DE20022875U1 - Device for receiving and dispensing liquid substances - Google Patents

Description

I U1234 Patent Attorney Office Pfeiffer & Partner, Winzerlaer Str. 10, 07745 Jena I

Device for receiving and dispensing liquid substances
Description

The invention relates to a device for the controlled uptake and dispensing of liquid substances, preferably for uptake and dispensing from or into micro- and nanotiter plates, wherein preferably all cavities of at least one row of a titer plate can be detected simultaneously.

&iacgr;&ogr; In the macroscopic area, suction lifters for the absorption of larger volumes are known in which pipettes are provided in the form of a rake and are equally spaced from one another, whereby all pipettes are connected together to a balloon, piston or similar assembly that can be subjected to overpressure or underpressure, so that a liquid substance can be removed simultaneously from several containers arranged next to one another.

A reactor for microchemical and/or microbiological reactions comprising a pipette with a dosing attachment is also known (DE 196 42 777 A1), wherein a reactive solid phase carrier with at least one immobilized reaction partner is provided in the pipette near its lower, narrowed end. Such designs, as also described in DE 197 23 469 A1, cannot be miniaturized at will for mechanical reasons and are also not the subject of the present invention.

■ ■ .■■■■'

Preferably, the surface of this elevation is made hydrophobic or solvent-repellent on the outside and inside by means of a chemical coating or by means of a physical structuring or combinations of both (e.g. a self-cleaning surface).

The invention is based on the object of specifying a device with the aid of which a large number of different liquid substances can be taken from microtiter or nanotiter plates at the same time, can be released again in the same grid in, if required, defined partial volumes and the possibility of carrying out one or more chemical or

biological reactions in the device itself and the simultaneous absorption of liquid substances of different viscosities should be possible.

The problem is solved by the characterizing features of the first claim. Advantageous embodiments are covered by the subordinate claims.

The essence of the invention is that at least in one row, capillary cannulas are provided which are equally spaced from one another and

&iacgr;&ogr; are brought into a communicating connection with a chamber which can be subjected to an overpressure or a negative pressure, wherein the capillary cannulas are embedded in a plate and a sieve-like membrane is assigned to at least the capillary cannula ends on the inside of the pressure chamber and a space is provided above each capillary cannula end

is intended for the absorption of a liquid substance within which it is possible to carry out chemical or biological reactions, whereby the chambers are separated from one another and all chambers are arranged together within the chamber which can be subjected to an overpressure or negative pressure, whereby the capillary cannulas are designed in such a way that their internal volume is smaller than the volume which can be absorbed by the space assigned to each capillary.

The present invention allows a highly parallel liquid transfer and the removal of substance, in particular from any designed micro or nano titer plates or comparable containers.

The proposed device can be used for solid-phase coupled syntheses as well as for liquid-phase syntheses in all variants. The decisive advantage of the device is that defined volumes of different viscosities can be absorbed and released simultaneously, ensuring a highly parallel and efficient liquid transfer.

In particular, transfer operations for bioassay applications can be carried out effectively with this device, e.g. dilution series of library substances in the assay.

• · · •••■•••••&phgr;·· ·&phgr; φφ ····· · · · · · &phgr; · &phgr;· ···· *· ··· ···-·■ · &phgr;&phgr;&phgr;&phgr; φ · ·

• · · ······ &phgr; φ·φ φ φφ

This means that bioassays can be carried out after washing, introducing the target substance into solution and after photo-splitting the synthesized library substances. Another possible use is to remove substances for further analysis processes by transferring them to appropriate analysis vessels. The integration of bioassay and synthesis made possible by the device also allows software-based evaluation.

&iacgr;&ogr; The invention will be explained in more detail below using schematic embodiments. They show:

Fig. 1 shows a possible embodiment of the device for receiving and dispensing liquid substances in a longitudinal section;

Fig. 2a shows a first possible embodiment of parts of the device that are essential to the invention,

Fig. 2b shows a second possible embodiment of parts of the device that are essential to the invention,

Fig. 2c a third embodiment of inventive

ual parts of the device,

Fig. 3 shows a preferred embodiment of the device with the formation of spaces of defined volume within which reactions can be carried out and Fig. 4 shows an example of a lower view of the device, which in

several rows and columns are provided with cannulas, the mutual spacing of which corresponds to the cavity grid of a presentable titer plate.

Figure 1 shows a possible embodiment of the device in a longitudinal section. In this case, capillary cannulas 1 are provided in a row, which are equally spaced from one another and are connected together with a chamber 2 that can be subjected to overpressure or underpressure via a nozzle 8, the capillary cannulas 1, which are designed in particular as steel cannulas, being embedded in a plate 3 and fixed by means of an adhesive.

