WO2015091189A1

WO2015091189A1 - Selective patterning of filtration membranes

Info

Publication number: WO2015091189A1
Application number: PCT/EP2014/077330
Authority: WO
Inventors: Godefridus Johannes Verhoeckx; Ron Martinus Laurentius Van Lieshout; Toon Hendrik Evers; Olli-Heikki Huttunen; Ralph Liedert; Inka PAKKILA; Sari TAIPALE
Original assignee: Koninklijke Philips NV
Current assignee: Koninklijke Philips NV
Priority date: 2013-12-16
Filing date: 2014-12-11
Publication date: 2015-06-25
Anticipated expiration: 2016-06-16

Abstract

The invention relates to a filter, a filter unit/module or a complete microfluidic device (e.g. a disposable cartridge for diagnostic purposes) with integrated filtration membrane for filtering a component or fluid from a sample and a method of manufacturing the filter, the filter unit/module or the complete microfluidic device with integrated filtration membrane, wherein the filter or filter unit/module or microfluidic device comprises a base portion comprising a microfluidic element to collect some filtered sample, and a web portion (10) made of a filter material an arranged on top of the base portion, wherein the web portion (10) comprises predetermined zones (40) of collapsed pores of the filter material, which define a filtering active area covering at least a part of said microfluidic element, the collapsed pores being adapted, to inhibit the filtering function of the filter material.

Description

Selective patterning of filtration membranes

FIELD OF THE INVENTION

The invention relates to the field of filters, filter units/modules or complete microfluidic devices (e.g. disposable cartridges for diagnostic applications) with integrated filtration membranes, which enable roll-to-roll or sheet-based manufacturing. BACKGROUND OF THE INVENTION

It is known to use filter in microfluidic cartridges or filter units to filter some components or fluids from a sample, e.g., blood. In this connection, a filter is usually a matrix containing pores through which only a part of the sample can go through and is therefore filtered.

Such filters can be used for detection of marker molecules in bodily fluids. An example of a marker molecule is troponin-I (cTnl) used for the detection of cardio-vascular disease. The filter is used to separate the cell fraction (e.g. erythrocytes, leucocytes) from the liquid fraction (plasma), and thereby generate plasma. To optimize the operation of the filter and/or reducing the sample size needed for filtering, it is known to selectively close some pores of the filter by using use some filling materials. This is described for example in the WO 2013/111059 Al .

Fig. 1 shows a schematic cross section of a blood filter which is built up of a first layer 10 with pores that are large enough to capture and to filter out cells and a second layer 20 with small pores that can not be penetrated by cells to facilitate transportation of the plasma. Due to the large amount of cells the filter needs to have a large volume to prevent clogging of the filter. This leads to a large dead volume inside the filter, also on the small- pore side and increases the contact time of the plasma with the filter. Due to the small pores in the plasma transport region, the internal surface area of the filter is relatively large. This can potentially lead to a retention of the proteins and/or sheering forces, which may result in lower or variable protein concentration in the generated plasma sample or a protein that is, due to the conformation change, not detectable by the system.. It would be advantageous to reduce the internal surface area and volume of the small pore size side, while maintaining a large volume on the large pore size side for maximum storage capability of cells and prevention of clogging.

In the field of electronic devices, roll-to-roll processing, also known as web processing, reel-to-reel processing or R2R, is the process of creating electronic devices by a process of applying coatings, printing, or performing other processes starting with a roll of a flexible material and re-reeling after the process to create an output roll. Once the rolls of material have been coated, laminated, printed or otherwise treated they are normally slit to their finished size on a slitter rewinder. Some R2R processes of manufacturing filters are known, e.g. from US 6,803,019. However, these processes require many steps of manufacturing. Thus, as regards manufacturing micro fluidic filter units for filtering a sample (e.g. blood) through it and collecting the filtered sample, and possibly processing it thereafter (e.g. for analysis purpose), such conventional procedures are not desirable. Moreover, the described product concepts prevent handling (positioning, re-orientation) of individual fragile pieces of filter membrane by e.g. pick and place techniques.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide improved filter units or filters with filtration membranes of reduced dead volume and reduced amount of retention and/or sheering, without loosing filtering ability.

