WO2007042964A1

WO2007042964A1 - A method and apparatus for printing a pattern of distinct dots of different reagent fluids using a printing head comprising a set of nozzles

Info

Publication number: WO2007042964A1
Application number: PCT/IB2006/053589
Authority: WO
Inventors: Anke Pierik; Johan F. Dijksman; Martin M. Vernhout; Adrianus T. A. M. Raaijmakers; Leonardus J. C. Van Den Besselaar; Antonius J. J. Wismans; Hendrik R. Stapert
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2005-10-07
Filing date: 2006-10-02
Publication date: 2007-04-19

Abstract

Method for printing a pattern of distinct dots of different reagent fluids on a number of substrates (8) , which printed substrates (8) are generally used as chemical assays. The application also relates to an apparatus (1) for use in said method. It improves the printing of these substrates (8) by using a printing apparatus (1) comprising a printing head (10) that contains a set of several nozzles, in combination with a specific sequence of printing from different nozzles. The application leads towards a faster production time, while maintaining the high requirements for printing of substrates that are to be used as chemical assays. The printing apparatus (1) has a controller (15) for coordinating the specific sequence for printing the pattern.

Description

A METHOD AND APPARATUS FOR PRINTING A PATTERN OF DISTINCT DOTS OF DIFFERENT REAGENT FLUIDS USING A PRINTING HEAD COMPRISING A SET OF NOZZLES

The invention relates to a method for printing a pattern of distinct dots of different reagent fluids on a number of substrates, which printed substrates are used for chemical assays. The invention also relates to an apparatus for use in said method.

In US 4877745 a system is disclosed for a method of printing reagent fluids on a print medium. The printing of reagent fluids is required in the manufacturing of chemical assay strips. Selected reagents are printed in a desired configuration on strips of paper. The strips may then be used as a disposable diagnostic tool to determine the presence or absence of a variety of chemical components.

To perform a chemical assay with a strip, the strip is exposed to a fluid to be tested, such as blood, serum or urine. Additional reagents may be used in exposing the strip to the fluid to be tested. The interpretation of the test strips after exposure may be simply visual, e.g. by inspection for a colour change. In US 4877745 an embodiment of a printing apparatus is disclosed having a jetting tube, or nozzle, aligned with a printing medium, such that a droplet jetted from the nozzle impacts on a precise position on the medium. After repositioning either the nozzle or the printing medium, another droplet may be expelled from the nozzle. The process may be repeated until a desired configuration of the reagent fluid is printed on the medium. As an example of a system that can be used, a commercially available pen plotter is mentioned, wherein a jetting tube replaces the pen.

However, when it is required that the printed substrate is capable of performing various different tests, the substrate consequently has to be printed with different reagent fluids. This requirement, which is not dealt with in US 4877745, poses some serious problems in printing these substrates, as encountered by the inventors.

Specifically, the use of one single nozzle, i.e. one ejection unit having a chamber for a fluid to be ejected from a nozzle, is cumbersome when different fluids have to be applied per substrate. For instance, this implies a thorough cleaning of the chamber that contains the fluid, in order to prevent that a next fluid contains traces of the preceding fluid. This is a highly stringent requirement in this context, because contamination of the reagents which are printed on the substrates, would adversely affect the reliability of the assay in which the substrate is used. Thus, the known printing method is time-consuming because each time another fluid has to be printed, the process is interrupted. In addition, it is remarked that because of the intended application of the printed substrates, it is a prerequisite that all fluids are printed on each substrate in the form of distinct dots, i.e. they occupy a (predetermined) spot which is surrounded by a non-printed area.

In addition, as the printing of substrates is economically more viable when large amounts of substrates can be printed by the apparatus, there is a general need that the apparatus used is apt to print a large number of substrates.

Finally, the printing of substrates for chemical assays requires a very accurate and precise printing of distinct dots which imposes further problems, with regard to the positioning of substrates, the positioning of the printing head, the ejection power of nozzles and adverse effects of movements of reagent fluid in the printing process.

It is an object of the invention to provide a printing method and a printing apparatus that enables the elimination or reduction of the above drawbacks of the known methods and products, and/or complies more or less with the above general needs and requirements.