At least the capillary cannula ends 11 on the inside of the pressure chamber, which in the example are flush with the pressure chamber-side plane of the plate 3, are initially assigned a sieve-like membrane 4, above which a space 5 is provided for each capillary cannula end to accommodate a liquid substance, whereby the spaces 5 are separated from one another and all spaces 5 are arranged together within the chamber 2 which can be subjected to overpressure or underpressure, thereby ensuring that all capillary cannulas 1 can be subjected to an identical pressure. Depending on the design, i.e. depending on the size of the

1, it can be achieved that a defined volume presented to the respective capillary cannulas can be drawn into the spaces 5 with sufficient negative pressure, or with sufficiently small perforations of the sieve-like membranes 4, depending on the surface tension of the respective liquid substances, only the capillary cannulas 1 up to the membrane 4 are affected by any volume presented, because the sieve-like membranes 4 prevent the liquid substances from passing through. In the latter case, a defined volume of the liquid substances is also taken up, with the advantage that substances of different viscosities can be taken up simultaneously with one and the same device.

In the example, each room 5, if it is to be used as a reaction room, should have a volume of 10 nl to 2 μl. The associated capillaries should have a volume of 1 nl to 120 nl. Depending on the specific circumstances, any other dimensions are possible with regard to the volumes mentioned, but if reactions are to be carried out in the rooms 5, it must be ensured that the respective rooms 5 have a larger volume than the capillary cannulas assigned to them in order to prevent crosstalk of reaction liquids between the rooms 5.

Figure 2a shows a first possible embodiment of parts essential to the invention of the device shown in Fig. 1. In this example, the spaces 5 and the sieve-like membranes 4 are separated by a

a one-piece component 6 is formed, into which several recesses for forming the spaces 5 are made up to a floor area 61 and the remaining floor areas are provided with a perforation 62.

Figure 2b shows a second possible embodiment of parts of the device shown in Fig. 1 that are essential to the invention. In this example, the spaces 5 are formed by a component 6, into which several continuous recesses 63 are initially made, which are provided with separate sieve-like

&iacgr;&ogr; membranes 4.

Finally, Figure 2c shows a third possible embodiment of parts essential to the invention of the device shown in Figure 1. In this example, the sieve-like membrane 4 is formed by a continuous membrane which covers all recesses 63 together and which is introduced as a net between the plate 3 and the component 6 by gluing.

A preferred embodiment of the device with the formation of spaces 5 of defined volume within which reactions can be carried out is shown in Figure 3. Two one-piece silicon or glass wafers 6a and 6b are provided, in each of which congruent recesses are made down to the bottom area and sieve-like membranes 4; 7 are introduced into the remaining bottom areas by selective etching, which is known per se and therefore does not need to be explained further here. The wafers 6a and 6b produced in this way are connected to one another on the side opposite the sieve-like membranes 4; 7 by anodic bonding, gluing or other joining techniques, whereby these are also common methods that do not require any further explanation here.

Other manufacturing processes for producing the embodiments corresponding to the wafers 6a, 6b described above, such as structures molded in PE, with which sieves with openings between 0.5 μl and 35 μl and chamber sizes of the reaction spaces 5 between 10 nl and 8 μl can also be realized, are also within the scope of the invention.

ft···

What is essential in the example described above is that the space 5 provided above each capillary cannula end, formed by the recesses provided in the two wafers 6a, 6b, is closed off on the side facing the pressure chamber 2 (not shown in Fig. 3) by a second sieve-like membrane 7 in a gas-permeable manner, whereby the perforations of this second membrane 7, depending on the surface tension of the liquid substance used and the magnitude of an applied negative pressure, are smaller than those of the capillary cannula ends 11 assigned to the pressure chamber inside.

β sieve-like membrane 4 are designed such that a liquid passage through the second sieve-like membrane 7 is prevented. In the example, the sieve-like membrane 4 has a sieve hole width of 10 µm and the membrane 7 has a sieve hole width of 1 µm. The respective spaces 5, in each of which a reaction is to be carried out, have a volume of 1 µm in the example and the capillary cannulas 1 have a capacity of 100 nl.

A liquid reaction can be carried out as follows: Five different dissolved reagents are each taken up one after the other with the device using a suitably set negative pressure and drawn through the capillary-side sieve 4 so that the volume remains in the reaction chamber. During this process, each additional volume taken up is mixed with the volume in the reaction chamber. The finer-pored membrane 7 prevents liquid from passing into the chamber 2. Depending on the materials used for the device, reactions can also be carried out at elevated temperatures.

Furthermore, it is within the scope of the invention to make the chamber 2, which can be subjected to a positive or negative pressure, detachable from the plate 3 (as indicated in Fig. 1) or at least openable above the recesses 63 (not shown in more detail) in order to create a second access option to the spaces 5, so that the spaces 5, in the case of designs according to Figs. 1 and 2a to 2c from above, can be filled with an agent if necessary using a second device designed analogously to the device described. Likewise, in the

The intended opening option of chamber 2 enables the rooms 5 to be flooded over a large area.

When sieve-like membranes are mentioned in the above specific description, this also includes structures with irregularly distributed openings or passages, such as:

Frits, if they fulfill the same function as the sieve-like membranes.

In extreme cases, the function of these membranes could also

be realized by a single, sufficiently small hole, which, however, is not necessarily a preferred embodiment.

