DE102020202271A1 - Device for trapping target cells in a blood vessel - Google Patents

Abstract

Device (1) for capturing target cells (2) in a blood vessel (3) having a capture body (4) with a capture surface (5) which is at least partially coated with a coating (6) with capture molecules (7), the capture molecules (7) can ensure the desired capture by binding to cell-specific molecules (8) on the surface (9) of the target cells (2), the device (1) having at least one electrode array (10) which is designed to produce an electrical Generate field (11) in the vicinity of the catcher body (4), which exerts a force on the target cells (2) with an effective direction towards the catcher surface (5).

Description

State of the art

Circulating tumor cells (CTCs) have established themselves in the past few years as promising and clinically relevant biomarkers for the diagnosis and adapted therapy of malignant tumors and metastases. Their early and reliable detection in the human body, especially from blood or other suitable body fluids, has therefore long been one of the main research areas of modern oncology - known as liquid biopsy.

Current separation processes are based on differences in the biological properties of tumor cells and healthy blood cells. Catchers / markers are usually used here, which can ensure the desired capture by binding to cell-specific molecules on the surface of the target cell (e.g. EpCAM = Epithelial Cell Adhesion Molecule). Such target cells include tumor cells of epithelial origin that are circulating in the blood. It is estimated that 80% of all cancers (= malignant tumors) occurring worldwide are caused by degenerate epithelial cells (carcinomas). Catchers or markers are also molecules that can interact with the corresponding cell-specific molecules on the surface of the target cell and can bind.

The challenge in this context, however, is the fact that tumor cells can only be found in extremely small quantities: A blood sample with a normal size comprises a blood volume of 10 ml (milliliters). The 10 ml blood sample from a cancer patient contains, depending on the type of cancer and state of health, in addition to several million (around 50 million) peripheral blood mononuclear cells (PBMNs), only 10 to 10,000 CTCs. Such a sample also usually contains around 50 billion erythrocytes (red blood cells without nucleons). For a clinically meaningful analysis, therefore, significantly larger sample volumes (e.g. several tens of milliliters to around a hundred milliliters) are ideally necessary, which, however, cannot be taken from a patient at once during a routine examination for health reasons. A typical amount of blood drawn from a patient, for example during a blood count, is a few milliliters.

In WO 2010/145824 A1 describes an antibody-coated metal wire (= probe) which is introduced intravenously into the blood vessel system of the patient via a cannula for the capture of circulating tumor cells. A sufficiently long retention time of the wire in the body (for example 30 minutes or more) can ensure that the sample volume flowing past and thus the number of tumor cells that can potentially be captured is sufficiently large.

Even with this solution, however, the possibility of capturing tumor cells is limited by the fact that the tumor cells have to come into very close proximity to the capture molecules so that the bonds between the markers and the capture molecules can occur. The forces that exist in these bonds are purely chemical in nature. Such a binding is usually a protein binding. Various forms of chemical bonds can be involved in a protein bond, namely in particular ionic bonds, hydrogen bonds, dipole-dipole interactions and hydrophobic interactions. All of these types of bonds can be referred to as chemical bonds. They only have a very short range. Almost immediate contact is required for these forces to occur, act on tumor cells, and form bonds.

For this reason, despite the potentially very large amount of blood that flows past the catcher body, even with this solution, due to the very low chemical range of the antibodies used and the relatively high flow rate of the blood (in the cephalic vein or "head vein") up to 20 cm / s) the yield of tumor cells (CTCs) is usually too low.

Disclosure of the invention

Described herein is an improved solution for trapping circulating tumor cells (CTCs) in the bloodstream.

What is described here is a device for capturing target cells in a blood vessel, comprising a capture body with a capture surface which is at least partially coated with a coating with capture molecules, the capture molecules being able to ensure the desired capture by binding to cell-specific molecules on the surface of the target cells, wherein the device has at least one electrode array which is set up to generate an electric field in the vicinity of the catcher body, which field exerts a force on the target cells with an effective direction towards the catcher surface.

The device described here and in particular its catcher body are introduced directly into a blood vessel in which the blood to be examined flows. It is a device that is used in vivo.