A further object of the present invention is to provide a method of manufacturing filter units or filters with improved handling options.

This object is achieved by a filter device according to claim 1, a micro fluidic

(e.g. diagnostic) device according to claim 6 and a manufacturing method according to claim 7 or 8 or as described in this specification.

Accordingly, filter or filter units can be patterned by selectively inactivating or inhibiting the filtering function of the filter material, by collapsing and/or clogging the pores, e.g. by using an adapted solvent or chemical compound. This allows a patterning of the filter device, avoiding dead volumes or functionalizing the filter device. Furthermore, the contact area of the filter device can be reduced by selective patterning. Thereby, a large part of the area of the filter device is reduced while the ability to filter out a large amount of cells is kept.

This also reduces the retention of the filter device.

Moreover, the proposed product and manufacturing concepts prevent handling

(e.g. positioning, re-orientation, etc.) of individual fragile pieces of a filter membrane by e.g. pick and place techniques. Selective patterning of the filtration membrane allows the use of larger pieces of membrane or even a continuous web for better compatibility with roll-to-roll processing. This is potentially helpful in assembly of filtration cartridges since small pieces of filter are difficult to handle. By using patterning of the filtration membrane material, e.g. with tetrahydroiuran (THF), the "effective" filtration area of the membrane can be clearly defined, thereby preventing lateral flow of sample or filtrate into regions of the filter which are not required for the filtering or transport function and the filter can be optimized for maximum filtration speed (related to the "top" volume) and minimal retention (related to the "bottom" internal surface area and dead volume (related to the bottom internal volume). According to a first option, a chemical component may be arranged on the predetermined zones to collapse the pores. Thereby, a quick and efficient inhibition (at least a part thereof) of the filtering function can be achieved.

More specifically, the chemical compound may be a solvent, specifically tetrahydroiuran, and the filter material may be a polysulfone-based membrane. This provides the advantage of rapid dissolving and evaporation so that the solvent has no time to spread over a wider area.

According to a second option which can be combined with the above first option, the web portion may comprise a first layer with larger pores (e.g. for preventing clogging) and a second layer with smaller pores (e.g. for generating or filtering plasma from blood). Then, the chemical compound may be arranged so as to pattern the first layer and the second layer or the second layer only. In the first case, the total internal pore area of the filter device can be reduced. In the second case, the side with the larger pores is kept open to prevent clogging of the filter device. The confinement of a sample (fine pores and large pores) in the above first case enables roll-to-roll manufacturing, with a (virtually) endless web. It also enables manufacturing based on sheets with multiple products at a time.

According to a third option which can be combined with the first or second option, the filter device may comprise a foil or cover arranged on top of the web portion opposite to the base portion and comprising an aperture extending over at least a part of the filtering active area. Thus, the applied sample can be directed via the aperture to the filtering active area.

According to another embodiment, the invention proposes a method of manufacturing filter units for filtering samples and collecting the filtered samples, the method comprising the steps of:

(a) providing a web made of a filter material; and (b) making a first filter unit comprising:

(bl) providing a first base portion comprising a first micro fluidic element to collect some filtered sample;

(b2) applying a first portion of the web onto the first base portion; and (b3) inhibiting at least partly the filtering function of the filter material in predetermined zone(s) of the first portion of the web, so as to define, in other zone of the first portion of the web, a first filtering active area covering at least a part of said first microfluidic element.

Optionally, this method further comprises the steps of:

(c) making a second filter unit comprising:

(cl) providing a second base portion comprising a second microfluidic element to collect some filtered sample;

(c2) applying a second portion of the web onto the second base portion; and

(c3) inhibiting at least partly the filtering function of the filter material in predetermined zone(s) of the second portion of the web, so as to define, in other zone of the second portion of the web, a second filtering active area covering at least a part of said second microfluidic element.

