DE102020202274A1 - Microfluidic channel element for improved separation of target particles from non-target particles within a medium on the basis of dielectrophoresis - Google Patents

Abstract

Microfluidic channel element for improved separation of target particles (1) from non-target particles (2) within a medium on the basis of dielectrophoresis, comprising a base (21) and an electrode arrangement (3, 4) which has a plurality of planar electrodes (3, 4 ) each having at least one edge, the electrode arrangement (3, 4) being arranged on the bottom (21) in such a way that the medium flows past the electrode arrangement (3, 4) so that the target particles (1) are within the medium captured by the planar electrodes (3); and wherein the electrode arrangement (3, 4) is covered with an insulator material (15) in such a way that a trough-shaped free space (18) with a depth (16) and a width (17) in the region of the at least one edge (20) of the respective planar Electrodes (3, 4) is shaped so that the captured target particles (1) are protected from the non-target particles (2) and the medium flowing past by the trough-shaped free space (18).

Description

State of the art

The present invention relates to a microfluidic channel element for improved separation of target particles from non-target particles within a medium on the basis of dielectrophoresis or to a device comprising the microfluidic channel element.

Dielectrophoresis is a well-known phenomenon about the movement of electrically uncharged / neutral particles in a spatially inhomogeneous electric field, which induces a dipole moment in the respective particles, so that the particles experience a force due to the interaction of the dipole moment and the inhomogeneous electric field and move as a result . In practice, the movement of the particles, which are made up of target particles and non-target particles, is manipulated by controlling the electric field, so that the target particles are separated from the non-target particles.

The target particles can be, for example, circulating tumor cells, the detection of which from blood is of great importance for the diagnosis and therapy of malignant tumors and metastases. However, the circulating tumor cells are extremely rare in the blood and their cell properties (heterogeneity) are very inconsistent, which is why a reliable separation of circulating tumor cells (target particles) from healthy blood cells (non-target particles) proves to be a major challenge.

The separation of the target particles by means of dielectrophoresis is normally realized by planar electrodes which are arranged in a microfluidic channel that is very limited in length, width and height (e.g. length and width <50 mm, height <100 μm). A medium, comprising the target particles and the non-target particles, flows through the microfluidic channel past the planar electrodes. In order to be able to separate (receive) the target particles from the non-target particles by the planar electrodes, different parameters with regard to the dielectrophoresis in connection with the fluid mechanics have to be defined in advance and regulated in real time. The parameters are, for example, flow speed of the medium, density of the particles in the medium, electrical field strength, etc.

However, the separation purity and the separation efficiency can only be increased with difficulty, despite the most optimal design of the parameters due to the extreme space restriction of the microfluidic channel and the resulting possible increased dipole-dipole interactions and mechanical-hydrodynamic interactions between the particles, because the target particles with the non-target particles and other target particles can easily cluster.

Therefore, in addition to the parameters, it is conceivable that the trapping traps can be better constructed in relation to the planar electrodes, for example by forming physical barriers in the area of the electrodes, which can prevent the particles from clustering. This increases the separation purity and separation efficiency. This is particularly advantageous for the separation of circulating tumor cells from blood cells because of their extreme rarity and / or the separation of target particles from non-target particles which have very similar dielectric properties and distributions within a medium.

Disclosure of the invention

Proceeding from this, a particularly advantageous microfluidic channel element for the improved separation of target particles from non-target particles within a medium on the basis of dielectrophoresis is described here. Advantageous further developments are specified in the dependent claims. The description, in particular in connection with the figures, explains the invention and specifies further advantageous design variants. The features mentioned individually in the patent claims can be combined with one another as desired and / or specified / exchanged with features of the description.

