DE19927533B4 - Miniaturized analysis system - Google Patents

Abstract

The invention relates to the manufacture and construction of microstructured analysis systems. The method according to the invention enables the production of plastic analysis systems which have a liquid- and gas-tight channel structure in which thin-film electrodes can be located at any point.

Description

The invention relates to the manufacture and the construction of miniaturized analysis systems, in particular those with control and measuring device for electrical Conductivity.

Miniaturized analysis systems, especially those with a microfluidic channel structure increasingly important. Miniaturized ones are of particular interest Analysis systems, the possibilities for the electrophonetic separation and analysis of samples.

Analysis units for such Applications can be used usually consist of a base plate (substrate) and a lid, between which there are microchannel structures, electrodes and other required functionalities such as detectors, reactors, valves etc. are located.

To the claims made on a microfluidic Analysis system must be put heard sufficient stability in terms of mechanical, chemical, electrical and thermal effects. For the Channel structures mean mechanical stability especially dimensional and volume stability, what important requirement for e.g. is a quantitatively reproducible sample task. Even inner ones pressure stability of the microchannels is with regard to the use of e.g. Pumps for filling the microchannels necessary. The materials used must of course be chemical inert to that in the channels transported medium. As far as electrodes are inserted in the channel, these should be positioned in the channel with high accuracy (a few μm) be e.g. reproducible results when used as a detector electrode to be able to deliver. It is also a prerequisite that the contact surfaces are free of contaminants within the channel. The electrodes should also a low internal resistance and a potentially high one Allow current flow. This applies in particular to so-called power electrodes with which depending on the medium used within the channels creates an electrokinetic flow can be. Ultimately, the electrodes should be easy to connect.

As a material for making such Analysis units are often used Silicon or glass. However, the disadvantage of these materials is that they are not cheap Mass production of the analysis systems are suitable. There are materials for this on a plastic basis much more suitable. The components like Substrate and lid, which contain the actual microstructures, can then manufactured inexpensively by known methods such as hot stamping, injection molding or reaction molding become.

For the closing the resulting open microstructures with lids has been around for Plastic components are not mass production techniques. this applies especially for those microchannel structures in which additional metallic electrodes anywhere within a closed channel structure to be positioned.

In EP 0 738 306 describes a method for closing microchannel structures, wherein a dissolved thermoplastic is spun onto the structured polymer substrate. This dissolved thermoplastic has a lower melting temperature than the parts to be glued. The cover and substrate are thermally bonded at 140 ° C. The surface of the channel therefore consists of the thermoplastic adhesive.

In US 5,571,410 For example, microfluidic structures with laser ablation are created in Kapton ^TM and welded with a KJ ^® coated Kapton ^TM film.

Becker et al. (H. Becker, W. Dietz, P. Dannberg, "Microfluidic manifolds by polymer hot embossing for μTAS applications, "Proceedings Micro Total Analysis Systems 1998, 253-256, Banff, Canada) report on the Manufacture of microfluidic channels in hot-stamped PMMA, which is achieved through chemically-supported bonding be closed with PMMA lids.

WO 97/38300 describes a method described in which a lid with a homogeneous polydimethylsiloxane (PDMS) adhesive layer is wetted and with a fluid structure Polyacrylic base is glued.

All of the methods mentioned above enable by connecting a substrate to a lid microchannel structures but they do not allow the integration of electrodes, which have direct contact with the medium in the channels.

In EP 0 767 257 describes a method for the integration of electrodes in microstructures, but this method does not allow liquid-insulated contacting, since the metal in the channels must be rinsed with metal salt solutions in order to photochemically deposit them.

A method of integrating Electrodes anywhere in a microstructured Channel with the possibility for liquid insulated Contacting of the electrodes was carried out by Fielden et al. (P.R.-Fielden, S.J. Baldock, N.J. Goddard, L.W. Pickering, J.E. Perst, R.D. Snook, B.J.T. Brown, D.I. Vaireanu, "A miniaturized planar isotachophoresis separation device for transition metals with integrated conductivity detection ", Proceedings Micro Total Analysis Systems '98, 323-326, Banff, Canada). The authors have a microfluidic channel structure in silicone (PDMS) molded and press this mechanically against a circuit board provided with electrodes (copper). The canals are thus limited by two different materials. Around the resulting channels to keep closed must constant mechanical pressure can be maintained. By the In this system, pressure on the silicone cushion easily causes deformation of the channel structures.

