WO2000011461A1

WO2000011461A1 - Device for transporting very small quantities of liquid and method for producing same

Info

Publication number: WO2000011461A1
Application number: PCT/EP1999/006044
Authority: WO
Inventors: Wolfram Dietz; Hartmut Blum; Holger Becker; Lutz MÜLLER; Peter Dannberg; Harald Kiessling; Andreas BRÄUER
Original assignee: Jenoptik Aktiengesellschaft; Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.
Priority date: 1998-08-19
Filing date: 1999-08-18
Publication date: 2000-03-02
Also published as: CN1275202A; JP2002523741A; EP1023593A1

Abstract

The invention relates to a device for transporting very small quantities of liquid and a method for producing same, where said device comprises a support which contains a system of microstructured hollow spaces. The aim of the invention is to meet increased accuracy requirements as regards the shape and cross-section of said microstructures even when these are produced economically and in large numbers. The invention also aims to ensure improved conditions for optical analysis measurement techniques. The support, which apart from the microstructured hollow spaces has a monolithic structure, is produced by introducing a dissolved connecting layer between the plate-like support elements. The material composition of said layer is similar to that of the support elements and its thickness is significantly smaller than the width and depth of the microstructured hollow spaces. Said device is used as analytical instrument, primarily in medicine, biotechnology and pharmacology.

Description

Device for transporting the smallest quantities of liquid and process for their production

The invention relates to a device for transporting the smallest amounts of liquid and a method for their production, in which a carrier contains a system of microstructured cavities.

Such cavities are necessary, for example, for microfluidic applications in biotechnology, where precise knowledge of an enclosed liquid volume in the picoliter range is essential. If the cavities are designed as microchannels, liquids can be transported continuously electrokinetically or by pressure. Closed cavities are used to enclose precisely defined sample volumes and prevent the very small sample quantities from evaporating. Comparable structures are also necessary in the field of microfluidic displays, in which colored liquids have to be brought to precisely defined positions through microchannels.

A large number of technical solutions that have become known underlines that the microstructuring of analytical instruments for predominantly use in medicine, biotechnology and pharmacology has gained considerable importance in recent years.

For the analyzes originally carried out in glass capillaries, plate-shaped microfluidic components with branching channel structures have become increasingly popular. If the channel structures were first introduced into the silicon wafer by etching, as is known from semiconductor technology for the production of integrated circuits, the aim now is to use plastics. The motivation for their use is not only determined by the inexpensive fabrication, but also the advantageous material properties such as optical transparency, biocompatibility and low fluorescence in certain wavelength ranges.

The substances introduced into the channels as liquids and reacting with one another at channel branches are to be analyzed in a continuous channel area using optical means. Since defined cross-sectional dimensions for the channels in the range from previously 10 Om to 100 Om are required for this purpose, high demands are placed on the production of such products. For example, according to US Pat. No. 5,376,252 for a microfluidic component, it is known to place an elastic intermediate layer between two planar, dimensionally stable base layers, which layer contains a microstructured channel system produced by molding. Such a construction has the disadvantage that deformations of the elastic intermediate layer affect the entire component. Dosing and tightness problems are sequelae that negatively affect usability. Another known solution in the form of an integrated device for electrophoretic purposes is described in US Pat. No. 5,770,029. The device, which is essentially composed of two parts, contains microstructures in the form of microchannels in a base plate, for the sealing of which a cover plate is used. The microchannels contain an enrichment channel and an electrophoretic main flow path which are arranged so that waste does not enter the main flow path but can exit the device through a separate outlet opening. As an inexpensive variant for single use, it is proposed to manufacture all components from plastic. Changes in the shape and cross-section of the channels can be expected in the manufacturing technology described there if width and depth dimensions of a size of 10 μm and smaller are required and if in particular the fluctuation range of these dimensions should be less than 5%.

In the field of microfluidic displays, too, high demands are placed on the production technology for the graphic display device, in which, in accordance with the image content, at least two are located in the

Contrast-distinguishing liquids in a meandering micro-channel structure can be conveyed by micropumps. After the pumps have been switched off, a stationary pattern consisting of liquid segments is formed, which shows the display content. The decisive advantage for the user is that

Availability of an alphanumeric display of good visibility with low

Current consumption compared to LCD displays, since the display is shown without current when stationary. If a change in the image content is necessary, the old image content is displaced by the new image content and pushed into a separator, at the outputs of which the separated liquids are again available to the respective micropumps. The principle requires the use of optically transparent plastic materials with microchannels the size of a few 10 μm. In order to achieve a correct representation of the symbols by means of the two liquids, special demands are placed on these microchannels with regard to the accuracy and reproducibility during production. This applies in particular to the reproducibility and constancy of the channel cross sections in order to precisely define the position of a liquid segment, and to an extremely low surface roughness in order to keep the pressure drop in the microchannel as small as possible.

