WO2024013215A1

WO2024013215A1 - Cover for the head of a printing device for the synthesis of biomolecules

Info

Publication number: WO2024013215A1
Application number: PCT/EP2023/069277
Authority: WO
Inventors: Adrian Horgan; Damiano VERARDO; Beatrice ADELIZZI; Daniel RODRIGUEZ-PINZON
Original assignee: Dna Script
Priority date: 2022-07-12
Filing date: 2023-07-12
Publication date: 2024-01-18

Abstract

The present invention relates to a printing device (1) comprising a printing head (2), a supporting platform (18) receiving a substrate plate (16), and a cover (34) for covering the printing head (2), the supporting platform (18) comprising a receiving area (32) for receiving the cover (34) and a receiving area (20) for receiving the substrate plate (16), the supporting platform (18) being movable between a first position with the receiving area (20) facing the printing head (2) and a second position with the receiving area (32) facing the printing head (2), the printing device (1) comprising reversible securing means (38) for reversibly securing the cover (34) to the printing head (2), which are activated according to the position of the supporting platform (18).

Description

DESCRIPTION

TITLE: COVER FOR PRINTING DEVICE HEAD FOR THE SYNTHESIS OF BIOMOLECULES

The present invention relates to the field of devices for the enzymatic synthesis of biomolecules, and more particularly devices for the synthesis of oligonucleotides such as RNA and DNA by inkjet printing.

DNA and/or RNA polynucleotides are linear polymers of nucleotide monomers or analogues thereof that are capable of specifically binding to other oligonucleotides through a regular pattern of interactions between monomers. The size of polynucleotides generally varies from a few monomers, for example from 5 to 40 monomers when they are usually called "oligonucleotides", to several thousand monomers. Usually, polynucleotides include the four natural nucleotides, for example deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine for DNA or their ribose equivalents for RNA, linked by phosphodiester bonds; however, they may also include non-natural nucleotide analogues, for example modified bases, sugars or intemucleoside linkages.

When an inkjet printing device is used in an apparatus for enzymatic synthesis of DNA and/or RNA, defined quantities of an enzyme solution can be delivered to precise locations on a substrate at a relatively low cost and with minimal waste. The enzymatic solution can for example be deposited on the substrate in the form of drops of ink via a print head equipped with nozzles, these nozzles making it possible to deliver the ink to the substrate.

Sometimes ink residue sticks to the nozzle and then dries, creating patches of dried ink. These plates of dried ink can detach and fall onto the substrate, and/or disrupt the deposition of liquid ink by creating satellite drops of ink which are deposited on the substrate plate outside of the locations provided for this purpose, or by blocking the ejection of ink from the nozzles.

In order to limit these difficulties, it is known from the prior art to move, before or after certain stages of the enzymatic synthesis, the printing head and its nozzles towards a dedicated station of the printing device where this head print can be covered with a cover preventing the ink from drying at the head printing. Alternatively, it is possible to place a cover on the substrate, but such a solution presents risks of damage or contamination of the substrate.

The present invention fits into this context by proposing a cover for equipping a print head with a printing device, this cover being used in the context of the use of a substrate which can be moved within this printing device.

The main object of the present invention is thus a printing device configured for the synthesis of biomolecules, comprising a printing station equipped with a print head configured to deposit drops of ink containing synthesis reagents on a plate. of substrate, the printing device comprising a support platform configured to receive the substrate plate and a cover intended to cover the print head, the support platform comprising a zone for receiving the cover and a zone for receiving the the substrate plate, the support platform and/or the print head being movable between a first position in which the reception zone is facing the print head and a second position in which the reception zone is facing the print head, the printing device comprising means for reversibly fixing the cover on the print head, the reversible fixing means being activated as a function of the position of the support platform relative to the printhead.

The printing device according to the invention allows the enzymatic synthesis of polynucleotides, for example fragments of interest or even complete biomolecules. The printing device includes several stations dedicated to different stages of such enzymatic synthesis. A substrate plate is movable between these stations, that is to say it can be moved from one station to another, for example by computer control, to take working positions in each of these stations . The substrate plate can be moved via a support platform, which for this purpose includes a receiving area where the substrate plate can be deposited. Alternatively or additionally, the print head may be movable.

The support platform further includes a docking area that is configured to receive a cache. This cover is intended to cover a print head of the printing device when the latter is not controlled to deposit drops of ink containing synthesis reagents on the substrate plate, in particular in order to form a wet zone to prevent the ink from drying. The cache also makes it possible to avoid the deposit of dust on the print head. Additionally, the presence of the cover makes it possible to avoid untimely or involuntary deposits which could disrupt or contaminate the enzymatic synthesis on this substrate plate if drops of ink fell on it.

In order for the cover to attach to the print head, the printing device includes reversible fixing means. These reversible fixing means can alternately be activated and deactivated to allow the attachment and detachment of the cover and the print head. Such activations and deactivations are dependent on a position of the support platform relative to the print head. The support platform is in fact movable between a first position in which it is the reception zone of the substrate plate which is facing the print head, and a second position in which it is the zone of home of the cache which is next to this print head.

According to one characteristic of the invention, the reversible fixing means comprise at least one electromagnet.

Such an electromagnet allows reversible attachment between the cover and the print head when an electric current passes through it; we understand that the fixation is then magnetic. Such reversible fixing means can be implemented quickly as soon as the cover is facing the print head.

According to another characteristic of the invention, the reversible fixing means comprise at least one permanent magnet.

In addition to the electromagnet, the reversible fixing means include a permanent magnet. The combination of these two types of magnets provides security in the event of electrical power outages which would deactivate the electromagnet, with the permanent magnet then ensuring the fixation alone. Such security prevents the cache from falling on the support platform in an inappropriate manner.

According to an alternative characteristic, the reversible fixing means comprise at least one suction member.

