WO2010023596A1

WO2010023596A1 - Reconfigurable microfluidic filter

Info

Publication number: WO2010023596A1
Application number: PCT/IB2009/053635
Authority: WO
Inventors: Johannes T. A. Wilderbeek; Jacob M. J. Den Toonder
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2008-08-25
Filing date: 2009-08-18
Publication date: 2010-03-04

Abstract

The invention provides a method for filtering a microfluidic sample including particles. The method comprises a filling of the microfluidic sample into a microfluidic environment having a selectively changeable cross section. Further, the method comprises a retaining of particularly sized particles due to the geometrical dimensions of the cross section. The invention further provides a microfluidic filter for carrying out the above method. The filter comprises a microfluidic environment having a selectively changeable cross section and controlling means adapted to selectively change the cross section of the microfluidic environment.

Description

Reconfigurable microfluidic filter

FIELD OF THE INVENTION

The invention relates to a method for filtering a microfluidic sample including particles. The microfluidic sample is filled into a microfluidic environment having a selectively changeable cross section, and particularly sized particles are retained due to the geometrical dimensions of the cross section. Further, a microfluidic filter for carrying out the above method is provided. The filter comprises a microfluidic environment having a selectively changeable cross section. Controlling means for selectively changing the cross section of the microfluidic environment are also provided in the filter, according to the invention.

BACKGROUND OF THE INVENTION

Analyses of micro fluids are usually carried out by means of a lab-on-a-chip system for medical, life-science, forensic and environmental applications.

A key aspect when performing analyses on a lab-on-a-chip device is sample preparation. Ideally, all preparation steps should be done on-chip in order to allow the use of raw, unprocessed samples as input. Essential preparation steps are filtration of the samples prior to processing and providing a high concentration of the analyte in the sample to increase the sensitivity of the device.

In some cases, a specific target cell population has to be extracted from a heterogeneous cell mixture. For example, hematopoietic stem cells, antigen-specific lymphocytes and circulating tumor cells from peripheral blood and fetal cells from maternal blood are analytes to be isolated prior to processing.

A common approach for microfluidic filtering has been the creation of flow restriction devices, e.g. by use of porous membranes, mesh structures or arrays of cylindrical pillars. Such structures can be realizes by deep reactive ion etching in silicon or by lithography in polymeric materials.

For example, US 5,427,663 is related with a sorting apparatus for fractionating and simultaneously viewing individual microstructures such as free cells, viruses, macromolecules in a fluid medium. The apparatus comprises a receptacle and sifting means positioned within the receptacle in the migration direction. The sifting means are for interacting with the microstructures to partially hinder the migration of the microstructures. The sifting means may be an array of obstacles (obtained by substrate etching) upstanding from the floor of the receptacle and arranged in a pre-determined and reproducible pattern. The sorting of the microstructures is carried out by placing the microstructures in a fluid medium and introducing the fluid medium into one end of the apparatus. The microstructures are then induced (for example by an electric field) to migrated in the fluid through the array of obstacles.

The performance of those traditional micro fluidic filter devices is independent from the complex composition of the sample (including one or more analytes and a fluid medium) introduced into the filter devices and merely rely on differences in size between the particles. Thus, the main disadvantage of such devices is their lack of flexibility; the devices operate in a kind of digital way: they retain particles larger than the apertures in the structure and let smaller particles flow through. As a consequence, the filter structures of the devices have to be carefully designed to perform a specific task dependent on the size of the analyte to be processed, and new structures have to be fabricated for each application. In addition, particles captured in such structures cannot be easily released for downstream processing, but can only, for example, be redistributed into the section preceding the filter by reversing the flow direction. Another major problem with traditional devices is the fact that they become easily clogged with cells or microparticles.

SUMMARY OF THE INVENTION

There is therefore a need to provide a simple microfluidic filter which can be used for diverse applications and which prevents any clogging of particles. Further, there is a need to provide a method which allows to accurately control the migration of the particles through the filter.

These issues are solved by a filter of the present invention. The filter may be reconfigured, for example, to change the sieve size, vary the distributions of pillars in an array or remove the obstacles completely to release the captured particles or prevent clogging.

