DE102013203050A1 - Producing microsieve useful for enrichment or extraction of cells from cell-containing body fluids, preferably blood, urine, biopsy fluid, saliva, comprises e.g. providing carrier, and applying polymer film on carrier - Google Patents

Abstract

Producing a microsieve (161) comprises (i) providing a carrier (211), (ii) applying a polymer film (111) on the carrier, (iii) applying a metal layer (213) on the film, (iv) applying a photo-patternable layer (121) to the film, (v) partially covering the photo-patternable layer with a mask, (vi) exposing the photo-patternable layer and developing the photopatternable layer, (vii) wet-chemical etching the metal layer, (viii) dry etching the film, (ix) removing the metal layer and the photo-patternable layer, and (x) detaching the polymer film patterned to the microfilter from the carrier. Producing a microsieve (161) comprises (i) providing a carrier (211), (ii) applying a polymer film (111) on the carrier, (iii) applying a metal layer (213) on the polymer film, (iv) applying a photo-patternable layer (121) to the polymer film, (v) partially covering the photo-patternable layer with a mask for determining the structure of the microsieve, (vi) exposing the photo-patternable layer by exposure of radiation and developing the photopatternable layer, (vii) wet-chemical etching the metal layer for transmitting the structure of microsieve in the metal layer, (viii) dry etching the polymer film, (ix) removing the metal layer and the photo-patternable layer, and (x) detaching the polymer film patterned to the microfilter from the carrier.

Description

The invention relates to a method for producing a microsieve.

Microsieves, also known as microfilters, are increasingly being used today for demanding separation tasks, for example in medical technology or biotechnology. Thus, the enrichment or extraction of certain cells from human blood by filtration of the blood through a microsieve can be done (microfiltration). Microsieves, in contrast to the conventional microfilters sponge-like polymer or ceramic membranes have a defined pore geometry and are therefore much more efficient and better classifying. To optimize a filtration process, a freely selectable pore geometry and pore density and distribution of the microsieve is desirable. In contrast to sponge-like filter membranes, the retained particles hardly or not at all penetrate into the surface of micro-sieves. Thus, on the one hand they are easier to identify microscopically and on the other hand they can be more easily removed from the filter if further analysis methods require it.

One type of known microsieves are the so-called track-etched membranes. In these, a polymer film is bombarded with heavy ions and the trace left by the heavy ions in the film is subsequently expanded to a pore with an etching process. These membranes have due to their manufacturing process on a spatially irregular pore distribution. Depending on the pore size, the maximum number of pores per unit area is considerably limited. For example, with track-etched membranes with a pore diameter of 8 micrometers, it is only possible to achieve a maximum pore fraction of the membrane's total area of 5%. In addition, a plurality of pores does not pass through the base material of the membrane perpendicularly, but obliquely. Furthermore, double pores occur which give a common pore with a larger than the nominal diameter.

From the WO 2011/139445 A1 For example, a method for the production of micro-sieves is known in which a photostructurable dry-resist film, for example epoxy resin film, is structured to a microsieve by means of a photolithographic process. Subsequently, a detachment step for dissolving the microsieve from the carrier used in the preparation takes place, for example by means of an etching step. A disadvantage of the known method is that it sets the thickness of the microsieve lower limits, since it is very difficult to process epoxy films that are thinner than about 10 microns.

It is an object of the present invention to provide an improved method for producing a microsieve, with which the above-mentioned disadvantage is avoided. In particular, the production of micro-sieves should be made possible, which are thinner than 10 microns.

This object is achieved by a method having the features of claim 1. The subclaims relate to advantageous embodiments of the method.

