EP1858645A1 - Systeme microfluidique et procede de commande correspondant - Google Patents

Systeme microfluidique et procede de commande correspondant

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Publication number
EP1858645A1
EP1858645A1 EP06723476A EP06723476A EP1858645A1 EP 1858645 A1 EP1858645 A1 EP 1858645A1 EP 06723476 A EP06723476 A EP 06723476A EP 06723476 A EP06723476 A EP 06723476A EP 1858645 A1 EP1858645 A1 EP 1858645A1
Authority
EP
European Patent Office
Prior art keywords
electrodes
manipulation
centering
electrode
microfluidic system
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06723476A
Other languages
German (de)
English (en)
Inventor
Torsten Müller
Thomas Schnelle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PerkinElmer Cellular Technologies Germany GmbH
Original Assignee
Evotec Technologies GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Evotec Technologies GmbH filed Critical Evotec Technologies GmbH
Publication of EP1858645A1 publication Critical patent/EP1858645A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C5/00—Separating dispersed particles from liquids by electrostatic effect
    • B03C5/02—Separators
    • B03C5/022—Non-uniform field separators
    • B03C5/026—Non-uniform field separators using open-gradient differential dielectric separation, i.e. using electrodes of special shapes for non-uniform field creation, e.g. Fluid Integrated Circuit [FIC]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C5/00—Separating dispersed particles from liquids by electrostatic effect
    • B03C5/005—Dielectrophoresis, i.e. dielectric particles migrating towards the region of highest field strength

Definitions

  • the invention relates to a microfluidic system and an associated driving method according to the preamble of the independent claims.
  • Such microfluidic systems are known, for example, from Müller, T. et al. : "A 3D microelectrode for handling and caing single cells and particles", Biosensors and Bioelectronics 14, 247-256, 1999 known and have a flat carrier flow channel for receiving a carrier stream with particles suspended therein (eg biological Cells) with a dielectrophoretic electrode assembly in the carrier flow channel to manipulate the suspended particles.
  • a carrier stream with particles suspended therein eg biological Cells
  • the suspended particles in the carrier stream may be centered by a funnel-shaped electrode arrangement ("funnel") or fixed by a so-called "hook”.
  • a disadvantage of the known microfluidic retention systems for example the above-mentioned dielectrophoretic hooks, is the fact that the particles from the dielectrophoretic electrode arrangements in the carrier flow channel can be pushed upwards or downwards in the direction of the channel wall, which is particularly troublesome in biological cells ,
  • biochips are known in which suspended particles are manipulated by electrophoresis.
  • this patent application also discloses planar dielectrophoretic field cages, each positioning a suspended particle in a bore of a plate.
  • this type of fixation leads deliberately to a physical contact between the fixed particles and the channel boundary, which is particularly disturbing in biological cells.
  • the invention is therefore based on the object of improving or simplifying the known microfluidic retaining systems described at the outset, in which case it is to be prevented that the suspended particles are pressed by the electrode arrangement in the direction of the channel wall.
  • the invention includes the general technical teaching of arranging upstream of the manipulation electrodes (e.g., a so-called "hook") centering electrodes which focus the particles suspended in the carrier stream in the central plane of the carrier flow channel and thereby prevent the suspended particles from being forced towards the channel wall.
  • the manipulation electrodes e.g., a so-called "hook” centering electrodes which focus the particles suspended in the carrier stream in the central plane of the carrier flow channel and thereby prevent the suspended particles from being forced towards the channel wall.
  • the term centering or focusing used in the context of the invention preferably means that the suspended particles are centered or focused at right angles to the flow direction.
  • the microfluidic system according to the invention has an electrode arrangement with at least two manipulation electrodes and at least two centering electrodes arranged upstream of the manipulation electrodes.
  • the two manipulation electrodes may, for example, be so-called hooks ("hooks”), which in themselves are already known from the publication by Müller, T. et al. : “A 3D microelectrode for handling and caging single cells and particles", Biosensors and Bioelectronics 14, 247-256, 1999 are known, so that the content of this publication of the present description in the design of the manipulation electrodes in full account is.