To this aim, the invention provides a method of printing a pattern of distinct dots of different reagent fluids on a number of substrates with a printing apparatus, wherein the printing apparatus comprises a moveable printing head comprising a set of nozzles for the ejection of different reagent fluids wherein each nozzle is in fluid connection with a reservoir of a reagent fluid, and a moveable support for supporting a number of substrates to be printed, and wherein the method of printing comprises a sequence of steps of: a) a positioning step of positioning a substrate to be printed vis-a-vis a nozzle of the set, by moving the support and/or the printing head, b) a printing step of printing a distinct dot of reagent fluid on the substrate by ejecting reagent fluid from the nozzle, wherein the sequence a)-b) is repeated for different reagent fluids as well as for said number of substrates. In the above method, less time is needed for printing different fluids in a pattern on a number of substrates compared with the known method, because the replacement of fluids per nozzle is reduced by a factor equal to the number of nozzles comprised in the set. Furthermore, each nozzle is independently controlled so that dependent on the fluid and the type of dot to be printed, the ejection power and ejection volume can be set, the timing of ejections from different nozzles can be adapted easily, etc.. By repeating the sequence a)-b) for different reagent fluids, and by consequence, for different nozzles, the idle time for a nozzle is short, which minimizes the risk of clogging by drying out of an idle nozzle from which no fluid is ejected for a longer time. With regard to the description of the invention, a nozzle comprises herein an ejecting port having a fluid connection with a container holding a reservoir of reagent fluid, thus ensuring a continuous availability of fluid for printing. For clarity's sake, it is remarked that according to the invention, a different reagent fluid shall be ejected from a different nozzle, although different nozzles may eject the same fluid. The reagent fluids that are printed on the substrates contain mostly biological reagents. Preferably, the reagent fluid is an aqueous solution of a reagent, in general having a concentration of 1-500 micromole. Advantageously, the formulation is cross-linkable in order to graft the reagent fluid to the porous substrate after the fluid has been printed on the substrate. The positioning of dots on one substrate is herein called distinct, which is in this context to be construed as synonymous to discrete, i.e. the dot is surrounded by an area that does not contain printed reagent fluid.

The number of substrates may be, for example, several hundreds of substrates to be printed in one batch.

Especially envisaged in the invention is the printing of substrates which are porous. When such a porous substrate is used for chemical assays, it is preferably positioned as a diaphragm in a flow-through container having an inlet and an outlet, so that a sample to be tested which is led through the container, necessarily passes through the porous substrate. Because of the cylindrical dimensioning of the flow-through container (in the form of a small tube, for instance), the substrates are advantageously circular in form, so as to fit in a closing manner between the inner walls of the container as a diaphragm. Alternatively, the substrates are non-porous, e.g. of glass material on which a sample to be tested is applied, i.e. different from the application in a flow-through container.

Specifically, the porous substrate that can be used as a diaphragm, has a diameter of approx. 6 mm, contains 130 distinct dots, each dot covering an area of approx. 200 micrometer in diameter. Because of the relatively small dimensioning, the dots can appropriately be named micro-dots. Obviously, the amount of dots - up to, for instance, 300- 400 or even 1000 or more - that can be printed on a substrate, raises the number of tests that can be done using one (blood) sample. In practice, some different positioned micro-dots may contain the same fluid, so as to raise the reliability of the test, i.e. lowering the chances of an error in the test.

Advantageously, the printer comprises a controlling unit for coordinating the sequence a)-b) for different reagent fluids as well as for the number of substrates, as will be discussed in detail below.

In manufacturing the substrates for chemical assays, following the printing of distinct dots according to a certain pattern, some subsequent steps may be performed on the substrate. These steps may comprise a washing step, in order to wash off excess of fluids not adhered on the substrate, and a blocking step, in order to block the surface of the membrane that has not been covered with the printed fluids.

The measure as defined in claim 2 achieves that in printing a row of substrates, the nozzle itself does not have to pass through the row, but the row passes the nozzle. As such, the movement of the nozzle is limited which improves the preciseness of ejecting fluid from a nozzle, as with the movement of a nozzle, the fluid present in the nozzle is also moved, possibly leading to fluctuations in the ejecting action.

The measure as defined in claim 3 has the advantage that because the movement direction of the printing head is different from that of the support, they cooperatively establish that the printing head has a range which encompasses an area composed of multiple rows of substrates. Advantageously, said directions are perpendicular to each other.