Object of the present invention is therefore to provide an improved microfluidic analysis system its substrate and lid made of polymeric organic materials exist and are firmly connected. and in that at any Make electrodes with possibilities for liquid insulated Contacting can be introduced. If electrodes in the Analysis system to be integrated, there is an additional task in that the Electrodes integrated at any point in the duct system can be and not be damaged or detached by the bonding process.

It was found that the combination a new process for the production of adhesive precious metal layers on plastic surfaces with a special bonding technique for joining two Plastic components it allows microfluidic analysis systems with the in the prior art and in to produce properties discussed for the task.

Object of the present invention is therefore a process for the production of microstructured analysis systems, more precisely a unit with a microchannel structure for analysis systems, which essentially includes the following step:

• a) providing at least one substrate and at least one plastic lid, at least one Component is microstructured, i.e. has a channel system;
• b) Wetting either substrate or lid with adhesive by methods such as roller application or pad printing, the channels being free stay from glue;
• c) adjusting the components;
• d) pressing the components together;
• e) curing of the glue.

Preferred embodiment of the method according to the invention is to use at least one component in step a) which on its surface adhering electrodes is provided.

The subject of the invention is furthermore an analysis system or a unit with a microchannel structure for analysis systems, produced by the method according to the invention.

Preferred embodiment of the unit with micro-channel structure for analysis systems is a system that electrodes with an adhesive layer made of chromium oxide and has a layer of precious metal.

1 shows an example of a possible structure of two components of an analysis system.

2 and 3 show two options for contacting the electrodes.

As microfluidic analysis systems with Measuring and Control devices for electrical conductivity apply to systems according to the invention, in which by putting them together of at least two components, e.g. Substrate and lid, micro-channel structures can be generated the liquid and / or gas tight can be closed. The substrate and lid are firmly connected to each other. In addition, these can Systems at any point in the duct system contain electrodes, that are in free contact with the interior of the channel.

The microfluidic analysis systems can by Variation of various parameters, such as the channel structure, the connection of other systems, such as pumps, supply lines etc., any arrangement of electrodes etc. for different applications can be adapted. Particularly preferred are the analysis systems according to the invention for applications in the field of electrophonetic separation and analysis, for example for capillary electrophoresis or isotachophoresis as well as for micropreparative Synthesis or derivatization of substances.

The components of the systems exist preferably from commercially available thermoplastics, such as PMMA (polymethyl methacrylate), PC (Polycarbonate) or PMP (polymethylpentene), cycloolefinic copolymers or thermosetting plastics, such as epoxy resins. All components preferably exist, i.e. Substrates and lids, of a system made of the same material.

The components can be produced by methods known to the person skilled in the art. Components that contain microstructures can be produced, for example, by established processes such as hot stamping, injection molding or reaction molding. Components that can be reproduced using known techniques for mass production are particularly preferably used. Microstructured components can have channel structures with cross-sectional areas between 10 and 250000 μm ² .

The electrodes used in the analysis systems according to the invention are typically used to generate a river of ions or for Detection purposes used. You must have adequate adhesive strength have on the plastic components. This is both for joining the individual components as well as for the later Use of the analysis systems of importance.

For The choice of electrode material is primarily the planned use of the analysis system is crucial. Because systems with micro-channel structures and integrated electrodes mainly in the field of analytics should be used, the electrodes should be made of chemically inert materials, such as. Precious metals (platinum, gold) exist.

The choice of such materials and methods of application are known to the person skilled in the art. Typically, plastic surfaces are metallized by electrochemical deposition of metals from metal salt solutions. For this it is common practice to first chemically or chemically process the plastic surface in a multi-stage process pretreat mechanically, apply a discontinuous primer and finally carry out the electrochemical deposition. Descriptions of these metallization techniques can be found, for example, in US 4,590,115 . EP 0 414 097 . EP 0 417 037 and with Wolf and Gieseke (GD Wolf, N. Gieseke, "New Process for the Full-Surface and Partial Metallization of Plastics," Galvanotechnik 84, 2218-2226, 1993). What the wet-chemical processes have in common is that relatively complex pretreatment processes are necessary in order to achieve adequate To achieve adhesive strengths.

In DE 196 02 659 describes the adherent application of copper to multiphase polymer mixtures by means of vapor deposition or sputtering. The cause of the good adhesion is the composition of the polymer mixtures. Accordingly, the mixtures must contain polyarylene sulfides, polyimides or an aromatic polyester.