  • hooks hooks
  • the manipulation electrodes do not necessarily have to be one-piece or continuous. Rather, there is also the possibility that the individual manipulation electrodes consist of a plurality of sub-electrodes, wherein the individual sub-electrodes of the manipulation electrodes can be controlled separately. For example, the individual manipulation electrodes can also be interrupted by passivation layers.
  • the manipulation electrodes are curved against the direction of flow, as is the case for example with the known so-called hooks.
  • hook-shaped manipulation electrodes instead of hook-shaped manipulation electrodes, however, there is also the possibility that the manipulation electrodes are arc-shaped (eg semicircular) or annularly closed. They can also have the shape of a rectangle or part of a rectangle, a hexagon, or generally a polygon. The shape is therefore just as with the centering electrodes almost arbitrary.
  • the manipulation be circular electrodes, which allows the arrangement of multiple particles on closed paths.
  • the invention provides that the centering electrodes are at least partially enclosed by the manipulation electrodes arranged downstream of them.
  • the associated centering electrode is preferably arranged between the two legs of the hook-shaped manipulation electrode.
  • the associated centering electrode can be arranged inside the manipulation electrode.
  • the invention provides that the centering electrodes have a smaller spatial extent transversely to the flow direction than the manipulation electrodes, which is not the case in the case of the above-mentioned field cages with eight cubically arranged cage electrodes.
  • the centering electrodes are preferably triangular, rectangular, hexagonal, circular, circular or elliptical in shape, wherein the centering electrodes are transversely to the flow direction, preferably smaller than the manipulation electrodes.
  • the two centering electrodes can be controlled electrically separately from each other, so that the centering electrodes can be electrically driven in antiphase.
  • manipulation electrodes on the one hand and the centering electrodes on the other hand are electrically separately controlled, since the manipulation electrodes and the respectively associated centering electrodes should be electrically driven in anti-phase to achieve a centering effect.
  • the two manipulation electrodes and / or the two centering electrodes are each preferably substantially planar (i.e., plane), wherein the two manipulation electrodes on the one hand and the two centering electrodes are preferably arranged in pairs substantially coplanar.
  • the individual electrodes are arranged in two mutually parallel planes, wherein in each plane in each case a manipulation electrode and an associated centering electrode is located.
  • the proposed arrangement is more robust to offset, which simplifies the manufacture of the systems.
  • the centering electrodes and the manipulation electrodes are in this case arranged in the flow direction at a distance from each other, which is preferably in the range of 1/8 to twice the distance of the electrode planes.
  • a distance from each other which is preferably in the range of 1/8 to twice the distance of the electrode planes.
  • this is preferably in the range of 5 microns to 80 microns, with a distance of about 40 microns has been found to be particularly advantageous.
  • the electrode arrangement has a plurality of manipulation electrode pairs and these associated Zentrierelektrodencovere on.
  • the individual manipulation electrode pairs may be arranged side by side or one behind the other in the carrier flow channel with respect to the flow direction.
  • This array arrangement allows simpler and better long-term culturing of biological cells in microfluidic chips compared to conventional dielectrophoretic cages. For example, a plurality of so-called hooks can be arranged next to one another in the flow direction in order to fix suspended particles.
  • the individual manipulation electrode pairs can be electrically connected to one another, which enables a common electrical actuation, with the individual manipulation electrodes of a pair of manipulation electrodes being driven in antiphase in a conventional manner.
  • the individual manipulation electrode pairs may be at least partially electrically separated from one another and to be actuated at least partially electrically separately, which enables simple selective detection of the suspended particles.
  • the goal of the invention is to minimize the thermal loading of the suspended particles, which is particularly important in biological cells.
  • the thermal loading of the suspended particles depends on the electrode width and electrode spacing, which parameters also affect the force exerted by the electrode assembly on the suspended particles.
  • the lateral electrode width is in the range of 10% to 50% of the electrode spacing between the planes, since the ratio of the desired force to the unreacted desired heating of the suspended particles in this area is particularly good.
  • the carrier flow channel of the microfluidic system according to the invention preferably has a flow cross-section which is in the range of 0.006 mm 2 to 0.6 mm 2 , which is customary in microfluidic systems.