Such a suction member is an alternative to the electromagnets previously mentioned or a complementary means of fixing. This suction member is for example a suction cup which allows fixation by creating a vacuum. According to one characteristic of the invention, the reversible fixing means are arranged to allow movements of attraction and repulsion substantially parallel to a direction of ejection of ink from the print head.

The ejection of the ink from the print head is done substantially perpendicular to the substrate plate which receives the synthesis reagents contained in this ink. The movements of attraction and repulsion, which correspond to the direction of attachment of the cover relative to the print head as well as the direction of its detachment from it, are therefore substantially perpendicular to a plane in which s 'mainly extends the substrate plate.

According to one characteristic, the reversible fixing means are arranged on the print head.

We understand that the reversible fixing means are embedded on a housing of this print head. The reversible fixing means are arranged on the periphery of the projection nozzles.

According to another characteristic of the invention, the reversible fixing means are arranged on a lower face of the print head intended to be facing the support platform, this lower face carrying projection nozzles.

The fixing means are here arranged on the lower face of the print head so that the cover is attracted and pressed against this lower face, to cover the projection nozzles which deliver the ink, thus preventing the drying of the ink in these projection nozzles or at the outlet thereof.

According to one characteristic, the reversible fixing means are activated remotely.

The reversible fixing means are for example activated by computer. Such activation can for example correspond, for the electromagnet, to the passage of an electric current. Activation occurs when the support platform is in its second position, that is to say when the reception area carrying the cover is facing the print head.

According to one characteristic, reversible fixing members cooperating with the reversible fixing means of the print head are arranged on the cover.

Thus, the cover carries reversible fixing members which are the counterpart of the reversible fixing means carried by the print head. These reversible fasteners are for example magnets or inserts made of ferrous metals, and/or they may include a vacuum suction member. Similar to the reversible fixing means, their activation and deactivation can lead to the cover being fixed to the print head and detached from the latter.

According to one characteristic of the invention, the reversible fixing members are carried by an upper wall of the cover intended to be facing the print head, this upper wall being opposite a lower wall of the cover facing the zone d home of the support platform.

We understand here that the cache comprises two walls opposite each other, including an upper wall and a lower wall. The upper wall is that which faces the print head and which is intended to come, through the cooperation of the means and the reversible fixing members, into contact with the reversible fixing means carried by this head. 'impression. Conversely, the lower wall is the one which rests on the reception area of the support platform.

According to another characteristic of the invention, the cover has a cavity configured to cover a plate of projection nozzles of the print head, this cavity extending from the upper wall.

This cavity forms a recess so as to cover these projection nozzles. The cavity extends from the top wall and towards the bottom wall. Thus, it is possible to press the upper wall of the cover against the print head without coming into contact with the projection nozzles and therefore without risking damaging them. The cavity also makes it possible to receive ink which would be ejected from the projection nozzles, during an ejection step implemented in a voluntary and controlled manner to avoid the subsequent drying of the ink at the level of the nozzles. projection.

According to one characteristic, the reception area of the support platform comprises reversible fixing systems, the reversible fixing systems cooperating with reversible fixing instruments arranged on a lower wall of the cover facing the reception area.

This is a particular embodiment of the printing device according to the invention, in which it comprises, in addition to reversible fixing means arranged on the print head and reversible fixing members arranged on the upper wall of the cover, on the one hand reversible fixing instruments which are arranged on the wall lower part of the cover, that is to say opposite the reversible fixing members, and on the other hand reversible fixing systems arranged on the reception area of the support platform and which are intended to cooperate with the instruments of reversible attachment. The solutions implemented for the cooperation of the reversible fixing means with the reversible fixing members, and for example the magnets and/or the vacuum members, can be applied in the same way to the reversible fixing systems and instruments.

According to another characteristic, the cache is equipped with a fluid circulation channel extending within a volume of the cache.

According to one characteristic of the invention, the fluid circulation channel is fluidly connected to at least one orifice provided in the upper wall of the cover.

This fluid circulation channel helps, for example, to regulate the humidity within the cover cavity configured to house the projection nozzles, in order to prevent the ink from drying. Alternatively or additionally, the fluid circulation channel can allow purging of the cover, by allowing evacuation of the ink which may have been deposited there while the cover covers the projection nozzles. The fluid circulation channel crosses the cover from side to side and extends between the upper wall and the lower wall. The fluid circulation channel can communicate with the cavity via an orifice in the upper wall of the cover.

According to another characteristic, the cache is equipped with a fluid reservoir extending within a volume of the cache. The fluid reservoir can in particular be placed near the cavity, so as to provide humidity as close as possible to the projection nozzles.

According to another characteristic, an O-ring is placed against the upper wall of the cover.

This O-ring is for example placed in a groove dug in this upper wall of the cover. This O-ring helps ensure the seal between the cover and the print head when these two elements are in contact with each other.

According to one characteristic, the cover is equipped with a humidity sensor and/or a liquid accumulation sensor.

A humidity sensor is used to ensure that environmental conditions are suitable so that the ink does not dry out at the projection nozzles. A captor Liquid accumulation ensures that ink does not unintentionally leak from these jet nozzles.

According to one characteristic, the upper wall carries keying means.

These keying means facilitate the positioning of the cover relative to the print head, so that the projection nozzles of this print head are correctly received by the cavity of the cover.

According to another characteristic, the cover has an absorbent portion configured to absorb ink from the print head.

The invention further relates to a printing method by a printing device as mentioned above, comprising a first positioning step during which the support platform and/or the print head is positioned, within of the printing station, in the first position, a printing step during which drops of ink containing synthesis reagents are deposited on the substrate plate, a second positioning step during which the platform support and/or the print head is moved into the second position, and a fixing step during which the cover is lifted and fixed to the print head by activation of the reversible fixing means when the support platform is in the second position.