The influence of plasma pretreatments to achieve better adhesive properties of metals on plastic surfaces by Friedrich (J. Friedrich, “Plasma Treatment of polymers ", glue & seal 41, 28-33, 1997) using the example of various commercially available Thermoplastics summarized. The general goal of plasma pretreatment is polar functional Groups on the polymer surface to generate so that a increased adhesive strength metallic layers results. The effect is exemplary of chrome as an adhesive layer in the metallization of plastics described. As the cause of the good adhesion of chrome e.g. becomes an interaction polar groups, e.g. Carbonyl or ester groups, with 3d orbitals called the chrome.

The electrode structures are particularly preferred on the plastic components using a new two-layer technique generated. For this purpose, according to the invention, a adhesion-promoting layer made of chromium oxide. It was found that chromium oxide unlike precious metals, it has excellent adhesive properties Plastic surfaces has. In addition, chromium oxide is in contrast to elemental chromium and other transition metals much more stable across from Redox processes. This is then on the chromium oxide adhesive layer Precious metal, such as platinum or its alloys or Gold, applied.

The selective application of chromium oxide and the layer of precious metal to be deposited on plastic substrates is preferably carried out using the lift-off method or using so-called shadow mask technology or structuring from initially the whole area applied metallic layers. These process techniques are standard processes in microstructure technology. The following will be the for the two-shift technique required for the steps mentioned Procedure briefly described.

Lift-off procedure: The selective one Plastic component to be metallized is coated with a photoresist. This photoresist may be the plastic part to be metallized do not or only slightly dissolve. For PMMA e.g. a photoresist from Allresist, Berlin (AR 5300/8) proven suitable. After exposure and development of the metallized The metallic layers are applied in structures a sputtering system. The chrome oxide layer is applied while of the sputtering process by typically introducing oxygen into it used argon plasma from the sputtering system. As a sputtering target used a conventional chrome target. Typical chromium oxide layer thicknesses are 20-50 nm. Alternatively, a chromium oxide target can be used directly become. The sputtering of platinum or its alloys or of Gold turns right afterwards under standard conditions, i.e. in argon plasma. By doing actual lift-off process the still existing photoresist and with it the one on the lacquer Metal layer in a developer from Allresist (AR 300-26) detached from the plastic component.

Shadow mask technique: The selective Plastic part to be metallized is provided with a so-called shadow mask covered. This has cutouts in the areas to be metallized. Through this, the metal layers become analogous to the lift-off process sputtered.

Structuring flat metallic layers: On a plastic part to be selectively metallized, one is first applied over the entire surface Metal layer applied in analogy to the sputtering process already described. This is done in subsequent process steps, either by selective removal using e.g. Laser ablation (gold and platinum) or e.g. structured by selective wet chemical etching. to Structuring by means of wet chemical etching on the metal layer first a photoresist (Hoechst AG, Germany; AZ 5214) applied, exposed and developed. Gold then appears in cyanide solution in the exposed areas replaced.

The adhesive strength of with chrome as well as with chromium oxide as an adhesive layer using sputtering technology Electrodes were checked using tear tests. The adhesive strength of the Chromium oxide layers are significantly larger. Even with ultrasound treatment in alkaline solution are the metal layers, which are made with chromium oxide as an adhesive layer were compared to metal layers using chrome as the adhesive layer were manufactured, much more stable.

After production and preparation of the individual components, they are assembled using the process according to the invention. A component, the substrate, is preferably microstructured and provided with bores on the back for filling the channels and / or contacting the electrodes. Furthermore, there is also the use of a so-called sealing lip, ie one of the channel structures completely enclosing survey on the substrates with heights between typically 0.5 to 5 μm, has proven to be very advantageous with regard to the bonding process. The other component, the cover, is used for covering and is provided with the electrodes, for example in electrophoretic analysis systems. In this case, the cover is referred to as an electrode cover. Since the method according to the invention does not only relate to the manufacture of the measuring and control device of the analysis systems, certain applications of the systems may require a functionalization of the components which differs from this preferred arrangement. In this case, for example, more than two components, for example two lids and a substrate etc., can be joined together in order to produce channel structures lying one above the other, or further functionalities such as detection systems, reaction chambers etc. can be integrated into the components. According to the invention, all parts of the analysis systems that are joined together by means of a bonding method are referred to as components. They can be microstructured, provided with electrodes or have other functionalities. A subdivision of the components into substrates and covers or also electrode covers, if the corresponding component is provided with electrodes, only serves to provide a more detailed description of the embodiment of the special components and does not restrict the further properties of the components, such as microstructuring etc., or their combination with one another represents.