According to the present invention, particles included in a fluid sample to be analyzed are filtered due to a reconfigurable filter apparatus. The term "particles" includes biological cells or other biological species in the sample. In particular, the cross section of the microfluidic environment through which the sample flows can be changed, for example, to adapt the process conditions to the size of the particles.

According to the present invention, a method for filtering a microfluidic sample including particles is provided. The method comprises a filling of the microfluidic sample into a microfluidic environment. The environment has a selectively changeable cross section. Further, the method comprises a retaining of particles of a particular size due to the geometrical dimensions of the cross section.

Microfluidic samples may include a fluid medium and microparticles as, for example, hematopoietic stem cells, antigen-specific lymphocytes and circulating tumor cells from peripheral blood and fetal cells from maternal blood. A "fluid" may be a liquid or a gas, for example, saliva, blood, semen, air.

The microfluidic environment may be the space through which the fluid sample flows during the analysis process. This space/environment may be surrounded by any receptacle for microfluidic samples, for example, a channel or a reservoir. The cross section of the microfluidic environment is the surface perpendicular to the fluid flow through the environment.

The selective change of the cross section of the microfluidic environment may be realized by polymeric micron-sized materials reversibly actuated by an external stimulation. For instance, electrostatic stimulation may be used. For example, the walls of the microfluidic environment may consist of a polymer covered with a thin metal layer. In the off-state, the wall provides its original shape, and upon application of a voltage, in the on- state, the walls bend inside or outside the environment due to electrostatic attraction. The composition of the polymers and materials used may, for example, be the same as in WO 2007/091197 Al, further describing the principle of the process of changing the shape of particular materials. Due to a selective change (for example, by carefully adjusting the voltage) of the shape of the material, for example, the cross section of the microfluidic environment is also selectively changed. Thus, the particles flowing through the environment may be retained by the changed (for example, smaller) cross section of the microfluidic environment. Hence, the geometrical dimensions of the cross section of the microfluidic environment may be adapted to a particular particle size and may be selectively changed dependent on the analysis process. Such a completely reconfigurable filter can be used in applications ranging from simple valve structures to complex arrangements with adjustable sieve size. In a particular embodiment, the method further comprises an actuating of at least one obstacle arranged in the microfluidic environment in order to selectively change the cross section of the microfluidic environment.

An obstacle may be an element made from one of the polymeric materials discussed above. The obstacle is arranged in the microfluidic environment and may be covered, for example, with a thin metal layer. Preferable, the shape of the element changes in response to an actuation, as for example an electrostatic force discussed above. Due to this selective change in shape of the element, the cross section of the microfluidic environment through which the fluid flow of the sample is performed also changes selectively. In a particular embodiment, at least two obstacles may be arranged in the microfluidic environment. The obstacles may be separately actuated to selectively change the cross section of the microfluidic environment.

If there are more than one obstacles in the microfluidic environment, these obstacles may be separately actuated to provide a more complex cross section of the microfluidic environment. In doing so, a particularly located clogging of particles may be prevented without abandoning the filtering operation at a different location in the microfluidic filter.

In a particular embodiment, the obstacles may change their shape in response to the actuation and thereby perform the selective change of the cross section of the microfluidic environment.

Due to the change of shape of the obstacles, the microfluidic environment's cross section perpendicular to the direction of the fluid sample's flow may be configured and adapted to the components and/or particles included in the sample. Thus, the microfluidic environment and, further, the whole microfluidic filter may be adjusted to the sample to be analyzed or to a specific analyzing process.

In a particular embodiment, the method further comprises the step of changing the geometrical dimensions of the cross section of the microfluidic environment on a time- resolved basis.

Preferable, the cross section of the microfluidic environment may be changed at once and, after a pre-determined time period, the cross section may be re-changed or differently changed, for example, by an external actuation, e.g. electrostatic and/or magnetic actuation and/or by applying a light beam and/or by a temperature change.

A reconfigurable microfluidic filter being controllable on a time -resolved basis may enable the user to carry out any analyzing process without the need to permanently observe the filter in operation. Thus, the user may carry out many analyzing processes simultaneously or may control the filter at a remote location.

According to the present invention, a microfluidic filter for carrying out the method as described above is provided. The microfluidic filter comprises a microfluidic environment having a selectively changeable cross section. Further, the filter comprises controlling means adapted to selectively change the cross section of the microfluidic environment.