Capture molecules are, for example, EpCAM antibodies. The coating with the capture molecules is preferably applied to areas of the electrodes. The entire catcher body is preferably provided with the coating. The catcher body is also preferably passivated.

The coating preferably has several (in particular two) coating planes with different functions, which can be distinguished. A passivation layer forms an (optional) lower layer on the electrode metal. This layer can also be referred to as the “protective layer”. There is a (actual) catcher layer on it, which has catcher molecules and, if necessary, can also consist exclusively of catcher molecules. An (exclusive) coating with the capture layer (for example with EpCAM antibodies) may not provide sufficient and, in particular, complete (chemical) passivation, e.g. B. to avoid electrochemical reactions between the electrodes and the surrounding medium. An additional passivation layer can be provided in particular when the electrode material is a base metal (for example copper). If the electrode material is noble metal such. B. gold, etc. is used, can optionally be dispensed with an additional passivation layer.

A base material of the coating is preferably an inert and biocompatible polymer such as. B. PDMS. The capture molecules can be introduced into the coating or applied to the coating.

Another possible material for the coating is, for example, Teflon, since it is also well suited to reduce non-specific bonds between cells flowing past and the surface of the capture device. Nonspecific bonds are bonds that could also be entered into with cells other than the target cells and which could thus reduce and possibly even prevent the capture of target cells.

Regardless of the material used for the protective layer, unspecific bonds could still be reduced by a subsequent PEG coating (coating with polyethylene glycol) on it.

In addition, the device must not only be set up for the capture of target cells, but ideal protection of patients in whose blood vessels the device is used is also necessary.

In particular, a suitable coating should ensure that under no circumstances can electrochemical reactions or the like occur between the catcher body (and in particular the metallic electrodes) and the patient's blood.

The species released in the process would be transported through the blood vessel system into the organism and could cause considerable damage to health!

The protective layer of the coating preferably has a layer thickness of a few micrometers, for example between 100 nm [nanometers] and a few 1000 nm. The coating preferably also serves to round off tips of the probe that may otherwise be too sharp for a painless and wound-free insertion. The specified thickness refers here to a minimum thickness of the coating that can be technically produced. In order to enable an ideal preparation of the electrical field within the blood vessel, the smallest possible layer thickness is desirable. In particular if such a rounding is to be achieved, the coating can be significantly thicker, for example several 10 µm [micrometers]

The electrode array is preferably arranged under the catcher surface of the catcher body, oppositely charged electrodes being arranged alternately with one another under the catcher surface. The electric field is built up locally between two oppositely charged electrodes arranged adjacent to one another.

The force exerted by the electric field on the tumor cells is caused by the mechanism of dielectrophoresis (DEP). The mechanism underlying this force is the movement of (also uncharged) polarizable particles in a non-homogeneous electric field. In order to exert the force on the tumor cells, either an attractive (positive dielectrophoresis, pDEP) or a repulsive (negative dielectrophoresis, nDEP) force effect can generally be produced. A negative dielectrophoresis is particularly helpful in order to purposefully displace cells other than target cells / tumor cells and thus to promote an opposing movement of target cells / tumor cells towards the catcher surface. Whether an attractive effect on target cells or a repulsive effect on other cells in the blood is in the foreground depends on whether the corresponding cells (target cells / tumor cells) are more or less polarizable than the surrounding medium.

The device described here is used in whole blood / blood plasma with high media conductivity. The blood plasma is usually more conductive than the target cells / tumor cells and also the other particles or cells in the blood (leukocytes, erythrocytes, etc.). Because of this chemical structure of whole blood, as a rule no positive dielectrophoretic forces are triggered on isolated - ie individual - particles in the blood, but rather only negative dielectrophoretic forces are preferred. This is due to the fact that the particles contained in the whole blood / blood plasma are less polarizable than the surrounding medium in the entire frequency range.

If the concentration of the particles (target cells / tumor cells and other particles) in the medium is extremely high, as well as (in the case of erythrocytes) in whole blood, then, due to strong dipole-dipole interactions, sufficiently high field strengths and frequencies between about 100 kHz and 10 MHz appear the surrounding medium is less polarizable and “parasitic” positive dielectrophoretic forces (pDEP) arise. However, these forces are no longer / less strongly selectively possible for individual cell types, as is the case with isolated particles, but instead have to be viewed as a collective / aggregated state (phase separation).