According to the invention, preference is given to assembling the components first on the microstructured component at the places where there is no structuring there is an adhesive applied. The layer thickness is between 0.5 and 10 μm, preferably between 3 and 8 μm. Typically, the application is carried out using one from printing technology known flat Walzenautrag. The adhesive used may be the surface of the Do not, or only slightly, dissolve components so that the electrodes do not during the gluing process detached from the adhesive or to be interrupted. It is therefore preferred that the adhesive Product NOA 72, thiol acrylate from Norland, New Brunswick NJ, USA used. This adhesive is cured photochemically. It can however for The process also uses other types of glue meet the above requirements.

After applying the glue the second component with the thin-film electrodes, for example appropriately positioned on an exposure machine to the substrate and pressed on. Prefers is the use of strong glass plates as a pressing surface, so that directly photochemical curing of the adhesive by irradiation with an Hg lamp (emission wavelength 366 nm) can be.

Positioning the lid on the substrate can for the gluing process is typically visually under manual control, passively mechanically with the help of a locking device, optically mechanically under With the help of optical alignment marks or electrically mechanical with the help of electrical brands (contacts).

In another preferred embodiment the component provided with the electrodes on the areas that when assembling the two components is not above one Channel or must be electrically contacted with wetted the glue. Therefor becomes, for example, a method known in printing technology (Pad printing) used. The component with the channel structures is subsequently suitable to its counterpart positioned and pressed on. The curing takes place as described above.

The method according to the invention enables for the first time the manufacture of closed microchannel structures in which Electrodes positioned anywhere within the channels can be. Structured components (substrates) can be liquid and gas tight for example, electrode covers are provided. By using it mostly commercially available Plastics and simple processing steps can Analysis systems according to the invention economical and in large Numbers are produced. By the method according to the invention to put together or bonding, the components are wetted with adhesive so that after Put together no glue inside the duct system, i.e. into the channels, the walls or electrodes or other devices protruding into the duct system arrives. The manufactured according to the invention Analysis systems with measuring and control device for electric conductivity fulfill all the requirements that must be placed on such a system:

• • She show high dimensional and volume stability of the channels.
• • By the strength of the adhesive connections, they are pressure-resistant inside the channels.
• • It there is a big one variability in terms of the usable plastics.
• • It can chemically inert materials for Components and electrodes are used.
• • All four channel walls preferably consist of the same material.
• • The Electrodes are accurate to within ± 10 μm anywhere in the channels positionable.
• • The contact surfaces the electrodes are free from contamination by adhesive.
• • The Electrodes can can be easily connected.
• • The Systems show low internal resistance and potentially allow high current densities.

1 shows an example of the two functionalized components of a microstructured analysis system. component 1 , the electrode cover four electrodes (E) for generating an ion flow and three electrodes (D) for electrical or electrochemical detection. component 2 is microstructured. When joining the two components, the ends of the electrodes of the cover meet exactly in the channels of the substrate.

2 and 3 show two options for contacting the electrodes.

In 2 the lid protrudes ( 1 ) with the electrode ( 3 ) about the microstructured component ( 2 ) with the adhesive layer ( 4 ) out. After joining the two components, the electrode can be moved over its outer area ( 3b ) can be contacted.

In 3 have lids ( 1 ) and substrate ( 2 ) the same dimensions. After joining, the electrode cannot be contacted from the side. Instead, there is an additional hole in the substrate ( 5 ) over which the electrode ( 3 ) can be contacted for example by means of a spring pin.

Even without further versions it is assumed that a Expert can use the above description in the broadest scope. The preferred embodiments and examples are therefore only as descriptive, not as in any way limiting disclosure.

The complete revelation of all and listed below Applications, patents and publications are incorporated by reference into this application.

Claims (4)

Method for producing a unit with a microchannel structure for analysis systems, characterized in that a) at least two components made of plastic are provided, at least one component being microstructured, ie having a channel system; b) at least one component is wetted with adhesive by methods such as roller application or pad printing in such a way that the interior of the duct system is not coated with adhesive after assembly; c) the components are adjusted; d) the components are pressed together; e) the adhesive is cured. Method of manufacturing a unit with a microchannel structure for analysis systems according to claim 1, characterized in that at least one component for step a) previously on its surface adhering electrodes is provided. Unit with micro-channel structure for analysis systems manufactured according to a method according to claim 1 or 2. Unit with micro-channel structure for analysis systems accordingly Claim 3, characterized in that the electrodes have an adhesive layer made of chromium oxide and a layer of precious metal.