Within the scope of the invention, it is advantageous to provide the walls of the spaces 5, at least the inner walls of the capillary cannulas 1 and the surfaces of the sieve-like membranes 4; 7 with a hydrophobic surface and/or a self-cleaning physical microstructure (lotus effect) or with a solvent-repellent detergent, which facilitates the required cleaning of the device.

Finally, Figure 4 shows an example of a lower view of a device, wherein a plurality of capillary cannulas 1 are introduced into the plate 3 in a matrix-like manner and corresponding to the cavity distribution of a titer plate (not shown here), which are equally spaced apart from one another in rows Z and columns Sp, each of which is assigned a space 5 (not shown in Figure 4) for the possibility of receiving a liquid substance.

-S-

Reference list Capillary cannula 1 Capillary cannula ends 11 - (Pressure) chamber 2 plate 3 sieve-like membranes 4.7 .- (Reaction) space one-piece component 6 Bottom area of component 6 61 - Perforation in the bottom area 61 62 - continuous recesses 63 - Support 8th Lines Z columns Sp -

Claims (12)

1. Device for receiving and dispensing liquid substances, wherein at least in one row capillary cannulas ( 1 ) are provided which are equally spaced from one another and which are brought into a communicating connection with a chamber ( 2 ) which can be subjected to an overpressure or a negative pressure, characterized in that the capillary cannulas ( 1 ) are embedded in a plate ( 3 ) and a sieve-like membrane ( 4 ) is assigned to at least the capillary cannula ends ( 11 ) on the inside of the pressure chamber and a space ( 5 ) is provided above each capillary cannula end for the possibility of receiving a liquid substance, wherein the spaces ( 5 ) are separated from one another and all spaces ( 5 ) are arranged together within the chamber ( 2 ) which can be subjected to an overpressure or a negative pressure. 2. Device according to claim 1, characterized in that said spaces ( 5 ) and the sieve-like membranes ( 4 ) are formed by a one-piece component ( 6 ) into which several recesses are made down to a bottom region ( 61 ) and the remaining bottom regions are provided with a perforation ( 62 ). 3. Device according to claim 1, characterized in that said spaces ( 5 ) are formed by a component ( 6 ) into which a plurality of continuous recesses ( 63 ) are introduced, which are provided with the sieve-like membrane ( 4 ) on the side facing the capillary cannulas ( 1 ). 4. Device according to claim 3, characterized in that the sieve-like membrane ( 4 ) is formed by a continuous membrane which covers all recesses ( 63 ) together. 5. Device according to claim 2, characterized in that the one-piece component ( 6 ) is formed by a silicon or glass wafer into which the recesses are introduced down to the bottom region and the sieve-like membranes ( 4 ) are introduced into the remaining bottom regions by selective etching. 6. Device according to claim 1, characterized in that the space ( 5 ) provided above each capillary cannula end is closed off on the side facing the pressure chamber ( 2 ) by a second sieve-like membrane ( 7 ) in a gas-permeable manner, the perforations of this second membrane ( 7 ), depending on the surface tension of the liquid substance used and the magnitude of an applied negative pressure, being designed to be smaller than those of the sieve-like membrane ( 4 ) assigned to the capillary cannula ends ( 11 ) on the inside of the pressure chamber, so that liquid is prevented from passing through the second sieve-like membrane ( 7 ). 7. Device according to claim 6, characterized in that said spaces ( 4 ) are formed by two one-piece silicon or glass wafers ( 6a , 6b ) into which congruent recesses are made down to the bottom area and the sieve-like membranes ( 4 ; 7 ) are introduced into the remaining bottom areas by selective etching and these wafers are connected to one another on the side opposite the sieve-like membranes ( 4 ; 7 ) by anodic bonding, gluing or other joining techniques. 8. Device according to claim 1, characterized in that the chamber ( 2 ) which can be subjected to an overpressure or a negative pressure is designed to be detachable from the plate ( 3 ) or at least openable above the recesses ( 63 ) in order to create a second access possibility to the spaces ( 5 ). 9. Device according to claim 1, characterized in that the walls of the spaces ( 5 ), the capillary cannulas ( 1 ) and the surfaces of the sieve-like membranes ( 4 ; 7 ) are provided with a hydrophobic surface and/or a self-cleaning physical microstructure (lotus effect) or with a solvent-repellent detergent. 10. Device according to claim 1, characterized in that the capillary cannulas ( 1 ) are formed by steel cannulas glued into the plate ( 3 ). 11. Device according to claim 1, characterized in that a plurality of capillary cannulas ( 1 ) are introduced into the plate ( 3 ) in a matrix-like manner and corresponding to the cavity distribution of a titer plate provided, which capillary cannulas are arranged in rows (Z) and columns (Sp) at equal distances from one another, each of which is assigned a space ( 5 ) for the reception of a liquid substance. 12. Device according to claim 1, characterized in that each capillary cannula ( 1 ) is designed such that its internal volume is smaller than the volume that can be accommodated by the space ( 5 ) assigned to it.