In a particular embodiment, the microfluidic environment and the fluid sample have the same features as described above in connection with the method of the invention. Further, any definitions and explanations mentioned in connection with the method also apply to the features of the microfluidic filter of the invention and vice versa.

The selective change of the cross section of the microfluidic environment is actuated by controlling means. In particular, the controlling means may provide an electrostatic force affecting a change of the geometrical dimensions of the cross section. Thereby, the flow-through cross section available for the fluid sample to be analyzed may be selectively chosen by carefully adjusting, for example, the voltage via the controlling means.

In a particular embodiment, the selective change of the cross section of the microfluidic environment may be caused by the microfluidic environment being adapted to change its shape in response to an actuation. As discussed above, the microfluidic environment may be made from a material adapted to change its shape upon an actuation, for example, an external stimulation, e.g. by an electrostatic force.

An external actuation or external stimulation is an actuation done by the controlling means, wherein the controlling means are arranged outside the microfluidic environment. The actuation carried out by the controlling means may be the trigger for the change of the shape of the microfluidic environment.

In a particular embodiment, the microfluidic environment comprises at least one obstacle adapted to change its shape in response to an actuation. Thereby, the obstacle may be adapted to perform the selective change of the cross section of the microfluidic environment.

An obstacle may be an element made from one of the polymeric materials discussed above. The obstacle is arranged in the microfluidic environment and may be covered, for example, with a thin metal layer to be actuated as explained in connection with the method of the invention. In particular, the elements used as obstacles in the microfluidic environment may have an essentially rectangularly shaped geometrical design. However, the geometrical design of the elements in an actual implementation is not limited to rectangularly shaped structures, but may also incorporate different shapes, such as tapered structures, square shaped structures, oval shaped structures, or completely irregularly shaped elements of different sizes and combinations thereof. In a specific embodiment, the obstacles are laminar and do not have the shape of a ciliary.

In a particular embodiment, the microfluidic environment comprises a substrate. In this case, at least one obstacle may be attached to the substrate of the microfluidic environment.

In particular, the microfluidic environment may be surrounded by a receptacle, for example a reservoir having the substrate as lower surface, and, e.g., additionally provided with side walls integral with the substrate, and a cover for closing the reservoir. The reservoir may further comprise a first and second opening as inlet and outlet for the fluid sample. In case a cylindrically shaped channel is used as the receptacle, the substrate is defined as the cylindrically shaped wall of the channel. The substrate may be made, e.g., from cyclo-olefm (co)polmers, polyethylene, polystyrene, polycarbonate, or polymethylmetacrylate to also enable an optical analysis of the fluid sample.

Particularly, the positioning and arrangement of the obstacles may vary throughout the microfluidic environment. For example, the obstacles may be present on one side and/or one discrete position of the microfluidic environment, e.g. on the bottom surface of the environment, for example on the upper surface of the substrate. Similarly, the obstacles may be present on, for example, the lower surface of the cover. In a further embodiment, the obstacles may be present at more than one surfaces of a receptacle. In particular, the relative placement of the obstacles in the microfluidic environment may be adjusted such that at least two of them are adapted to physically contact each other or to partially or entirely overlap each other. Thereby, a temporary reinforcement of an obstacle may be realized if necessary.

For example, the original off-state shape of the obstacles may be a curled shape due to internal mechanical stress resulting from the processing. Upon application of an actuation, e.g. electrostatic force, in the on-state, the obstacle extends due to the (electrostatic) attraction and entirely or partially unroll (for example, depending on the amount of voltage applied). By partially unrolling the obstacles, passage of the fluid sample may be allowed, at least for the components of the sample not being retained by the changed cross section of the micro fluidic environment.

In a particular embodiment, the controlling means is adapted to selectively change the cross section, for example, by applying an electrostatic force and/or a magnetic force and/or a light beam and/or a temperature change.

In a particular embodiment, the microfluidic environment comprises at least two obstacles. Further, the controlling means may be adapted to separately actuate the obstacles.

If there are more than one obstacle in the microfluidic environment, these obstacles may be adapted to be separately actuated to provide a more complex cross section of the microfluidic environment. The individually addressing of the obstacles may be carried out by the controlling means. The controlling means may, for example, be provided with patterned counter electrodes and/or continuous and/or discontinuous counter electrodes.