This force exerted by the electric field has a significantly greater range on target cells / tumor cells than the force exerted by chemical bonds and which is ultimately used to bind the target cells / tumor cells. The spatial range of the force exerted by the electric field is approximately in the order of magnitude of the dimension of the force-generating or the field-generating structure itself. The order of magnitude of the force-generating or field-generating structure is largely defined by the distance between the differently charged electrodes.

In dielectrophoresis, an inhomogeneous electric field - in direct voltage mode (DC) and / or in alternating voltage mode (AC) - is operated to manipulate particles. Dielectrophoresis works in principle with direct voltage and with alternating voltage. For the use of dielectrophoresis to capture biological cells (target cells / tumor cells), however, due to electrochemical effects (electrolysis, electrode polarization, etc.), AC voltage is preferably used, with frequencies of typically more than 10 kHz being selected. The decisive factor for the effect of the electric field on the target cells / tumor cells is that the field is spatially inhomogeneous. In simple terms, the inhomogeneity of the electric field means that different densities of the electric field prevail on two opposite sides of the target cell / tumor cell. This induces a dipole moment in the target cells, which then interacts appropriately with the applied field.

A dipole moment is always induced when a voltage is applied to the electrodes - i.e. for both an inhomogeneous and a homogeneous electric field. This applies as long as the field is not equal to ZERO and the absolute net permittivities between the particle / cell and the surrounding medium and thus their polarizabilities are different. The Maxwell-Wagner interface polarization is relevant in this context. The polarizability is therefore only a consequence of the material properties of the target cells / tumor cells and the surrounding medium.

The difference lies in the type of interaction of the induced dipole with the externally applied E-field.

An inhomogeneous field generates different field strengths on two opposite sides of the cell, which interact with the dipole moment. A larger / smaller electrical force then acts on one side of the dipole moment (e.g. on the positive net charge) and a smaller / larger electrical force on the other side (e.g. on the negative net charge) . In total, there is then a net force and thus also a movement of the particle / cell.

For a homogeneous E-field, the net force is zero, since the forces on both sides are exactly the same, but directed in opposite directions. The dipole aligns itself only parallel to the E-field and remains at rest.

The target cells / tumor cells are thereby exposed to a force in the field and moved. The alignment and strength of the field and the dipole moment can generally cause the target cells to move to areas of high field strength (positive dielectrophoresis) or to move to areas of low field strength (negative dielectrophoresis). When used for whole blood, induced dipoles for frequencies between 100 kHz and 10 MHz and sufficiently high amplitudes of the field strength are felt in such a way that positive dielectrophoresis is generated and thus a phase separation of target cells / tumor cells and the surrounding medium occurs.

I. E. there is no polarization / pDEP in the “classical” sense for a single isolated particle, but rather the effects of dielectrophoresis are used for the phase separation described. Depending on which effect is to be used here, the parameters of the electric field can be set accordingly.

The presented device supports the in vivo isolation of circulating tumor cells directly from the blood of the, previously only antibody-based Patients with the help of a fine catcher body injected intravenously via a cannula or catheter with the aim of an overall greater yield of tumor cells (CTSs)

With the help of a suitably arranged electrode array on the surface of the metal wire, a necessary, inhomogeneous electrical field can be generated in such a way that a noticeable dielectrophoretic force effect can be implemented on selected target particles with certain electrophysiological properties (here: CTCs). Depending on the surrounding medium and the cell properties, this force can be set to be positive. Attractive forces can be exerted on certain cells by means of positive dielectrophoresis. By means of negative dielectrophoresis, repulsive forces can also be exerted on other cells, for example non-tumor cells, and if this is still sufficiently large, then target cells can in the course of their flow movement through the blood vessel over the coated wire surface by attracting the electrodes within reach of the chemical Bonds of the applied antibodies are brought. Otherwise this would be too low, which would make capturing the cells with it conventionally very difficult. With attractive forces on certain cells and with repulsive forces on certain cells it is meant here that the attractive forces or repulsive forces acting on certain cells (e.g. the tumor cells / target cells) are larger or smaller than on the other components of the respective medium (in particular the other components of the blood in the blood vessel). Basically, the effects apply to the entire medium. However, due to the different size of the respective effects, selectivity can be achieved here.