  • the height of the carrier flow channel may be, for example, in the range of 1 .mu.m to 400 .mu.m, while the width of the carrier flow channel may be, for example, in the range of 5 .mu.m to 1.5 mm.
  • the cross section of the carrier flow channel may be different, it may be rectangular or trapezoidal, for example.
  • Centering electrodes of the electrode assembly to be offset in the flow direction to each other.
  • the offset in the flow direction may be in the range of 5% to 95%, 10% to 90%, 20% to 80% or 30% to 70% in relation to the distance between the manipulation electrodes and the centering electrodes.
  • the possibility of offsetting the electrodes has the advantage that as a result the manufacturing process does not have to be set as high as, for example, in the already known field cages, where precise alignment of the electrodes for the functionality is fundamental.
  • the invention includes not only the microfluidic system according to the invention but also a biological device (eg a cell sorter) with such a microfluidic system.
  • a biological device eg a cell sorter
  • the invention comprises an associated drive method for such a microfluidic system.
  • the manipulation electrodes, on the one hand, and the centering electrodes assigned thereto, on the other hand are preferably driven in an ephemeral manner in order to achieve the desired centering effect.
  • the arrangement can also be operated only single-phase.
  • the activation takes place as described above, wherein the second phase is replaced by ground or free potential. This represents a significant simplification compared to the known field cage (2 or 4).
  • the centering electrodes are switched off when a particle has been fixed by the associated manipulation electrodes.
  • the trapped particles remain in the hydrodynamic flow in the central plane in front of the downstream manipulation electrodes. This reduces the thermal and electrical load on the trapped particles, which is particularly important for biological cells.
  • the deactivation of the centering electrodes can optionally be done by the centering electrodes are switched to ground or floating, the centering electrodes at a ner floating circuit have a floating electrical potential.
  • centering electrodes are briefly actuated with an increased electrical voltage before being switched off.
  • the flow velocity in the carrier flow channel can be increased shortly before the deactivation of the centering electrodes.
  • the centering electrodes serve not only for centering the suspended particles in the carrier flow channel, but also for examining the suspended particles.
  • the centering electrodes may first cause centering of the suspended particles until the suspended particles are trapped by the downstream manipulation electrodes.
  • the manipulation electrodes and the centering electrodes are electrically driven in anti-phase, as explained above.
  • the centering electrodes can then be used as measuring electrodes.
  • the centering electrodes are disconnected from the electrical control and connected to a corresponding measuring device.
  • the centering electrodes can be used as impedance measuring electrodes and perform an impedance spectroscopic examination of the trapped particles.
  • the electrode arrangement has annular manipulation electrodes both on the upper channel wall of the carrier flow channel and on the lower channel wall of the carrier flow channel.
  • the manipulation electrodes are actuated on the upper channel wall on the one hand and on the other hand on the lower channel wall on the other hand in an out-of-phase manner.
  • the manipulation electrodes on the lower channel wall are grounded and only the manipulation electrodes on the upper channel wall are electrically driven.
  • manipulation electrodes on the upper channel wall are grounded and only the manipulation electrodes on the lower channel wall are electrically driven. Furthermore, there is the possibility that the manipulation electrodes on the upper channel wall on the one hand and on the lower channel wall on the other hand are electrically controlled with a phase difference of 90 °, for example, to generate rotational fields.
  • the centering electrodes are preferably located in the center of the annular manipulation electrodes.
  • the centering electrodes can be electrically grounded.
  • the electrical control of the centering electrodes takes place on the upper channel wall on the one hand and on the other hand on the lower channel wall in electrically opposite phase.
  • annular manipulation electrodes are interrupted and in each case consist of several Reren circle segment-shaped electrode segments exist, but which are electrically connected to each other.
  • the interruptions between the individual electrode segments advantageously permit the entry of particles into the electrode arrangement or the emergence of particles from the electrode arrangement.
  • a multiplicity of electrode arrangements arranged in the form of a matrix are provided, each of which has at least one centering electrode and at least one manipulation electrode.