Further, the spatial arrangement of the obstacles may be such that multiple obstacles are placed in rows, in herringbone arrangement, in repetitive arrangements, or at entirely irregular patterns, distances or intervals from each other.

Furthermore, an effective sieve size may be realized due to the selective change of the shapes of one or more obstacles. The effective cross section of the microfluidic environment equals A = ml * m2 (see Fig. 3(a)), where ml (maximally equal to "h_z", which is the maximum height of the microfluidic environment) and m2 denote the respective net resulting height and width of the obstacle. Hence, by choosing a suitable effective sieve size, a microfluidic environment may be constructed that may function as a capturing site retaining particles having a larger diameter.

The possibility for selective/individual addressing of the obstacles by the controlling means may have an important advantage over traditional filters, since not only the effective sieve size can be modified and reconfigured, but the effective sieve size can also be adjusted in time and preferably dependent on the actual processing conditions.

In a particular embodiment, the controlling means is adapted to actuate the obstacles on a time-resolved basis. Preferable, the controlling means adapted to change the cross section of the microfluidic environment at once may be further adapted to re-change the cross section after a pre-determined time period, or to differently change the cross section. This may be done, for example, by an external actuation of the controlling means, e.g. by electrostatic and/or magnetic actuation and/or by applying a light beam and/or by a temperature change. The individual/selective and/or time -resolved addressing of the obstacles opens up a completely new possibility for carrying out analysis processes in the technical field of filtering micro fluids. For instance, potential clogging problems or problems in connection with selecting and filtering multimodal collections of particles may be overcome. For example, a filter strategy may be configured allowing for the initial filtering of, for instance, large particles. In this example, small particles are initially passing through the filter and can be collected, after which the larger particles are subsequently collected by changing the cross section of the micro fluidic environment of the filter. Similarly, multiple batches of virtually monodisperse particles may be formed, essentially resulting in an effective microfluidic fractionation tool. Moreover, partial changing of the shape (e.g. partial unrolling) of some of the obstacles may allow for the control of the flow and flow rate of the fluid sample, whereas still other obstacles may form the discussed reconfigurable sieve structure.

According to the present invention, an array of microfluidic filters for fractionation of fluid samples including particles is provided. The array comprises at least two of the microfluidic filters as discussed above, wherein the microfluidic filters are arranged parallel or in series in flow direction of the fluid samples.

For example, if the microfluidic filters are arranged in series, a fluid sample including a multimodal distribution of particles is introduced into the first filter. The first filter may retain larger particles and pass smaller ones. The smaller particles then reach the second filter further retaining larger particles, so that merely the smallest particles may pass through the second filter. Due to the reconfigurable filters in the array, the analysis process may be adapted to particular process conditions and/or the particular multimodal distribution of particles in the fluid sample. Particularly, if the microfluidic filters are arranged parallel to each other, different sizes of the particles may be retained to obtain particularly filtered fluid samples from one an the same original fluid sample, for example, useful for any later processing step. Alternatively, the parallel arrangement of the filters may be used to calibrate the analysis process to maybe eliminate measurement errors. In a further embodiment, at least three microfluidic filters as discussed above are provided, wherein two of them are arranged parallel, and the third one is connected in series to the first and second one. In this case, for example, the cross section of the filters may be changed separately from each other, for example, to initially retain the largest and middle-sized particles, but then - on a time-resolved-basis - let the middle-sized particles and finally the largest particles pass the array.

In view of this, an array of micro fluidic filters is provided allowing the selective filtering of multimodal distributions of particles in a single device without the need to re-direct the fluid flow.

In a particular embodiment, the array of micro fluidic filters further comprises a central unit adapted to regularize the operation of any controlling means of the micro fluidic filters.

A central unit may be connected to each of the controlling means of the micro fluidic filters in the array. In particular, the central unit (e.g. a processor) may control/regularize the mode of operation of each controlling means. Hence, the analysis process carried out by using the array may be centrally controlled without requiring time- consuming separate adjustments of the filters so that the change of each cross section in the array may be automatically adapted to a particular process condition. In a particular embodiment, the array of micro fluidic filters comprising the central unit is adapted to modify the operation of any controlling means of the micro fluidic filters in response to the receipt of an external signal.

