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Title:
A MICROELECTRONIC SENSOR DEVICE COMPRISING A CARRIER WITH ELECTRICAL CONDUCTORS
Document Type and Number:
WIPO Patent Application WO/2009/040721
Kind Code:
A1
Abstract:
The invention relates to a microelectronic sensor device and a method for optical examinations at a contact surface (12) of a carrier (11), wherein said carrier (11) comprises at least one conductor wire (14). The microelectronic sensor device preferably comprises a light source (21) for emitting an input light beam (L1) into the carrier (11) such that it impinges onto the contact surface (12), wherein the conductor wire (14) runs substantially parallel to the plane of incidence of the input light beam (L1). The conductor wire(s) (14) may for example be used for generating magnetic fields or for a local heating. With the described aligned orientation of conductor wire(s) (14) and input light beam (L1), a minimal interference (shadowing) of the input light beam (L1) is achieved.

Inventors:
VERSCHUREN, Coen Adrianus (AE Eindhoven, NL-5656, NL)
IMMINK, Albert Hendrik Jan (AE Eindhoven, NL-5656, NL)
KLUNDER, Derk Jan Wilfred (AE Eindhoven, NL-5656, NL)
PRINS, Menno Willem Jose (AE Eindhoven, NL-5656, NL)
Application Number:
IB2008/053840
Publication Date:
April 02, 2009
Filing Date:
September 22, 2008
Export Citation:
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Assignee:
KONINKLIJKE PHILIPS ELECTRONICS N.V. (Groenewoudseweg 1, BA Eindhoven, NL-5621, NL)
VERSCHUREN, Coen Adrianus (AE Eindhoven, NL-5656, NL)
IMMINK, Albert Hendrik Jan (AE Eindhoven, NL-5656, NL)
KLUNDER, Derk Jan Wilfred (AE Eindhoven, NL-5656, NL)
PRINS, Menno Willem Jose (AE Eindhoven, NL-5656, NL)
International Classes:
G01N21/03; G01N21/64; G01N33/543; G01N33/58; G01N35/00
Domestic Patent References:
WO2007072415A2
WO2006079998A1
Foreign References:
DE10126152A1
US20060055042A1
DE10202713A1
US20060197960A1
US20050048599A1
Attorney, Agent or Firm:
SCHOUTEN, Marcus, M. (High Tech Campus 44, AA Eindhoven, NL-5656, NL)
Download PDF:
Claims:

CLAIMS:

1. A microelectronic sensor device for optical examinations, comprising a) a carrier (11) with a contact surface (12) and at least one conductor wire (14) embedded within the carrier (11); b) a light source (21) for emitting an input light beam (Ll) into the carrier (11) such that it impinges onto the contact surface (12), wherein the conductor wire (14) runs substantially parallel to the plane of incidence of the input light beam (Ll).

2. The microelectronic sensor device according to claim 1, characterized in that the input light beam (Ll) is reflected at the contact surface (12) as an output light beam (L2), preferably by total internal reflection.

3. The microelectronic sensor device according to claim 1, characterized in that it comprises an array of apertures in a non- transparent material that is disposed on the contact surface (12) of the carrier (11), wherein the apertures have a first dimension parallel to the plane of the contact surface that is below the diffraction limit of the light in the medium that fills the apertures, which allows the generation of evanescent fields upon illumination.

4. The microelectronic sensor device according to claim 3, characterized in that the input light beam (Ll) is adapted to excite at least one luminescent particle (53) within one of the apertures, so that a luminescent light is emitted as an output light beam (L3) by said luminescent particle (53).

5. The microelectronic sensor device according to claim 2 or 4,

characterized in that it comprises a light detector (31, 33) for determining a characteristic parameter of the output light beam (L2, L3).

6. The microelectronic sensor device according to claim 1, characterized in that it comprises a control module (51) connected to the conductor wire (14) for selectively supplying and/or receiving electrical signals to or from the conductor wire (14), particularly for the generation of magnetic fields and/or for a temperature control at the contact surface (12).

7. The microelectronic sensor device according to claim 1, characterized in that it comprises at least one complementary- electrode (16) disposed a distance away from the carrier (11) above the contact surface (12).