A microfluidic channel element is described here for the improved separation of target particles from non-target particles within a medium on the basis of dielectrophoresis, comprising a base and an electrode arrangement which has a plurality of planar electrodes each having at least one edge, the electrode arrangement such as: the ground is arranged so that the medium flows past the electrode arrangement so that the target particles within the medium are captured by the planar electrodes; and wherein the electrode arrangement is covered with an insulator material in such a way that a trough-shaped free space is formed with a depth and a width in the region of the at least one edge of the respective planar electrodes, so that the captured target particles pass through the trough-shaped free space in front of the non-target particles and the flowing past Medium to be protected.

The described microfluidic channel element can be used in particular in a microfluidic system of any kind (e.g. lab-on-chip system) for the separation of target particles (e.g. biological cells) from non- Target particles are used on the basis of dielectrophoresis.

The microfluidic channel element generally has at least one inlet so that liquid can flow through the at least one inlet into the microfluidic channel element. There is also preferably at least one outlet for a pressure drop through which the medium can flow off. This is necessary, for example, for a pressure-operated drive of the liquid). The particles composed of target particles and non-target particles are diluted by a medium. The medium with the particles thus flows as a liquid through the at least one inlet into the microfluidic channel element, the bottom of the microfluidic channel element serving, for example, to carry the medium flowing past. The medium preferably flows out of the microfluidic channel element again through at least one outlet. I. E. the medium usually contacts the ground as it flows through the microfluidic channel element.

At least one positive electrode and at least one negative electrode are required to generate an electric field. Electrodes arranged next to one another are usually polarized alternately with one another. This means, for example, that a positively polarized electrode (+ -electrode) is (only) arranged adjacent to negatively polarized electrodes (--electrodes). The electrodes used here are planar electrodes whose thickness (d _electrode ) is much smaller than the size of the target particles (d _{target particles} ), e.g. B. only a few hundred nm (nanometers) to a few µm (micrometers). The electrodes can be divided into working electrodes and reference electrodes, the working electrodes being relevant for receiving the target particles and the reference electrodes being relevant for generating electrical fields. However, there may be no physical differences between working electrodes and reference electrodes.

All electrodes powered by electricity (“+” and “-”) are involved in the generation of electrical fields. In this way, the target particles within reach can (s) also be drawn to all participating electrode edges in the case of positive mediated forces (pDEP).

At least a plurality of electrodes are arranged on the floor, which electrodes exert effective forces on the target particles by applying current signals. Thus, the target particles that flow past the ground are caught by the electrodes as catching traps, the captured target particles usually being collected at the edges of the electrodes.

The dielectrophoretic force on a (spherical) particle can be calculated in the simplest case with the help of the so-called Clausius-Mossotti factor f̃ _CM. It links microscopic and macroscopic polarization effects or perceptions and is of decisive importance for calculating the sign and the amplitude of the dielectrophoretic force. The Clausius-Mossotti factor f̃ _CM can be calculated as follows: $${\tilde{f}}_{\mathrm{C.}\mathrm{M.}}=\frac{{\tilde{\epsilon }}_p-{\tilde{\epsilon }}_m}{{\tilde{\epsilon }}_p+2\cdot {\tilde{\epsilon }}_m}$$

> im allgemeinsten Fall für ein räumlich stationäres elektrisches Feld wie folgt berechnen: $$<{\overrightarrow{F}}_{DEP}>=2\cdot \pi \cdot {\epsilon }_m\cdot Re\left({\tilde{f}}_{CM}\right)\cdot R^3\cdot \overrightarrow{\nabla }{\left|{\overrightarrow{E}}_{RMS}\right|}^2$$

Here ε̃ _p corresponds to the absolute complex electrical permittivity of the particle and ε̃ _{m to} the absolute complex electrical permittivity of the medium. The time-averaged dielectrophoretic force < ${\overrightarrow{\mathrm{F.}}}_{\mathrm{D.}\mathrm{E.}\mathrm{P.}}$