  • the individual electrode arrangements can in this case be constructed in accordance with the variants described above.
  • For each line of the electrode arrangements in this case preferably two line control lines are provided, wherein the a row control line is connected to the centering electrodes of the electrode arrays of the respective row, while the other row control line is connected to the manipulation electrodes of the electrode arrays of the respective row.
  • each column control line is provided for each column, wherein one column control line is connected to the centering electrodes of all the electrode arrangements of the respective column, while the other column control line is connected to the manipulation electrodes of all the electrode arrangements of the respective column ,
  • Each centering and manipulation electrode is thus connected in each case to a row control line and a column control line.
  • FIG. 1 shows a simplified perspective illustration of a microfluidic system according to the invention
  • FIGS. 2A-2D show various views of a conventional microfluidic system
  • FIGS. 3A-3D show views corresponding to FIGS. 2A-2D in the case of the microfluidic system according to the invention
  • 4A, 4B show different views of an electrode arrangement of another exemplary embodiment of a microfluidic system according to the invention
  • FIGS. 5A, 5B show a further exemplary embodiment of an electrode arrangement according to the invention
  • Figures 6A-6C further variants of possible orders in a Elektrodenan- "according to the invention mikroflu- idischen system,
  • FIGS. 7A, 7B show further exemplary embodiments of electrode arrangements which can be used in a microfluidic system according to the invention
  • FIG. 8 is a graph showing the heating produced by the electrode assembly and the force applied to the suspended particles as a function of electrode width and electrode spacing;
  • FIGS. 9A-9E show further variants of electrode arrangements in a microfluidic system according to the invention.
  • FIG. 10 shows different views of an electrode arrangement in a further exemplary embodiment of a microfluidic system according to the invention
  • FIG. 11 shows different views of further electrode arrangements
  • FIG. 12 shows different views of further electrode arrangements, in which the centering electrodes on the one hand and the manipulation electrodes on the other hand are driven with different frequencies
  • FIGS. 13A, 13B show a variant of the embodiment according to FIGS. 5A and 5B
  • 14A, 14B show a further variant of an embodiment according to the invention with circular centering electrodes and annular manipulation electrodes
  • FIGS. 15A, 15B show yet another embodiment of an arrangement according to the invention with circular centering electrodes of annular manipulation electrodes, wherein the control of the centering electrodes takes place in a different manner
  • FIG. 16B shows an alternative embodiment with circular segment-shaped manipulation electrodes and circular centering electrodes
  • 17A, 17B show a further embodiment with annular manipulation electrodes and circular centering electrodes
  • FIGS. 19A-19C show further variants of electrode structures according to the invention.
  • FIG. 20 shows an electrode structure according to the invention with a plurality of electrode arrangements, each of which has centering and manipulation electrodes.
  • FIG. 1 shows a carrier flow channel 1 of a microfluidic system, as can be used, for example, in a cell sorter for sorting biological cells.
  • the cell sorter itself may in this case be designed in a conventional manner, so that a detailed description of the cell sorter can be omitted below.
  • the carrier flow channel 1 in this case has a rectangular cross-section with a height of 40 microns and a width of 150 microns and carries a carrier stream with particles suspended therein, with only a biological cell 2 is shown schematically for simplicity.
  • the carrier stream with the biological cells 2 suspended therein flows in the carrier flow channel 1 in the x-direction, as illustrated by the arrows.
  • an electrode assembly 3 is arranged, which consists of two hook-shaped manipulation electrodes 4, 5 and two circular centering electrodes 6, 7.
  • the two manipulation electrodes 4, 5 are formed in a conventional manner and are driven accordingly, which from the already mentioned above publication by Müller, T. et al. : “A 3D microelectrode for handling and caging single cells and particles", Biosensors and Bioelectronics 14, 247-256, 1999 is known so as to avoid
  • the two manipulation electrodes 4, 5 are each formed planar and coplanar with each other, wherein the manipulation electrode 4 is disposed on the upper channel wall of the carrier flow channel 1, while the other manipulation electrode 5 at the lower channel wall of Carrier flow channel 1 is arranged.
