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

Abstract

A a chip and a method for producing the chip with a plurality of measurement regions which are provided with electrodes for electrically detecting reactions in which, in order to reliably separate the individual measurement regions from one another, a monolayer of a fluorosilane is formed on the chip surface which has strongly hydrophobic properties. Therefore, during spotting with a liquid, the drops of liquid applied by spotting can be reliably prevented from coalescing, and thus, causing mixing of the substances in the drops of liquid which are supposed to be immobilized in the measurement regions.

Claims

1. Chip having a plurality of electrically addressable measurement regions, wherein a compartmental structure separates the measurement regions from one another on the chip surface, wherein the compartmental structure has a hydrophobic layer, wherein the hydrophobic layer contains a photoresist or is a photoresist and wherein the chip surface is planar and the compartmental structure is raised relative thereto.

2. Chip according to claim 1, wherein the photoresist is a polyamide-based photoresist.

3. Chip according to claim 1, wherein electrically contactable electrode pairings are structured in each of the measurement regions on the chip.

4. Chip according to claim 1, wherein the compartmental structure surrounds each measurement region completely or annularly with a hydrophobic layer or a hydrophobic intermediate region.

5. Chip according to claim 1, wherein the compartmental structure or hydrophobic layer is of lattice-shaped and/or honeycomb-shaped configuration.

6. Chip according to claim 1, wherein the compartmental structure or hydrophobic layer is smaller in height than in width and the width between two adjacent measurement regions is greater than the height relative to the chip surface carrying the measurement regions by at least a factor 5.

7. Chip according to claim 1, wherein the compartmental structure or hydrophobic layer forms hydrophobic intermediate regions between the measurement regions.

8. Chip according to claim 7, wherein the intermediate regions between the measurement regions have a width between the measurement regions of more than 20%, of a measurement region.

9. Chip according to claim 7, wherein the intermediate regions have a width between the measurement regions of more than 5 μm.

10. Chip according to claim 1, wherein the compartmental structure or the hydrophobic layer has a contact angle with water of at least 90°.

11. Chip according to claim 1, wherein the compartmental structure or hydrophobic layer is at least briefly chemically and physically stable at temperatures up to 150° C.

12. Method for producing a chip having a plurality of electrically addressable measurement regions, comprising: structuring electrically contactable electrode pairings on the chip in each of the electrically addressable measurement regions, and forming the measurement regions by producing a compartmental structure that comprises a hydrophobic layer that separates the measurement regions from each other, wherein the hydrophobic layer is produced by applying a hydrophobic coating in the form of photoresist to the chip, resulting in a compartmental structure that is raised relative to a planar chip surface.

13. A chip having a plurality of electrically addressable measurement regions produced by the process of claim 12.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1 to 4 show selected steps of a first embodiment of the method according to the invention,

(2) FIGS. 5 to 7 show selected manufacturing steps of another embodiment of the method according to the invention,

(3) FIG. 8 shows a detail of the surface of the chip of an embodiment of the chip according to the invention as a three-dimensional view, and

(4) FIG. 9 shows a schematic representation of the chip in the connected and installed state.

DETAILED DESCRIPTION OF THE INVENTION

(5) FIG. 1 shows the detail of a chip 11 made of silicon. However, the chip 11 may also be made of a different material.

(6) Particularly preferably, the chip 11 comprises or contains electronic circuits and/or electrode arrangements 23 not shown in FIG. 1 (cf. FIGS. 8 and 9).

(7) The chip 1 preferably has a hydrophobic coating 12 which may take the form of a monolayer and/or may preferably contain or be formed from a fluorosilane compound.

(8) Preferably, a fluorosilane compound, particularly as described above, has first been vapour deposited on the chip 11 in a desiccator, in the course of which the fluorosilane compound has formed a self-assembled monolayer 12 on the chip surface 13. After this, a photo-structurable coating 14 has been applied to the monolayer 12. Using a perforated mask 15, the regions that are intended to form the measurement regions 16 subsequently are illuminated with light 17 (cf. also FIG. 4).

(9) FIG. 2 shows the photo-structured coating 18 after the photo-structurable coating 14 has been developed. In this way, the hydrophilic regions which subsequently produce the measurement regions 16 are defined. They appear as windows 19 in the photo-structured coating 18.

(10) FIG. 3 shows how the hydrophilic regions have been produced in the oxygen plasma. The monolayer 12 has been removed in the region of the windows 19, apart from the chip surface 13. In this way the hydrophilic measurement regions 16 are formed. Then the photo-structured coating 18 has also to be removed from the monolayer 12. This can be seen in FIG. 4. FIG. 4 also shows how different liquids 20a, 20b are applied to the measurement regions 16 in order to functionalize these measurement regions (spotting method). In this way the finished functionalized chip 11 is produced.

(11) The method according to FIGS. 5 to 7 also works with a photo-structurable coating 14 and a hydrophobic coating or a monolayer 12 (cf. FIG. 6). However, the order of application of these two coatings is precisely reversed, compared with the method described according to FIGS. 1 to 4. According to FIG. 5, first of all, the photo-structurable coating 14 is applied to the surface 13 of the chip 11.