For example, the array may be controlled by collecting analysis data while the analysis process is running. In particular, a computer collecting the data may recognize any predefined process condition by evaluating the data, and may then generate the external signal. The central unit may be adapted to receive the external signal and may then, for example dependent on the kind of signal, modify the operation of one or more of the controlling means to further change one or more cross sections in the array. For example, the external signal may inform the central unit that clogging occurs in a particular filter, or that the fluid flow through a particular filter has finished (and that, e.g., the largest particles are already retained).

In view of this, the analysis process of filtering a microfluidic sample is further improved and automated to obtain fast and reliable results of filtration.

The advantages of the above, for example disposable, lab-on-a-chip systems are their easy use, the low fabrication costs, low fluid volumes and low reagents consumption, large integration of functionalities, high throughput due to massive parallelization of analyses, and increased process control due to a faster response of the system. Further, the claimed invention may be used in connection with proven addressing mechanisms, e.g. electrostatic addressing, magnetic addressing, photonic addressing, addressing by changing temperature, etc. This enables the concept of the present invention also to be used in, for instance, ion-rich environments (e.g. difficult for electrostatic and (positive-) dielectrophoretic addressing), opaque environments, or for applications where high electrical fields are undesirable (e.g. where, for instance, (negative-) dielectrophoretic addressing is not a suitable option).

In view of the present invention, a possibility for sorting and selecting of individual components in complex fluid samples, such as blood, saliva, urine etc. is provided. In particular, a more reliable and powerful separation tool for components in complex fluid samples is realized by using selective and time-resolved trapping of particles and by providing possibilities for fractionating particles with multimodal distribution by means of arrays. Further, the occurring of any clogging may be prevented by actuating the obstacles or the material of the environment accordingly. These and other aspects of the invention will be apparent from and exemplified with reference to the embodiments described hereafter.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 schematically shows the principle of means changing their shape in response to an actuation;

Fig. 2 (a)-(d) schematically shows obstacles adapted to change their shape and being arranged in a microfluidic environment;

Fig.3 (a)-(b) schematically shows two embodiments how to arrange obstacles in a microfluidic environment; Fig.4 schematically shows the mode of operation of a microfluidic filter; and

Fig. 5 schematically shows an array of sieve elements for, e.g., selecting and sorting particles.

DETAILED DESCRIPTION OF EMBODIMENTS Fig. 1 schematically shows how the shape of an element can be changed by applying an electrostatic force. For example, polymer element 71, e.g. made from a polymeric material, is actuated by electrostatic forces and may be used as material for the walls of a microfluidic environment and/or as obstacle in such a microfluidic environment. The element 71 comprises a polymer MEMS 10 (micro-electro-mechanical system) including an electrode 11 (e.g. a conductive layer) and an attachment means 12 for attaching the polymer MEMS 10 to the inner side 61 of the wall 14 of a micro fluidic environment, as for example a channel, including a counterelectrode 15. In an "off-state", i.e. without applying an electrostatic force, the polymer MEMS 10 is bending in a curled shape due to a force Fi resulting from an internal mechanical moment in the element 71, caused by the prior processing of the element 71. The arrow F₂ represents the actuation of the polymer MEMS 10 by an electrostatic force generated by an electrical potential difference V applied by a generator 13 between the electrode 11 and the counterelectrode 15. The electrostatic force thus generated on the element 71 causes the element 71 to move in the direction of the wall 14. In other words, the Force F₂ tends to straighten the polymer MEMS 10 thus bringing it in the "on-state". For an even more detailed description of the main principle explained above and alternative actuation forces for the elements 71, it is referred to the disclosure of WO 2007/091197 Al.

Figs. 2 (a) - (d) show an embodiment of micro fluidic receptacles having a cover 101 and a substrate 102, as well as an inlet A and outlet B for fluidic samples including particles.

According to Fig. 2 (a), a first obstacle 110 and a second obstacle 112 are provided, wherein the first obstacle 110 is in its "off-state" (not actuated by any force) and works as a valve-like structure, whereas the second obstacle 112 is straightened by application of a, e.g. electrostatic, force. In this case, the obstacles may be separately actuated by the force, for example, by patterned counterelectrodes at the outer wall of the receptacle (not shown in Fig. 2).

