Method for producing a plurality of measurement regions on a chip, and chip having a plurality of measurement regions

Abstract

A method for producing a plurality of measurement regions on a chip, and a chip having a plurality of measurement regions which is obtainable by the method.

Claims

1. Method for producing a plurality of measurement regions, in the form of cavities, on a chip, wherein: (a) in a first method step, a coating composition based on at least one organic polymer is applied to a chip surface of the chip, wherein the coating composition is a photoresist and wherein the coating composition is applied to the chip surface with a layer thickness in the range of from 2 to 15 m, (b) in a subsequent method step, the photoresist coating composition is cured at least in part only in some regions by the application of radiation, and (c) in another subsequent method step, the photoresist coating composition is removed only in regions in which the photoresist coating composition has not been cured, so that individual measurement regions are fixed on the finished chip within remaining portions of the photoresist and at least one three-dimensional hydrophobic structure is formed on the chip surface bounding the measurement regions, wherein the measurement regions have a volume of from 0.2 to 500 pl.

2. Method according to claim 1, wherein the coating composition is applied to the chip surface over the complete surface thereof and wherein the removal of the coating composition in at least some regions is performed without the use of a mask.

3. Method according to claim 1, wherein the coating composition is applied to the chip surface with a layer thickness in the range of from 4 to 7 m.

4. Method according to claim 1, wherein the coating composition is applied to the chip surface at least substantially over the complete surface.

5. Method according to claim 1, wherein the coating composition is applied to the chip surface by means of one of pouring, knife-coating, rolling, and spin-coating.

6. Method according to claim 1, wherein the coating composition is liquid with a Brookfield viscosity at 20 C. in the range of from 20 to 5,000 mPas.

7. Method according to claim 1, wherein the coating composition is liquid with a Brookfield viscosity at 20 C. in the range of from 150 to 400 mPas.

8. Method according to claim 1, wherein the coating composition is a solution or dispersion of the at least one organic polymer that comprises at least one solvent or dispersing agent selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, alcohols, aldehydes, ketones and nitriles and mixtures thereof.

9. Method according to claim 1, wherein the coating composition is a solution or dispersion of the at least one organic polymer that comprises aromatic hydrocarbons.

10. Method according to claim 8, wherein the coating composition comprises the solvent or dispersing agent in amounts of from 30 to 60 wt. %, based on the coating composition.

11. Method according to claim 1, wherein the at least one organic polymer is obtainable by polymerization or oligomerization from acrylic acid, methacrylic acid, esters of acrylic acid with C.sub.1- to C.sub.6-alcohols, esters of methacrylic acid with C.sub.1- to C.sub.6-alcohols, styrene, cyclobutarenes and mixtures thereof.

12. Method according to claim 11, wherein the at least one organic polymer is obtainable from monomers of the groups of ##STR00002##

13. Method according to claim 1, wherein the at least one organic polymer has a weight-average molecular weight M.sub.w in the range of from 800 to 15,000 g/mol.

14. Method according to claim 1, wherein the at least one organic polymer has a number-average molecular weight M.sub.n in the range of from 1,000 to 100,000 g/mol.

15. Method according to claim 1, wherein the coating composition comprises the at least one organic polymer in amounts of from 25 to 55 wt. %, based on the coating composition.

16. Method according to claim 1, wherein the coating composition comprises at least one photoinitiator in an amount of from 0.01 to 10 wt. %, based on the coating composition.

17. Chip having a multiplicity of electrically addressable measurement regions formed on a surface of the chip, wherein the measurement regions are bounded by a hydrophobic structure formed of a photoresist provided fixed on the finished surface of the chip, and wherein the hydrophobic structure is formed three-dimensionally with a layer thickness of from 1 to 10 m, and wherein the electrically addressable measurement regions have a volume of from 0.2 to 500 pl.

18. Chip according to claim 17, wherein the chip surface is formed at least substantially flat and the hydrophobic structure is raised relative to the chip surface.