An arrangement including contacting required for this can be expanded inexpensively and relatively easily from a manufacturing point of view to form a slightly modified probe.

The handling of such a system is simple, precise and only requires a limited number of additional components and is harmless and painless for the patient.

The invention thus provides an equally attractive and simple possibility to (significantly) increase the previously observed yield for the in vivo separation of circulating tumor cells using antibody-coated metal probes and to facilitate the further analysis of such extremely rare cell populations.

The force effect is proportional to the volume of the target cells / tumor cells. Target cells / tumor cells can be moved selectively according to their size through a suitable choice of the electrical field or targeted activation and deactivation. A selectivity exists insofar as larger cells (nucleated cells, also CTCs) in blood (in comparison to ex-vivo / in-vitro experiments relatively strongly concentrated with cells) actually (significantly) stronger forces in the direction of the catcher surface experienced as small cells (e.g. erythrocytes).

Nonetheless, all cells experience a force with the same sign.

The approach described here of moving target cells / tumor cells in vivo according to their dielectric properties in order to transport them into the vicinity of a catcher surface with catcher molecules appears to be very promising. This approach is independent of markers and scalable on a large scale as well as being simple, contact-free and versatile.

It is particularly advantageous if the catcher body of the device comprises a flexible wire which is suitable for being introduced into a blood vessel through a catheter.

It is also advantageous if the electrode array has at least one first electrode with a first electrical contact and at least one second electrode with a second electrical contact that is electrically separated from the first electrode, the electrical field in the vicinity of the first electrode and the second electrode Catcher body can be generated, wherein the first electrode and the second electrode are arranged on the catcher surface adjacent to one another at a distance of between 30 microns and 100 microns.

The electrode array preferably comprises a multiplicity of first electrodes and second electrodes, all first electrodes being connected to a first electrical contact and all second electrodes being connected to a second electrical contact. In this way, the entire electrode array can be electrically controlled via a total of two electrical contacts.

The electrodes are preferably arranged below a catcher surface of the catcher body. Because of their distance of between 30 µm and 100 µm, preferred. approx. 50 to 70 μm, a large number of locally limited electrical fields are generated above the catcher surface in the blood which flows past the catcher surface in the blood vessel. Through a suitable Activation of the electrodes or the electrical contacting of the electrodes with a controller, effective forces in the direction of the catcher surface can be generated specifically on cells of a certain size. Since tumor cells regularly have a certain size or accumulate with a certain size, which can be distinguished from the size of the other cells present, more tumor cells can thus be transported to the catcher surface.

The preferred transport of target cells / tumor cells to the capture surface can also be argued on the basis of probabilities / probability distributions.

All intact cells that flow past the electrode array within an effective effective range (enveloping volume around the catcher body / wire) are moved towards the surface of the wire.

In particular, the wire forms a base body or a base structure of the device, which is particularly suitable for being introduced into a blood vessel. It is a question of the probability how many CTCs are contained in this volume that envelops the wire and how many CTCs reach the surface of the wire.

In fact, tumor cells / target cells are on average (significantly) larger than blood cells and especially erythrocytes, which is why they also have (significantly) stronger forces in the direction of the wire surface.

Overall, compared to a catcher body without an electrode array, the situation is improved in each case and the probability is (significantly) increased that a CTC will come into contact with antibodies.

It is also advantageous if the catcher body has a length and a diameter, first electrodes and second electrodes being arranged alternately in a circumferential direction of the catcher body.