(12) For structuring the photo-structurable coating 14, an illuminating mask 21 is preferably used which consists of a transparent sheet and has a lightproof coating 22 in the region of what will subsequently be the measurement regions 16. The photo-structurable coating 14 is structured by means of the light 17.

(13) As can be seen from FIG. 6, the photo-structured coating 18 remains in the measurement regions 16, while the surrounding areas have been exposed right down to the surface of the chip 13. These regions are then coated with the hydrophobic coating or self-assembling monolayer 12, particularly of fluorosilanes.

(14) As can be seen from FIG. 7, the photo-structured coating 18 is then removed, exposing the measurement regions 16. These are located directly on the chip surface 13. The functionalizing of the measurement regions 16, as described previously, is carried out by a spotting process in which the liquids 20a, 20b are applied.

(15) Alternatively, the measurement regions 16 may also only be exposed later. The measurement regions 16 are then protected by the photo-structurable coating 14 or the photo-structured coating 18, i.e., by a protecting coating, or by a photoresist or the like which forms it, for example, until the chip 11 has been separated from other chips (not shown) of a wafer or the like, and/or until the chip 11 has been electrically connected (bonded) and/or provided with a passivation layer on the outside and/or cast into position or installed in a housing.

(16) To form the photo-structurable coating 14 it is particularly preferable to use a photoresist. Particularly preferably, a polyamide-based photoresist is used, especially on account of its thermal stability.

(17) According to another alternative, the structurable or structured coating 14, 18 or the photoresist is preferably used instead of the monolayer 12 or fluorosilane compound to form the hydrophobic layer 12 or compartmental structure 24. The photo-structurable coating 14, as indicated in FIG. 5, then forms the hydrophobic layer or coating in the desired regions and hence the compartmental structure 24 or intermediate regions 27. The method is thereby simplified, as preferably only the coating 14 or the photoresist has to be removed to form the measurement regions 16, i.e. there is no need to apply a second coating. In this case the photoresist is then preferably of a correspondingly hydrophobic nature or can be rendered hydrophobic by an alternative method.

(18) FIG. 8 shows a detail of the edge of a measurement region 16 on the chip surface 13. The measurement region 16 comprises an electrode pairing or arrangement 23 which preferably consists of a first electrode 23a and a second electrode 23b. These electrodes preferably comprise fingers which preferably mesh with one another. This electrode arrangement 23 reacts with great sensitivity to the fact that functional molecules (not shown in detail) which are immobilized in the measurement region 16, react with molecules that are to be detected.

(19) The measurement region 16 is also surrounded by a compartmental structure 24, only a detail of which is shown. Part of this detail is shown on a larger scale, showing that the compartmental structure 24 is preferably formed from the layer or monolayer 12. This consists particularly of molecules of the fluorosilane compound, these molecules being docked with their functional group 25 on the surface 13 of the chip 11, whereas the molecular residue 26 which produces the highly hydrophobic properties of the monolayer 12 projects upwardly or away from it.

(20) Preferably, the compartmental structure 24 or the hydrophobic coating 12—particularly on its free surface—forms a hydrophobic intermediate region 27 between the (adjacent) measurement regions 16, so that liquids 20a, 20b not shown in FIG. 8 do not flow into adjacent measurement regions 16 or mix or combine fluidically with adjacent liquids during spotting, i.e. during the application of drops of liquid to the measurement regions 16, particularly for immobilizing scavenger molecules or the like (not shown).

(21) The compartmental structure 24 or the hydrophobic coating 12 or the respective intermediate region 27 is therefore preferably hydrophobic, particularly strongly hydrophobic.

(22) Particularly preferably, the contact angle of the compartmental structure 24 or the hydrophobic coating 12 or the intermediate regions 27 with water is at least substantially 90°, preferably more than 120°, most preferably more than 150°, in each case measured under normal conditions with distilled water.

(23) FIG. 9 shows, in a highly diagrammatic plan view, the proposed chip 11 in the connected, installed state, or the chip 11 with or in a housing 28.

(24) Preferably, the chip 11 together with other chips 11 is produced in a conventional process, for example by the CMOS method, on a common carrier or substrate, particularly a so-called wafer. Then the chips 11 are separated from one another, connected electrically and preferably installed, particularly in an associated housing 28 or the like.

(25) In the embodiment shown, the chip 11 is preferably electrically connected to contact surfaces or terminals 29, particularly by electrical connections 30 indicated by dashed lines. This is only schematically shown here. The electrical connection of the chips 11 is usually referred to as bonding.

(26) In the installed state, at least the measurement regions 16 are accessible for receiving samples (not shown) that are to be measured.

(27) FIG. 9 shows the compartmental structure 24 which with its intermediate regions 27 or hydrophobic layers 12 (completely) surrounds the measurement regions 16 and/or separates them from one another. In particular, a lattice-like or honeycomb-shaped structure is formed, each measurement region 16 preferably being annularly defined.

(28) As already mentioned, the measurement regions 16 may be covered or protected by a protective layer, particularly a coating 14, particularly preferably of photoresist. This protective coating is then preferably not removed until after the cutting or division of the chips 11 and/or after the electrical connection and/or installation of the chip 11 in question. However, it is also possible to expose the measurement regions 16 earlier.