> in the most general case for a spatially stationary electric field, calculate as follows: $$<{\overrightarrow{\mathrm{F.}}}_{\mathrm{D.}\mathrm{E.}\mathrm{P.}}>=2\cdot \pi \cdot {\epsilon }_m\cdot \mathrm{R.}e\left({\tilde{f}}_{\mathrm{C.}\mathrm{M.}}\right)\cdot {\mathrm{R.}}^3\cdot \overrightarrow{\nabla }{\left|{\overrightarrow{\mathrm{E.}}}_{\mathrm{R.}\mathrm{M.}\mathrm{S.}}\right|}^2$$

der räumlichen Feldinhomogenität und ${\overrightarrow{E}}_{RMS}$

der zeitgemittelten elektrischen Feldstärken. Die Gleichung (2) basiert auf der sogenannten Multipol-Entwicklung in der ersten Ordnung. Kraftausdrücke höherer Ordnung sind Multipolmomenten zuzuweisen, die ab Ordnung 2 aber dann auch per Definition bereits keine „Dielektrophorese“ mehr sind (z. B. n =2: Quadrupolmonent, n=3: Oktupolmonent, usw.).Where R corresponds to the radius of the particle, $\overrightarrow{\nabla }$

the spatial field inhomogeneity and ${\overrightarrow{\mathrm{E.}}}_{\mathrm{R.}\mathrm{M.}\mathrm{S.}}$

the time-averaged electric field strengths. The equation (2) is based on the so-called multipole expansion in the first order. Stronger expressions of higher order are to be assigned to multipole moments that are from order 2 but then, by definition, they are no longer “dielectrophoresis” (e.g. n = 2: quadrupole moment, n = 3: octupole moment, etc.).

Furthermore, the absolute complex electrical permittivity ε̃ can be calculated as follows: $$\tilde{\epsilon }=\epsilon -j\cdot \frac{\sigma }{\omega }$$

der komplexen Einheit, σ der elektrischen Leitfähigkeit und ω der Kreisfrequenz des angelegten elektrischen Feldes.Here ε corresponds to the absolute real electrical permittivity, $j=\sqrt{-1}$

the complex unit, σ the electrical conductivity and ω the angular frequency of the applied electric field.

Depending on the sign of the real part of the Clausius-Mossotti factor Re (f̃ _CM ), which is dependent on the frequency of the electric field and the relative coordination between frequency-dependent absolute real electrical permittivity ε and electrical conductivity σ between medium and particle (inner) , for manipulation, either an attractive (pDEP) or a repulsive (nDEP) dielectrophoretic force can be produced on individual particles. It will the frequency at which the force effect for a particular type of particle just changes its sign is referred to as the transition frequency f _c .

• < F_pDEP>: zeitgemittelte dielektrophoretische Kraft auf ein Zielpartikel
• < F_pDEP,z>: zeitgemittelte dielektrophoretische Kraftkomponente in z-Richtung auf ein Zielpartikel
• < F_pDEP,_y>: zeitgemittelte dielektrophoretische Kraftkomponente in y-Richtung auf ein Zielpartikel
• F_Steric,_y: durch den Boden bei Kontakt vermittelte sterische Kraft in y-Richtung auf ein Zielpartikel
• F_Lift: auftreibende „Hydrodynamic-Lift-Force“ in y-Richtung auf ein Zielpartikel F_Steric,_z: durch eine Wand bei Kontakt vermittelte sterische Kraft in der Strömungsrichtung des Mediums in z-Richtung auf ein Zielpartikel
• F_Stokes: Strömungskraft in der Strömungsrichtung des Mediums in z-Richtung
• < F_{Destabilizing}>: zeitgemittelte destabilisierende Kraft als Überlagerung aus sämtlichen störenden fluktuierenden Einflüssen (z. B. Temperatureinflüsse, etc.) auf ein Zielpartikel in z-Richtung

In order to be able to receive the target particles, at least forces with regard to fluid mechanics in connection with dielectrophoresis are considered as follows:

• <F _pDEP >: time-averaged dielectrophoretic force on a target particle
• <F _{pDEP, z} >: time-averaged dielectrophoretic force component in the z-direction on a target particle
• <F _pDEP , _y >: time-averaged dielectrophoretic force component in the y-direction on a target particle
• F _Steric , _y : steric force imparted by the soil upon contact in the y-direction on a target particle
• F _Lift : upward “hydrodynamic lift force” in the y-direction on a target particle F _Steric , _z : steric force in the flow direction of the medium in the z-direction on a target particle mediated by a wall upon contact
• F _Stokes : flow force in the direction of flow of the medium in the z-direction
• <F _{Destabilizing} >: time-averaged destabilizing force as a superposition of all disruptive fluctuating influences (e.g. temperature influences, etc.) on a target particle in the z-direction

The direction of flow of the medium is called the z-direction and the direction perpendicular to the z-direction is called the y-direction. The y-direction is preferably oriented parallel to the weight of the particles. In a simplifying assumption for the considerations, the channel is extended infinitely in the x-direction, the electric field and the flowing fluid thus have no components in the x-direction. The forces therefore act in the z-direction and y-direction and maintain the equilibrium in the two directions in the trapped state.

In the y direction, the time-averaged dielectrophoretic force component in the y direction <F _pDEP , _y > should be at least greater than the force F _Lift so that a target particle can be attracted by a working electrode. During / after contact with the ground or in the trapped state, the time-averaged dielectrophoretic force component in the y-direction <F _pDEP , _y > (in the negative y-direction) should be equal to the sum of the force F _{Steric, y} and the force F _Lift (in positive y-direction).

Aus der Gleichung (4) geht hervor, dass der Abfall in der Separationseffizienz umso größer ist, je kleiner <ΔF_pDEP,_z> gegenüber der Strömungskraft F_Stokes ist. Dies trifft insbesondere auf dielektrisch sehr ähnliche Partikel mit geringen Unterschieden in den Übergangsfrequenzen f_c zu. Daher kann der Durchsatz durch die Steigerung der Strömungsgeschwindigkeit des Mediums nur in beschränktem Maß erhöht werden, wenn es kein in y-Richtung überzogenes Isolatormaterial gibt, da die resultierende Strömungskraft F_Stokes auf keinen Fall die dielektrophoretische Kraftkomponente parallel zur Strömungsrichtung der Zielpartikel < F_pDEP,_z> dominieren oder die Zielpartikel gar beschädigen darf. Daher können die Separationsreinheit und die Separationseffizienz trotz der optimalsten Auslegung der oben beschriebenen Parameter mit klassischen planaren Elektroden nur schwer erhöht werden.In the z-direction, the time-averaged dielectrophoretic force component <F _pDEP , _z > at an operating frequency between the transition frequencies of the target particles and the non-target particles (target particles with pDEP vs. non-target particles with nDEP) in relation to the flow force F _{Stokes can be} calculated as follows regard: $$\frac{<\Delta {\mathrm{F.}}_{\mathrm{D.}\mathrm{E.}\mathrm{P.},z}\left(f_c\right)>}{{\mathrm{F.}}_{\mathrm{S.}tOkes}}=\frac{\frac{1}{2}\cdot \left(<\left|{\mathrm{F.}}_{p\mathrm{D.}\mathrm{E.}\mathrm{P.},z}\left(f_c\right)\right|+|{\mathrm{F.}}_{n\mathrm{D.}\mathrm{E.}\mathrm{P.},z}\left(f_c\right)>\right)}{{\mathrm{F.}}_{\mathrm{S.}tOkes}}\to 1$$

From equation (4) it can be seen that the decrease in the separation efficiency is greater, the smaller <ΔF _pDEP , _z > is compared to the flow force F _Stokes . This applies in particular to dielectrically very similar particles with slight differences in the transition frequencies f _c . Therefore, the throughput can only be increased to a limited extent by increasing the flow velocity of the medium if there is no insulating material coated in the y-direction, since the resulting flow force F _Stokes in no case does the dielectrophoretic force component parallel to the flow direction of the target particles <F _pDEP , _z > dominate or even damage the target particles. Therefore, the separation purity and the separation efficiency can only be increased with difficulty with classic planar electrodes, despite the most optimal design of the parameters described above.

