematische Darstellung einer Abdeckung mit Mikrotiterplatte in einer zweiten bevorzugten Ausführungsform der Erfindung,
• 3 eine schematische Darstellung einer Abdeckung in einer dritten bevorzugten Ausführungsform der Erfindung,
• 4 eine schematische Darstellung der Funktionsweise der erfindungsgemäßen Abdeckung in der zweiten Ausführungsform und
• 5 eine schematische Explosionsdarstellung eines Kits mit Mikrotiterplatte und Abdeckung in der ersten bevorzugten Ausführungsform der Erfindung.

The invention will be explained below in embodiments with reference to the accompanying drawings. Show it:

• 1 a schematic representation of a cover with a microtiter plate in a first preferred embodiment of the invention,
• 2 a schematic representation of a cover with a microtiter plate in a second preferred embodiment of the invention,
• 3 a schematic representation of a cover in a third preferred embodiment of the invention,
• 4 a schematic representation of the operation of the cover according to the invention in the second embodiment and
• 5 a schematic exploded view of a kit with microtiter plate and cover in the first preferred embodiment of the invention.

1 shows the cover according to the invention 1 when used as intended, placed on a microtiter plate 40 in a preferred embodiment. Shown is the cover according to the invention 1 in plan view, as well as in oblique view on two cut edges AA and BB.

The cover according to the invention 1 includes a plate in the illustrated embodiment 10 on which a grid of in lines 16a and columns 16b adjacent tiles 20 is arranged. The grid 16 is in the embodiment shown by four limiting elements 11 framed, as stops for the tiles 20 serve. In one to the position 1 - 1 adjacent area is in the form of an interruption of a first limiting element 11 an alternative position 14 arranged. This alternative position 14 has at least the size of a tile 20 on.

As seen in the sectional view, the boundary elements are 11 in the embodiment shown integral with the plate 10 designed.

The boundary elements 11 can along the abutting edges between tiles 20 and limiting element 11 a guide rail 15 which preferably comprises an area in which parts of a tile 20 with sections of a boundary element 11 overlap. These guide rails 15 For example, as a groove 15b - Feather 15b System be formed.

In addition, is also integral with the plate 10 designed a frame 13 arranged at this. The frame 13 includes at least three frame elements 13 the at least three adjacent edges of the plate 10 are arranged. In the embodiment shown, the frame elements form 13 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 can 14 frame elements 13 which, in the form of a frame around the plate 10 or on the plate 10 are arranged. In the embodiment shown, the frame is 13 trained, at least part of the microtiter plate when used as intended 40 to include, in particular the microtiter plate 40 in their 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 element stabilizes the position of the microtiter plate 40 opposite the cover. Alternatively or additionally, the frame element 13 designed as a clip.

The plate 10 points in the form of a grid 16 , That is, in clearly arranged by a line number and a column number writable positions through holes 12 on. The passage openings 12 are congruent with the openings of cavities when used as intended 41 the microtiter plate 40 arranged. The size corresponds to a passage opening 12 essentially the size of an opening of a cavity 41 , In conventional substantially round cavities 41 the microtiter plate 40 is a passage opening 12 also round, preferably with the same diameter as that of the cavity 41 , executed. Is the cover, however, for microtiter plates 40 formed, the irregularly shaped cavities 41 has, as for example Protein crystal biography can be used. So the through hole 12 the plate 10 the entire circumference of the cavity 41 describe each one to a single cavity 41 includes corresponding recesses, or consist of a plurality of through holes corresponding to the individual wells of a cavity 41 are arranged.

Alternatively, through holes 12 formed by interstices of a grid, wherein the grid struts along the abutting edges of the tiles 20 run. In this embodiment has a through hole 12 a substantially rectangular, in particular square shape.

The plate 10 Optionally points to the tiles 20 facing side and / or the tiles 20 side facing away from a sealing element (not shown), which cohesively to the plate 10 is arranged and the intended use of the cavity 41 against the plate 10 and / or the plate 10 against a tile arranged on it 20 seals.

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

Optionally, the tile faces 20 on the plate 10 opposite side a means 22 which is suitable to arrange a tool or a finger and lock it to some extent, so that the tile 20 about one to this agent 22 arranged tool can be moved. The middle 22 is preferably a recess and / or an elevation, which is adapted in shape and size to the preferred tool, such as the face of a pin, a spatula edge or a human finger.