According to a fourth option, said inhibition step can be implemented by different methods, such as:

applying a first and/or a second (chemical) substance(s) (during, respectively, said step (b3) and/or (c3)) to collapse pores in said predetermined zones;

locally filling up the pores of the filter material in said predetermined zones with a fluid or solid filling material and/or by making that region very hydrophobic by the application or generation of a hydrophobic filling material to the pores of the filter material. There are several ways to echive this, for example:

^■ saturating said predetermined zones with a minimal amount of glue/wax as filling material followed by curing (thermally or with UV radiation).

^■ saturating said predetermined zones with a minimal amount of hydrophobization fluid (as filling material), possibly followed by curing (thermally or with UV radiation). Suited hydrophobization fluids comprise for example: siloxanes (e.g. octadecyltrichlorosilane); oleaginous materials; (mineral) oil; Zonyl 8857A (DuPont, USA); DURALON UltraTec (COTEC GmbH, Karlstein, Germany); AF1600, AF2400 Fluoropolymers (DuPont); EGC-1700 (3M, USA); Halar® ECTFE (Solvay Solexis); Tefzel® ETFE (DuPont); or Teflon® FEP (DuPont) (wherein a selection has to be made in relation to assay interference of these chemicals).

^■ bringing said predetermined zones in contact with a thin wax layer (as filling material) and applying local reflow by local heating or by laser induced reflow.

According to a fifth option which can be combined with any of the first to fourth options, steps (b2) and (c2), or steps (b3) and (c3), or steps (b) and (c) of said manufacturing method may be implemented simultaneously using a continuous web. These measures allow efficient roll-to-roll manufacturing of filter devices.

According to a sixth option which can be combined with any of the first to fifth options, an adhesive layer may be applied between the first base portion and the first portion of the web and/or an adhesive layer may be applied between the second base and the second portion of the web, the adhesive layer being provided with a through hole facing, respectively, the first and second filtering active area. The adhesive layer may act as a lid to close micro fluidic channels of the micro fluidic element.

According to a seventh option which can be combined with any of the first to sixth options, the top foil or cover and the adhesive layer may be provided by using the same layer which has been folded to cover the web and to be sandwiched between the web and the base portion. This allows efficient manufacturing of both layers.

According to an eighth option which can be combined with any of the first to seventh options, a cut-out step may be provided to cut out the web so as to separate the first and the second filter units. Again a measure which allows efficient roll-to-roll manufacturing of filter modules or complete filter devices with integrated filter function.

According to a ninth option which can be combined with any of the first to eighth options, said first and the second substance may be applied by ink jet or micro droplet deposition. This measure allows accurate patterning by a controlled collapse of the porous structure of the web.

It shall be understood that the filter device of claim 1 and said manufacturing method have similar and/or identical preferred embodiments, in particular, as defined in the dependent claims.

It shall be understood that a preferred embodiment of the invention can also be any combination of the dependent claims or above embodiments with the respective independent claim. These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following drawings:

Fig. 1 shows schematic cross section of a two-layered blood filter; Fig. 2 shows a schematic top view of blood filter with a ring-shaped blocking area according to a first embodiment;

Fig. 3 shows a photographs of a portion of a filter processed according to the invention;

Fig. 4 shows a diagram indicating the signal response per unit of concentration of target (cTnl) for a conventional filter (left bar "F") and the filter with reduced filter area according to first embodiment (right bar "THF-F);

Fig. 5 shows two further examples of patterned filters according to second and third embodiments;

Fig. 6 shows a flow diagram of a manufacturing process according to a fifth embodiment; and

Figs. 7a to 7i show cross sections of a diagnostic device or cartridge with integrated blood filtration function during different assembling steps.