The printing process according to the invention therefore involves a first positioning step which makes it possible to place the support platform in the first position, that is to say so that the substrate plate is facing the head printing. The substrate plate is then ideally positioned for the printing step which results in a deposition of synthesis reagents on this substrate plate, via projection nozzles which eject ink containing these synthesis reagents. . Once the printing step has been completed, the support platform is moved again during the second positioning step to take the second position, in which it is the reception area carrying the cover which is placed opposite of the print head. A fixing step then occurs, during which the cover is lifted from the reception area to come into contact with the print head and be fixed there. Such a fixing step involves reversible fixing means. These reversible fixing means are inactive in a neutral state; they change state when the support platform arrives in the second position, then allowing the attachment of the cover to the print head. According to one characteristic, the printing process comprises a release step during which the cache is released and deposited on the reception area, the support platform being moved to an imaging station and/or a station cleaning steps separate from the printing station, then returned to the printing station between the fixing step and the unhooking step.

This unhooking step allows you to detach the print head cover and place it back on the support platform. Such a detachment step corresponds to an inactivation of the reversible fixing means; during this step, the support platform is in its second position. Prior to this unhooking step, the support platform leaves the printing station and is directed towards other stations of the printing device. The support platform can thus be taken to an imaging station where operations to verify the enzymatic synthesis are carried out, or to a cleaning station where the substrate plate can undergo washing or rinsing.

According to another characteristic, at the end of the second positioning step a distance between the print head and the cover is less than three millimeters.

Such a distance makes it possible on the one hand to avoid oversizing of the reversible fixing means and on the other hand to limit the impact of the shock between the cover and the print head when the reversible fixing means are activated and the cover is pressed against the print head.

According to one characteristic of the invention, at the end of the fixing step the lower face of the print head is affixed to the upper wall of the cover, the O-ring ensuring a seal between the print head and the hidden.

According to one characteristic, a direction of attachment of the cover corresponds to a direction substantially perpendicular to a plane of movement of the support platform and/or the print head between the first position and the second position.

In other words, the direction of fixing of the cover is carried out in a direction substantially parallel to the direction of ink ejection.

The printing process according to the invention is integrated more generally into a synthesis cycle which can successively comprise the printing itself, an imaging step and/or an incubation step, a rinsing step and a drying step. THE The cover is reversibly attached to the print head after the printing step and remains in position until a new printing step is implemented.

The invention finally relates to a computer program product comprising program code instructions recorded on a computer-readable medium for implementing the steps of the printing process as mentioned above when the program operates on a computer. In particular, the computer program product is configured to generate remote activation of the reversible fixing means arranged on the print head, and more particularly when the cover is brought opposite the print head.

Other characteristics, details and advantages of the invention will emerge more clearly on reading the description which follows on the one hand, and examples of embodiment given for informational and non-limiting purposes with reference to the appended drawings on the other hand. , on which ones :

[Fig. 1] illustrates, schematically, a printing device according to the invention, in a perspective view;

[Fig. 2] illustrates, schematically, part of the printing device of Figure 1;

[Fig. 3] illustrates, schematically, a cover of the printing device;

[Fig. 4] illustrates, schematically, a top view of the cover of Figure 3 and a bottom view of a print head of the printing device showing cooperation between these two components;

[Fig. 5] illustrates, schematically, a side view of the cover of Figure 3 and the print head of the printing device;

[Fig. 6] illustrates, schematically, the steps of a printing process involving the printing device of Figure 1;

[Fig. 7] illustrates, schematically, a particular embodiment of the cache of Figure 3

The characteristics, variants and different embodiments of the invention can be associated with each other, in various combinations, to the extent that they are not incompatible or exclusive with respect to each other. In particular, it will be possible to imagine variants of the invention comprising only a selection of characteristics described subsequently in isolation from the other characteristics described, if this selection of characteristics is sufficient to confer a technical advantage and/or to differentiate the invention from the prior art.

In the figures, elements common to several figures retain the same reference.

Figures 1 and 2 thus illustrate, schematically, an inkjet printing device 1, such a printing device being configured for the enzymatic synthesis of polynucleotides. These polynucleotides can be biomolecules such as DNA and/or RNA molecules, whether in the form of single strands or double strands.

The printing device 1 comprises a print head 2 equipped with projection nozzles 4, one of these nozzles 4 being particularly visible in Figure 2. The printing device 1 is configured so that ink 6 can circulate from ink cartridges to the projection nozzles 4. The ink 6 used in the printing device 1 contains enzymatic synthesis reagents which are necessary for an elongation reaction, such as enzymes, nucleotides , cofactors, viscosity modifiers, surface tension modifiers, cosolvents or others. More specifically, these enzymatic synthesis reagents may comprise a nucleoside triphosphate, the 3' end of which is protected, as well as an elongation enzyme. This elongation enzyme can for example be a polymerase: if the molecule to be synthesized is a DNA molecule, the polymerase will be a DNA polymerase, while if an RNA molecule is sought, the polymerase will be an RNA. polymerase. The nucleoside triphosphate contained in the enzymatic synthesis reagents is protected, that is to say it is associated with a protecting group of formula -R1NR2 ² where Ri is chosen from H, O, -COOH, CN, a group linear or branched alkyl of 1 to 6 carbon atoms, an aryl group, preferably chosen from H, O, a linear or branched alkyl group of 1 to 6 carbon atoms, and where R2 is chosen from H or a linear alkyl group or branched with 1 to 6 carbon atoms, so as to block its elongation. In a preferred embodiment, the protecting group is an aminoxyl.