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

In the embodiment shown the 1 are the tiles 20 arranged in two directions against each other slidably on the plate. For better stabilization and guidance, each have two, in particular adjacent edges of each tile 20 a feather 23 and the opposite edges of the tile 20 one to the feathers 23 corresponding groove 24 on.

In particular, the boundary elements 11 , the plate 10 , the frame 13 as well as the tiles 20 can also in the remarks of others 2-5 as in 1 be designed described.

2 shows a further embodiment of the cover according to the invention 1 , also in the perspectives where the already in 1 shown embodiment is shown. In essence, both embodiments are the same design, with some features that are independent of each other with the features of in 1 shown and described embodiment can be combined to those in 1 are different. In particular, the differences between the 2 shown embodiment received. In contrast to the embodiment of the 1 points the cover 1 the embodiment of the 2 not just an alternative position 14 on, but rather along a line (capitalized hereby) several alternative positions 14 arranged according to the number of columns (numbers 1 - 12 ) corresponds. Between adjacent columns is along the abutting edge of adjacent tiles 20 one guide element each 15 arranged, which in particular runs continuously over the length or width of the grid and optionally also the type of the alternative positions 14 extends that there are adjacent fallback positions 14 separates each other. In the embodiment shown prevents a guide element 15 that tiles 20 perpendicular to the guide element 15 that is, along a line 16a , are mutually displaceable. On the other hand, neighboring tiles of a row are not prevented 16a touch. 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 another side a groove 15b on that with a groove 24 or a spring 23 in the on the guide element 15 adjacent tile 20 corresponds. Because a shift of the tiles 20 along a line 15a in the embodiment shown is not possible in this embodiment, a groove / spring system along a column 16b adjacent tiles 20 waived.

The tiles 20 in the in 2 shown embodiment, in contrast to the embodiment of the 1 no through-hole, but this is merely an embodiment and is not limited thereto. Thus, it can also be provided that the tiles as in 1 described with a through hole 21 and / or a means 22 are equipped.

In the 3 shown embodiment of the cover according to the invention 1 pays special attention to a variant of guide elements 15 , which in the embodiment shown as guide webs on the plate 10 are arranged. Here are along the abutting edges of the tiles 20 (not shown here) arranged in each case at the intersections of column and row insertion bars, so in the closed grid in each case four tiles 20 with a guide bar 15 are in contact. In addition, the boundary elements serve 11 also as guide elements 15 in that they have a recess in which the tiles with the guide element 11 overlap so that the return acts as guide rails. The features mentioned are with each of the in 1 and 2 described features combined. This refers in particular to the execution of several alternative positions 14 , the design of the tiles 20 , Limit 11, Frame 13 and guide elements 15 as well as the passage openings 12 ,

In 3 For example, the embodiment with only one avoidance position adjacent to the position 1 - 1 shown, the guide elements described 15 However, they are also explicitly preferred with an arrangement of several alternative positions along a row or a column.

In the 3 shown cover 1 shows only a section of the cover, as the tiles 20 also part of the cover according to the invention 1 are not shown. This allows a view of the through holes 12 , The embodiment shown is to a microtiter plate 40 adapted for protein crystallography. Therefore, the through holes have 12 not a round shape but an irregular shape, which transforms the irregular wells of a cavity for protein crystallography.

In 4 is the opening of any position (here position 2 - 2 ) exemplary of the embodiment of a cover according to the invention 1 with an evasive position 14 shown and takes place accordingly in any other embodiment. The design of the tiles 20 , the boundary elements 11 and the other features is only illustrative and rather is executable in one of the variants described above. In the partial view A of the 4 is the cover 1 in the initial state, what does this mean all positions of the grid 16 and thus all through holes 12 and therefore all cavities 41 the under the cover arranged microtiter plate 40 are closed. To open any cavity 41 will be the tile first 20 the position 1 - 1 in the avoidance position 14 pushed. This opens the position as shown in part B 1 - 1 of the grid. The underlying passage opening 12 in the plate and the underlying cavity 40 become accessible. Based on this, it is now possible to work with adjacent positions, ie with the position 2 - 1 or 1 - 2 , just do this by putting each one in the position 1 - 1 is moved. Alternatively, multiple tiles can be moved along a row or column at the same time, so (with respect to the example above) each tile 20 one of the line 1 or each tile of the column 2 about a position towards the badge position 14 is moved. The steps mentioned can also be carried out directly one after the other, so that first of all one or more tiles 20 Move one line towards the alternate position and then one or more tiles 20 the column in which a passage opening 12 is exposed, is moved towards this free position. The result is the opening shown in partial view C of any position (position 2 - 2 in 4C ).