DETAILED DESCRIPTION OF EMBODIMENTS

Various embodiments of the invention are now described based on patterned blood filter design where pores of a filtering material are selectively collapsed by using a specific solvent (e.g. tetrahydrofuran (THF)) in order to define a functional area from a commercial blood filtration membrane on a defined area. THF is a very aggressive solvent to polysulfone (PES) based materials and dissolves it rapidly. This causes a collapse of the pores within the membrane and effectively clogs all pores that could transfer any liquid and especially plasma through the membrane. This enables the use of larger (THF patterned) pieces of membrane in blood filtration cartridges which is potentially helpful in assembly of blood filtration cartridges since small pieces of filter are difficult to handle.

According to various embodiments, the area of the filter is reduced while keeping the filter capacity and preventing clogging due to large amount of cells. The filter may be patterned only on the side where the plasma is transported through the filter in order to only pattern the side with the small pores. The patterning is done by dosing of the above solvent for the filter material. Dissolution of the filter material causes the pores to collapse and become impermeable for the plasma. Patterning of only the small pores can be achieved by carefully balancing the dosed amount and using the strong capillary pull of the area with smaller pores to localize the patterning liquid.

By using the proposed patterning of the blood filtration membrane material with THF or another suitable solvent, the "effective" filter size of the membrane can be clearly defined and optimized for speed at the required amount of sample and the internal area can be reduced for increased plasma recovery and lower analyte retention. More specifically, by patterning the filter with the solvent the filter material is dissolved. When the solution evaporates, the filter material hardens again into a solid piece and thus blocks the flow of liquid.

The solvent can be deposited by ink jet and micro droplet onto the porous polysulfone blood filtration membrane. To pattern the polysulfone membrane in a very defined area requires a solvent which dissolves PES very rapidly, such as THF. THF is a very aggressive solvent to PES based filtration membranes and dissolves it rapidly. THF effectively causes the collapse of the pores within the membrane and clogs all fluidic pathways which could transfer any liquid and especially plasma through the membrane. The quick evaporation ensures that the solvent has no time to spread within the pores of the filter membrane over a wider area. If a less aggressive solvent is used (e.g. toluene), the solvent has time to spread all over the membrane before it evaporates and no accurate patterning can be achieved.

A typical method to assemble blood filtration membrane patches onto diagnostic test strips is by pick-and-place technology. This requires filter membrane patches which are aligned and/or pre-sorted on e.g. a material feeding belt or box. The problem with pick-and-place handling of filtration patches is that the orientation of the filter membrane also has to be considered. E.g., as shown in Fig. 1, the top side of the filter membrane may contain larger pores and the bottom side of the filter membrane may contain finer pores, so that wrong orientation of the membrane compromises the functionality of the filtration patch. This issue is solved automatically when the filter region is part of a continuous web.

As another point of consideration, a polysulfone (PES) membrane is an extremely brittle material and difficult to handle with pick-and-place equipment. As the PES raw material is delivered as a roll stock, patterning of the filter membrane with a printing method (e.g. THF ink) eases the process immensely, since the membrane patterning can be achieved at any point of the assembly process with very easy and robust printing methods. Fig. 2 shows a schematic top view of a filter according to a first embodiment, which is patterned on both sides (i.e. large and small porous layer) to prevent blood from spreading. A THF solution is deposited on top of the filter, i.e., on the first layer 10 with the larger pores, to thereby create a ring-shaped area 40 where both the large and the small pores area of the filter are blocked, so that the filter area surrounded by the ring-shaped area 40 is confined. Inkjet printing or micro droplet deposition of THF onto a PES-based blood filtration membrane enables accurate patterning of an "effective" filtration area by a controlled collapse of the porous structure of the filtration membrane on the borders of the filtration area. In this way, the confined total internal pore area of the filter is reduced and analyte retention is reduced.