  • the two centering electrodes 6, 7 are also planar and aligned coplanar with each other, wherein the centering electrode 6 is disposed on the upper channel wall of the carrier flow channel 1, while the centering electrode 7 at the lower channel wall of the carrier flow channel 1 is arranged.
  • the centering electrode 6 thus lies with the manipulation electrode 4 in a plane, while the centering electrode 7 lies with the manipulation electrode 5 in a plane.
  • the manipulation electrodes 4, 5 are electrically driven in opposite phase to each other, as well as the centering electrodes 6, 7 are electrically driven in opposite phase to each other.
  • the centering electrode 6 is also driven in phase opposition to the associated manipulation electrode 4, just as the centering electrode 7 is also driven in antiphase to the associated manipulation electrode 5.
  • the suspended biological cells 2 are focused in the carrier flow channel 1 in the central plane, whereby a contact contact of the biological cells 2 with the channel walls of the carrier flow channel 1 is prevented.
  • the centering electrodes 6, 7 and the manipulation electrodes 4, 5 do not have to be controlled exactly in antiphase (ie with a phase shift of 180 °). Rather, other phase shifts are possible within the scope of the invention.
  • This phase shift may be arbitrary between the electrodes at the upper channel wall and at the lower channel wall, said shift generally being between 90 ° and 270 °.
  • the displacement is generally in the range of 135 ° -225 ° (180 ° + 45 °).
  • the centering electrodes 6, 7 and the manipulation electrodes 4, 5 can also be driven with different frequencies and voltages, as will be described in detail later.
  • FIGS. 3A-3D show different views of the electrode arrangement 3 in the case of the microfluidic system according to the invention, FIGS. 3B-3C showing the respective electric field distribution.
  • FIGS. 3A and 3B show a plan view of the electrode arrangement 3 in the z-direction, while FIGS. 3C and 3D reproduce sectional images in the y-z plane and the x-z plane, respectively.
  • FIGS. 2A-2D show, for comparison, corresponding views in a conventional electrode arrangement without the centering electrodes 6, 7. It can thus be seen that the biological cells 2 are pressed in the direction of the channel wall in the conventional electrode arrangement, in particular from FIGS. 2C and 2D is apparent. In contrast, the biological cells 2 in the inventive
  • Electrode arrangement 3 centered, as can be seen in particular from Figures 3C and 3D.
  • FIGS. 4A and 4B show an alternative embodiment of an inventive electrode arrangement with semicircular manipulation electrodes 8, wherein the illustrations on the left side show a corresponding conventional electrode arrangement without centering electrodes, while the illustration on the right side shows the field distribution in an electrode arrangement according to the invention with a centering electrode 9 show. It can also be seen from these illustrations that the centering electrode 9 has centering of the biological cells 2 in the central plane of the carrier power cable. nals 1 and additionally causes a fixation against the flow in the x direction.
  • FIGS. 5A and 5B show an alternative exemplary embodiment of an electrode arrangement according to the invention, in which an annular manipulation electrode (with rim 10, 11) and also a concentric, centrally arranged centering electrode 12 are provided.
  • the manipulation electrode (10, 11) and the centering electrode 12 are in this case arranged in a common plane on the upper channel wall or on the lower channel wall of the carrier flow channel 1 and thus aligned coplanar.
  • the biological cells 2 can be arranged in this embodiment on closed tracks, as can be seen in particular from the illustration in Figure 5A.
  • Figures GA-6C show further alternative embodiments of electrode assemblies according to the invention 13, 13 'and 13 ", each having a manipulation electrode 14, 14', or 14" and a centering electrode 15, 15 ', 15 ".
  • such an electrode arrangement 13, 13 'or 13 " is respectively arranged on the upper channel wall and on the lower channel wall.
  • FIGS. 7A and 7B show further exemplary embodiments of electrode arrangements 16 and 17 according to the invention, in which a plurality of hook-shaped manipulation electrodes 18-21 are arranged next to one another in the carrier flow channel 1 in the flow direction. Upstream of the individual manipulation electrodes 18-21, in each case a centering electrode 22-25 is arranged in order to center the biological cells 2 in the central plane of the carrier flow channel 1.