8. A carrier (11) for optical examinations, particularly a carrier (11) for a microelectronic sensor device according to claim 1 , comprising a) an array of apertures in a non-transparent material that is disposed on a contact surface (12) of the carrier (11), wherein the apertures have a first dimension parallel to the plane of the contact surface that is below the diffraction limit of the light in the medium that fills the apertures, which allows the generation of evanescent fields upon illumination; b) at least one conductor wire (14) embedded within the carrier (11).

9. The microelectronic sensor device according to claim 1 or the carrier (11) according to claim 8, characterized in that the conductor wire (14) runs parallel to the contact surface (12).

10. The microelectronic sensor device according to claim 1 or the carrier (11) according to claim 8,

characterized in that the distance between the conductor wire (14) and the contact surface (12) has a value between 0.1 to 100 times the maximal diameter of the conductor wire (14).

11. The microelectronic sensor device according to claim 1 or the carrier (11) according to claim 8, characterized in that the carrier (11) comprises a plurality of such conductor wires (14) running parallel to each other.

12. A method for making optical examinations in a carrier (11) with a contact surface (12) and at least one conductor wire (14) embedded within a carrier (11), comprising the emission of an input light beam (Ll) into the carrier (11) such that it impinges onto the contact surface (12), wherein the conductor wire (14) runs substantially parallel to the plane of incidence of the input light beam (Ll).

13. Use of the microelectronic sensor device or the carrier according to any of the claims 1 to 11 for molecular diagnostics, biological sample analysis, or chemical sample analysis.

Description:

A MICROELECTRONIC SENSOR DEVICE COMPRISING A CARRIER WITH ELECTRICAL CONDUCTORS

The invention relates to a microelectronic sensor device and a method for making optical examinations at the contact surface of a carrier. Moreover, it relates to an associated carrier and to the use of such a device and/or carrier.

The US 2005/0048599 Al discloses a method for the investigation of microorganisms that are tagged with particles such that a (e.g. magnetic) force can be exerted on them. In one embodiment of this method, a light beam is directed through a transparent material to a surface where it is totally internally reflected. Light of this beam that leaves the transparent material as an evanescent wave is scattered by microorganisms and/or other components at the surface and then detected by a photodetector or used to illuminate the microorganisms for visual observation. A problem of this and similar devices is that magnetic actuation fields for moving magnetic particles require either comparatively high electrical currents in external electromagnets or even the presence of electrical wires close to the examination region, where they may however hinder the optical measurements.

Based on this situation it was an object of the present invention to provide means for making optical examinations at a contact surface of a carrier while simultaneously allowing electrical operations, e.g. the generation of magnetic fields, with minimal mutual interference and/or a limited power dissipation.

This object is achieved by a microelectronic sensor device according to claim 1, a carrier according to claim 8, a method according to claim 12, and a use according to claim 13. Preferred embodiments are disclosed in the dependent claims.

The microelectronic sensor device according to the present invention serves for optical examinations, wherein the term "examinations" is to be understood in a broad sense, comprising any kind of manipulation and/or interaction of light with some entity. The examinations may preferably comprise the qualitative or quantitative detection of target components comprising label particles, wherein the target components may for example be biological substances like biomolecules, complexes, cell fractions or cells. The microelectronic sensor device comprises the following components: a) A carrier with a "contact surface" and with at least one conductor wire that is embedded in the carrier. The carrier will usually be made from a transparent material, for example glass or poly-styrene, to allow the propagation of light of a given spectrum. The term "contact surface" is chosen primarily as a unique reference to a particular part of the surface of the carrier, and though particles will in many applications actually contact (and bind to) said surface, this does not necessarily need to be the case. The term "conductor wire" shall comprise any elongated structure that conducts electrical current; it is typically made from a metal like aluminum, chromium, gold, or some alloy. The conductor wire usually has a constant cross section along its axial extension, particularly a circular, elliptical or rectangular cross section. It may serve for different purposes, for example the sensing of physical quantities (e.g. temperature) or measurement signals or for the generation of heat or magnetic fields. Moreover, it should be noted that the conductor wire is usually not an isolated object inside the carrier but connected at its ends via leads to some electrical circuitry. The term "conductor wire" will therefore often refer to a limited subsection of some longer electrical lead, wherein this subsection is however disposed in a region where an interference with the light beam mentioned below may occur. b) A light source for emitting an "input light beam" into the carrier such that it impinges onto the contact surface, wherein the conductor wire runs substantially parallel to the plane of incidence of the input light beam. As usual, the "plane of incidence" is in this context a plane that comprises the wave vector of the input light beam and that is perpendicular to the contact surface. Moreover, two lines or planes are

considered as being "substantially parallel" if they include an angle of less than 20 degree, preferably less than 10 degree.