In Fig. 2 (b), the substrate as well as the cover of the receptacle provide first obstacles 114a, 114b and second obstacles 116a, 116b. Similar to Fig. 2 (a), the first obstacles 114a, 114b are in their "off-state", whereas the second obstacles 116a, 116b are in their "on-state" (actuated by a force). According to this example, the obstacles provide hinge- like structures in the "off-state", completely closing the cross section in the height direction of the micro fluidic receptacle.

Fig. 2 (c) shows a mirror- like double structure of first (118a, 118b) and second (120a, 120b) obstacles. Likewise to Fig. 2 (b) the first obstacles 118a, 118b close the cross section of the receptacle in a height direction, whereas the second obstacles 120a, 120b are in their on-state, i.e. actuated by a force. In contrast to the configuration in Fig. 2 (b), in this example, the obstacles 118b and 120b attached to the cover are arranged as mirrored structures of the obstacles 118a and 120a attached to the substrate. Similar to Fig. 2 (b), in this example, the grade of actuation for the second obstacles 120a and 120b may be the same, but may differ from the actuation of the first obstacles 118a, 118b. For example, the pattern of counterelectrodes attached to the outside walls of the receptacle may be configured to simultaneously actuate the first obstacles 118a and 118b, whereas the second obstacles 120a, 120b are simultaneously actuated after a pre-determined time period.

In Fig. 2 (d), a mirror-like double structure is provided, similar to that shown in Fig. 2 (c). However, in this example, the obstacles 122a, 122b, 124a, 124b each are separately actuated by an external force to selectively change the cross section of the receptacle. Fig. 3 schematically shows an example of a spatial arrangement of obstacles

210, 212 in rows, arranged on a substrate 201 of a receptacle having the height h_z and a cover 202. Similar to Fig. 2, Fig. 3 (a) specifies an inlet/outlet A and an outlet/inlet B for fluid samples including microparticles. However, the direction of any fluid flow is not defined and can be chosen by the user. By selectively addressing one or more obstacles 212, for example at a given moment in time, an effective sieve size for the filter may be realized. In this case, the effective sieve size for the second row of obstacles equals ml * m2 as shown in Fig. 3 (a).

Fig. 3 (b) schematically shows a spatially circular arrangement of tapered obstacles 210 on a substrate 201, i.e. in this case a circular microchannel. In the particular embodiment (α), the obstacles 210 may at least partly overlap to leave a small opening 230 of pre-determined and adjustable size. Preferably, the size of the opening may be controlled by the controlling means or a central unit. Alternatively, the obstacles 210 may entirely overlap not to leave any opening in their "off-state". According to examples (β) and (γ) in Fig. 3 (b), and similar to the embodiments as described above, the obstacles 210 may be separately actuated to change the cross section of the microchannel 201. Such a configuration may, for example, allow for a flow control to pass only small components/particles within the fluid sample. For instance, this embodiment may be useful for artificial heart valves.

Fig. 4 illustrates the selective addressing of individual obstacles 310, 312 resulting in a reconfigurable filter. Obstacle 310 provides a curled shape, whereas obstacle 312 is actuated to change its shape, in this case, to extend/straighten. According to Fig. 4 (a), particles 340 and 341 having a diameter smaller than the effective sieve size of the cross section of the receptacle are allowed to flow through the whole filter. Larger particles, as the particle 350 in Fig. 4 (b) will be blocked by the obstacles 310 and are thus retained in the filter. Fig. 5 schematically shows an array of micro fluidic filters. The filters B and C are arranged parallel to each other, whereas the filter A is arranged in series to filters B and C. The filters A, B, and C may be any kind of filters as explained above. In a particular embodiment of a filtering process, a fluid sample 440 may, for example, be filled into the array via inlet 410 and flows in the direction of the arrow towards filter A as indicated in Fig. 5. For example, the fluid sample may contain a multimodal particle distribution (e.g. microparticles of different diameters).