  • the difference between the embodiments according to FIGS. 7A and 7B consists in the electrical supply of the manipulation electrodes 18-21 and the centering electrodes 22-25.
  • the manipulation electrodes 18-21 of the electrode assembly 16 are electrically driven together according to Figure 7A and are therefore electrically connected to each other.
  • the manipulation electrodes 18-21 are electrically separated from one another, so that the manipulation electrodes 18-21 are also not electrically connected to one another.
  • the centering electrodes 22-25 are electrically driven together, which is also the case with the electrode arrangement 17 according to FIG. 7B.
  • FIGS. 7A and 7B In the carrier flow channel of the microfluidic system according to the invention, several of the electrode arrangements 16 and 17 illustrated in FIGS. 7A and 7B can also be arranged one behind the other in the flow direction. This provides the ability to store particles in defined arrays.
  • FIG. 7A / B Several electrode arrangements according to FIG. 7A / B can be found in FIG. 7A / B.
  • Flow direction can be arranged one behind the other so as to be able to store particles in defined arrays.
  • Figure 8 shows a diagram showing the functional dependence of several different sizes on the electrode width and the electrode spacing.
  • a curve 26 indicates the dependence of the heating ⁇ T of the suspended biological cells 2 as a function of the ratio between electrode width and electrode spacing between the planes at constant voltage again. It can be seen from the course of the curve 26 that the heating ⁇ T of the suspended cells 2 increases with the electrode width and decreases with the electrode spacing. It should be noted that the heating of the biological cells 2 by the dielectrophoretic electrode arrangement for the biological cells 2 can be harmful and therefore undesirable.
  • a further curve 27 shows the dependence of the force F exerted on the biological cell 2 by the dielectrophoretic electrode arrangement as a function of the ratio of the electrode width to the electrode spacing. It can be seen from the course of the curve 27 that the exerted force F increases with the electrode width and decreases with the electrode spacing.
  • Another curve 28 shows the ratio of the desired force F to the unwanted heating ⁇ T of the suspended cells as a function of the ratio of electrode width to electrode gap. It can be seen from the course of the curve 28 that a certain operating range is particularly advantageous, in which the ratio of electrode width to electrode gap is approximately between 0.15 to 0.5. In this region, the force exerted by the electrode assembly on the suspended particles is relatively large relative to the undesirable heating ⁇ T.
  • FIGS. 9A to 9E show further exemplary embodiments of electrode arrangements which can be used in a microfluidic system according to the invention.
  • the individual electrode arrangements each consist of a centering electrode 29 and a manipulation electrode 30.
  • the centering electrode 29 would thus take the place of the centering electrodes 6 and 7 in the embodiment according to FIG. 1, while the manipulation electrode 30 replaces the manipulation electrodes 4 and 5.
  • the different electrode arrangements according to FIGS. 9A to 9E differ here by the shape of the centering electrode 29.
  • the centering electrode 29 can be rectangular, triangular, drop-shaped, angular or box-shaped, as can be seen from the various figures.
  • FIG. 10 shows different views of a further exemplary embodiment of an electrode arrangement in a microfluidic system according to the invention. This embodiment is largely consistent with the embodiment described above and shown in Figures 1 and 3, so reference is made to avoid repetition of the above description.
  • a special feature of this embodiment is that the upper manipulation electrode 4 is arranged offset in the flow direction with respect to the lower manipulation electrode 5.
  • the upper centering electrode 6 is offset relative to the lower centering electrode 7 in the flow direction.
  • the offset here corresponds to half the distance between the manipulation electrodes 4, 5 and the associated centering electrodes 6, 7.
  • the images on the left side of FIG. 10 show field distributions that arise when the manipulation electrodes 4, 5, on the one hand, and the centering electrodes, on the other hand, are driven with the same electrical voltage.
  • FIG. 11 shows different views of a further exemplary embodiment of an electrode arrangement in a microfluidic system according to the invention. This embodiment is largely consistent with the embodiment described above and shown in Figures 1 and 3, so reference is made to avoid repetition of the above description.