As mentioned previously, the ink 6 used in the printing device 1 can be stored in ink cartridges. Thus, the number of ink cartridges depends on the number of nucleoside triphosphates protected at their 3' end necessary for the elongation reaction and available in the printing device 1. These nucleoside triphosphates can be modified adenine, cytosine modified, modified guanine, modified thymine and/or modified uracil. Therefore, there may be, as illustrated in Figure 1 according to an illustrative and non-limiting embodiment, a first ink cartridge 8 for the ink 6 containing the modified adenine and the elongation enzyme, a second ink cartridge 10 for the ink 6 containing the modified cytosine and the elongation enzyme, a third ink cartridge 12 for the ink 6 containing the modified guanine and the elongation enzyme and a fourth ink cartridge 14 for the ink 6 containing modified thymine and/or modified uracil and elongation enzyme.

The enzymatic synthesis reagents present in the ink 6 are intended to be deposited on a substrate plate 16. This substrate plate 16 can be glass, silica, silicon oxide, plastic, metal or similar surfaces, but also other surfaces such as for example biological tissues. It can be transparent, semi-transparent, opaque, colored or uncolored. Such a substrate plate 16 is here arranged on a support platform 18, which in particular allows the movement of the substrate plate 16 between various stations or operating stations of the printing device 1, or even within the same operating station. It is thus understood that the substrate plate 16 is mobile within the printing device 1. Such mobility can for example be implemented by computer control, in particular via software installed on a computer.

This substrate plate 16 is more particularly arranged on a reception zone 20 of the support platform 18, which will be described in more detail later. This reception zone 20 is configured to receive the substrate plate 16 and hold it in position, for example during movements of the support platform 18 within the printing device 1.

The substrate plate 16 includes several reaction sites. In some embodiments, each reaction site is distinct from the other reaction sites and they do not overlap; in other words, the reaction sites are not contiguous. Certain other embodiments dedicated to specific applications may, however, have overlapping reaction sites. Each reaction site is defined by at least one initiator whose 3' end is free, also called initiator fragment. This initiator fragment can for example attach locally to a covering material which lines the substrate plate 16, thus defining a reaction site.

The initiator fragment is an oligonucleotide generally comprising 10 to 40 nucleotides, which is immobilized at its 5' end on a solid support. The elongation of the initiator fragment results in a polynucleotide, for example a DNA polynucleotide or even an RNA polynucleotide.

The reaction sites are for example arranged in rows, these rows extending perpendicular to a longitudinal direction L corresponding to a main direction of extension of the substrate plate 16. The rows are arranged successively on the substrate plate 16 according to this longitudinal direction L.

The printing device 1 according to the invention is implemented as part of a method for the enzymatic synthesis of such polynucleotides. This method of enzymatic synthesis involves various steps, with the completion of these steps forming a cycle. At the end of a cycle, at least some of the initiator fragments will have been extended by one nucleotide each. The repetition of several cycles leads to the synthesis of polynucleotides, and the appropriate selection of the type of ink, that is to say the type of nucleoside triphosphates projected at a given time on a given reaction site, at each cycle allows to obtain polynucleotides of a predetermined sequence.

As mentioned previously, the support platform 18 is mobile. Such mobility involves for example a transport plate of the printing device 1. The support platform 18 can thus be moved, within the printing device 1, to a printing station within which the ink 6 can be deposited on the substrate plate 16. For this purpose, the receiving zone 20 carrying the substrate plate 16 is positioned under the print head 2 of the printing station and more precisely under the projection nozzles 4 of this print head 2. When the reception zone 20 is facing the print head 2, the support platform 18 is in a first position which is illustrated in Figure 2. Within the printing station, this first position of the support platform 18 can alternatively be obtained by moving the print head 2 to position itself above the reception zone 20. In certain embodiments, at both the support platform 18 and the print head 2 are mobile within the printing station.

Once the substrate plate 16 carried by the support platform 18 is adequately positioned under the print head 2, i.e. in its first position, ink 6 is ejected by the projection nozzles 4. These projection nozzles 4 thus deliver drops of ink 6 to the reaction sites of the substrate plate 16, which allows the deposition of enzymatic synthesis reagents in these reaction sites. The role of the elongation enzyme contained in ink 6 is to extend the initiator fragments present in the reaction sites, using nucleoside triphosphates modified so that their 3' ends are protected and which are also contained in ink 6. More precisely, the elongation enzyme adds a single modified nucleotide to a free 3' end of a terminating nucleotide of a given initiator fragment, which generates an elongated initiator fragment. Due to the modified nature of the nucleotides which are blocked at their 3' end, for example with an aminoxyl protecting group, in a given drop of ink, once a first nucleotide modified in this way is grafted to the fragment initiator, no other nucleotide can be grafted since the free end of the strand thus formed is protected. In other words, for a given drop of ink, only one of the nucleotides present in the drop is capable of being linked to the free terminating nucleotide of the initiator fragment. This protection ensures that nucleotides are added to the initiator fragment one by one for each cycle, thus avoiding uncontrolled elongations and homopolymer formation.

The elongation reaction can occur during an incubation step, which corresponds to a duration necessary for this elongation.

The printing device 1 can, as part of the operation stations mentioned above, include an imaging station. Such an imaging station, which allows verification of the progress of the enzymatic synthesis before incubation or during it, comprises a microscope incorporating a digital camera 22 which is implemented in the context of detection of the presence and/or positioning of the ink drops on the substrate plate 16. The camera 22 thus generates images of the substrate plate 16. Such images are then processed by software integrated into the printing device 1, this software being capable of analyzing information such as the presence, absence, size, shape or even the content of the drops of ink 6 deposited on the substrate plate 16, for example to ensure that the drops of ink 6 do not overlap or have not overflowed from the reaction sites.