The measure as defined in claim 4 has the advantage that the most time- efficient printing per row passage is achieved. One row passage means in this description a movement such that all nozzles pass the substrates of one row. Alternatively, only fluid from one nozzle can be ejected during one row passage, and this procedure is repeated for each nozzle containing a different fluid.

When a row of substrates is printed with the fluids available in the nozzles, according to one of the above procedures, the printing head is shifted towards a next row by movement of the printing head. The printing of a row is then repeated in the same manner, up till all rows are printed. Thereafter the reagent fluids are changed, so that the nozzles become in fluid connection with other reagent fluids that also are comprised in the pattern to be printed. The measure as defined in claim 5 has the advantage that three nozzles is the most practical number of nozzles, considering amongst others, the amount of fluids to be used in printing a substrate, and the dimensioning of the printing head.

The measure as defined in claim 6 has the advantage that adjacent nozzles in the set are positioned vis-a-vis adjacent substrates in one row. Preferably the distances between adjacent nozzles are equal to or a multiple integer of the distance between adjacent substrates. As such, the adjacent nozzles are positioned vis-a-vis adjacent substrates, so that when an a)-b) sequence is repeated serially for different nozzles, the positioning step a) is minimized, because each nozzle is already in the right position for printing the respective substrate.

The measure as defined in claim 7 has the advantage that it is a highly efficient printing process, requiring as little movement as possible from the printing head per printing of one row, and using all nozzles from a set in one row passage. By serially repeating in step i) is meant that different nozzles eject fluid in so far this is required by the pattern of dots to be printed, before the shift of step ii) follows.

The measure as defined in claim 8 has the advantage that a precise and secured positioning of substrates on the support is achieved, which makes the coordination of the printing and positioning steps a)-b) more easy. Preferably the substrates are arranged by the positioning plate in an order of a grid of rows and columns. According to a second aspect, the invention relates to a printing apparatus for use in a method of printing a pattern of distinct dots of different reagent fluids on a number of substrates, wherein the printing apparatus comprises a base provided with suspension means for suspending a moveable printing head which comprises a set of nozzles for the ejection of different reagent fluids wherein each nozzle is in fluid connection with a reservoir of a reagent fluid, said base further comprising a moveable support for supporting a number of substrates to be printed, which support can be positioned vis-a-vis a nozzle of the printing head, a controlling unit for coordinating a sequence of steps including: a) a positioning step of positioning a substrate to be printed vis-a-vis a nozzle of the set, by moving the support and/or the printing head, b) a printing step of printing a distinct dot of reagent fluid on the substrate by ejecting reagent fluid from the nozzle, wherein the sequence a)-b) is repeated for different reagent fluids as well as for said number of substrates.

The printing apparatus being suitable for the printing method of the invention, achieves the same advantages as explained above for the method of printing according to the independent claim 1.

The measure as defined in claim 10 has the advantage that, because the movement direction of the printing head is different from that of the support, they cooperatively establish that the printing head has a range which encompasses an area composed of multiple rows of substrates. Preferably, the first and second directions are perpendicular to each other.

The measure as defined in claim 11 has the advantage that the most time- efficient printing per row passage is achieved. Alternatively, only fluid from one nozzle is ejected during one row passage, and this procedure is repeated for each nozzle containing a different fluid. The measure as defined in claim 12 has the advantage that three nozzles is the most practical number of nozzles, considering amongst others, the amount of fluids to be used in printing a substrate, and the dimensioning of the printing head.

The measure as defined in claim 13 has the advantage that a precise and secured positioning of substrates on the support is achieved, which makes the coordination of the printing and positioning steps a)-b) more easy. Preferably the substrates are arranged by the positioning plate in an order of a grid of rows and columns.

The measure as defined in claim 14 has the advantage that adjacent nozzles in the set are positioned vis-a-vis adjacent substrates in one row. Preferably the distances between adjacent nozzles are equal to or a multiple integer of the distance between adjacent substrates. As such, the adjacent nozzles are positioned vis-a-vis adjacent substrates, such that when an a)-b) sequence is repeated serially for different nozzles, the positioning step a) is minimized because each nozzle is already in the right position vis-a-vis a substrate.