The length of the catcher body describes in particular the length provided with the coating with catcher molecules. This length is usually matched to the flow conditions and the diameter of the respective blood vessel in which the device is used. So that tumor cells flowing further away from the catcher body parallel to the catcher body can be caught by the electric field or the force generated by this field, the catcher body needs a sufficient length. This is due in particular to the fact that the force of the electric field, which is perpendicular to the surface of the catcher, is usually very small in relation to the flow / Stokes force that acts on a cell in the blood vessel through the moving blood plasma in the direction parallel to the blood vessel In relation to the flow / Stokes force, which acts in the blood vessel on a cell through the moving blood plasma in the direction parallel to the blood vessel, allow the tumor cells to travel at an extremely low speed perpendicular to the surface of the catcher. By a length of the catcher body of, for example, 3 to 5 cm [centimeters], preferably more than 4 cm with a diameter of, for example, 500 μm [micrometers], which is large compared to the dimensions of the cell but comparable to the dimensions of the blood vessel, it can be achieved a capture of tumor cells is possible even with a very small force. If the catcher body were too short, the blood flow might have already carried this tumor cell past the catcher body before the tumor cell reaches a near area on the catcher surface in which the chemical bonds of the catcher molecules can act on the catcher body.

The diameter of the catcher body is preferably between 250 µm [micrometers and 1] mm [millimeters]. The diameter of the catcher body is preferably matched to the respective blood vessel in which it is to be used. The larger the diameter of the catcher body, the smaller the area around the catcher body in which blood flows through the blood vessel. The diameter of a cephalic vein is about 1.8 mm + - 1.1 mm. The diameter of the wire should therefore be chosen to be (significantly) smaller. For a wire with a diameter of 500 µm, depending on the patient, there is a "blockage" of around 2.87% ... 50% in a cephalic vein. However, the greater the flow resistance that the catcher body causes in the blood vessel and the more the blood flow decreases in the respective blood vessel. In addition, there is an acceleration of the remaining blood flow because the blood vessel is narrowed the more the catcher body blocks it. A blockage of the blood vessel is not that bad as long as the area is (significantly) larger / thicker than the effective range of the DEP force (e.g.> 100 µm).

When designing the diameter of the catcher body, the permanent movement of catcher body and patient must also be taken into account.

It is advantageous that as the diameter of the wire increases (linearly) with an otherwise planar surface, the possible interaction surface with cells also increases.

However, it is problematic if a wire that is too thick can only be pulled out of the blood vessel "with difficulty", which would result in shearing or damage to cells already trapped on the inner wall of the cannula and blood vessel and, furthermore, unnecessary additional pain would be inflicted on the patient.

It is also advantageous if the first electrodes and second electrodes of the electrode array are designed as a metal layer which are applied to a base body by thermal vapor deposition or a lithographic method. The vapor deposition and lithographic processes can also be used in addition to one another. The structure of the electrodes is preferably initially defined (positive or negative) lithographically (using light-sensitive lacquer).

After that, it is now possible to either vapor-deposit a metal exactly where it should stay “later” (positive) and / or etch away the metal exactly where it is not wanted “later” (negative).

In both cases, the photosensitive lacquer is preferably removed in the last step (wet or dry chemical).

It is also advantageous if the first electrodes and second electrodes of the electrode array have a thickness of 5 nm to 100 nm [nanometers].

Such electrodes with such a thickness are particularly suitable for generating the electric fields described, since the inhomogeneity of the electric field at the (sharp) electrode edges is very high. Much thicker electrodes are usually not shown too sharp / edged, but rather rounded. Such electrodes can be produced particularly effectively by thermal vapor deposition or lithographic processes.
It is also advantageous if the first electrodes and second electrodes of the electrode array are coated with a protective layer made of biocompatible polymer, the catcher surface with the coating comprising catcher molecules being applied to this protective layer.

Such a protective layer in particular provides electrical insulation, which ensures that only electrical fields are generated with the electrodes, but no relevant electrical currents can flow. Such a protective layer also ensures that biological incompatibility of the electrode material is not a problem. In addition, such a protective layer can serve as a carrier for the coating with the capture molecules to provide the capture surface. In addition, an additional coating directly on the surface avoids or at least reduces unspecific cell-surface interactions.

It is also advantageous if the first electrodes and second electrodes of the electrode array are formed by a plurality of first metal wires and second metal wires that are wound around a base body, first metal wires and second metal wires being arranged alternately in the circumferential direction of the catcher body.