The object of the invention is to meet the increased accuracy requirements with regard to the shape and cross section of the microstructures, even in the case of cost-effective production in large numbers. Improved conditions for optical analysis techniques are also to be guaranteed.

According to the invention, the object is achieved by a device for transporting the smallest amounts of liquid, which contains a system of microstructured cavities in a carrier, in that the carrier has essentially a structure of a monolithic body except for the microstructured cavities.

Since the material of the carrier should not interact with the sample substances, it consists of a thermoplastic material.

The uniform structure of the carrier, corresponding to a monolithic body, is produced in that the carrier is made from plate-shaped carrier parts with a connecting layer, the material composition of which in one

Solvent is similar to that of the plate-shaped carrier parts. Of special

It is important that the thickness of the layer is significantly smaller than the width and depth dimensions of the microstructured cavities. As a result, the microstructured cavities keep their, by hot stamping z. More colorful

Vacuum conditions generated with high precision parameters. Edge rounding,

Material compression, bending and similar changes are excluded and so the flow behavior of the filled in the cavities

Liquids positively influenced. Characterized in that the layer is introduced in the dissolved state between the plate-shaped carrier parts, this connects reactively after the volatilization of the solvent with the surfaces of the two plate-shaped parts. Even by electron microscopy, no edge structure can be seen on the connecting surfaces, so that a carrier produced in this way has the structure of a monolithic body except for the microstructured cavities. This has a particularly positive effect on the accuracy of measurements on enclosed samples because the carrier contains no foreign materials and no jumps in the material properties. Influences due to a spatial variation of physical parameters such as refractive index, absorption coefficient and thermal conductivity coefficient are excluded.

The invention also relates to a method for producing a device for transporting the smallest amounts of liquid, which contains a system of microstructured cavities in a carrier. To form a structure of the carrier corresponding to a monolithic body, a connecting layer is introduced in a dissolved state between plate-shaped parts, the material composition of which is similar to that of the plate-shaped carrier parts and the layer thickness of which is significantly less than the width and depth dimensions of the microstructured cavities.

The invention will be explained below with reference to the schematic drawing.

The figure shows in the direction of the arrow the sequence in the manufacture of a device for sample analysis in three steps, the method of illustration being intended to emphasize the principle and therefore in no way corresponds to the actual proportions.

According to the figure, the manufacture of the device according to the invention begins with the fact that in a first step a first polymeric, plate-shaped carrier part 1 with an impression tool 2 by hot stamping z. B. microstructures 3 can be introduced under vacuum conditions. The carrier part 1 consists of polymethyl methacrylate (PMMA). However, other materials, in particular thermoplastics such as. As polycarbonate (PC) or polyethylene (PE) can be used. First, using micro-technical methods, a structural negative of the desired micro structure 3 is made of a very hard material, typically metal or silicon manufactured. For example, a step from a method which is known under the name UGA technology (LIGA process, Microelectron. Eng. 4 (1986) 35-56) is suitable for the production of metallic tools. A resist layer is exposed to synchrotron radiation using a mask in an X-ray lithographic process. For this purpose, a device can be used, for example, which is described in German patents DE 44 18 779 C1 and DE 44 24 274 C1. The shape resulting after the development of the resist is galvanically filled with the intended material, so that after the resist is removed, the structural negative of the microstructure 3 is present as an impression tool 2. For example, the known methods of wet chemical etching of silicon or surface processing with reactive ion etching are suitable for producing structure negatives from silicon.

Using an impression device for microsystem structures, e.g. B. according to DE 196 48 844 C1, the molding tool 2 is heated together with the polymeric carrier part 1 to a temperature above the glass transition temperature of the polymer material. The structures contained in the molding tool 2 are preferably transferred to the carrier part 1 under vacuum conditions in that the two parts are pressed against one another under high pressure. By cooling the carrier part 1 and the molding tool 2 while they are still in close contact to a temperature below the glass transition temperature of the polymer material, the structures in the carrier part 1 solidify. As a result, the microstructures 3 are retained after removal of the molding tool. Of course, replication techniques such as. B. casting, UV reaction molding, injection molding or other embossing processes applicable.

