The invention relates to a multi-duct fluid dispenser for withdrawing liquid (14) from a plurality of cavities (12) formed in a reservoir platter (10) and spraying it onto a receiving platter (16). It comprises:    The ducts are formed in a plurality of flexible plates (18) joined together by their part (24) that comprises the second ends of the ducts. They are each formed of two polymer sheets (34, 36) sealed together and of which at least one is endowed with an array of convergent grooves forming the ducts.

The present invention relates to the production of miniaturized high-density arrays of samples of biological substances (oligonucleotides, DNA, etc), often known as “biochips”, so that they can be treated.

The invention relates more specifically to a multi-duct fluid dispenser making it possible to withdraw liquid from a plurality of cavities formed in a reservoir platter then to deposit an array of microdrops thereof on to a receiving platter as to constitute a “biochip”.

The dispenser according to the invention is of the type comprising:a plurality of flexible ducts arranged in a convergent bundle, the first ends of which are intended to be immersed in the cavities of the reservoir platter and the second ends of which are assembled in a miniaturized array,means of filling the ducts, from their first ends, with the liquid contained in the cavities, andmeans of expelling a drop of liquid from the second end of each duct toward the receiving platter.

A device of this type is described in document WO 98/29736. The ducts are formed of a bundle of capillary filaments gathered together onto an impression head. They are all controlled together.

Documents U.S. Pat. No. 4,058,146 and EP 0 955 084 propose similar embodiments, but the expulsion of liquid is therefore done by simple contact with the receiving platter. The same is true of the device described in document U.S. Pat. No. 4,621,665 but, in this case, there is no change in format between the reservoir platter and the receiving platter.

The present invention aims to provide a dispenser that constitutes an improved version of the aforementioned systems of the prior art.

In order to achieve this objective, this dispenser according to the invention is characterized in that:the ducts are formed in a plurality of flexible plates so as to converge from their first ends toward their second ends;these plates are joined together by their part that comprises the second ends of the ducts;each plate comprises two polymer sheets sealed together and of which at least one is endowed with an array of convergent grooves forming the ducts,each duct has a first narrowing near its second end and a second narrowing at said end; andsaid expelling means comprise a piezoelectric actuator arranged on an exterior wall of the duct, between its two narrowings, and the purpose of which is to deform said at this point so as to reduce the thickness of the duct.

Advantageously, the dispenser according to the invention also has the following main characteristics.The reservoir platter is sealed closed by a lid through which the ducts pass and the filling means are arranged in such a way as to raise the pressure in the space lying between the lid and the cavities.The filling means comprise a bellows connecting the lid and its platter at their periphery.The expelling means comprise a second piezoelectric actuator identical to the first one and arranged facing it on the other exterior wall of the duct.The piezoelectric actuator is formed as a stack which comprises, starting from the exterior wall of the duct, a lower metal electrode, an insulating layer, a layer of piezoelectric material, a further insulating layer and an upper metal electrode.The expelling means are designed in such a way as to be able to act on each duct individually.

FIGS. 1 and 2show at10a reservoir platter, made of glass or rigid plastic, provided with a plurality of cavities12arranged in a two-dimensional array, in each of which cavities there is a biological liquid14samples of which need to be deposited, in the form of microdrops, onto a miniaturized receiving platter16, also made of glass or rigid plastic (nylon).

It will immediately be seen on referring toFIG. 3because, for obvious reasons, this is not visible inFIGS. 1 and 2, that the two platters are of very different sizes. Typically, the reservoir platter10has a surface area of about 100 cm2(12.5 cm×8.5 cm) and has 384 cavities12, of a volume of around 100 μl, arranged in a two-dimensional array of 16 columns of 24 rows and about 4.5 mm apart, between centers. By contrast, the receiving platter16does not have cavities and has a surface area of about 1 cm2only (1.2 cm×0.8 cm).

In order to withdraw liquid contained in the cavities12and spray an array of microdrops thereof onto the receiving platter16, the device according to the invention has a plurality of flexible transfer plates18joined together. These plates are made of polyimide, for example, and have a thickness of the order of 50 to 150 μm.

Each plate18has a lower part in the form of an isosceles trapezium20, forming a fluid interface, the long base of which is roughly the same length as the width I1of the reservoir platter10and is crenellated in such a way as to end in as many end portions22as the reservoir platter has columns of cavities12, namely16in the example described. The crenellations are sized in such a way that the portions22can enter the cavities12.

The trapezium-shaped fluid interface20is extended, from its short base, via a rectangular part24the length of which corresponds roughly to the width I2of the receiving platter16.

Each flexible plate18is provided with a bundle of ducts26which originate in each of its end portions22and terminate, parallel to one another, in the upper part24. Typically, in the exemplary embodiment described, the ducts26are then 0.5 mm apart, between centers.