• – Bereitstellen eines Trägers,
• – Aufbringen einer Polymerfolie auf den Träger,
• – Aufbringen einer Metallschicht auf die Polymerfolie,
• – Aufbringen einer fotostrukturierbaren Schicht auf die Polymerfolie,
• – teilweises Abdecken der fotostrukturierbaren Schicht mit einer Maske zur Festlegung der Struktur des Mikrosiebs,
• – Belichten der fotostrukturierbaren Schicht mittels Einwirkung von Strahlung und Entwickeln der fotostrukturierbaren Schicht,
• – nasschemisches Ätzen der Metallschicht zur Übertragung der Struktur des Mikrosiebs in die Metallschicht, – Trockenätzen der Polymerfolie,
• – Entfernen der Metallschicht und der fotostrukturierbaren Schicht.
• – Ablösen des Mikrosiebs vom Träger.

The method according to the invention for producing a microsieve comprises the following steps:

• Providing a carrier,
• Applying a polymer film to the carrier,
• Applying a metal layer to the polymer film,
• Applying a photoimageable layer to the polymer film,
• Partially covering the photopatternable layer with a mask to define the structure of the microsieve,
• Exposing the photopatternable layer by exposure to radiation and developing the photopatternable layer,
• Wet-chemical etching of the metal layer for transfer of the structure of the microsieve into the metal layer, dry etching of the polymer film,
• - Removing the metal layer and the photoimageable layer.
• - detachment of the microsieve from the carrier.

The method thus produces a microsieve or a plurality of microsieves, which essentially consist of a polymer film. Suitable materials for the polymer film include polycarbonate (PC), polyimide (PI), polyethylene terephthalate (PET), polyarylate or polytetrafluoroethylene. The polymer film is in particular a prefabricated, in particular commercially available, polymer film. As the metal for the metal layer, aluminum is preferably used. The application of the metal layer is preferably carried out by means of electron beam evaporation or sputtering.

The advantage of the use of polymer films for the production of micro-sieves is their ease of manufacture, for example in the film casting process, which leads to a high availability in the suitable for use as a microfilter layer thickness of about 5 microns to 15 microns. The layer thickness of existing polymer films is additionally very homogeneous. It is particularly advantageous that the films are optically transparent, whereby they are suitable for use with a transmitted light microscope. Finally, the polymer films have a high biocompatibility. The lithographic processes used are advantageously widespread and allow a high substrate throughput and thus a cost-effective production.

In particular, the mask is designed such that the microsieve acquires a hole structure, the holes having a, in particular uniform, diameter between approximately 1 micrometer and approximately 50 micrometers. It is a particularly preferred embodiment that the holes have a uniform diameter between 5 microns and about 25 microns, in particular between about 7 microns and about 15 microns. Alternatively, slots can also be used, ie holes with an oval or rectangular cross section, for example, with a width of 5 microns and a length of 20 microns.

• – Bereitstellen eines Trägers, wobei der Träger eine thermisch oder durch Strahlung aktivierbare Ablösungsschicht ist, die bei Einwirkung der Strahlung oder bei Erreichen einer Schwelltemperatur die chemische Bindung an die Polymerfolie löst,
• – Auflaminieren der Polymerfolie auf die Ablösungsschicht.

According to one embodiment, the provision of the polymer film comprises the following steps:

• Providing a carrier, wherein the carrier is a thermally or radiation activatable release layer which dissolves the chemical bond to the polymer film upon exposure to radiation or upon reaching a threshold temperature,
• - laminating the polymer film on the release layer.

In other words, a release layer which can be activated thermally or by radiation is used directly as support, ie substrate. There is no further support such as a silicon substrate more used, but the entire processing takes place exclusively on the release layer. This material is advantageously saved in the production of micro-sieves, which is not used anyway for the microsieves. An example of a release layer is known as a "thermal release" film and when a threshold temperature is reached it dissolves the chemical bond to the polymer film so that it is separated non-destructively. Another variant of a release layer is known as a "UV release" film and dissolves under the action of, for example, UV radiation, the chemical bond to the polymer film, so that it is separated without destroying.

A particular advantage of using the release layer as a carrier is that the manufacture of the microsieves can thus take place in the roll-to-roll process.