The base body can be formed from a plastic material or a flexible metal, for example. In order to wind such a base body with metal wires, a particularly effective method is to form electrodes on a catcher body.

It is also advantageous if the device has a line routing area in which a separation insulation is inserted between the first metal wires and the second metal wires, which prevents a reduced distance between the first metal wires and the second metal wires and the first metal wires and the second Metal wires can each be connected to a power source.

If there are places where the metal wires are particularly close to one another or where the distance between the metal wires is significantly smaller than in the area in which the metal wires are supposed to develop their effect as electrodes on tumor cells, this is a certain problem because this results in a strong local concentration of the electric field in the area of the constriction. The effect of the electrodes described is therefore severely impaired. As long as the rest of the metal wires are supplied with a desired operating voltage, i.e. at no point before there is a short circuit between neighboring metal wires that forces an extremely unfavorable voltage divider ratio, this effect can be controlled.

This can be ensured by suitable operation of the source for supplying the arrangement with electrical voltage. The separation insulation is preferably used in such a way that first metal wires from first electrodes are led directly to one side of the separation insulation, while second metal wires are led from second electrodes directly to another side of the separation insulation. In addition, the separation insulation preferably has properties which impede an electric field in the area of the separation insulation. Through the separation insulation and through a separation / separation of the first Metal wires and the second metal wire without points of close contact, it is ensured that the electrical field is formed at the electrodes as desired.

It is also particularly advantageous if the device has a voltage source for supplying first electrodes and second electrodes of the electrode array, which with a two-phase alternating voltage having a maximum voltage of between 1 volt and 50 volts, preferably between 5 volts and 25 volts, particularly preferably approx 10 volts and a frequency of between 10 kHz and 10 MHz, preferably between 50 kHz and 5 MHz, particularly preferably about 1 MHz. The two-phase alternating voltage is preferably harmonic. The voltage is described here as the maximum voltage difference between the upper amplitude and the lower amplitude of the alternating voltage. A voltage of 10 volts thus corresponds, for example, to an alternating voltage between -5 volts and +5 volts. In order to avoid destroying the cells (“rupturing” the cell membrane if the transmembrane voltage is too high), the maximum voltage with an electrode spacing of <100 µm is preferably even less than 5 volts to avoid potential danger to the patient from excessive electrical currents.

It has been found that such electrical voltages with the frequencies mentioned generate alternating fields on the electrodes, which produce the desired dielectric effect and the resulting forces (positive dielectrophoresis) in a particularly advantageous manner.

• 1: eine Prinzipskizze der Wirkung der beschriebenen Vorrichtung,
• 2: eine beschriebene Vorrichtung,
• 3: eine erste Variante eines Fängerkörpers im Querschnitt,
• 4: eine zweite Variante eines Fängerkörpers im Querschnitt, und
• 5: eine dreidimensionale Ansicht des Fängerkörpers aus 4.

The device is explained in more detail below with reference to the figures, with preferred exemplary embodiments being shown. Show it:

• 1 : a schematic diagram of the effect of the device described,
• 2 : a device described,
• 3 : a first variant of a catcher body in cross section,
• 4th : a second variant of a catcher body in cross section, and
• 5 : a three-dimensional view of the catcher body 4th .

1 shows a schematic diagram of the mode of operation of the device described. The sketch "hides" healthy blood cells (erythrocytes, leukocytes and platelets) in the background or greatly understates the number of target cells / tumor cells and the surrounding medium. In fact, a blood vessel is filled with cells in an extremely concentrated manner, with only a very small amount of target cells / tumor cells in the blood vessel.

Nevertheless, a tumor cell, even in the midst of a pile of cells, will have a force effect in the direction of the surface of the catcher body, with which the probability of an interaction between antigen and antibody is (greatly) increased.