The measure as defined in claim 15 has the advantage that it can perform a highly efficient printing process, requiring as little movement as possible from the printing head per printing of one row, and using all nozzles from a set in one row passage.

These and other aspects of the invention are apparent from and will be elucidated with reference to the embodiments described hereinafter. In the drawings:

Fig. 1 is a schematic 3-dimensional view of an embodiment of a printing apparatus for the method according to the invention.

Fig. 2 is a top view of the printing apparatus of Fig. 1 showing details of the printing head.

Fig. 3 shows an embodiment of a table according to Fig. 1, on which a so- called registration plate is mounted.

Fig. 4 shows a top view of a porous substrate printed with distinct dots of different fluids according to the invention.

Fig. 1 shows a printing apparatus 1 comprising a base 2, on which a bridge 4 is mounted in a fixed position that spans a table 6, on which multiple porous substrates to be printed 8 are placed in a grid-like pattern of rows and columns. It is noted that for the sake of clarity, a smaller number of substrates is shown in Fig. 1 than in normal practice, wherein one batch may consist of several hundreds of substrates applied on one table. A printing head 10 is moveably connected to the bridge 4 so that it can move in the direction indicated by arrow Y. The table 6 is moveably connected to the base 2 so that it can move through a guiding slot 12 in the direction indicated by arrow X. In the base 2 a controller 15 is provided for controlling the movements of the table 6 and the printing head 10. Furthermore, the controller 15 controls the printing from the nozzles of the printing head 10, as will be shown and explained in detail with regard to Fig. 2. The movements of table 6 and printing head 10 are actuated by motors which are not depicted and which are controlled by drive signals sent from the controller 15. For sake of clarity, and also in connection to other drawings, X, Y and Z directions are indicated in the right bottom corner. The printing apparatus is designed to print on all substrates of a batch one single pattern of dots of fluids. An example of such a pattern is shown in Fig. 4.

Fig. 2 shows a detailed top view of the printing apparatus 1 of Fig. 1, wherein only two rows of substrates 8 are depicted for the sake of simplicity. The printing head 10 comprises three nozzles 12, marked by 12A, 12B, and 12C, each nozzle being connected to a container or cartridge for a fluid to be ejected through the nozzle 12, the container or cartridge not being depicted. Preferably, each nozzle 12 ejects a specific fluid which is different from the fluid ejected by another nozzle 12. The nozzles 12 are so-called single nozzles, i.e. they are separate nozzles in that the printing action of each nozzle 12 is independently controlled via a separate signal circuit which is not depicted. Through each signal circuit the controller 15 sends the appropriate print signals to a nozzle 12. The nozzles 12 are spaced apart equidistant Iy. The distance between two neighbouring nozzles 12 is indicated by dn, in the field also known as 'nozzle pitch'. The substrates 8 are equidistantly aligned in rows in X-direction, as indicated by ds. The magnitude of ds is equal to dn. The rows of substrates 8 are aligned thus forming equidistant columns, which are numbered I, II, III, IV, V.

A pattern of dots 20 denoted by 2OA, 2OB, and 2OC has been printed on the substrates 8 in the first depicted row. The printed dots 2OA, 2OB, and 2OC were printed by the nozzles 12A, 12B, and 12C respectively. For sake of clarity a simple pattern is depicted, although in practice the pattern may comprise more than one dot 2OA, 2OB, or 2OC printed on one substrate. In general, one or several ejections or drops of fluid from a nozzle 12 suffice to form a dot 20 on a substrate. For the second row of substrates 8, on which no pattern of dots 20 is indicated as printed yet, it is below explained how the printing method is performed. The controller 15 is programmed to achieve a printing action from nozzle 12 A,

12B, and 12C sequentially. An example of an appropriate sequence for the depicted pattern consists of three ejections at separate moments wherein each nozzle 12 delivers one ejection. This sequence of printing action is repeated several times in order to print all substrates on the table. In order to apply a fluid from a nozzle 12 at the correct spot according to the pattern depicted for the first row, most of the times a small adjustment in the position of the nozzle 12 is required prior to the printing action. The adjustment is relatively small because it encompasses the printing area of one substrate 8. The adjustment involves a movement of either table 6, printing head 10, or a combination of both. This relatively small movement from one spot position to another spot position is herein referred to as 'spot movement'. The controller 15 controls the spot movement and its timing, as well as the subsequent printing action of a nozzle 12 at the spot reached.