19. Chip according to claim 17, wherein the hydrophobic structure separates the measurement regions from one another.

20. Chip according to claim 17, wherein the hydrophobic structure is formed in a grid-shaped and/or honeycombed pattern.

21. Chip according to claim 17, wherein the hydrophobic structure forms hydrophobic regions between the measurement regions.

22. Chip according to claim 17, wherein regions between the measurement regions have a width of more than 10%, of the diameter of a measurement region.

23. Chip according to claim 17, wherein regions between the measurement regions have a width between the measurement regions of more than 5 m.

24. Chip according to claim 15, wherein the ratio of the height of the hydrophobic structure to the width of the hydrophobic structure in the regions between the measurement regions is at least 1:5.

25. Chip according to claim 15, wherein the ratio of the height of the hydrophobic structure to the width of the hydrophobic structure in regions between the measurement regions is in the range of from 1:5 to 1 to 1:20.

26. Chip according to claim 17, wherein the hydrophobic structure has a contact angle to water of at least 60 or more.

27. Chip according to claim 17, wherein the hydrophobic layer has a contact angle to water in the range of from 60 to 180.

28. Chip according to claim 17, wherein the measurement regions have a diameter of from 50 to 500 m.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a side view of the chip according to the invention obtainable by the method according to the invention;

(2) FIG. 2 is a simplified plan view of the chip according to the invention in the installed state;

(3) FIG. 3 is an enlarged perspective view of the edge region of a measurement region;

(4) FIG. 4 shows a part step of the method according to the invention in which the chip surface is provided with a coating composition;

(5) FIG. 5 shows an embodiment of the method according to the invention in which a mask is applied to the cured coating composition;

(6) FIG. 6 shows a part step of the method according to the invention according to a particular embodiment in which the coating composition between the mask has been removed;

(7) FIG. 7 shows an alternative and preferred embodiment of the method according to the invention, in which regions of the coating composition are exposed to light through a photomask; and

(8) FIG. 8 is a sectional view through a chip according to the invention, wherein the coating composition is cured in some regions.

DETAILED DESCRIPTION OF THE INVENTION

(9) The present inventionaccording to a second aspect of the present inventionfurther provides a chip having a multiplicity of electrically addressable measurement regions, wherein a hydrophobic structure, in particular a hydrophobic layer, defining the measurement regions is provided on the chip surface, wherein the hydrophobic structure (4) is formed three-dimensionally.

(10) In the context of the present invention, it is preferable for the chip surface to be formed at least substantially flat and for the hydrophobic structure to be raised relative to this. The hydrophobic structure or the hydrophobic layer is thus preferably a raised structure or layer.

(11) Chips of particular performance are obtained in the context of the present invention if the hydrophobic structure has a layer thickness of from 0.5 to 20 m, in particular 1 to 10 m, preferably 2 to 8 m, more preferably 3 to 7 m, particularly preferably 4 to 6 m. In the context of the present invention, it is preferable in particular for the hydrophobic structure to have a layer thickness of 5 m. With layer thicknesses in the above-mentioned rangesas already stated aboveon the one hand an unambiguous and defect-free functionalizing of the individual measurement regions by the spotting process can be ensured, and on the other hand sufficiently large volumes of reagents can be filled into the measurement regions and also be removed again without residue, so that the chip can be wetted several times in succession with various sample or reagent solutions without problems.

(12) In the context of the present invention, the hydrophobic structure conventionally not only defines the measurement regions, but rather also separates them from one another. In particular, it is preferable for the measurement regions to be surrounded completely by the hydrophobic structure, for example in a ring-like manner. It is equally preferable for the regions between the individual measurement regions to be covered with the hydrophobic structure, since in this manner undesirable accumulations of reagents, which are conventionally water-based, are avoided.