Fig. 3 shows a sectional top view of an exemplary filter membrane with the first layer 10 of larger pore width patterned with 100% THF by inkjet printing. The applied THF ink collapses the filter membrane 10 sufficiently to block liquid flow across the barrier pattern. Three ring-shaped areas 40 (i.e. barrier rings with line width: e.g. 1mm; distance between rings: e.g. 1mm) were printed to provide additional barrier rings in case of leakage through one of the inner rings. However, one barrier ring can be sufficient already. In the ring-shaped areas 40, collapsed pores are shown in comparison to the remaining pores of the non-patterned areas of the first layer 10. A plurality of patterned filters as shown in Fig. 2 or 3 can be arranged in a row or matrix on a continuous web to allow R2R or sheet-based manufacturing.

Fig. 4 shows a diagram indicating signal response for a conventional filter (left bars "F" in Fig. 4) and the filter with reduced filter area according to first embodiment (right bars "THF-F" in Fig. 4). As can be gathered from Fig. 4, the signal response is increased when reducing the filter area with THF. The increase of the signal change has the same factor as the decrease of area of the filter. The filter is brought into contact for 5 min with spiked plasma by totally submerging it into a certain volume. After incubating it, the signal response is increased (higher protein concentration or less degradation) with the same ratio as the decrease of the area of the filter, which indicates that the retention and/or sheering of the protein (marker) is less in the patterned filter.

In the previous case of the first embodiment, the patterning was obtained throughout the whole filter, i.e. through both layers of Fig. 1. However, in an application the area of the first layer on top of the filter (large pores) needs to be as large as possible to prevent any clogging of the filter with cells. By depositing the patterning liquid (e.g. THF) on the side with the small pores, in a sufficiently low amount, the patterning liquid is only transported throughout the second layer with the smaller pores by low volume and the difference in capillary forces, so that the side of the first layer with the larger pores can be kept open.

Fig. 5 shows bottom views and cross-sectional views of patterned filters with other specific patterns, where only the side of the second layer 20 with the small pores is blocked in order to facilitate plasma flow and reduce the surface area of the filter. Spaces are left un-patterned to facilitate transport of plasma.

A third embodiment is shown in the upper portion of Fig. 5, where the first layer 10 is not patterned and the second layer 20 is patterned into radial lines separated by segments of THF deposition areas 40.

Furthermore, a fourth embodiment is shown in the lower portion of Fig. 5, where the first layer 10 is not patterned and the second layer 20 is patterned by circular segments of THF deposition areas 40.

Since the area of the second layer 20 with smaller pores has a high internal surface area, the blocking of this area decreases binding/absorption of biomarkers to the material to a large extent.

For application in R2R manufacturing it is furthermore required to confine of the sample and filtrate within an active filter area. To achieve this, the first layer with large pores must additionally be blocked in a way similar to that shown in Fig. 1. Thus, the filter patterns shown in Fig. 5 can be surrounded by a ring-shaped blocking region, which is a collapsed area for the small- and large-pore side, to confine the sample.

Again, a plurality of the patterned filters shown in Fig. 5 can be arranged in a row or matrix on a continuous web to allow R2R or sheet-based manufacturing.

The filter or filter units according to the above embodiments are especially suitable for R2R manufacturing. This manufacturing method relies on the fact that the filter membrane is part of a continuous web of the same material and is separated from that web after it has been assembled to other parts (foils or tapes) of the filter, filter unit or cartridge. The proper functioning of such R2R manufacturing relies on the fact that the filter membrane is partly blocked on both sides, thus preventing lateral flow of plasma or sample into regions of the membrane that are not effective in delivery of sample to the rest of the device.

This blocking can be achieved as described in the above embodiments.