The light source may for example be a laser or a light emitting diode (LED), optionally provided with some optics for shaping and directing the input light beam.

The proposed design of the microelectronic sensor device has the advantage that disturbing effects of the conductor wire on the input light beam are minimized due to the described alignment of wire and beam. In particular, the shadow (if any) that is cast by the conductor wire onto the contact surface by the light of the input light beam is independent of the angle of incidence of the input light beam as long as the plane of incidence remains constant. Moreover, a possible diffraction of the input light beam at the conductor wire will imply diffraction orders with perpendicular components with respect to the plane of incidence of the input light beam, which can readily be filtered out by spatial filtering. The input light beam that is directed towards the contact surface may be used for many different purposes, for example to initiate chemical reactions, to heat fluid or particles, to stimulate fluorescence, or just to illuminate some region for visual inspection. In a preferred first embodiment of the invention, the input light beam is reflected at the contact surface as a beam that will be called "output light beam" in the following. Preferably, this reflection takes place as a "total internal reflection" (TIR), which requires that the refractive index of the carrier is larger than the refractive index of the material adjacent to the contact surface. This is for example the case if the carrier is made from glass (n = 1.6 - 2) and the adjacent material is water (n = 1.3). It should be noted that the term "total internal reflection" shall include the case called "frustrated total internal reflection" (FTIR), where some of the incident light is lost (absorbed, scattered etc.) during the reflection process.

According to a second embodiment of the invention, the carrier comprises an array of one or more apertures in a nontransparent material that is disposed on the contact surface of the carrier, wherein the apertures have a first dimension (parallel to the plane of the contact surface) that is below the diffraction limit of the medium that fills the apertures and allow the generation of an evanescent field upon illumination with

light. This enables highly surface specific detection of luminescently labeled particles (such as luminescently labeled biomolecules) inside the apertures by imaging the generated luminescence on a detector, as disclosed in WO 2006136991 Al and PCT/IB2006/054940, which are incorporated into the present text by reference. The diffraction limit in a medium is defined as the ratio between half the wavelength of the light that illuminates the apertures (i.e. here light of the input light beam) and the index of refraction of the medium that fills the apertures. For apertures with a second dimension (parallel to the plane of the contact surface) that is above the diffraction limit, the generation of evanescent fields requires illumination with R- polarized light that is characterized in that the projection of the electric field on the contact surface of the carrier is parallel to the second dimension of the aperture. Preferably, the first dimension is less than 50 % of the diffraction limit, more preferably less than 40 % of the diffraction limit, and most preferably less than 30 % of the diffraction limit. For an excitation wavelength of 633 nm, this corresponds with a preferred first dimension of less than 120 nm, a more preferred first dimension of less than 95 nm, and a most preferred dimension of less than 70 nm. The non-transparent material may particularly be made from some electrically conducting metal like aluminum, copper, gold and/or some alloy. With the help of the array of one or more apertures, an evanescent field can be generated at the contact surface of the carrier, wherein particles to be investigated in said field can favorably enter the space in the non- transparent material that is defined by the apertures. The array of apertures can also be composed of an array of wires (also referred to as a wire-grid), in which case the second dimension (parallel to the plane of the contact surface) of the aperture is substantially above the diffraction limit in the medium that fills the space between the wires. Preferably, the non-transparent material is a metal. Therefore, these wires could in principle be supplied with currents that generate for example magnetic fields for particle manipulation.

In the described embodiments of the invention in which an output light beam is generated (e.g. by FTIR or luminescence), the microelectronic sensor device may optionally comprise a light detector for detecting a characteristic parameter of the output light beam. The characteristic parameter may particularly be related to the

amount of light in the output light beam, expressed for example as the intensity of this beam in its cross section or part of its cross section. The light detector may comprise any suitable sensor or plurality of sensors by which light of a given spectrum can be detected, for example photodiodes, photo resistors, photocells, a CCD chip, or a photo multiplier tube.