After one sequence, the following print result is obtained: on the substrate in column III a printed dot 2OA is created, on the substrate in column II a printed dot 2OB is created, and on the substrate in column I a printed dot 2OC is created. After this first sequence, the table is moved to the left in X-direction by one ds, so that the substrates 8 are moved with regard to the printing head 10, resulting in the nozzles 12 being in a position above substrates of a next right column. For example, nozzle 12A is, after the movement of the table 6, not longer positioned above substrate 8 in column III but in column IV, so that a substrate in column IV can now be applied with a dot 2OA once the spot movement is performed subsequently. This principle accounts for nozzles 12B and 12C as well, with regard to columns III and II respectively. The relatively large movement of the table 6 (i.e. a movement exceeding the printing area of one substrate), is herein referred to as 'column movement' and indicated as cm. The column movement cm can be combined with a first spot movement of a next sequence, so that for example in one fluent movement the nozzle 12A (being the first to sequentially eject fluid in the next sequence) is brought in correct position for printing a dot 2OA on the substrate of column IV.

As an alternative, it is also part of the invention that the controller is programmed so that in a first sequence dots 2OA are printed on one row of substrates, and subsequently 2OB on the same row, and finally 2OC on the same row. This printing sequence has the advantage that a small adjustment, i.e. a spot movement has to be made only once for printing at a certain spot on a whole row by moving the table 6 in steps of ds. However, more movements of the table 6 are required in comparison to the first explained order of printing. As explained above, the patterns printed on a substrate may comprise fluids being printed at multiple spots on one substrate. The sequence of ejecting fluids will accordingly be adapted so that one nozzle 12 delivers more than one ejection per substrate, before a column movement is made. The skilled person can see that the controller has to be reprogrammed in order to achieve such kind of printing actions, though this does not materially affect the printing principle outlined in the above paragraphs.

Fig. 3 shows a table 6 such as shown in Fig. 1, on which a so-called registration plate 50 is mounted. This plate 50 is provided with a grid of circular recesses 52, which have an inner diameter 54. This inner diameter 54 is similar to the outer diameter of the circular substrates 8, so that in each recess 52 one substrate 8 can be positioned. The table mounted with such a registration plate 50 enables thus a precise and predetermined positioning of the substrates 8 according to the grid pattern of recesses 52.

Fig. 4 shows a top view of one porous substrate 8 printed with distinct dots 62 of different fluids according to the invention. The diameter 64 of one dot 62 is approximately 0.2 mm, and the distance indicated with dd, between two neighbouring dots 62, is approximately 0.4 mm. The diameter of one porous substrate 8 is approximately 6 mm and the total number of dots printed on one substrate 8 is 130.

The above indicated preferred embodiments are not to be construed as limiting to the scope of the invention, but are merely presentations of preferred embodiments as such. Also, the reference signs cited in the appended claims are not to be construed as limiting to the scope of the respective claims, the reference signs merely serve as to illustrate a feature that appears in appended drawings.

Claims

CLAIMS:

1. A method of printing a pattern of distinct dots (62) of different reagent fluids on a number of substrates (8) with a printing apparatus (1), wherein the printing apparatus (1) comprises a moveable printing head (10) comprising a set of nozzles (12A, 12B, 12C) for the ejection of different reagent fluids wherein each nozzle is in fluid connection with a reservoir of a reagent fluid, and a moveable support (6) for supporting a number of substrates (8) to be printed, and wherein the method of printing comprises a sequence of steps of: a) a positioning step of positioning a substrate (8) to be printed vis-a-vis a nozzle (12A, 12B, 12C) of the set, by moving the support (8) and/or the printing head (10), b) a printing step of printing a distinct dot (62) of reagent fluid on the substrate (8) by ejecting reagent fluid from the nozzle (12A, 12B, 12C), wherein the sequence a)-b) is repeated for different reagent fluids as well as for said number of substrates (8).

2. A method according to claim 1 wherein said number of substrates (8) are arranged in one or more rows on the support (6), and the support (6) moves at least in a first direction similar to the direction of a row.

3. A method according to claim 2, wherein the printing head (10) moves at least in a second direction being different from the first direction of movement of the support (6).