Fig. 6 shows an exemplary process flow for manufacturing of a blood filtration module according to the above embodiments and Figs. 7a to 7i show respective cross sections of the blood filtration module during the different assembling steps of the process flow. In a first step S501, a transfer tape 60 with release liner 50, 52 on both sides (e.g. 15 g/m² pure acrylic adhesive) is provided, as shown in Fig. 7a. Then, in step S502, circular holes and a perforate middle line are generated by a respective die-cutting tool 70 or a laser (not shown), as shown in Fig. 7b. It is noted that the perforate middle line is not a perforate in the sense that the cutting is partial over the length of the line (dashing). Rather, it is a partial cut in depth (also referred to as "kiss cutting"). Thereafter, in step S503, the upper release liner 50 is removed, as shown in Fig. 7c. In a subsequent step S504, a top cover laminate 80 (left) and a base part 90 which may contain microfluidic and other functions 92, such as supporting detection of the analyte (right) are added, as shown in Fig. 7d. In fact, the base part 90 could be a single part or a subassembly, containing several functions, if the end product is a complete cartridge with integrated filter. Now, in step S505, the assembly is flipped around, as shown in Fig. 7e. Then, in step S506, the remaining lower release liner 52 is removed, as shown in Fig. 7f. In a subsequent step S507, a blood filtration membrane 100 is added on top of the flipped part 90 and aligned with the part 90, as shown in Fig. 7g. Thereafter, in step S508, the blood filtration membrane is patterned with THF solvent 120 by an ink jet printing or flexography mechanism 110 to obtain solvent deposition areas (or non- filtering zones) 130, as shown in Fig. 7h. This solvent selectively collapses pores of the filtration membrane 100, inhibiting locally (in zones 130) at least partly its filtering function. Finally, in step S509, the obtained sheet or web is diced and folded into individual cartridges, as shown in Fig. 7i.

Alternatively to or in combination with the use of a solvent, predetermined zones 130 or other zones can be inhibited by other ways, such as for example the local filling up of the pores of the filtration membrane 100 in said predetermined zones with a fluid or solid filling material and/or by making that region very hydrophobic by the application or generation of a hydrophobic filling material to the pores of the filter material. There are several ways to echive this, for example:

^■ saturating said predetermined zones with a minimal amount of hydrophobization fluid (as filling material), possibly followed by curing (thermally or with

UV radiation). Suited hydrophobization fluids comprise for example: siloxanes (e.g. octadecyltrichlorosilane); oleaginous materials; (mineral) oil; Zonyl 8857A (DuPont, USA); DURALON UltraTec (COTEC GmbH, Karlstein, Germany); AF1600, AF2400 Fluoropolymers (DuPont); EGC-1700 (3M, USA); Halar® ECTFE (Solvay Solexis); Tefzel® ETFE (DuPont); or Teflon® FEP (DuPont) (wherein a selection has to be made in relation to assay interference of these chemicals).

As regards now to steps S501 and S502 of the above manufacturing process, laminate patterning may be achieved by knife plotter cutting, where a knife plotter is used in sheet process, whereas die-cutting or a laser can be used in the roll-to-roll process. In step S503, a hydrophobic spacer tape may be used for sheet assembly of e.g. five blood filtration modules simultaneously. The laminate sheet may be fixed on the assembly table by a tape with the protective top liner 50 removed.

Furthermore, in step S509, the top cover is folded over (from left to right) on top of the base part 90. The glue contact may be increased by rolling over the filter stack with a silicone roller. The filter cartridges 90 can now be diced into individual devices (achieved here by the perforation cuts on the device borders which are already added in step S502).