In another embodiment of the invention, the microelectronic sensor device comprises a control module that is connected to the at least one conductor wire for selectively exchanging electrical signals (e.g. currents and/or voltages) with said wire to achieve some desired effect. This effect may particularly be the generation of magnetic fields at the contact surface and in a sample volume adjacent to said surface, wherein the magnetic fields can for example be used to move or otherwise manipulate magnetic particles. Another effect of electrical signals supplied to the conductor wire by the control module may be the generation of heat for a temperature control in a sample adjacent to the contact surface. Electrical signals provided by the conductor wire can be sensed by the control module and for instance be used for temperature detection, because the electrical resistance of the conductor wire is a function of the temperature.

The microelectronic sensor device may further comprise at least one electrode, which will be called "complementary-electrode" in the following, disposed a distance away from the carrier above the contact surface. This complementary-electrode can cooperate with the conductor wire in the carrier and for example generate an electrical field across the intermediate free space. This free space comprises the contact surface and will typically be used as a sample chamber where a sample to be examined can be provided. In another example, the complementary-electrode can be used for heating purposes. The sample space between the complementary-electrode and the conductor wire can then be heated from two opposite sides, yielding a uniform temperature profile throughout the sample.

The invention also relates to a carrier for optical examinations, particularly a carrier that is suited for a use in a microelectronic sensor device, wherein said carrier comprises the following components: a) An array of apertures in a non-transparent material that is disposed on a contact surface of the carrier, wherein the apertures have a first dimension below the

diffraction limit and allow the generation of evanescent field inside the aperture upon illumination. b) At least one conductor wire embedded within the carrier.

For the description of the details, advantages and further developments of the carrier, reference is made to the preceding description of the corresponding embodiment of the microelectronic sensor device.

In the following, various developments of the invention will be described that relate both to the microelectronic sensor device and the carrier described above.

In general, the conductor wire may have an arbitrary, e.g. inclined orientation with respect to the contact surface and/or it may be curved. In a preferred embodiment, the conductor wire runs however substantially parallel to the contact surface and/or is substantially straight.

The material and dimensions of the conductor wire will have to be chosen according to the requirements of the particular application it is intended for. In preferred embodiments, the conductor wire will have a cross section that ranges between about 0.1 μm 2 to about 10 μm 2 . With these cross sections and a material like aluminum or gold, a reasonable compromise between space requirement and electrical resistance can be achieved.

In many applications the conductor wire will be used to interact physically at the contact surface with some sample that is disposed beyond said surface (e.g. generate magnetic fields inside the sample or sense magnetic fields originating in the sample). It is therefore preferred that the distance of the conductor wire to the contact surface (measured from a peripheral point of the conductor wire, not from its central axis) has a value between about 0.1 to 100 times the maximal diameter of the conductor wire, wherein said diameter is measured perpendicularly to the axis of the wire.

Up to now microelectronic sensor devices were considered that may comprise just one single conductor wire. In most practical applications it is however preferred or even necessary that the carrier comprises a plurality of conductor wires of the kind mentioned above that are embedded in the carrier and run parallel to each other. Such a plurality of conductor wires is for example required to generate magnetic fields in a sample adjacent to the contact surface that cover a sufficient volume without requiring

too large currents in the wires. Furthermore, currents can be switched on and off in different conductor wires. In this way lateral magnetic forces can be generated that can be used to move magnetic particles over the contact surface. This may be needed for stringency during a magnetic washing step or to let the magnetic particles interact with a larger surface area in order to increase binding probability.

The invention further relates to a method for making optical examinations in a carrier which has a contact surface and at least one embedded conductor wire. The method comprises the emission of an input light beam into the carrier such that it impinges onto the contact surface, wherein the conductor wire runs substantially parallel to the plane of incidence of the input light beam.