  • a special feature of this embodiment is that on the other hand there is a phase shift of 90 ° between the manipulation electrode 4 and the centering electrode 6 on the upper channel wall on the one hand and the manipulation electrode 5 and the centering electrode 7 on the lower channel wall.
  • manipulation electrodes 4, 5 on the one hand and the centering electrodes 6, 7 on the other hand driven with a phase shift of 90 °. This is shown in the left column of FIG.
  • FIG. 12 shows different views of a further exemplary embodiment of an electrode arrangement in a microfluidic system according to the invention. This embodiment is largely consistent with the embodiment described above and shown in Figures 1 and 3, so reference is made to avoid repetition of the above description.
  • a special feature of this embodiment is that the manipulation electrodes 4, 5 on the one hand and the centering electrodes 6, 7 on the other hand are driven with different frequencies.
  • the images in the left-hand column show the field distribution for the case in which the manipulation electrodes 4, 5 and the centering electrodes 6, 7 are driven with the same voltage values, the drive frequency Fl or F2 being selected such that the cells 2 are equal experience strong polarization in both fields.
  • the polarization of the particle relative to the medium at the frequency F2 is only 1/4 of the polarization at the frequency Fl.
  • FIGS. 13A and 13B corresponds largely to the exemplary embodiments described above and to FIGS. 5A and 5B, so that reference is made to the above description for avoiding repetitions, the same reference numerals being used for corresponding components.
  • a special feature of this embodiment is the diameter of the manipulation electrode 10, which is lower compared to the embodiment according to Figures 5A, 5B.
  • manipulation electrodes 10, 11 on the one hand and the centering electrode 12 on the other hand be driven in opposite phase in this embodiment, as can be seen from the phase indication in Figure 13B.
  • this embodiment also follows an opposite-phase control of the electrodes on the upper channel wall on the one hand and on the -unteren channel wall on the other.
  • the manipulation electrode 10 on the upper channel wall on the one hand and the manipulation electrode 10 are driven in anti-phase to the lower channel wall.
  • the centering electrodes 12 on the upper channel wall are driven in opposite phase to the centering electrodes 12 on the lower channel wall.
  • the electric fields are formed in this electrode structure in such a way that the cells 2 are caught centrally and not on a ring, as in FIG. 5.
  • FIGS. 14A and 14B corresponds largely to the exemplary embodiment described above and illustrated in FIGS. 13A and 13B, so that reference is made to the above description for avoiding repetitions, the same reference numerals being used for corresponding components.
  • a special feature of this embodiment is that the centering electrodes 12 are connected to ground. As a result, the trapped cells 2 are brought in the Z direction in the vicinity of the manipulation electrode 10 and thus in flow-stabilized zones. This has the advantage that a stable holding in free solution can be realized with reduced electrical (heating) power.
  • FIGS. 15A and 15B again largely agrees with that described above and in FIG 14A and 14B illustrated embodiment, so reference is made to avoid repetition of the above description, wherein the same reference numerals are used for corresponding components.
  • a special feature of this embodiment is the electrical control of the centering electrodes 12 on the upper side and the underside of the carrier current channel.
  • the control of the centering electrode 12 at the upper channel wall is performed with ground, while the centering electrode 12 is driven at the lower channel wall in opposite phase to the upper manipulation electrode 10 as can be seen from the phase indication in Figure 15B.
  • FIGS. 16A and 16B corresponds largely to the exemplary embodiment described above and illustrated in FIGS. 13A and 13B, so that reference is made to the above description for avoiding repetitions, the same reference numerals being used for corresponding components.
  • the manipulation electrode 10 consist of four annular segment-shaped electrode segments 3IA, 31B, 31C and 31D.
  • the individual electrode segments 31A-31D are in this case electrically connected to each other and therefore only spatially separated from each other so that the trapped cells 2 can more easily enter and leave the X-direction and Y-direction in the field cage.
  • FIGS. 17A and 17B largely corresponds to the exemplary embodiments described above, so that reference is made to the above description in order to avoid repetition, wherein FIG the same reference numerals are used for corresponding components.