The enzymatic synthesis method comprises, following imaging, a deprotection step, during which the elongated fragments protected at their 3' ends are deprotected to form elongated fragments having a free 3' end. The deprotection step is therefore a removal of the protective groups from the elongated fragments, so that the elongated fragments can be elongated again in a subsequent cycle. The deprotection step is carried out by a deprotection solution which contains specific reagents such as enzymatic cleavage enzymes or even reducing agents, for example a sodium nitrite solution. The substrate plate 16 carried by the support platform 18 can for example be transported to a cleaning station of the enzymatic synthesis apparatus, where it is either immersed in a bath of this deprotection solution or covered with the solution. deprotection by spraying for the implementation of this deprotection step. The deprotection step may be followed by a rinsing step, during which the substrate plate 16 is immersed in a bath of rinsing or cleaning solution or covered with such a solution by spraying. Residual solutions can then be evacuated by a peristaltic pump. The enzymatic synthesis method may include, following the rinsing step, a drying step.

The support platform 18 will now be described in more detail in relation to Figures 1 and 2.

The support platform 18 has a substantially rectangular shape. It has two longitudinal partitions 24 which extend in the longitudinal direction L and two lateral partitions 26 each arranged at a longitudinal end of the support platform 18. These longitudinal 24 and lateral partitions 26 are connected to each other by a partition 28 , which here is an upper partition 28, as well as a lower partition 30. These upper partitions 28 and lower 30 are opposed to each other in a vertical direction perpendicular to the longitudinal direction L. The longitudinal partitions 24, lateral 26, upper 28 and lower 30 delimit between them a volume of the support platform 18.

The reception zone 20 of the substrate plate 16 corresponds to a portion of the upper partition 28 of the support platform 18. This reception zone 20 is dimensioned so as to be able to accommodate the substrate plate 16, whether the latter is housed partially in the thickness of the support platform or covering the upper partition of the support platform. The reception zone 20 can for example extend over approximately half of the upper partition 28 of the support platform 18.

Another portion of the upper partition 28, distinct from that receiving the substrate plate, is intended to form a reception zone 32 of a cover 34 of the printing device 1. As is particularly visible in Figure 2 , this reception zone 32 can form a clearance 35 within the volume of the support platform 18. The cover 34 is intended to prevent drying of the ink at the level of the projection nozzles 4 by forming around them a humid zone unfavorable to such drying. This makes it possible in particular to avoid the formation of patches of dried ink which could hinder the circulation of the ink 6 within the projection nozzles 4 and deflect this ink 6 when it is ejected, or even prevent the ejection of ink 6 from the projection nozzles 4. The cover 34 also makes it possible to prevent drops of ink 6 from being deposited undesirably on the substrate plate 16, that is to say outside of the voluntary deposit ink 6 containing the enzymatic synthesis reagents within the reaction sites.

The cover 34 can for this purpose be lifted from its reception area 32 and be fixed to the print head 2. The print head 2 has a lower face 36 which is intended to be facing the support platform 18 when this is positioned in the printing station, this lower face 36 also carrying the projection nozzles 4. Although this is not illustrated thus in Figure 2, which is a schematic representation for illustrative purposes, the upper wall 44 of the cover 34 extends substantially at the same level as the substrate plate 16 so as to avoid interference between the cover 34 and the print head 2 during printing. Such an arrangement is necessary due to a reduced distance between the print head 2 and the substrate plate 16; a distance measured between the lower face 36 of this print head 2 and the substrate plate 16 on the one hand, and between the lower face 36 of the print head 2 and the upper wall 44 on the other hand, is for example between 0.5 and 3 mm.

So that the cover 34 comes to cover this print head 2 and the projection nozzles 4, the printing device 1 comprises reversible fixing means 38. These reversible fixing means are configured to cooperate with fixing members reversible which are carried by the cover 34 and which will be detailed later in the description. As is particularly visible in Figures 2, 4 and 5, these reversible fixing means 38 are arranged on the print head 2, and more particularly on its lower face 36.

According to one embodiment of the invention, the reversible fixing means 38 comprise magnets including at least one electromagnet. The activation and deactivation of the reversible fixing means are then done respectively by supplying electricity to the electromagnet and cutting off the power at the appropriate time. As an example of an operating mode of the invention, the at least one electromagnet is only powered when the cover must be fixed to the print head to cover the projection nozzles.

The reversible fixing means 38 may also comprise at least one permanent magnet, the combination of the presence of at least one electromagnet and at least one permanent magnet making it possible to ensure that the cover is maintained in position even in the event of cutting of the electrical supply necessary for the operation of the electromagnet. As is particularly visible in Figure 4, which is a top view of the cover 34 and bottom view of the print head 2 so as to illustrate the cooperation between these two elements, the lower face 36 of this print head 2 here comprises four electromagnets as reversible fixing means 38, these electromagnets each being arranged at a corner of the lower face 36 and therefore so as to surround the projection nozzle plate. Such an arrangement of the reversible fixing means 38 ensures that the projection nozzle plate 4 will be correctly covered by the cover 34, this plate being surrounded by the reversible fixing means 38.

Alternatively and/or in a complementary manner, and although not shown in the figures, at least one of the means for reversibly fixing the cover 34 to the print head 2 could take the form of at least one suction member, for example example a suction cup.

The cover 34 has a shape dependent on that of the print head 2, this shape being here substantially parallelepiped. It is formed by longitudinal walls 40 and lateral walls 42 joined to each other. These longitudinal 40 and lateral 42 walls extend mainly in planes parallel to planes in which the longitudinal 24 and lateral partitions 26 of the support platform 18 extend respectively when the cover 34 is received in its reception zone 32 The cover 34 further comprises an upper wall 44 and a lower wall 46, which are opposed to each other and joined by the longitudinal walls 40 and side walls 42. When the cover 34 rests on the support platform 18 at within the printing station, the upper wall 44 faces the print head 2 while the lower wall 46 faces the upper partition 28 of this support platform 18, and more precisely its zone d welcome 32.