(13) In general, in the context of the present invention the hydrophobic structure is formed in a grid-like and/or honeycombed manner. The hydrophobic layer thus preferably forms a sub-division on the chip, so that the measurement regions, in particular measurement vessels, are in each case formed over the electrode pairs. The individual measurement regions here preferably have a circular base area.

(14) According to a preferred embodiment of the present invention, the hydrophobic layer forms hydrophobic regions between the measurement regions. In this connection it is preferable in particular for the hydrophobic regions between the measurement regions to have a width of more than 10%, in particular more than 20%, of the diameter of a measurement region. In this manner it is ensured that, during the spotting process in particular, mixing of the functionalizing reagents is avoided.

(15) In the context of the present invention, it has equally proved advantageous for the hydrophobic regions between the measurement regions to have a width of more than 5 m, in particular more than 10 m, in particular more than 20 m, particularly preferably more than 50 m.

(16) In order to avoid mixing of the functionalizing reagents during the spotting, it has proved appropriate if the ratio of the height of the hydrophobic structure to the width of the hydrophobic structure in the regions between the measurement regions is at least 1:5, in particular 1:8, preferably 1:10.

(17) Likewise, the ratio of the height of the hydrophobic structure to the width of the hydrophobic structure in the regions between the measurement regions can be in the range of from 1:5 to 1:100, in particular 1:8 to 1:50, preferably 1:10 to 1:20.

(18) The hydrophobic layer conventionally has a contact angle to water in the range of from 60 to 180, in particular 70 to 150, preferably 80 to 100.

(19) The hydrophobic layeras already stated aboveis conventionally formed on the basis of an organic polymer.

(20) According to a preferred embodiment, the hydrophobic layer is formed on the basis of a photoresist. In particular, the coating composition employed for producing the coating is preferably a photoresist or contains a photoresist.

(21) In the context of the present invention, the measurement regions can moreover have a diameter of from 50 to 500 m, in particular 70 to 400 m, preferably 90 to 300 m, more preferably 100 to 250 m, particularly preferably 120 to 180 m. These diameters of the preferably circular measurement regions in combination with the layer thickness of the hydrophobic layer on the one hand make available a sufficiently large volume for carrying out and detecting the chemical reactions, but on the other hand render possible a quick and complete replacement of various reaction solutions.

(22) As regards the volume of the measurement regions, in particular the measurement vessels, this can vary within wide ranges depending on the chemical and biological detection reactions carried out in each case. However, it has proved appropriate if the measurement regions have a volume of from 0.2 to 500 pl, in particular 0.5 to 300 pl, preferably 1 to 150 pl, more preferably 5 to 100 pl, particularly preferably 10 to 50 pl.

(23) In the context of the present invention, it is moreover preferable for the hydrophobic layer to be chemically and/or physically stable at least in the short term at temperatures of up to 250 C., in particular up to 300 C., preferably up to 350 C. The hydrophobic layer should thus be stable at least when temperature peaks occur, such as may occur, for example, during sawing of a wafer into individual chips.

(24) In the context of the present invention, the chip is in general obtainable or produced by the method according to the invention.

(25) For further details on this aspect of the invention, reference may be made to the previous statements on the method according to the invention, which apply accordingly with respect to the chip according to the invention.

(26) The subject matter of the present invention is explained in the following with the aid of preferred embodiments in the drawings, but without limiting this to the embodiments shown. Further modifications and characteristics of the method according to the invention and of the chip according to the invention are clear to the person skilled in the art on reading the description and the following description of the drawings.

(27) FIG. 1 is a sectional view of a chip 1 according to the invention which is constructed from a substrate 2, in particular elemental silicon, on which a surface layer 3 is arranged. The surface layer 3 is preferably made of silicon dioxide or silicon nitride, the use of silicon nitride being preferred since silicon nitride prevents the diffusion of metal atoms, in particular of gold atoms, which is preferably used for the electrodes of the measurement regions, into the substrate 2.