Actually, in Figs. 7a-7i, the base part 90 could represent a complete base part with microfiuidic and detection functions on board. The product sketched in Fig 7i then represents a complete disposable cartridge or diagnostic device with an integrated filter function. A filter module (subassembly to be mounted to any device) can be made by keeping part of the top liner 50 and removing that just before mounting. Thus, filter units or modules can be manufactured, which can be assembled onto any device or cartridge. In this case, only the left part of the top liner 50 would be removed in step S503, enabled by "kiss cutting" through the top liner 50. Thus, filter units for filtering samples and collecting the filtered samples can be manufactured by providing one continuous web made of a filter material (i.e. filtration membrane 100) and then obtaining a first filter unit by providing a first (rigid) base or base portion comprising a first microfiuidic element to collect some filtered sample, then applying a first portion of the web onto the first (rigid) base or base portion, and then applying a substance onto predetermined zones of the first portion of the web so as to define a first filtering active area covering at least a part of the first microfiuidic element. Additionally, a second filter unit can be obtained by providing a second (rigid) base or base portion comprising a second microfiuidic element to collect some filtered sample, then applying a second portion of the web onto the second (rigid) base or base portion, and then applying a substance onto predetermined zones of the second portion of the web so as to define a second filtering active area covering at least a part of the second microfiuidic element. As regards the applied substance, any substance (e.g. THF) can be used, which, after or without a further treatment, inhibits at least partly the filtering function of the filter material. The application of the web portions or the substances for the first and second filters or even the complete assembly of the two filters can be done simultaneously.

As another option, application of the substance for the first filter could be implemented after or before the application of the web portion for the first filter, and application of the substance for the second filter could be implemented after or before the application of the web portion for the second filter. However, the web tends to warp (due to the liquid solvents deposited onto the filtering membrane) when it is not attached to a solid base. In a mass-manufacturing environment this might lead to web shrinkage and to downstream alignment problems. Therefore, the web should be exposed to the solvent after it has been attached to a rigid base.

Additionally, an adhesive layer can be applied between the first (rigid) base and the first portion of the web and/or between the second (rigid) base and the second portion of the web. The adhesive layer may be provided with a through hole facing, respectively, the first and second filtering active area. Optionally, this adhesive layer can act as a lid to close the microfluidic channels comprised in the microfluidic elements. As another option, this adhesive layer is one or a combination of the following: acrylic adhesive film sandwiched between the web and the bases or a printed layer of adhesive material directly deposited onto the web.

As a further option, a top foil or cover may be applied onto the surface of the web opposite to the surface of the web applied to the (rigid) bases. The foil or cover comprises a first aperture and a second aperture for covering, respectively, at least a part of the first filtering active area and at least a part of the second filtering area. The top foil or cover and the adhesive layer can be made of the same layer which has been folded to cover the web (and acts as a top foil or cover) and to be sandwiched between the web and the base (and acts as an adhesive layer).

As a still further option, a cut-out step may be provided to cut out the web so as to separate the first and the second filter units (and possibly the foil or cover if any)

The above first and second (rigid) bases may be two portions of a single (rigid) board, and a cut-out step may be provided for cutting out the assembly of the first (rigid) base and first portion of the web from the assembly of the first (rigid) base and the second portion of the web, so as to separate the first and the second filters or filter units. The functionality of the proposed filter stack can be evaluated by the effects of leakage over pattern borders (i.e. question whether leakage of whole blood or plasma can be observed over the THF patterned area in the filter stack), sufficient contact between filter and cartridge, cartridge filling speeds, and filtration and cartridge filling success rate.

To summarize, a filter, a filter unit/module or a complete microfluidic diagnostic device (e.g. disposable cartridge) with integrated filtration membrane for filtering a component or fluid from a sample and a method of manufacturing the filter, the filter unit/module or the complete diagnostic microfluidic device with integrated filtration membrane have been described, wherein the filter or filter unit/module or microfluidic (diagnostic) device comprises a base portion comprising a microfluidic element to collect some filtered sample, and a web portion made of a filter material an arranged on top of the base portion, wherein the web portion comprises predetermined zones wherein the filtering function has been inhibited (e.g. pores of the filter material have been collapsed in these zones or pores have been filled-up by a filling material as previously explained), which define a filtering active area covering at least a part of said microfluidic element, said collapsed pores being adapted to inhibit at least partly the filtering function of the filter material. The filter function can be used in many microfluidic devices (e.g. reactors, which are not intended for diagnostic purposes).

Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims.

In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality.

A single unit or device may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

Any reference signs in the claims should not be construed as limiting the scope.