The method comprises in general form the steps that can be executed with a microelectronic sensor device of the kind described above. Therefore, reference is made to the preceding description for more information on the details, advantages and improvements of that method. The invention further relates to the use of the microelectronic device and/or the carrier described above for molecular diagnostics, biological sample analysis, or chemical sample analysis, food analysis, and/or forensic analysis. Molecular diagnostics may for example be accomplished with the help of magnetic beads or luminescent particles such as fluorescent particles that are directly or indirectly attached to target molecules.

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiment(s) described hereinafter. These embodiments will be described by way of example with the help of the accompanying drawings in which:

Figure 1 shows schematically a microelectronic sensor device according to a first embodiment of the present invention;

Figure 2 shows schematically a luminescent microelectronic sensor device according to a second embodiment of the present invention.

Figure 3 illustrates the shadowing of the contact surface by conductor wires running perpendicular to an input light beam;

Figure 4 illustrates in a perspective view the geometry of conductor wires and light beams at the contact surface for a setup according to the invention.

Like reference numbers in the Figures refer to identical or similar components.

Figure 1 shows a general setup with a microelectronic sensor device according to the first embodiment of the present invention. A central component of this setup is the carrier 11 that may for example be made from glass or transparent plastic like poly-styrene. The carrier 11 is located next to a sample chamber 2 in which a sample fluid with target components to be detected (e.g. drugs, antibodies, DNA, etc.) can be provided. The sample further comprises magnetic particles, for example superparamagnetic beads, wherein these particles are usually bound as labels to the aforementioned target components. For simplicity only the combination of target components and magnetic particles is shown in the Figure and will be called "target particle 1" in the following. It should be noted that instead of magnetic particles other label particles, for example electrically charged or fluorescent particles, could be used as well.

The interface between the carrier 11 and the sample chamber 2 is formed by a surface called "contact surface" 12. This contact surface 12 may be coated with capture elements (not shown), e.g. antibodies, which can specifically bind the target particles. The sensor device may comprise a magnetic field generator 41, for example an electromagnet with a coil and a core, for controllably generating a magnetic field at the contact surface 12 and in the adjacent space of the sample chamber 2. With the help of this magnetic field, the target particles 1 can be manipulated, i.e. be magnetized and particularly be moved (if magnetic fields with gradients are used). Thus it is for example possible to attract target particles 1 to the contact surface 12 in order to accelerate the binding of the associated target particle to said surface.

The sensor device further comprises a light source 21, for example a laser or an LED, that generates an input light beam Ll which is transmitted into the carrier 11 through an "entrance window". As light source 21, a commercial DVD (λ = 658 nm) laser-diode can be used. A collimator lens may be used to make the input light beam Ll parallel, and a pinhole of e.g. 0.5 mm may be used to reduce the beam diameter.

The input light beam Ll arrives at the contact surface 12 at an angle larger than the critical angle θ c of total internal reflection (TIR) and is therefore totally internally reflected as an "output light beam" L2. The output light beam L2 leaves the carrier 11 through another surface ("exit window") and is detected by a light detector 31. The light detector 31 determines the amount of light of the output light beam L2 (e.g. expressed by the light intensity of this light beam in the whole spectrum or a certain part of the spectrum). The measured sensor signals are evaluated and optionally monitored over an observation period by an evaluation and recording module 32 that is coupled to the detector 31. It is to be noted that the device according to the first embodiment can alternatively be used for sampling fluorescence light emitted by fluorescent particles 1 which are stimulated by the evanescent wave of the input light beam Ll . This fluorescence light may for example be spectrally discriminated from reflected light L2. Thus, though the description of this first embodiment concentrates on the measurement of reflected light, the principles discussed here can mutatis mutandis be applied to the detection of fluorescence. In this regard, the person skilled in the art will be able to adapt easily this first embodiment of the invention to a luminescent sensor. In particular, it is obvious for the person skilled in the art that in this case the detector 31 may be placed with respect to the carrier at a position that enables detection of luminescence generated by the luminophores instead of reflected light. In this regard, in the case of such alternative of the first embodiment, the output light may correspond to said luminescent light.