  • a special feature of this embodiment is the electrical control of the manipulation electrode 10 and the centering electrodes 12.
  • the manipulation electrode 10 at the top of the channel wall and the manipulation electrode 10 at the bottom of the channel wall are driven in this embodiment with a phase difference of 90 °.
  • the two centering electrodes 12 are driven in opposite phase at the top or at the bottom of the carrier flow channel. In this way, rotation fields are generated in the field cage.
  • FIG. 18 shows a matrix-like arrangement of a multiplicity of circular or annular electrode arrangements 32, the individual electrode arrangements 32 each having manipulation electrodes and centering electrodes, as described above.
  • the individual electrode arrangements 32 are actuated by line control lines 33 and column control lines 34.
  • the associated row control lines 33 and the associated column control lines 34 are switched to ground or free potential , With this, all the cells remain fixed with the exception of the cell held in the relevant electrode arrangement 32. In the affected electrode assembly 32, however, all electrodes are grounded, so that the particles therein can leave the associated electrode assembly 32 with the carrier flow.
  • FIGS. 19A-19C show different variants of electrode arrangements according to the invention with centering electrodes 35 and manipulation electrodes 36, the manipulation electrodes 36 each consisting of four segments surrounding the centering electrode 35.
  • manipulation electrodes 36 still have funnel-shaped electrode arrangements ("funnel"), as described initially in the description of the state of the art
  • FIG. 20 shows a multiplicity of electrode arrangements which largely correspond to the electrode arrangements according to FIGS. 19A-19C, so that reference is made to the above description to avoid repetition, the same reference symbols being used for corresponding components. 1
  • a special feature of this embodiment is that downstream of the individual electrode arrangements, in each case particle switches 37 are arranged, which make it possible to selectively convey the exiting particles into the downstream electrode structure or to deflect them laterally.

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  • Microelectronics & Electronic Packaging (AREA)
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Abstract

L'invention concerne un système microfluidique comportant un canal de flux porteur (1) destiné à recevoir un flux porteur contenant des particules en suspension (2), et au moins un système d'électrodes (3) disposé dans le canal de flux porteur (1), destiné à la manipulation des particules en suspension (2), ledit système d'électrodes (3) présentant deux électrodes de manipulation (4, 5). Selon l'invention, ledit système d'électrodes (3) présente, en plus des deux électrodes de manipulation (4, 5), deux électrodes de centrage (6, 7) destinées au centrage des particules. Les deux électrodes de centrage (6, 7) sont disposées en amont d'une des deux électrodes de manipulation (4, 5) dans le canal de flux porteur (1). L'invention concerne également un procédé de commande correspondant.
EP06723476A 2005-03-16 2006-03-16 Systeme microfluidique et procede de commande correspondant Withdrawn EP1858645A1 (fr)

Applications Claiming Priority (2)

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DE102005012128A DE102005012128A1 (de) 2005-03-16 2005-03-16 Mikrofluidisches System und zugehöriges Ansteuerverfahren
PCT/EP2006/002431 WO2006097312A1 (fr) 2005-03-16 2006-03-16 Systeme microfluidique et procede de commande correspondant

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EP1858645A1 true EP1858645A1 (fr) 2007-11-28

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US (1) US20090008254A1 (fr)
EP (1) EP1858645A1 (fr)
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WO (1) WO2006097312A1 (fr)

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ITTO20070771A1 (it) 2007-10-29 2009-04-30 Silicon Biosystems Spa Metodo e apparato per la identificazione e manipolazione di particelle
IT1391619B1 (it) 2008-11-04 2012-01-11 Silicon Biosystems Spa Metodo per l'individuazione, selezione e analisi di cellule tumorali
US10895575B2 (en) 2008-11-04 2021-01-19 Menarini Silicon Biosystems S.P.A. Method for identification, selection and analysis of tumour cells
US10274492B2 (en) * 2015-04-10 2019-04-30 The Curators Of The University Of Missouri High sensitivity impedance sensor

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WO2006097312A1 (fr) 2006-09-21
DE102005012128A1 (de) 2006-09-21
US20090008254A1 (en) 2009-01-08

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