The upper 44, lower 46, longitudinal 40 and lateral 42 walls define a volume of the cover 34. Within this volume, the cover 34 has a cavity 48 configured to cover the projection nozzles 4 of the print head 2. A such cavity is particularly illustrated in Figures 2 and 3. The cavity 48 extends from the upper wall 44 and towards the lower wall 46; we therefore understand that it corresponds to a recess within the volume of the cache 34.

As mentioned, the cover 34 may comprise reversible fixing members 50 which are intended to cooperate with the reversible fixing means 38 carried by the print head 2. The reversible fixing members 50 are in particular, if the reversible fixing means 38 are electromagnets and/or permanent magnets, magnets or metal inserts; alternatively, the reversible fixing members 50 can include at least one electromagnet, in particular to allow the cover 34 to be detached despite the magnetic attraction of the permanent magnets present on the print head or even include at least one suction member. Such reversible fixing members 50 are arranged on either side of the cavity 48. They can be two in number as is the case in Figure 3, or even four in number and arranged at the corners of the upper wall 44 as is the case in Figure 4. It is understood that the number of fixing members 50 arranged on the cover 34 is a function of the number of reversible fixing means 38 arranged on the print head 2.

According to a first embodiment, the reversible fixing means 38 can be activated or deactivated, their activation leading to the lifting of the cover 34 of the support platform 18 and its reversible fixing to the print head, while their deactivation causes the separation of these two elements and the deposit of the cover 34 on the reception zone 32 of the support platform 18. According to a second embodiment, it is the reversible fixing members 50 which can be activated or deactivated. It is thus understood that either the reversible fixing means 38 or the reversible fixing members 50 allow, when they are activated and deactivated and the cover 34 is facing the print head, respectively attraction and displacement movements. repulsion of the cover 34 relative to the print head 2. In this case of the first embodiment, the attraction allows the reversible fixation of the cover 34 on this print head 2, while the repulsion allows its detachment and therefore its deposit on the reception zone 32 of the support platform 18. Such movements of attraction and repulsion are, due to the arrangement of the reversible fixing means 38 and the reversible fixing members 50, substantially parallel to a direction of ink ejection 6 from the projection nozzles 4 of the print head 2, as shown by dotted lines in Figures 4 and 5. In other words, these movements of attraction and repulsion are therefore substantially perpendicular to the support platform 18 and to the reception zone 32 of the cache 34.

As mentioned, the activation and deactivation of the reversible fixing means 38 or the reversible fixing members 50 may in particular consist of a modification of the electrical power supply of an electromagnet, or even in an inversion of their polarity . Alternatively, this activation and this deactivation can respectively correspond to vacuum suction and the application of a positive pressure when the reversible fixing means 38 or the reversible fixing members 50 comprise a suction member; we thus understand that an air flow will circulate in two opposite directions to ensure activation and deactivation.

The reversible fixing means 38 are activated as a function of a position of the support platform 18, and more precisely of its position relative to the print head 2. The support platform 18 is in fact capable of taking two positions distinct when facing the print head, namely the first position as mentioned previously, in which the receiving zone 20 of the substrate plate 16 is facing the print head 2, and a second position in which the reception zone 32 of the cover 34 is facing this print head 2. The reversible fixing means 38 are activated when the support platform 18 is in its second position, then allowing the covering of the projection nozzles 4 by the cover 34 with which they are aligned in the direction of ink ejection. The reversible fixing means 38 and the reversible fixing members 50 are then in contact with each other, and the upper wall 44 of the cover 34 is pressed against the lower face 36 of the print head 2.

The reversible fixing means 38 can be activated remotely, in particular by an appropriate computer program, as soon as the positioning of the support platform 18 in its second position is detected within the printing device 1.

In order to ensure optimal fixation of the cover 34 to the print head 2, the cover 34 has, in the illustrated example, keying means 52. These keying means 52 are more precisely carried by the upper wall 44 of the cover 32. They can be pins or guides, as shown in Figure 3. Alternatively, and although this is not illustrated in the present figures, the keying means 52 can take the form of chamfers. The keying means 52 cooperate to ensure correct positioning of the cover 34 relative to the head printing 2 resulting in the covering of the projection nozzle plate 4 in the cavity 48 of the cover 34, with complementary means arranged on the lower face 36 of this print head 2.

In certain particular embodiments and as shown in Figure 7, the fixing of the cover 34 to the print head 2 and its detachment therefrom can be assisted by reversible fixing instruments 51 as well as systems reversible fixing 53. The reversible fixing instruments 51 are carried by the cover 34; they are more precisely arranged on its lower wall 46. They cooperate with the reversible fixing systems 53, which are arranged on the reception area 32 of the support platform 18. The reversible fixing instruments 51 and the reversible fixing systems 53 are thus in contact with each other when the cover 34 rests on the support platform 18. The reversible fixing instruments 51 and the reversible fixing systems 53 can be magnets such as electromagnets or permanent magnets. They may also include a suction member.

The reversible fixing instruments 51 and the reversible fixing systems 53 ensure that the cover 34 detaches from the print head 2 to rest on the receiving surface 32 of the support platform 18. As for example, if the reversible fixing instruments 51 are electromagnets and the reversible fixing systems 53 are permanent magnets, activation of the reversible fixing instruments 51 combined with deactivation of the reversible fixing means 38 will lead to the detachment of the cover 34 of the print head 2 so that it comes into contact with the support platform 18. Such a movement can be guided by keying means arranged on the lower face 46 of the cover 34 as well as on the reception area 32, for example complementary pins and grooves.

In addition, the reversible fixing instruments 51 and the reversible fixing systems 53 participate in supporting the fixing of the cover 34 to the print head 2. They can for example be configured so as to operate, if they are magnets, a magnetic repulsion of the cover 34 relative to the support platform 18.