The described microelectronic sensor device applies optical means for the detection of target particles 1. For eliminating or at least minimizing the influence of background (e.g. of the sample fluid, such as saliva, blood, etc.), the detection technique should be surface-specific. As indicated above, this is achieved by using the principle of

frustrated total internal reflection. This principle is based on the fact that an evanescent wave penetrates (exponentially dropping) into the sample 2 when the incident light beam Ll is totally internally reflected. If this evanescent wave then interacts with another medium like the bound target particles 1, part of the input light will be coupled into the sample fluid (this is called "frustrated total internal reflection"), and the reflected intensity will be reduced (while the reflected intensity will be 100% for a clean interface and no interaction). Depending on the amount of disturbance, i.e. the amount of target particles on or very near (within about 200 nm) to the TIR surface (not in the rest of the sample chamber 2), the reflected intensity will drop accordingly. This intensity drop is a direct measure for the amount of bonded target particles 1, and therefore for the concentration of target particles in the sample. When the mentioned interaction distance of the evanescent wave of about 200 nm is compared with the typical dimensions of antibodies, target molecules and magnetic beads, it is clear that the influence of the background will be minimal. Larger wavelengths λ will increase the interaction distance, but the influence of the background liquid will still be very small.

The described procedure is independent of applied magnetic fields. This allows real-time optical monitoring of preparation, measurement and washing steps. The monitored signals can also be used to control the measurement or the individual process steps. For the materials of a typical application, medium A of the carrier 11 can be glass and/or some transparent plastic with a typical refractive index of 1.52. Medium B in the sample chamber 2 will be water-based and have a refractive index close to 1.3. This corresponds to a critical angle θ c of 60°. An angle of incidence of 70° is therefore a practical choice to allow fluid media with a somewhat larger refractive index (assuming n A = 1.52, n B is allowed up to a maximum of 1.43). Higher values of n B would require a larger n A and/or larger angles of incidence.

Advantages of the described optical read-out combined with magnetic labels for actuation are the following:

Cheap cartridge: The carrier 11 can consist of a relatively simple, injection-molded piece of polymer material.

Large multiplexing possibilities for multi-analyte testing: The contact surface 12 in a disposable cartridge can be optically scanned over a large area. Alternatively, large-area imaging is possible allowing a large detection array. Such an array (located on an optical transparent surface) can be made by e.g. ink-jet printing of different binding molecules on the optical surface.

The method also enables high-throughput testing in well-plates by using multiple beams and multiple detectors and multiple actuation magnets (either mechanically moved or electro -magnetically actuated).

Actuation and sensing are orthogonal: Magnetic actuation of the target particles (by large magnetic fields and magnetic field gradients) does not influence the sensing process. The optical method therefore allows a continuous monitoring of the signal during actuation. This provides a lot of insights into the assay process and it allows easy kinetic detection methods based on signal slopes.

The system is really surface sensitive due to the exponentially decreasing evanescent field.

Easy interface: No electric interconnect between cartridge and reader is necessary. An optical window is the only requirement to probe the cartridge. A contact- less read-out can therefore be performed.

Low-noise read-out is possible. The manipulation of the magnetic particles 1 with the help of an external magnet 41, as it was described above, has the disadvantage to require comparatively large magnetic fields and therefore also large power-consuming currents. Moreover, the effect of the magnetic fields extend over a large volume and cannot be restricted to small local regions. Figure 1 therefore shows an improvement in which a plurality of parallel conductor wires 14 runs parallel to the contact surface 12 through the investigation region 13 (only one wire can be seen in the drawing because the other wires lie hidden behind it). As schematically indicated, these conductor wires 14 are connected to a control module 51 that supplies them with appropriate currents I and/or voltages according to the specific purposes the conductor wires are intended for. One such purpose may be the generation of local magnetic fields (or field-gradients) for the

manipulation (e.g. attraction, transportation and/or washing) of the magnetic particles 1. An alternative use of the conductor wires 14 embedded in the carrier 11 is for example local heating to control temperature, binding speed, viscosity, etc. Moreover, the control module 51 may be adapted to sense signals form the conductor wires 14, e.g. their electrical resistance that provides information about the temperature prevailing in the investigation region 13.

Substantial currents are needed for these purposes. This means that the cross-sectional dimensions of the wires 14 should be sufficiently large in order to keep the resistance at an acceptable level. Preferably the conductor wires 14 have a thickness of a few hundred nanometers or more, and a width in the range of 0.1 to 10 μm. As an example, a gold wire with a length of 100 μm (x-direction), a thickness of 0.5 μm (z- direction) and a width of 1 μm (y-direction) has a resistance R of:

S = P -U M - IO- 1 T 0 " 6 =44 ω A 1 10 "6 0.5 10 "6 with p = 2.2- 10 8 Ohm-rn (for bulk material properties; the thin film specific resistance may even be higher depending on the deposition technology).