• – Bereitstellen eines Trägers,
• – Aufbringen einer Ablösungsschicht auf dem Träger, wobei die Ablösungsschicht der späteren Ablösung des Mikrosiebs vom Träger dient,
• – Auflaminieren der Polymerfolie auf die Ablösungsschicht.

In an alternative embodiment of the invention, the provision of the polymer film comprises the following steps:

• Providing a carrier,
• Applying a release layer on the support, the release layer serving for later detachment of the microsieve from the support,
• - laminating the polymer film on the release layer.

In contrast to the previously mentioned possibility, a carrier separate from the release layer is used here. As a carrier, for example, a silicon or glass substrate can be used. Advantageously, a release layer is applied to the carrier before the polymer film is applied to the carrier. With the aid of this detachment layer, the microsieve or the microsieves is again detached from the carrier in a non-destructive manner.

Expediently, after removal of the photopatternable layer, detachment of the microsieve produced from the polymer film takes place from the carrier.

In one embodiment of the invention, a chemically dissolvable sacrificial layer is used as the release layer. It is expedient to carry out an etching step for detaching the microsieve from the carrier for the at least partial dissolution of the release layer. For example, the sacrificial layer can be removed wet-chemically, thereby eliminating the bond between the microsieve and the support.

Alternatively, the release layer can be a release layer that can be activated thermally or by radiation, which dissolves the chemical bond to the polymer film when exposed to the radiation or when a threshold temperature is reached. Appropriately, the detachment layer is then exposed to radiation or heated to dissolve the microsieve from the carrier.

The microsieve thus obtained can be used in particular for separating solids and / or for retaining solids from a liquid and / or gas stream. A micro-sieve can therefore generally also be understood to mean a microfilter element. The microsieve may in particular be a (separating) membrane.

In particular, the microsieve can be used for the enrichment or extraction of certain cells from cell-containing body fluids, e.g. from blood, urine, biopsy fluids, saliva, etc., including from human blood or from natural or engineered cell suspensions or dilutions thereof.

A preferred, but by no means limiting embodiment of the invention will now be explained in more detail with reference to the drawing. The features are shown schematically. It shows 1 shows steps of a first exemplary manufacturing process for making a microsieve 161 with a defined pore distribution and defined pore geometries using a polymer film with process steps of lithography.

In the first process step, a substrate, in this case a silicon substrate 211 provided. On the silicon substrate 211 becomes a thermally activated release layer 212 applied. The detachment layer 212 later used in the manufacturing process of the separation of microsieve 161 and silicon substrate 211 ,

The following is a polymer film, for example, a polyimide film 111 , on the silicon substrate 211 and thus on the detachment layer 212 applied. In the present example, the polyimide film 111 laminated. Typical thicknesses of microsieves 161 be between 5 microns and 25 microns. The polyimide film used in this example 111 has a thickness of 12 microns.

On the polyimide film 111 turn a metal layer 213 applied. In the present example, the metal layer 213 a 100 nm thick aluminum layer. The metal layer can be applied using the known methods of microsystem technology. Preferably, electron beam evaporation is selected. Alternatively, the layer can be sputtered on. Alternatively, the metal layer can also be made of platinum, gold, copper or titanium. The thickness of the metal layer can be selected between 20 nm and 500 nm, for example 200 nm.

In the next process step, a photoresist layer is formed 121 on the polyimide film 111 applied, for example by spin-coating. The photoresist layer 121 can be applied in known production variants, for example by spin coating or spraying. The photoresist layer 121 is generated from a liquid photoresist. This is a negative varnish in this example. As the thickness of the photoresist layer 121 For example, a thickness of 15 microns is chosen. As is known, before the further processing of the photoresist layer 121 a bake step, for example, at 110 ° C, take place.