Claims

CLAIMS:

1. A filter device for filtering a component or fluid from a sample, said filter device comprising:

a base portion (90) comprising a microfluidic element (92) to collect some filtered sample;

a web portion (100) made of a filter material arranged on top of the base portion;

wherein said web portion (100) comprises predetermined zones (40; 130) of collapsed pores of said filter material, which define, in other zone of the web portion (100), a filtering active area covering at least a part of said microfluidic element (92), said collapsed pores being adapted to inhibit at least partly the filtering function of the filter material.

2. The filter device as defined in claim 1, wherein the collapsed pores have been collapsed by application of at least one adapted chemical component on said predetermined zones (40; 130), and optionally the implementation of a further treatment.

3. The filter device as defined in claim 1, wherein the web portion (100) comprises a first layer (10) with larger pores and a second layer (20) with smaller pores, and wherein the said predetermined zones (120) are defined so as to pattern the first layer (10) and/or the second layer (20).

4. The filter device as defined in claim 3, wherein the sample is blood, the larger pores are arranged for preventing clogging and the smaller pores are arranged for filtering plasma from blood.

5. The filter device as defined in claim 1, wherein the filter device comprises a foil or cover arranged on top of the web portion (100) opposite to said base portion (90) and comprising an aperture extending over at least a part of the filtering active area.

6. A diagnostic apparatus comprising a filter device as defined in any one of claims 1 to 5.

7. A method of manufacturing filter units for filtering samples and collecting the filtered samples, the method comprising the steps of:

(a) providing a web made of a filter material; and

(b) making a first filter unit comprising:

(bl) providing a first base portion (90) comprising a first micro fiuidic element (92) to collect some filtered sample;

(b2) applying a first portion (100) of the web onto the first base portion

(90); and

(b3) applying a first substance (120) to collapse pores in predetermined zones (40; 130) of the first portion (100) of the web so as to define, in other zone of the first portion (100) of the web, a first filtering active area covering at least a part of said first micro fiuidic element (92), the substance (120) being adapted, after or without a further treatment, to inhibit the at least partly filtering function of the filter material.

8. The method as defined in claim 7, further comprising the steps of:

(c) making a second filter unit comprising:

(cl) providing a second base portion (90) comprising a second microfluidic element (92) to collect some filtered sample;

(c2) applying a second portion of the web onto the second base portion

(90); and

(c3) applying a second substance (120) to collapse pores in predetermined zones (40; 130) of the second portion of the web so as to define, in other zone of the second portion of the web, a second filtering active area covering at least a part of said second microfluidic element (92), the second substance being adapted, after or without a further treatment, to inhibit at least partly the filtering function of the filter material.

9. The method as defined in claim 8, wherein steps (b2) and (c2), or steps (b3) and (c3), or steps (b) and (c) are implemented simultaneously using a continuous web.

10. The method as defined in claim 8, wherein the first and the second substance are applied by ink jet or micro droplet deposition.

11. The method as claimed in claim 8, further comprising applying at least one of an adhesive layer between said first base portion (90) and the first portion (100) of the web and/or applying at least one of an adhesive layer between said second base (90) and the second portion (100) of the web, the adhesive layer being provided with a through hole facing, respectively, the first and second filtering active area.

12. The method as claimed in claim 11, further comprising applying a top foil or cover onto the surface of the web opposite to the surface of the web applied to the first and second base portions (90), after step (c), the foil or cover comprising a first aperture and a second aperture for covering, respectively, at least a part of the first filtering active area and at least a part of the second filtering active area.

13. The method as claimed in claim 12, further comprising providing a top foil or cover and the adhesive layer by using the same layer which has been folded to cover the web and to be sandwiched between the web and the base portion.

14. The method as claimed in claim 8, further comprising exposing the first portion (100) of the web to the first substance (120) after it has been attached to the first base portion (90).

15. The method as claimed in claim 8, further comprising a cut-out step to cut out the web so as to separate the first and the second filter units.