(28) On the surface layer 3 there is arranged a hydrophobic structure in the form of a hydrophobic layer 4, which defines and demarcates the measurement regions 5 by recesses. The ratio of the height of the hydrophobic layer 4 and the diameter of the preferably circular measurement regions 5 is chosen such that on the one hand a simple and defect-free spotting, i.e. a functionalizing of the measurement regions with chemical molecules, is possible, but on the other hand a faster and more complete replacement of reagents in the measurement regions is possible.

(29) FIG. 2 is a plan view of a simplified schematic drawing of the chip 1 according to the invention in the installed state. The hydrophobic layer 4 defines the individual measurement regions 5 and creates hydrophobic regions 6 between the measurement regions.

(30) In the measurement regions there are arranged electrode pairs 7, which comprise finger electrodes 7A and 7B closely intermeshed with one another. The hydrophobic layer 4 forms a chequered or grid-like pattern, in particular a compartment structure, on the chip surface.

(31) The chip is connected to or installed in a housing 8. Preferably, the chip 1 is produced together with other chips 1 in a conventional process, for example by the CMOS technique, on a common carrier or substrate, in particular a wafer. The chips 1 are then separated from one another, connected electrically and preferably installed, in particular in an assigned housing 8 or the like.

(32) According to the drawing, the chip 1 is preferably connected electrically to contact surfaces or terminals 9, in particular via the electrical connections 10 indicated by broken lines, as shown in a highly schematic drawing. The electrical connection of the chip 1 is conventionally called bonding.

(33) In the installed state at least the measurement regions 5 are accessible for accommodation of samples to be measured, which are not shown in the drawing.

(34) In FIG. 2 an electrode arrangement 7 is shown schematically only in one measurement region 5. In particular, such preferably identical or similar electrode arrangements 7 are formed or arranged in all the measurement regions 5. The formation of the electrode arrangement 7 is preferably carried out before production or application of the hydrophobic layer 4. The electrode arrangements 7 preferably lie substantially in the chip surface 3, on which the measurement regions 5 are formed and the hydrophobic layer 4 is constructed.

(35) In the embodiment shown, the hydrophobic layer 4 is continuous in formation, in particular the hydrophobic intermediate regions 6 between the individual measurement regions 5. However, it is also possible, although less preferable, that the hydrophobic layer 4 between the individual measurement regions 5 is not continuous, or is interrupted. Thus, for example, the individual measurement regions 5 can be merely surrounded by the hydrophobic structure 4 in a ring-like manner.

(36) The individual measurement regions 5 preferably have a width or an average diameter of more than 50 m, in particular more than 100 m. The measurement regions 5 moreover can have a width or an average diameter of less than 500 m, in particular less than 300 m, preferably less than 200 m. It is particularly preferable in this connection for the measurement regions to have a diameter of from 120 to 180 m.

(37) The electrode pairs 7A and 7B are preferably made of gold and are vapour-deposited on the chip surface 3 with the aid of mask technologies.

(38) The measurement regions 5 are functionalized with the aid of a spotting process such that a drop of liquid (not shown in the drawing) having a volume of from 1 to 500 pl is introduced into the measurement regions 5. The drop of liquid comprises a functionalizing reagent which reacts either with the chip surface 3 in the measurement regions or with the electrodes 7A and 7B in the measurement regions 5 such that a chemical bond forms between the chip surface 3 or the electrodes 7 and the functionalizing reagent.

(39) Due to the hydrophobic layer 4 and in particular intermediate regions 6, it is possible that the drops of liquid remain localised in the particular measurement regions 5 and do not mix with adjacent drops of liquid or flow into adjacent measurement regions 5. The spotting can in principle be carried out optionally before or after separation of the chip 1 and/or electrical connection and installation of the particular chip. The spotting is preferably carried out after connection and installation of the chip 1.