You can see a target cell 2 (for example, a tumor cell) that is in a blood vessel 3 along an undisturbed flow path 26th flows here as a dashed straight line parallel to the blood vessel 3 is indicated. On the surface 9 the target cell 2 there is a cell-specific molecule 8th . In the blood vessel 3 is a catcher body shown here only in sections 4th with a catcher surface 5 for capturing target cells 2 arranged. The catcher body 4th has one of a layer 6th formed catcher surface 5 on which capture molecules 7th are arranged with cell-specific molecules 8th at target cells 2 can interact and form bonds to capture target cells. On the surface of the catcher 5 or below the catcher surface 5 are also first electrodes 13th and second electrodes 15th an electrode array 10 arranged, which are suitable for electric fields 11 above the catcher surface 5 to generate that a force on target cells 2 exercise. This force ensures that target cells 2 instead of an undisturbed flow path 26th a deflected flow path 27 follow and on the catcher surface 5 to be led. This favors the connection of target cells 2 to capture molecules 7th considerably.

2 shows a blood vessel 3 in detail, in which the catcher body 4th a described device 1 through a catheter 12th is introduced. It can be seen that the catcher body 4th has a length L and a diameter d. The electrode array is indicated schematically 10 with the first electrodes 13th and the second electrodes 15th . A voltage source can also be seen 25th with which the electrode array 10 or the first electrodes 13th and the second electrodes 15th can be exposed to an alternating field.

3 shows a first possible realization of a catcher body 4th such a device in a sectional view, although other realizations are of course also possible. First of all, the diameter of the catcher body with the catcher surface can be seen 5 and the electric field 11 or the electric fields 11 surrounding the catcher body. The catcher body has first electrodes 13th and second electrodes 15th that are in the circumferential direction 18th around the catcher body 4th are arranged alternately.

The first electrodes 13th and the second electrodes 15th lie beneath a protective layer 20th . On the protective layer 20th is the coating 6th applied, which carries or provides the capture molecules not shown separately here. PEG (polyethylene glycol) can also be provided in this layer.

A first electrical contact 14th of the first electrodes 13th and a second electrical contact 16 of the second electrodes 15th takes place via an inner conductor 28 and via an outer conductor 29 , which are arranged concentrically within the catcher body and between which an insulator, not shown separately here, is arranged. The first electrical contact 14th and the second electrical contact 16 are indicated here with dashed lines. The outer conductor is preferred 29 Opened in some areas, so that a first electrical contact is made 14th or a second electrical contact 16 through the outer conductor 29 through to the inner conductor 28 can extend. The concentric arrangement of the outer conductor 29 and the inner conductor 28 ensures a good neutralization of field effects in the outside area, which are caused by the electrical contacting of the electrodes.

The first electrodes 13th and the second electrodes 15th the in 3 illustrated embodiment of a catcher body 4th microelectrodes in z. B. interdigital structure have been applied. The individual electrodes preferably have widths in the range of approximately 50 μm [micrometers], heights of a few nanometers and spacings 17th in the circumferential direction 18th to each other of approx. 50 µm. These dimensions of approx. 50 µm are in the range of the cell size of the target cells (especially tumor cells).

4th shows a second possible realization of a catcher body 4th such a device in a sectional view, although other realizations are of course also possible. As far as the embodiments according to 3 and 4th agree, is also referred to the explanations for 3 referenced. The catcher body 4th according to 4th has a basic body 19th on which in a circumferential direction 18th alternating first metal wires 21 and second metal wires 22nd are upset. The first metal wires 21 form first electrodes 13th that at first electrical contacts 14th are connected. The second metal wires 22nd form second electrodes 15th connected to second electrical contacts 16 are connected. The first electrodes 13th and the second electrodes 15th have in the circumferential direction 18th Distances of approx. 50 µm to each other. On the first electrodes 13th and the second electrodes 15th there is a protective layer 20th on which then in turn the coating 6th is applied with capture molecules not shown separately here.

the 4th shows an alternative embodiment of a catcher body 4th . The first metal wires 21 and the second metal wires 22nd fine metal wires are preferred (with a diameter of about 50 μm, for example). If necessary, these wires are connected by means of electrical insulating wires wound between them 30th electrically separated from each other. The basic body 19th is preferably an electrically passivated carrier wire with a diameter of, for example, 500 μm. The entire structure can then be electrically passivated, especially via the intravenously introduced area.