In the next process step, an exposure of the photoresist takes place. This is the photoresist layer 121 subjected to suitable radiation. The radiation is shadowed at certain points with a mask. The design of the mask defines the structure of the microsieve to be manufactured 161 fixed, so defines its edges and pores. The crosslinking of the photoresist in this process step leads to the formation of the actual microsieve structure. Furthermore, in this process step, in a manner known per se, a development of the photoresist takes place, for example with TMAH solution. Depending on whether a positive or negative resist is used, the parts of the photoresist layer dissolve 121 that were previously exposed or not exposed. The actual microsieve remains behind 161 or, if necessary, a plurality of microsieves 161 , In the present example remain from the negative resist the exposed portions.

The following process step is a wet-chemical etching which removes the microsieve structure from the photoresist layer 121 in the metal layer 213 transfers. The in the photoresist layer 121 previously opened areas are also in the metal layer 213 exposed.

In the following process step, a dry etching is performed. The remaining part of the photoresist layer 121 acts together with the remaining parts of the metal layer 213 in this process step as a mask and ensures the structure formation in the polyimide film 111 and thus for the formation of the actual microsieve 161 in the polyimide film 111 ,

In the subsequent process step, the remaining part of the photoresist layer 121 along with the remains of the metal layer 213 again from the polyimide film 111 away. For this purpose, a further wet-chemical etching step is carried out. The detachment of the metal layer 213 automatically removes the remnants of the photoresist layer 121 ,

The only thing left is the now structured polyimide film 111 on the silicon substrate 211 , In the last process step, the separation layer becomes 212 thermally activated by heating the body. This dissolves the polyimide film 111 So the microsieve 161 , from the release layer 212 and thus from the silicon substrate 211 , Then a separation of the microsieves obtained 161 respectively.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2011/139445 A1 [0004]

Claims (8)

Method for producing a microsieve ( 161 ) comprising the following steps: - providing a carrier ( 211 ), - applying a polymer film ( 111 ) on the carrier ( 211 ), - applying a metal layer ( 213 ) on the polymer film ( 111 ), - application of a photoimageable layer ( 121 ) on the polymer film ( 111 ), - partially covering the photoimageable layer ( 121 ) with a mask for determining the structure of the microsieve ( 161 ), - exposing the photoimageable layer ( 121 by exposure to radiation and development of the photopatternable layer ( 121 ), - wet-chemical etching of the metal layer ( 213 ) for transferring the structure of the microsieve ( 161 ) in the metal layer ( 213 ), - dry etching of the polymer film ( 111 ), - removing the metal layer ( 213 ) and the photoimageable layer ( 121 ), - detachment of the microsieve ( 161 ) structured polymer film ( 111 ) from the carrier ( 211 ). Method according to claim 1, wherein the removal of the photoimageable layer ( 121 ) by wet-chemical removal of the metal layer ( 213 ) he follows. Process according to Claim 1 or 2, in which the polymer film ( 111 ) consists essentially of a material of the following materials: polycarbonate, polyimide, polyethylene terephthalate, polyarylate, polytetrafluoroethylene. Method according to one of the preceding claims, wherein the polymer film ( 111 ) on the carrier ( 211 ) is laminated. Method according to one of the preceding claims, in which the provision of the carrier comprises the following steps: - providing a substrate ( 211 ), - application of a release layer ( 212 ) on the substrate ( 211 ), the release layer ( 212 ) of the later detachment of the microsieve ( 161 ) from the substrate ( 211 ) serves. A method according to claim 5, wherein as a release layer ( 212 ) a chemically dissolvable sacrificial layer is used and for detaching the microsieve ( 161 ) from the carrier ( 211 ) an etching step for the at least partial dissolution of the release layer (US Pat. 212 ) is carried out. A method according to claim 5, wherein as a release layer ( 212 ) a thermally or radiation activatable release layer ( 212 ), which upon chemical reaction or upon reaching a threshold temperature, the chemical bond to the polymer film ( 111 ) and to detach the microsieve ( 161 ) from the carrier ( 211 ) the release layer ( 212 ) is exposed to radiation or heated. Method according to one of the preceding claims, in which the provision of the support comprises the following steps: - providing a release layer ( 212 ).

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