When the reversible fixing means 38 and/or the reversible fixing members 50 are activated and the cover 34 is fixed to the print head 2, a seal between these two elements is ensured by an O-ring 54. This O-ring 54 is carried by the cover 34. More particularly and as visible in Figure 3, it is arranged in a groove provided for this purpose in the upper wall 44 of the cover 34. The groove and the O-ring 54 are arranged on the cover 34 so as to surround the cavity 48 intended to accommodate the projection nozzles 4. The O-ring 54 comes into contact with the lower face 36 of the print head 2 when the cover 34 is fixed there. It thus makes it possible to prevent drops of ink 6 from escaping through a possible gap which would remain between the upper wall 44 of the cover 34 and the lower face 36 of the print head 2 when these are in contact one from the other, filling such a gap. The cover 34 may also have an absorbent portion configured to absorb ink 6 from the print head 2, or else be equipped with a wiping element for cleaning and/or wiping the projection nozzles 4. By elsewhere, the cache 34 can be equipped with sensors such as humidity sensors, pressure sensors, or even a sensor detecting an accumulation of liquid within the cache. These sensors can be controlled to trigger, when they detect abnormal values, corrective actions within the printing device 1.

Thus, when ink 6 is collected within the cavity 48 of the cover 34, for example due to a purge, this ink 6 can be detected by the sensor detecting an accumulation of liquid, which triggers its evacuation from the cover 34. This has for this purpose at least one orifice 56 formed in its upper wall 44; in the representation of Figure 3, these orifices 56 are three in number. The orifices 56 allow the cavity 48 to be placed in communication with a fluid circulation channel 58 provided in the cover 34; it is understood here that these orifices 56 and this fluid circulation channel 58 are fluidly connected. The fluid circulation channel 58 extends within the volume of the cover 34. It thus crosses it right through, between a plane in which a bottom wall of the cavity 48 extends and a plane in which extends the lower wall 46 of the cover 34. As illustrated in Figures 3 to 5, the fluid circulation channel extends parallel to the longitudinal walls 40 of the cover 34 and it passes through each of its side walls 42.

The fluid circulation channel 58 also has the role of regulating the humidity within the cavity 48 when the cover 24 is fixed to the print head 2. A moist fluid can thus circulate in the fluid circulation channel 58 to humidify the cavity 48 passing through the orifices 56, and on this occasion prevent the ink 6 from drying out at the level of the projection nozzles 4.

Alternatively and although not shown in the present figures, such humidification of the cavity 48, and by extension of the projection nozzles 4, can make intervene a liquid reservoir, for example a reservoir of saturated saline solution. The liquid reservoir is then placed in a volume of the cover 34, between the bottom wall of the cavity 48 and the lower wall 46 of the cover 34. The saturated saline solution will be able to diffuse from the liquid reservoir towards the cavity 48 via the intermediate of the orifices 56. The use of the saturated saline solution can for example be triggered after the humidity sensor mentioned previously has detected an insufficient level of humidity at the level of the projection nozzles 4. When the cover 34 is equipped with such a liquid reservoir, the presence of the fluid circulation channel 58 is optional.

The cover 24 may also include additional conduits which allow evacuation of the ink 6 or debris, for example plates of dried ink. Such evacuation can in certain embodiments be ensured by a particular configuration of the fluid circulation channel 58, by the circulation of air or even by the application of suction within it. Suction through the fluid circulation channel 58 can also be used to create a vacuum when the reversible fixing means 38 are suction members.

A printing process 60 involving the printing device 1 as mentioned previously will now be described in relation to Figure 6.

The printing process 60 according to the invention comprises several successive steps which form a cycle allowing the implementation of the synthesis method described above. The printing process 60 begins with a first positioning step El, during which the support platform 18 is positioned within the printing station so that the reception zone 20 carrying the substrate plate 16 is in position. view of the print head 2, that is to say in the first position previously mentioned. Such a first position can be obtained, as mentioned previously, by moving the support platform 18 alone, by moving the print head 2 alone, or by moving these two components together. At the end of the first positioning step El, the substrate plate 16 is positioned under the projection nozzles 4 carried by this print head. The printing process 60 then continues with the printing step, mentioned previously in relation to the enzymatic synthesis method, which allows the deposition of ink 6 containing enzymatic synthesis reagents in the reaction wells of the plate substrate 16 provided for this purpose. A second positioning step E2 then occurs, during which the support platform 18 and/or the print head 2 are moved until the support platform 18 is in its second position, that is to say until the reception zone 32 of the cache 34 is opposite the print head 2. At the end of this second step positioning E2, a distance D measured between the print head 2 and the cover 34 is less than three millimeters. The cover 34 can then be lifted and then fixed to the print head 2 by activation of the reversible fixing means 38, in particular by computer control, which corresponds to a fixing step E3. Such fixing is carried out in a direction substantially perpendicular to a plane of movement of the support platform 18 and/or the print head 2 between the first position and the second position; in other words, the direction of attachment is substantially parallel to the direction of ejection. At the end of the fixing step E3, the lower face 36 of the print head 2 is in contact with the upper wall 44 of the cover 34. The seal between this lower face 36 and this upper wall 44, and therefore by extension between the print head 2 and the cover 34, is ensured by the presence of the O-ring 54 placed in the groove of this cover 34. Due to the reduced distance D between the print head 2 and the cover 34 at the end of the second positioning step, a shock resulting from the attachment between these two elements is limited.