(29) If the removal of the protective layer does not take place until after installation, the protective layer is particularly preferably configured to be of sufficient thermal stability. In fact, for installation, the chip 11 is cast into position, in particular. Because of the temperatures occurring, a conventional photoresist may harden. This would at least make it difficult, if not completely impossible, to remove it from the measurement regions 16 at a later stage. Therefore, preferably, a photoresist is used which is sufficiently thermally stable without hardening. A polyamide-based photoresist is particularly suitable for this purpose.

(30) FIG. 9 schematically shows an electrode arrangement 23 in only one measurement region 16, namely in the lower right-hand measurement region 16. In particular, electrode arrangements 23 of this kind which are preferably identical or similar, are formed or arranged in all the measurement regions 16.

(31) The electrode arrangements 23 are preferably formed before the production or application of the compartmental structure 24.

(32) The electrode arrangements 23 are preferably located at least substantially in the chip surface 13 on which the measurement regions 16 are formed and the compartmental structure 24 is created.

(33) The chip surface 13 is preferably configured to be at least substantially flat and/or preferably constitutes a flat side of the chip 11.

(34) In the embodiment shown, the hydrophobic layers 12 or intermediate regions 27 preferably adhere to one another and/or form a cohesive lattice. However, they may also form separate regions or portions on the chip surface 13 which surround or enclose one or more measurement regions 16.

(35) Preferably, different molecules for detection may be detected in the measurement regions 16 by means of the electrode arrangements 23. Corresponding detection signals are emitted electrically, in particular, by the chip 11 or can preferably be interrogated electrically.

(36) Preferably, the compartmental structure 24 is raised relative to the at least substantially flat ship surface 13.

(37) Preferably, the compartmental structure 24 surrounds each measurement region 16 completely or annularly with the hydrophobic layer 12 of the hydrophobic intermediate region 27.

(38) In particular, the compartmental structure 24 or hydrophobic layer 12 or monolayer or the intermediate region 27 is of lattice-like or honeycomb-shaped configuration.

(39) The compartmental structure 24 or hydrophobic layer 12 or intermediate regions 27 is or are preferably embodied as a flat and/or planar coating.

(40) Preferably, the compartmental structure 24 or hydrophobic layer 12 or the intermediate region 27 is smaller in height than width. Particularly preferably, the width between two adjacent measurement regions 16 is greater than the height relative to the chip surface 13 carrying the measurement regions 16 by a factor of at least 5, preferably by a factor of at least 10.

(41) Particularly preferably, the height of the compartmental structure 24 or hydrophobic layer 12 or the hydrophobic intermediate region 27 is less than 2 μm, more particularly less than 1 μm, and/or more than 10 nm, particularly more than 100 nm.

(42) Particularly preferably, the intermediate regions 27 have a width between the measurement regions 16 of more than 10%, particularly more than 20%, particularly preferably about 50% or more, of a measurement region 16.

(43) Particularly preferably, the intermediate regions 27 have a width between the measurement regions 16 of more than 5 μm, particularly more than 10 μm or 20 μm, particularly preferably more than 50 μm.

(44) The measurement regions 16 preferably have a width or an average diameter of more than 50 μm, particularly more than 100 μm, and/or less than 500 μm, preferably less than 300 μm, particularly less than 200 μm, most particularly preferably about 120 to 180 μm.

(45) Preferably, during the so-called spotting, drops of liquid 20a, 20b are applied to the individual measurement regions 16, particularly each having a volume of 1,000 to 2,000 pl, while the hydrophobic layers 12 or intermediate regions 27 ensure that the drops of liquid 20a, 20b remain in place on the respective measurement region 16 and do not mix with adjacent drops of liquid 20a, 20b and/or do not flow into an adjacent measurement region 16.

(46) The above-mentioned spotting may theoretically be carried out as desired, either before or after the division of the chips 11 and/or the electrical connection and installation of the chip 11 in question. Preferably, the spotting takes place after the connection and installation of the chips 11.

(47) The spotting or application of drops of liquid 20a, 20b serves, in particular, only to functionalize the individual measurement regions 16, i.e., particularly to precipitate or bind special molecules for trapping or reacting with molecules that are to be detected in a sample. The drops of liquid are removed again, in particular, after a desired immobilization or binding of the special molecules. Thus, spotting also serves in particular to prepare the chip 11 or the measurement regions 16.

(48) The sample liquid itself, containing molecules that are to be measured or detected, is subsequently applied to the chip 11 or the measurement regions 16—for example over the entire surface and/or using a membrane which covers, as flatly as possible, the measurement regions 16 with the sample liquid located thereon—when the chip 11 is used correctly. The membrane may interact with the compartmental structure 24, in particular may lie on it, in order to distribute the sample liquid over the measurement regions 16 and/or to achieve fluidic separation of the sample liquid in the various measurement regions 16 from one another.

(49) However, alternatively, it is also possible to apply one or more samples that are to be measured to the previously functionalized measurement regions 16 by spotting.

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