A second carrier part 4, which consists of the same polymeric material as the carrier part 1, serves to cover the microstructures 3. Microstructured cavities 5 are formed. At least some of the cavities 5 are connected to the environment via channels 6, so that filling and emptying is ensured. The channels 6 can be incorporated according to the figure in the carrier part 4 or in another way, for. B. be guided laterally to the environment. Between the two carrier parts 1 and 4, a layer 7 is introduced to connect them in accordance with step 2, which is in a solvent such as. B. methylacetoacrylate, contains only the material of the two support parts 1 and 4. Under certain circumstances it is also possible to use a polymer whose molecular structure is only very strong compared to that of the two carrier parts 1 and 4 resembles. The thickness of the layer 7 is of particular importance, since this has a decisive influence on the functionality of the microstructured cavities 5. It is therefore important to prevent layer material from entering the microstructures 3 or from their edge regions in particular being attacked by the solvent. With channel cross sections from 10 x 10 mm to 40 x 40 mm, a layer thickness of less than 0.6 mm is required. In addition, a negative effect of capillary effects when joining the two carrier parts 1 and 4 is to be avoided. Finally, it is important that the layer 7 have a uniform distribution over the entire connecting surface. If the layer material were to accumulate in the area of the channels 6, this would otherwise penetrate into the microstructures 3. For this reason, the channels 6 contained in the carrier part 4, which is preferably to be coated, are temporarily closed by suitably worked pins, as a result of which a sufficiently closed surface is created. The layer 7 is applied after a cleaning process, in which the carrier part 1 is also included. Particles adhering to the surfaces, which destroy the homogeneity of the layer 7 and thus would prevent a complete connection of the workpieces involved, can thereby be removed to a sufficient extent.

The surface of the carrier part 4 is first provided centrally with a small amount of the dissolved polymer material in the order of a few microliters, for example by pipetting. The required layer thickness is then set by rapid rotation of the carrier part 4 fastened on a turntable, for which the viscosity of the dissolved polymer material and the speed of rotation are mainly decisive. For example, if the microstructured cavities 5 in a PMMA carrier are to have width and height dimensions in the range of 10 Om, the number of revolutions is several thousand revolutions per minute (4000-6000 rpm) with a solvent ratio of 1: 7 - 1: 1 1 PMMA required for the solvent methylacetoacrylate. The thickness of the layer 7 achieved under these conditions reaches the above-mentioned range and thus significantly falls below the width and height dimensions of the microstructured cavities 5. Immediately after the layer 7 is applied, the two carrier parts 1 and 4 are connected to one another by mechanical contact, so that the microstructures 3 are delimited in a sealed manner by the carrier part 4. Tilting errors should be excluded, lateral misalignment prevented and even pressure conditions guaranteed. This can be done, for example, in a suitable device in which the two carrier parts 1 and 4 are placed on one another with an exact fit and without lateral play can be subjected to a uniform force by means of a stamp. Alternatively, the connection can also be made by a rolling step. For the permanent and homogeneous connection, quick assembly within 20 - 60 s is particularly important to prevent the solvent from evaporating prematurely. Otherwise a defined and long-term stable connection of both workpieces would be more or less impaired. Then the solvent evaporates at room temperature. Of course, the processing time can be shortened by increasing the temperature or by using a drying oven with or without vacuum support.

The final structure of a monolithic body 8 is formed in a third step in that the compounds broken up by the solvent in the surfaces are formed again when the solvent evaporates, the molecules in the region of a boundary layer on each surface with the molecules of the layer 7 commitments.

After the solvent has evaporated, a uniform carrier is formed, which consists of only one material and has no discontinuities in the material properties at the initially existing boundary layer of the surfaces involved. The introduction of the connecting layer is not limited to the method described here, although particularly good results can be achieved with it. In particular, rolling is also a very suitable method.

Claims

claims

1. Device for transporting the smallest amounts of liquid, which contains a system of microstructured cavities in a carrier, characterized in that the carrier has a structure of a monolithic body except for the microstructured cavities (5).

2. Device according to claim 1, characterized in that the carrier consists of a thermoplastic material.

3. Device according to claim 2, characterized in that the carrier is made of plate-shaped carrier parts (1, 4) with a connecting layer (7) whose material composition in a solvent is the same as that of the plate-shaped carrier parts (1, 4) and their layer thickness the width and depth dimensions of the microstructured cavities (5) fall significantly below.

4. Device according to claim 3, characterized in that the microstructured cavities (5) are formed by hot stamping under vacuum conditions at least in a plate-shaped carrier part (1).

5. Device according to claim 4, characterized in that the microstructured cavities (5) are designed as channels, of which parts are led out of the carrier.

6 A process for producing a device for transporting the smallest amounts of liquid, which contains a system of microstructured cavities in a carrier, characterized in that a connecting layer (1, 4) is formed between plate-shaped carrier parts (1, 4) to form a structure of the carrier corresponding to a monolithic body. 7) is introduced in a dissolved state, the material composition of which is the same as that of the plate-shaped carrier parts (1, 4) and the layer thickness of which is significantly less than the width and depth dimensions of the microstructured cavities (5).