(40) The measurement method with the functionalized measurement regions 5 is carried out in a manner in which a sample liquid (not shown in the drawing) or, in chronological sequence, several sample liquids with molecules to be detected or detecting molecules is or are introduced into the measurement regions 5. This can be carried out, for example, by wetting the entire chip surface and treatment with cleaning liquids. In particular, the chip, in particular the compartment structure, can be covered with a membrane for the actual measurement. The membrane here can interact with the compartment structure, in particular lie on this, in order to distribute the sample liquid over the measurement regions 5 and/or to achieve a fluid separation of the sample liquid in the various measurement regions 5 from one another.

(41) Alternatively, however, it is also possible to apply one or more samples to be measured to the already functionalized measurement regions 5 by spotting, but this is significantly more involved.

(42) FIG. 3 in turn is an enlarged view of the edge region of a measurement region 5. In particular, in the drawing the chip surface 3 is preferably covered over the largest possible surface by the electrode pairs 7A and 7B and a measurement vessel is formed over the base area of the measurement regions 5 by the hydrophobic layer 4.

(43) As can be seen from FIG. 4, in the context of the present invention to produce the chip 1 according to the invention a procedure is followed in which a coating composition 11 is applied to the chip surface 3, in particular is applied as homogeneously as possible and with a uniform layer thickness.

(44) FIG. 5 shows an embodiment of the present invention in which the coating composition 11 has been thermally cured, so that the hydrophobic layer 4 forms, but still has no recess for the measurement regions. In order to expose the measurement regions 5, a mask 12 is applied to the hydrophobic layer 4, which covers the regions of the hydrophobic layer 4 which are not to be removed. The regions of the hydrophobic layer 4 which are not covered by the mask 12 are then removed preferably by dry etching, in particular by mixtures of oxygen and carbon tetrafluoride or oxygen and sulphur hexafluoride in a plasma. The mask here can be either a soft mask, which is attacked by the etching reagent, or a hard mask, which is inert with respect to the etching reagent.

(45) FIG. 6 schematically shows the chip 1 according to the invention on which the measurement regions 5 have been exposed by the etching process. After the etching process has been carried out, the mask 12 is removed again and the chip 1 according to the invention can be used after optionally further cleaning steps, in particular the measurement regions 5 can be functionalized with the aid of a spotting process.

(46) FIG. 7 shows an embodiment which is preferred according to the invention, in which the hydrophobic layer 4 is produced by a photolithographic process. Here also, as with the exclusively thermal curing, a coating composition 11 is first applied to the chip surface 3. The coating composition 11 is then irradiated by UV radiation through a photomask 13. By this means, the regions of the coating composition 11 which are exposed to the UV radiation are preferably cured.

(47) FIG. 8 shows the situation after photochemical curing with a negative photoresist. The hydrophobic coating on the chip surface 3 comprises hydrophobic regions 4 which are cured at least in part and non-cured regions 11. The non-cured regions are preferably removed by chemical means, in particular by treatment with a solvent, in particular butyric acid n-butyl ester, as a result of which the measurement regions 5 are defined and exposed.

(48) After removal of the non-cured coating composition 11, the already photochemically cured layer 4 can be further treated thermally.

(49) A cleaning of the chip surface by etching processes is then also conventionally carried out, in particular by the dry etching processes described above, although in this case the action time of the plasma is preferably kept so short that the hydrophobic layer 4 is not damaged. The action time of the plasma is conventionally 10 to 60 seconds, in particular 20 to 50 seconds, preferably 25 to 40 seconds, more preferably 30 seconds.

(50) It is furthermore possible in the context of the present invention that an adhesion promoter layer (not shown in the drawing) is applied to the chip surface 3 before application of the coating composition 11. In this manner, the adhesion of the hydrophobic layer 4 to the chip surface 3 can be further improved significantly.

(51) Individual aspects and features of the various embodiments, variants and alternatives can also be implemented independently of one another, and also in any desired combination.