First of all, the smallest particles 442 may pass the filter A, whereas larger particles 441 are retained at this stage A of the array. If the obstacles in filter B are fully actuated, the particles are sorted towards B, if the obstacles at filter C are curled up (not actuated), and are collected at outlet 420. Subsequent increase of the effective sieve size at the stage of filter A, enables middle-sized particles 443 to pass to filter C, if filter B is de- actuated and filter C is actuated. Particles 443 may then be collected at outlet 430. Finally, the largest particles 441 may be allowed to pass filter A and are redirected to one of the filters B or C by actuating one of them and de-actuating the other one.

In doing so, a selection and sorting of particles from a fluid sample having particles with different diameters or sizes may easily and reliably be carried out.

In a particular embodiment, the actuation and de-actuation of the filters A, B, and C may be performed on a time -resolved basis, for example by individually addressing each filter according to pre-defined time intervals.

Further combinations and/or arrangements of arrays as explained above can be envisaged, allowing even more complex filtering steps and methods to be performed.

As an equivalent embodiment to the above general and specific description of the "off-state" and the "on-state" of the obstacles, it is also possible to have the extended/straightened shape of the obstacles as the (original) "off-state" without any actuation force applied. In this case, a particular arrangement of, for example, the electrodes at the obstacles and the corresponding counterelectrodes at the outer walls of the receptacle may result in a configuration in which the obstacles curl/lift upwards in an "on-state" if a force is applied. Such a configuration may, for example, be realized by arranging the counterelectrodes on the outer surface of the cover of the receptacle (instead of arranging them on the outer surface of the substrate) if the obstacles are arranged on the substrate.

While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and non-restrictive; the invention is thus not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art and 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 processor or other unit 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 considered as limiting the scope.

Claims

CLAIMS:

1. Method for filtering a microfluidic sample including particles (340; 341; 350), comprising the steps of:

(a) filling the microfluidic sample into a microfluidic environment having a selectively changeable cross section, (b) retaining particularly sized particles (350) due to the geometrical dimensions of the cross section.

2. The method of claim 1, further comprising the step of actuating at least one obstacle (110; 112; 210; 212; 310; 312) arranged in the microfluidic environment in order to selectively change the cross section of the microfluidic environment.

3. The method of claim 2, wherein more than one obstacles are arranged in the microfluidic environment and are separately actuated to selectively change the cross section of the microfluidic environment.

4. The method of claim 3, wherein the obstacles change their shape in response to the actuation and thereby perform the selective change of the cross section of the microfluidic environment.

5. The method of claim 1, further comprising the step of changing the geometrical dimensions of the cross section of the microfluidic environment on a time -resolved basis.

6. Microfluidic filter for carrying out the method of claim 1, comprising a microfluidic environment having a selectively changeable cross section, controlling means (13) adapted to selectively change the cross section of the microfluidic environment.

7. The microfluidic filter of claim 6, wherein the selective change of the cross section of the microfluidic environment is caused by the microfluidic environment being adapted to change its shape in response to an actuation.

8. The microfluidic filter of claim 6, wherein the microfluidic environment comprises at least one obstacle (110; 112; 210; 212; 310; 312) adapted to change its shape in response to an actuation and thereby adapted to perform the selective change of the cross section of the microfluidic environment.

9. The microfluidic filter of claim 8, wherein the microfluidic environment comprises a substrate (102; 201) and wherein the obstacle is attached to the substrate of the microfluidic environment.

10. The microfluidic filter of claim 6, wherein the controlling means (13) is adapted to selectively change the cross section by applying an electrostatic force and/or a magnetic force and/or a light-induced force and/or a force induced by a temperature change.

11. The microfluidic filter of claim 8, wherein the microfluidic environment comprises at least two obstacles and wherein the controlling means is adapted to separately actuate the obstacles.

12. The microfluidic filter of claim 11, wherein the controlling means is adapted to actuate the obstacles on a time-resolved basis.

13. An array of microfluidic filters for fractionation of fluid samples including particles, the array comprising at least two of the microfluidic filters of claim 6, wherein the microfluidic filters are arranged parallel or in series in flow direction of the fluid samples.

14. The array of microfluidic filters of claim 13, further comprising a central unit adapted to regularize the operation of any controlling means of the microfluidic filters.

15. The array of microfluidic filters of claim 14, wherein the central unit is adapted to modify the operation of any controlling means of the microfluidic filters in response to the receipt of an external signal.