The device according to the invention has as many identical plates18as the reservoir platter10has rows, namely24in the example described, the end portions22of each plate being intended to fit in one of the columns of the platter.

The flexible plates18are gathered together, at their upper part, parallel to one another, into a frame28to form an impression head the length of which roughly corresponds to the length L2of the receiving platter16and the width of which, as already mentioned, roughly corresponds to its width I2.

It goes without saying that the plates could also have a base of a length that corresponds to the length L1of the reservoir platter10.

AsFIGS. 1 and 2show, the reservoir platter10is sealed closed by a lid30through which the flexible plates18pass, also with sealing. The sealing around the periphery is provided by a bellows32, the purpose of which will become apparent later on.

Reference will now be made toFIG. 4which shows, on a larger scale, the way in which the flexible plates18and their ducts26are made. It can be seen that these plates are formed of two thin sheets of plastic34and36of which one, the upper sheet34in the figure, has been pre-scored, by any method well known to those skilled in the art, to define the outline of the ducts26and which are then joined together with a laminating process, also well known to those skilled in the art.

Typically, the sheets34and36have a thickness of 25 to 50 μm and the total volume of the ducts is about 0.5 to 3 μl.

In their rectangular part24, the plates18comprise, fixed to their upper sheet34, facing each duct26, a piezoelectric actuator38whose purpose is to deform the sheet at this point so as to reduce the thickness of the duct.

Above the actuator38, the duct26opens to the outside of the sheet via a narrowing that forms the spout40, whereas, on the other side, the duct has a narrowing42. In the example described, the spout40and the narrowing42have the same depth, from 10 to 40 μm, and the same width, from 40 to 90 μm. The dimensions of the narrowing may even be smaller than those of the spout.

FIG. 5shows that the actuator38is formed of a stack which comprises, starting from the sheet34, a lower metal electrode44, an insulating layer46, a layer of piezoelectric material48, a further insulating layer50and an upper metal electrode52. The two electrodes are associated with electrical conductors54for controlling the actuator.

The electrodes44and52are deposited by evaporation, while the insulating layers46and50are deposited by plasma and the piezoelectric layer48is deposited by magnetron-enhanced vapor deposition.

As depicted inFIG. 1, the electrical conductors powering the various actuators38end at a control circuit56which, under the command of a computer58, energizes them.

In operation, the assembly formed by the assembled transfer plates18is placed above the reservoir platter10whose cavities12contain the liquids14that are to be transferred onto the receiving platter16. Alignment is performed in such a way that having passed through the lid30, each of the end portions22of the transfer plates18lies vertically above a cavity12. When the ends of the plates are immersed in the liquid, this liquid is drawn up into the various ducts26through a capillary effect.

It is then necessary to press on the lid30in order to compress the bellows32so as to raise the pressure in the chamber by a few millibar, the pressure being read off a pressure gauge60. Because of this rise in pressure, the liquid continues to rise up inside the ducts26, passes through the narrowings42, and comes to a halt at the spouts40, through a surface tension effect.

In order to eject the liquid toward the receiving platter16, all that is then required is for the computer58to be commanded to apply to the terminals of the electrodes44and52of each actuator38an electrical impulse that causes narrowing of the corresponding duct26. Some of the liquid contained therein, prevented from flowing back by the narrowing42, is thus ejected through the spout40and sprayed on to the receiving platter16, at a clearly defined point.

The receiving platter16can thus receive an array of microdrops of liquid formed at the same number of rows and columns as the reservoir platter but, as already mentioned, at a greatly reduced scale. Typically, in the example described, the microdrops may have a volume from 20 pl to 1 nl.

Since the plates18contain a volume of liquid far greater than that of the ejected microdrops, several receiving platters16can then be used one after another.

In an alternative form of embodiment that has not been depicted, the ducts26could be subjected to the effect of two identical actuators38arranged face to face on the outside of each of the sheets that form the flexible plates. Such an arrangement allows better control over the direction in which the drops are ejected.

This description has been given with reference to a flexible plate formed of two sheets sealed together. As an alternative, the plates could be formed of three sheets, the central sheet of which would be pierced with through-openings forming the ducts.

There is thus produced a liquid dispenser that has the following main advantages:because the impression head24and the fluid interface20are combined as a single piece, the plates18, the path of the liquid is perfectly uniform and only a minimum amount of dead volume remains;because the plates18are flexible, it is easier to adapt the device to suit reservoir platters10and receiving platters16of different sizes;because the flexible plates18are formed of two polymer sheets assembled by lamination rather than bonding, any contamination with adhesive of the liquids flowing through the ducts is eliminated;because each duct26can be controlled individually by an impulse that ejects a single microdrop, the uniformity in terms of volume of the microdrops can be guaranteed.