In order to be able to further increase the separation purity and the separation efficiency in addition to the most optimal design of the parameters, the electrode arrangement is covered with a structured insulator material in the y-direction in such a way that a trough-shaped free space with a depth and a width in the area of the edges of the respective electrodes is formed will. As a result, physical barriers are formed which, for. B. can protect against clustering of particles.

The depth of the trough-shaped free space is oriented in the y-direction and the width in the z-direction. Thus, the target particles within the medium can be trapped by the trough-shaped free space of the respective electrodes like in a trap, and at the same time the trapped target particles are protected by the trough-shaped free space as a physical barrier from the non-target particles and the medium flowing past. Thus, the separation purity and the separation efficiency are increased.

With the planar electrode arrangement with the structured coating of insulator material in comparison with the classic planar electrode arrangement based on the trapping principle under otherwise identical operating conditions (equally undefined flow conditions, same medium, same voltage and frequency settings, etc.), the same dimensions of the microfluidic channels and the same density of electrodes arranged on the floor, the throughput of the medium with the particles contained therein (target and non-target particles) can be increased. Thus, the separation purity and the separation efficiency are increased.

The increase in throughput can be achieved, for example, by increasing the flow velocity of the medium and / or by increasing the particle charge density (i.e. the particles are less diluted with the medium).

In a preferred embodiment, the target particles are circulating tumor cells and the non-target particles are healthy blood cells.

The radius of the respective circulating tumor cells is typically larger than the radius of the respective healthy blood cells. Equation (2) shows that the amount of dielectrophoretic force of a particle depends on its radius. I. E. the larger the radius of a particle, the greater the time-averaged dielectrophoretic force when the particle is in the same electrical field and medium.

Tumor cells also have a higher normalized surface capacity (ie surface capacity per area) and are therefore more “wrinkled” than relatively smooth, healthy blood cells. Along with the size (aspect 1 ), arises with the "wrinkle" (aspect 2 ) a generally lower transition frequency for tumor cells than for healthy blood cells and thus (strongly) different dielectric properties.

Therefore, the separation of circulating tumor cells from healthy blood cells is achieved by controlling the dielectrophoretic force of the two cell types by selecting a suitable operating frequency between the transition frequencies of tumor cells and healthy blood cells according to equation (3). The operating frequency is usually selected in such a way that positive dielectrophoretic forces (pDEP) are exerted on tumor cells (target particles) and negative dielectrophoretic forces (nDEP) are exerted on healthy blood cells. Here, pDEP acts in the direction of the maximum field strength (e.g. towards the electrode edges), nDEP in exactly the opposite direction in the direction of the minimum field strength (e.g. away from the electrode edges). Thus, there is a countermovement to the separation of the two cell types.

In a further preferred embodiment, the depth of the trough-shaped free space is less than or approximately equal to the extent of the target particles.

The depth of the trough-shaped free space (h _trough ) corresponds to the thickness of the insulator material coated in the y-direction and must not be too large. Preferably, the upper limit of the depth _{must not exceed the extent of the target particles (d target particles} ) (ie h _well ≲ d _{target particles} ). Otherwise target particles in the medium flowing past will be removed far too far from the electrode edges if the insulator material is coated too high in the y-direction, so that the DEP force has rapidly decayed and no longer has any effect, so that the amount of the dielectrophoretic force component of the respective target particles <F _DEP , _y > Is not large enough to attract the target particles to the electrodes. On the other hand, the too high-coated insulator material prevents the trapped target particles from being reliably flushed out of the trap traps (ie tub-shaped free spaces) after the electrical fields have been switched off. In addition, the tub-shaped free spaces can only be filled with the medium (typically water-like) with difficulty if the depth (h _tub ) is too great.

In a further preferred embodiment, the depth of the trough-shaped free space is greater than half the extent of the target particles.