Accordingly, the opening of any position in the execution of the cover 1 with several alternative positions, wherein for opening any position only in each case only the displacement in one direction, namely along a column when the alternate positions 14 are arranged in a row or moving along a row when the alternate positions are arranged along a column.

In 5 is an exploded view of a kit according to the invention 100 shown. The version of the microtiter plate shown here 40 and the cover 1 as well as the tiles 20 is to be understood only as an example and can be combined with each of the aforementioned embodiments or individual features thereof. 5 pays special attention to an optional modular design of the kit according to the invention 100 , in particular the limiting elements are not in contrast to the embodiments shown above stuck with the plate 10 connected. Rather, the plate points 10 Supporting elements, which in the sense of a key-lock principle with three clip-like designed boundary and frame elements 11 . 13 correspond. The boundary elements 11 are designed such a clip that they both the edge of the cover 1 as well as the edge of the microtiter plate 40 enclose at the intended location, so that the position of the microtiter plate 40 in relation to the cover 1 is fixed. An additional limiting element 11a is parallel to the several alternative positions 14 arranged. It is depending on the arrangement on the plate 10 by inserting a fixing rail with the plate 10 positively connected. This releasable connection of the additional limiting element 11a allows removal of the tiles 20 , which in the embodiment shown with each other and with the limiting elements 11 are positively connected to each other by a tongue and groove system and thus in particular not by vertical lifting of the plate 10 can be solved.

LIST OF REFERENCE NUMBERS

1

cover

10

plate

11

limiting element

11a

additional limiting element

12

Through opening

13

Frame / frame element

14

evasive position

15

guide element

15a

feather

15b

groove

16

grid

16a

row

16b

column

16c

open position

20

tile

21

Through opening

22

Means (recesses and / or survey)

23

feather

24

groove

25

foil

40

microtiter plate

41

cavity

100

Kit

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 5096676 [0012]
• US 5130105 [0012]
• US 5221410 [0012]
• US 5400741 [0012]
• US 5419278 [0012]
• US 6039804 [0012]
• US 2002/0141905 [0012]
• US 2003/0010278 [0012]
• WO 0060345 [0012]
• WO 0188231 [0012]
• WO 02/102503 [0012]

Cited non-patent literature

• Chayen, N.E .; Stewart, P.D. S .; Maeder, D.L .; Blow, D.M .; J. Appl. Cryst, 1990, 23, 297-302; Chayen, N.E .; J. Crystal Growth. 1999, 196, 434-41 [0005]
• D'Arcy A .; Elmore, C; Stihle, M .; Johnston, J. E .; J. Crystal. Growth. 1996, Vol. 168, pp. 175-80 [0007]
• Chayen, N.E. and Saridakis, E .; Acta Cryst. 2002, Vol. D58, 921-27 [0009]
• Automation in biological crystallization, Acta Crystallographica Section F: Structural Biology Communications 70, 2014, 686-696 [0009]

Claims (10)

Cover (1) for placement on a microtiter plate (40) comprising a rectangular plate (10) for resting on a 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) to the tiles (20) correspondingly arranged passage openings (12) - The grid (16) is framed by at least three on the plate (10) arranged limiting elements (11), and wherein adjacent tiles (20) on the plate (10) are mutually displaceable. Cover (1) after Claim 1 , characterized in that the grid (16) of the tiles (20) in outer shape and size is adapted to a microtiter plate (40) such that when the cover (1) is arranged on a microtiter plate (40), each cavity (41) of the Microtiter plate (40) by one tile (41) can be covered. Cover (1) according to 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 (11), arranged with the grid (16) in such a way corresponds to a tile (20) on the plate (10) in the avoidance position (14) is displaceable. Cover (1) according to 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 (16a) and / or a column (16b ) of the grid (16). 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). Cover (1) according to one of the preceding claims, characterized in that the tiles (20) have a positive connection with each other and / or with the limiting elements (11), which is designed in particular as a tongue and groove connection. Cover (1) according to one of the preceding claims, characterized in that the plate (10), a tile (20) and / or a guide element (15) has a sealing element. 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. 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. Kit (100) comprising a microtiter plate (40) and a cover (1) for the microtiter plate (40) according to any one of the preceding claims.

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