5 shows a three-dimensional partial representation of the catcher body 4th the end 4th with further details of the device described. In the 5 should be shown in particular how the first electrical contact 14th and the second electrical contact 16 take place. The first metal wires 21 or the first electrodes 13th and the second metal wires 22nd or the second electrodes 15th are in a cable routing area 23 through separation insulation 24 separated from each other. The separation isolation 24 is an annular collar that wraps around the catcher body 4th extends around. First electrodes 13th or first metal wires 21 are on the outside of the separation insulation 24 led while second electrodes 15th or second metal wires 22nd on the inside of the separation insulation 24 be guided. This can ensure that the smallest distances 17th between the first metal wires 21 and the second metal wires 22nd in the areas where these are the first electrodes 13th and as second electrodes 15th act and the electric field around the catcher body 4th forms as desired.

QUOTES INCLUDED IN THE DESCRIPTION

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

Patent literature cited

• WO 2010/145824 A1 [0004]

Claims (10)

Device (1) for capturing target cells (2) in a blood vessel (3) having a capture body (4) with a capture surface (5) which is at least partially coated with a coating (6) with capture molecules (7), the capture molecules (7) can ensure the desired capture by binding to cell-specific molecules (8) on the surface (9) of the target cells (2), the device (1) having at least one electrode array (10) which is designed to produce an electrical Generate field (11) in the vicinity of the catcher body (4), which exerts a force on the target cells (2) with an effective direction towards the catcher surface (5). Device (1) according to Claim 1 wherein the catcher body (4) of the device (1) comprises a flexible wire which is suitable for being introduced through a catheter (12) into a blood vessel (3) Device (1) according to Claim 1 or 2 , wherein the electrode array (10) has at least one first electrode (13) with a first electrical contact (14) and at least one second electrode (15) with a second electrical contact (16) which is electrically separated from the first electrode (13), and wherein between the first electrode (13) and the second electrode (15) the electric field (11) can be generated in the vicinity of the catcher body (4), the first electrode (13) and the second electrode (15) on the catcher surface ( 5) are arranged adjacent to one another at a distance (17) of between 30 μm and 100 μm. Device (1) according to Claim 3 wherein the catcher body (4) has a length (L) and a diameter (d) and wherein first electrodes (13) and second electrodes (15) are arranged alternately in a circumferential direction (18) of the catcher body (4). Device (1) according to one of the preceding claims, wherein first electrodes (13) and second electrodes (14) of the electrode array (10) are formed as a metal layer which are applied to a base body (19) by thermal vapor deposition and / or a lithographic process . Device (1) according to one of the preceding claims, wherein first electrodes (13) and second electrodes (15) of the electrode array (10) have a thickness of 5 nm [nanometers] to 15 µm [micrometers], preferably up to 100 nm [nanometers] . Device (1) according to one of the preceding claims, wherein first electrodes (13) and second electrodes (15) of the electrode array (10) are coated with a protective layer (20) made of biocompatible polymer and wherein the catcher surface with the coating comprising catcher molecules on this protective layer is upset. Device (1) according to one of the preceding claims, wherein first electrodes (13) and second electrodes (15) of the electrode array (10) are formed by a plurality of first metal wires (21) and second metal wires (22) which are arranged around a base body ( 19) are wound, first metal wires (21) and second metal wires (22) being arranged alternately in the circumferential direction (18) of the catcher body (4). Device (1) according to Claim 8 , wherein the device (1) has a line routing area (23) in which a separation insulation (24) is inserted between the first metal wires (21) and the second metal wires (22), which prevents a reduced distance between the first metal wires ( 21) and the second metal wires (22) occurs and the first metal wires (21) and the second metal wires (22) can each be connected to a power source. Device (1) according to Claim 9 , having a voltage source (25) for supplying first electrodes (13) and second electrodes (15) of the electrode array (10) with a two-phase alternating voltage having a maximum voltage of between 1 volt and 50 volts, preferably between 5 volts and 25 volts, particularly preferably approx. 10 volts and a frequency of between 10 kHz and 10 MHz, preferably between 50 kHz and 5 MHz, particularly preferably approx. 1 MHz.

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