So that the absolute flow forces on a target particle (“slipstream effect”) and the probability of dipole-dipole interactions are reduced, the depth of the trough-shaped free space must not be chosen too small. The depth of the trough-shaped free space is preferably greater than half the extent of the target particles $\left(H_{\mathrm{W.}anne}>\frac{d_{Zielpartikel}}{2}\right).$

If the depth h _tub is large enough, target particles can be “relocated” to the edge areas of a modified flow profile with overall lower flow velocities and a clearer geometric separation of target and non-target particles can be brought about in two different levels.

Increasing flow forces in an imaginary stable trapping position as well as destabilizing disturbances can still be compensated more reliably _{by the thickness of the higher coated insulator material (i.e. h well} ) and a new counterforce emanating from it on the target particles in the form of a horizontal steric force F _Steric , _z.

In a further preferred embodiment, the width (b _trough ) of the trough-shaped free space is between one and three times the extent of the target particles.

In this way, in turn, the absolute flow forces on a target particle ("slipstream effect") and the probability of the dipole-dipole Interactions are reduced, the width of the trough-shaped free space b trough must not be chosen too large.

In particular, ideally, no non-target particles should be able to falsely enter a trough-shaped free space. On the other hand, the trough-shaped free space must be wide enough so that a target particle can be drawn into it completely without any problems under the intended flow conditions. Overall, the width is preferably between one and three times the extent of the target particles.

In a further preferred embodiment, the depth of the trough-shaped free space is 5 up to 30 µm and the width of the tub-shaped free space 10 up to 90 µm.

This dimension is particularly advantageous for the separation of the circulating tumor cells from the healthy blood cells, because the diameter (i.e. dimension) of the largest expected circulating tumor cells is approx. 30 µm, then, according to the conditions described above, the depth of the tub-shaped free space is 15 µm or the width of the trough-shaped free space 30 µm. The dimensions should preferably be based on all cells that can be found in the blood of a patient (other tests are possible).

In a further preferred embodiment, the insulating material is a photosensitive lacquer.

The photosensitive lacquer could either be laminated onto the electrode arrangement as a finished dry resist or spun onto the electrode arrangement as a lacquer and cured and opened in a final processing step photolithographically using a photomask and exposure (UV light) and development at the desired points.

In a further preferred embodiment, the insulator material is burned out of a film material by laser.

Alternatively, the tub-shaped free spaces can be "burned out" by laser (e.g. USP laser) from a polymer film (e.g. PC, PMMA, etc.) which, like the photosensitive dry resist, has the appropriate thickness (h _Tub ) was applied to the electrode assembly. However, it could also generally be any desired thin film material (e.g. metal with a sufficiently thick oxide layer, etc.) that is cut out.

In a further preferred embodiment, the electrode arrangement is a finished circuit board. The electrode arrangement can be implemented, for example, as a finished circuit board (PCB) or in silicon technology.

In a further preferred embodiment, the planar electrodes are arranged adjacently in an array, with potential differences being formed between the respective electrodes and their neighboring electrodes when the medium flows between the respective electrodes and their neighboring electrodes.

In a further preferred embodiment, a device for separating target particles from non-target particles is described which comprises at least one microfluidic channel element. Such a device can be a separator or a separation chamber, which can be used, for example, for a chip laboratory (lab-on-a-chip).

• 1 planare Elektrodenanordnung ohne Isolatormaterial in der Seitenansicht
• 2 planare Elektrodenanordnung mit Isolatormaterial in der Seitenansicht
• 3 planare Elektrodenanordnung ohne Isolatormaterial in der Aufsicht
• 4 planare Elektrodenanordnung mit Isolatormaterial in der Aufsicht
• 5 REM-Aufnahme von wannenförmigen Freiräumen auf der Basis von Flex-PCB-Technologie

The invention is explained in more detail below with reference to the figures. Show it:

• 1 planar electrode arrangement without insulator material in side view
• 2 planar electrode arrangement with insulator material in a side view
• 3 planar electrode arrangement without insulator material in plan view
• 4th planar electrode arrangement with insulator material in plan view
• 5 SEM recording of trough-shaped free spaces based on Flex-PCB technology

1 shows a planar electrode arrangement 3 , 4th , comprising an electrode 3 and an adjacent electrode 4th , without insulator material in the side view. A target particle is used here for the sake of simplicity 1 shown. In practice there should be several target particles 1 be present, then possess the target particles 1 In total, significantly different DEP properties and thus also different transition frequencies.