4. A method according to one of the preceding claims 2-3, wherein one row of substrates (8) is printed while the support (6) moves said one row in one row passage vis-a- vis the printing head (10), wherein the sequence of steps a)-b) is repeated so that the different reagent fluids present in the nozzles (12A, 12B, 12C) are ejected in said one row passage.

5. A method according to one of the preceding claims, wherein the set of nozzles (12A, 12B, 12C) comprises three nozzles.

6. A method according to one of the preceding claims 2-5, wherein the nozzles (12A, 12B, 12C) in the set are positioned in a row having a similar direction as the rows of the substrates (8) on the support, adjacent nozzles (12A, 12B, 12C) of the set being spaced apart by a fixed equal distance (dn), the adjacent substrates (8) in one row being spaced apart by a fixed equal distance (ds), and the distance of spacing between nozzles being similar to the distance of spacing between substrates.

7. A method according to claim 6, wherein the sequence of steps a)-b), is repeated, in the following steps of a cycle: i) serially repeating the sequence of steps a)-b) for adjacent nozzles (12A, 12B,

12C) of the set, wherein the adjacent nozzles (12A, 12B, 12C) eject reagent fluid on adjacent substrates (8), ii) followed by moving the substrates (8) so that a nozzle is shifted in a position vis-a-vis a next adjacent substrate (8), wherein the sequence i)-ii) is repeated for said number of substrates (8).

8. A method according to one of the preceding claims, wherein the substrates (8) are arranged in a fixed order on a positioning plate (50) which is provided on the support (6).

9. A printing apparatus (1) for use in a method of printing a pattern of distinct dots (62) of different reagent fluids on a number of substrates (8), wherein the printing apparatus (1) comprises a base (2) provided with suspension means (4) for suspending a moveable printing head (10) which comprises a set of nozzles (12A, 12B, 12C) for the ejection of different reagent fluids wherein each nozzle is in fluid connection with a reservoir of a reagent fluid, said base (2) further comprising a moveable support (6) for supporting a number of substrates (8) to be printed, which support (6) can be positioned vis-a-vis a nozzle of the printing head (10), a controlling unit (15) for coordinating a sequence of steps of: a) a positioning step of positioning a substrate (8) to be printed vis-a-vis a nozzle (12A, 12B, 12C) of the set, by moving the support and/or the printing head, b) a printing step of printing a distinct dot (62) of reagent fluid on the substrate (8) by ejecting reagent fluid from the nozzle (12A, 12B, 12C), wherein the sequence a)-b) is repeated for different reagent fluids as well as for said number of substrates (8).

10. A printing apparatus (1) according to claim 9, wherein the support (6) is moveable in at least a first direction, the printing head (10) being moveable in at least a second direction being different from the first direction.

11. A printing apparatus (1) according to one of the preceding claims 9-10, wherein the controlling unit (15) is designed to coordinate the printing of one row of substrates (8) in one row passage, by repeating the sequence a)-b) so that the different reagent fluids present in the nozzles (12A, 12B, 12C) are ejected in said one row passage.

12. A printing apparatus (1) according to one of the preceding claims 9-11, wherein the set of nozzles (12A, 12B, 12C) comprises three nozzles.

13. A printing apparatus (1) according to one of the preceding claims 9-12, wherein a positioning plate (50) for positioning the substrates (8) in a fixed order of rows is provided on the support, the adjacent substrates (8) within a row being spaced apart by a fixed equal distance (ds).

14. A printing apparatus (1) according to claim 13, wherein the nozzles (12A, 12B, 12C) in the set are positioned in a row having a similar direction as the first direction of movement of the support (6), adjacent nozzles (12A, 12B, 12C) of the set being spaced apart by a fixed equal distance (dn), and the distance of spacing between nozzles (dn) being similar to the distance of spacing between substrates (ds).

15. A printing apparatus (1) according to claim 14, wherein the controller (15) is designed to coordinate the sequence of steps a)-b), which are to be repeated in the following steps of a cycle: i) serially repeating the sequence of steps a)-b) for adjacent nozzles (12A, 12B,

12C) of the set, wherein the adjacent nozzles eject reagent fluid on adjacent substrates (8), ii) followed by moving the substrates (8) so that a nozzle is shifted in a position vis-a-vis a next adjacent substrate (8), wherein the sequence i)-ii) is repeated for said number of substrates (8).