Once the cover 34 is fixed to the print head 2, the support platform 18 can be directed towards other operating stations of the printing device, for example the imaging station comprising the camera 22 for a step imaging station E4, or even a cleaning station for a rinsing step E5 of the substrate plate 16. Once these steps E4, E5 have been carried out, the support platform 18 carrying the substrate plate 16 can return to the station printing in its second position for an unhooking step E6. During this unhooking step E6, the reversible fixing means 38 are deactivated, so that the cover 38 is released and placed on the reception area 32 of the support platform 18. Another cycle of the printing process 60 can then begin by reproducing the first positioning step EL

The present invention thus proposes a cover configured to equip a print head of a printing device and thus make it possible to avoid unwanted ink deposits on a substrate plate of the printing device and means allowing fixing simplified and fast of this cache.

The present invention cannot, however, be limited to the means and configurations described and illustrated here and it also extends to any equivalent means and configuration as well as to any technically effective combination of such means.

Claims

1. Printing device (1) configured for the synthesis of biomolecules, comprising a printing station equipped with a print head (2) configured to deposit drops of ink (6) containing synthesis reagents on a substrate plate (16), the printing device (1) comprising a support platform (18) configured to receive the substrate plate (16) and a cover (34) for covering the print head (2 ), the support platform (18) comprising a reception zone (32) of the cover (34) and a reception zone (20) of the substrate plate (16), the support platform (18) and/or the print head (2) being movable between a first position in which the reception zone (20) faces the print head (2) and a second position in which the reception zone (32) is facing the print head (2), the printing device (1) comprising means (38) for reversibly fixing the cover (34) on the print head (2), the means for reversible fixing ( 38) being activated depending on the position of the support platform (18) relative to the print head (2).

2. Printing device (1) according to the preceding claim, wherein the reversible fixing means (38) comprise at least one electromagnet.

3. Printing device (1) according to the preceding claim, wherein the reversible fixing means (38) comprise at least one permanent magnet.

4. Printing device (1) according to claim 1, wherein the reversible fixing means (38) comprise at least one suction member.

5. Printing device (1) according to one of the preceding claims, wherein the reversible fixing means (38) are arranged to allow attraction and repulsion movements substantially parallel to an ink ejection direction (6) from the print head (2).

6. Printing device (1) according to one of the preceding claims, wherein the reversible fixing means (38) are arranged on the print head (2).

7. Printing device (1) according to the preceding claim, in which the reversible fixing means (38) are arranged on a lower face (36) of the print head (2) intended to be facing the platform support (18), this lower face (36) carrying projection nozzles (4).

8. Printing device (1) according to any one of the preceding claims, wherein the reversible fixing means (38) are activated remotely.

9. Printing device (1) according to any one of the preceding claims in combination with claim 6, wherein reversible fixing members (50) cooperating with the reversible fixing means (38) of the print head (2) are arranged on the cache (34).

10. Printing device (1) according to the preceding claim, in which the reversible fixing members (50) are carried by an upper wall (44) of the cover (34) intended to be facing the print head ( 2), this upper wall (44) being opposite a lower wall (46) of the cover (34) facing the reception area (32) of the support platform (18).

11. Printing device (1) according to the preceding claim, in which the cover (34) has a cavity (48) configured to cover the projection nozzles (4) of the print head (2), this cavity (48) extending from the upper wall (44).

12. Printing device (1) according to any one of the preceding claims, in which the reception zone (32) of the support platform (18) comprises reversible fixing systems (53), the fixing systems reversible (53) cooperating with reversible fixing instruments (51) arranged on a lower wall (46) of the cover (34) facing the reception zone (32).

13. Printing device (1) according to any one of the preceding claims, in which the cover (34) is equipped with a fluid circulation channel (58) extending within a volume of the cover ( 34).

14. Printing device (1) according to the preceding claim, wherein the fluid circulation channel (58) is fluidly connected to at least one orifice (56) formed in the upper wall (44) of the cover (34).

15. Printing device (1) according to any one of the preceding claims in combination with claim 10, wherein an O-ring (54) is arranged against the upper wall (44) of the cover (34).

16. Printing device (1) according to any one of the preceding claims in combination with claim 10, in which the upper wall (44) carries keying means (52).

17. Printing device (1) according to any one of the preceding claims, wherein the cover (34) has an absorbent portion configured to absorb ink (6) from the print head (2).

18. Printing device (1) according to any one of the preceding claims, wherein the cover (34) is equipped with a humidity sensor and/or a liquid accumulation sensor.

19. Printing method (60) by a printing device (1) according to any one of the preceding claims, comprising a first positioning step (El) during which the support platform (18) and/or the print head (2) is positioned, within the printing station, in the first position, a printing step during which drops of ink (6) containing synthesis reagents are deposited on the substrate plate (16), a second positioning step (E2) in which the support platform (18) and/or the print head (2) is moved to the second position, and a fixing step (E3) during which the cover (34) is lifted and fixed to the print head (2) by activation of the reversible fixing means (38) when the support platform (18) is in the second position.

20. Printing method (60) according to the preceding claim, comprising an unhooking step (E6) during which the cover (34) is released and deposited on the reception area (32), the support platform ( 18) being moved to an imaging station and/or a cleaning station separate from the printing station, then returned to the printing station between the fixing step (E3) and the unhooking step (E6).

21. Printing method (60) according to any one of claims 19 and 20, wherein at the end of the second positioning step (E2) a distance (D) between the print head (2) and the cover (34) is less than three millimeters.

22. Printing method (60) according to any one of claims 19 to 21 in combination with claims 7 and 15, in which at the end of the fixing step (E3) the lower face (36) of the print head (2) is affixed to the upper wall (44) of the cover (34), the O-ring (52) ensuring a seal between the print head (2) and the cover (34).

23. Printing method (60) according to any one of claims 19 to 22, in which a direction of fixing of the cover (34) corresponds to a direction substantially perpendicular to a plane of movement of the support platform (18) and/or the print head (2) between the first position and the second position.

24. A computer program product including program code instructions recorded on a computer-readable medium (18) for implementing the steps of the printing process (60) according to any one of claims 19 to

23 when the program runs on a computer.