The target particle 1 typically has a larger extent d _{target particles} 7th on than the expansion of the non-target particles 2 . It also owns the target particle 1 a higher normalized surface capacity and is therefore more “wrinkled” than the relatively smooth non-target particles 2 . Together with the expansion, the result is the “wrinkle” for the target particle 1 an overall smaller transition frequency than for the non-target particles 2 and thus different dielectric properties.

The electric field 5 is through the electrode 3 and the adjacent electrode 4th generated at a selected operating frequency. The electrode 3 and the adjacent electrode 4th mutually positive and negative polarity, so that the electric field 5 has a potential difference (spatially inhomogeneous electric field). Thus, the dielectrophoretic force acts on the target particle 1 F _pDE p 8th towards the ridge 20th the electrode 3 (ie towards the direction of maximum field strength) and the dielectrophoretic force acts on the non-target particles 2 F _pDE p 9 in the direction away from the edge 20th the electrode 3 (ie towards the direction of minimum field strength).

The medium comprising the target particle 1 and the non-target particles 2 , flows in the direction of flow 6th on the electrode assembly 3 , 4th past. The dielectrophoretic force on the target particle 1 F _pDE p 8th is made up of the dielectrophoretic force component in the y-direction <F _pDEP , _y > 10 and the dielectrophoretic force component in the z-direction <F _pDEP , _z > 13th together.

To the target particle 1 to be able to attract (capture) by the electrode should be <F _pDEP , _y > 10 must be greater than F _lift , whereby the force F _lift corresponds to the uplifting "hydrodynamic lift force" in the y-direction.

On / after contact with the ground 21 or in the capture state should <F _pDEP , _y > 10 equal to the sum of the force F _Steric , _y and the force F _Lift 11 be where the force F _steric , _y the through the ground 21 corresponds to steric force imparted in contact in the y-direction. _{The sum of the force F Stokes} and the time-averaged destabilizing force <F _{Destabillizing} > is allowed further in the z-direction 12th not greater than the dielectrophoretic force component in the z-direction <F _pDEP , _z > 13th if there is no insulator material coated in the y-direction 15th as a barrier there. Otherwise the trapped target particle may 1 by the force F _Stokes and the force <F _{Destabilizing} >, which is in the direction of flow 6th are aligned out of the catching trap 19th escape easier. The force F _Stokes corresponds to the flow force in the z-direction and the time-averaged force <F _{Destabilizing} > corresponds to the destabilizing force as a superposition of all disruptive fluctuating influences (e.g. temperature influences, etc.) on the target particle 1 in the z-direction. Because the thickness of the electrodes d _electrode 14th much smaller than the size of the _{target particle} 7th of the target particle 1 is, almost none is effective here due to the thickness of the electrodes d _electrode 14th steric force imparted on contact in the direction of flow of the medium in the z-direction on the target particle 1 .

In addition, shows 1 the formation of clusters of the target particle 1 with the non-target particles 2 caught in the trap 19th , thereby the separation purity and the separation efficiency are reduced.

2 shows the planar electrode arrangement 3 , 4th with insulator material 15th in side view. The depth h _tub 16 of the tub-shaped free space 18th corresponds to the thickness of the insulator material coated in the y-direction 15th , where the depth h is _tub 16 greater than half the extent of the target particle d _{target particle} 7th and smaller than the dimension of the target particle d _{target particle} 7th is. The width b _tub 17th of the tub-shaped free space 18th has a distance between the adjacent insulating materials 15th in the z-direction, with the width b _tub 17th something between one and three times the size of the target particle d _{target particle} 7th amounts to.

With the help of the insulating material 15th must be the dielectrophoretic force component in the z-direction <F _pDEP , _z > 13th no longer greater than or equal to the sum of the force F _Stokes and the time-averaged force <F _{Destabilizing} > 12th be because the insulator material 15th protects against the trapped target particle 1 in the direction of flow 6th moves by the insulator material a reaction force F _Steric , _z in the opposite direction of the flow direction 6th exercises. This means that the flow velocity and / or the particle charge density can be increased. Thus, the separation efficiency is increased. In addition, the insulator material protects 15th or the tub-shaped free space 18th before the formation of clusters, thus increasing the separation purity.

3 shows the electrode arrangement 3 , 4th without insulator material in the top view. The medium flows in the direction of flow 6th on the electrodes 3 past. In doing so, the trapped target particles form 1 in the catch traps 19th due to the dipole-dipole interactions clusters both with target particles 1 as well as with non-target particles or the captured target particles 1 are relieved from the trap traps by the non-target particles 19th solved.

4th shows the electrode arrangement 3 , 4th with insulator material 15th in supervision. The dipole-dipole interaction is reduced by the trapped target particles 1 through the tub-shaped open spaces 18th before the non-target particles 2 to be protected. Thus, the trapped target particles remain 1 in the catch traps 19th and the non-target particles outside the capture traps 19th .

5 shows an SEM image of tub-shaped free spaces based on Flex-PCB technology. The depth h _{trough of} the trough-shaped free space is approximately 15 μm and the width b _{trough of} the trough-shaped free space is approximately 200 μm.

Claims (11)

Microfluidic channel element for improved separation of target particles (1) from non-target particles (2) within a medium based on Dielectrophoresis, comprising a base (21) and an electrode arrangement (3, 4) which has a plurality of planar electrodes (3, 4) each having at least one edge (20), the electrode arrangement (3, 4) such the bottom (21) is arranged so that the medium flows past the electrode arrangement (3, 4) so that the target particles (1) are captured within the medium by the planar electrodes (3); and wherein the electrode arrangement (3, 4) is covered with an insulator material (15) in such a way that a trough-shaped free space (18) with a depth (16) and a width (17) in the region of the at least one edge (20) of the respective planar Electrodes (3, 4) is shaped so that the trapped target particles (1) are protected from the non-target particles (2) and the medium flowing past by the trough-shaped free space (18). Microfluidic channel element according to Claim 1 wherein the target particles (1) are circulating tumor cells and the non-target particles (2) are healthy blood cells. Microfluidic channel element according to Claim 1 or 2 , the depth of the trough-shaped free space being less than or approximately equal to the extent of the target particles. Microfluidic channel element according to one of the preceding claims, wherein the depth (16) of the trough-shaped free space (18) is greater than half the extent of the target particles (7). Microfluidic channel element according to one of the preceding claims, wherein the width (17) of the trough-shaped free space (18) is between one and three times the extent of the target particles (7). Microfluidic channel element according to one of the preceding claims, wherein the depth (16) of the trough-shaped free space (18) is 5 to 30 µm and the width (17) of the trough-shaped free space (18) is 10 to 90 µm. Microfluidic channel element according to one of the preceding claims, wherein the insulating material (15) is a photosensitive lacquer. Microfluidic channel element according to one of the preceding claims, wherein the insulator material (15) is burned out of a film material by laser. Microfluidic channel element according to one of the preceding claims, wherein the electrode arrangement (3, 4) is a finished circuit board. Microfluidic channel element according to one of the preceding claims, wherein the planar electrodes are arranged adjacently in an array, and wherein potential differences are formed between the respective electrodes (3) and the adjacent electrodes (4) when the medium is between the respective (3) electrodes (3 ) and their adjacent electrodes (4) flows. Cartridge for a lab-on-chip system, which has a microfluidic channel element according to claims 1 to 10 for separating target particles (1) from non-target particles (2) within a medium.

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