A low resistance is important (except for the local heating purpose) for several reasons:

Dissipated power P becomes lower according to P = I 2 -R. The driving voltage (U = I R) is lower. This can be especially advantageous in battery operated devices, where generally supply voltage is in the order of 3 V or less. It should be noted that the above calculated resistance of 44 ω already leads to a voltage of 4.4 V at 100 mA.

On the other hand, it is preferred that multiple conductor wires 14 are present within each investigation region (bio-spot). Typical diameters of investigation regions 13 can be as small as 10 μm, thus limiting the allowed wire width and pitch to a few μm.

Furthermore, wire embedding should be robust: contact between wires and the liquid sample is not allowed to avoid wire-to-wire current leakage and/or electrolysis of the liquid. Moreover, the detection surface should preferably be smooth and flat. This may require lapping/polishing of the surface after covering the wires with

an electrically isolating layer, e.g. by spin coating (UV curable polymer, spin-on glass, etc.) or sputter deposition.

Due to the geometrical limitations described above, optical detection of magnetic particles 1 in the presence of conductor wires 14 is not trivial. As Figure 3 illustrates for a design with conductor wires 14' running perpendicular to the plane of incidence of the input light beam Ll and output light beam L2 (here the drawing plane), the required angle in FTIR is only between 20° and 30° from the contact surface 12, thus easily causing shadowing, partial blocking, and also scattering and diffraction of the incident and reflected light beams at the wires 14'. These effects may seriously limit the performance of the optical detection methods.

To address these issues, it is proposed here to use conductor wires 14 that are aligned substantially parallel to the plane of incidence of the input light beam Ll and the output light beam L2, as shown in Figure 1. In this way, shadowing effects and beam blocking are avoided for all relevant investigation regions, i.e. between the wires. This allows a much improved freedom in designing wire dimensions and spacing, while maximizing the useable detection area.

Figure 4 illustrates in a perspective view the geometrical relations at the contact surface 12. The geometrical, perpendicular projections Pw and P L of the conductor wires 14 and the light beams Ll, L2, respectively, onto the contact surface 12 run at least substantially parallel.

Depending on the wavelength of the light that constitutes the input light beam Ll in relation to the wire dimensions and spacing, more or less diffraction may occur. With the proposed alignment, there will be substantially less diffraction. Moreover, diffracted light will fall outside the detector area, thus not affecting the measurement. For larger multiplexed configurations appropriate spatial filtering may be provided if necessary to avoid influence of scattered/diffracted light from neighboring detection areas. Alternatively, neighboring detection areas can be illuminated and detected in (rapid) succession by separate light beams or a scanning light beam, thus also avoiding the cross-talk due to scattering and/or diffraction. Figure 2 shows a microelectronic sensor device according to a second embodiment of the invention. Here a grid of non-transparent lines, e.g. metal wires 15, is

disposed on the contact surface 12. This "wire-grid biosensor concept" is an attractive concept for highly surface specific detection of luminescently labeled biomolecules. The rapid decay of the evanescent field above the wire-grid yields a detection depth of the order of 30 nm. Upon illumination of the carrier with R-polarized excitation light Ll having an excitation wavelength, luminescent particles 53 in the space between the wires generate luminescent light, which corresponds in this second embodiment to the output light beam L3. This output light is imaged on a detector 33 by an imaging system 60 composed of two lenses 61, 63 and an emission filter 62 that blocks the excitation wavelength while substantially transmitting the luminescent light. Luminescent particles 51 outside the space between the wires 15 experience a substantially lower excitation power and therefore generate a substantially lower luminescent signal than luminescent particles 53. The detector 33 is typically a 1D/2D CCD array, Avalanche Photodiode, or Photomultiplier tube and is connected with a recording module 34. When using magnetic beads, one can use magnetic fields for the actuation of the luminescently labeled magnetic particles (i.e. luminescently labeled biomolecules plus magnetic beads) in order to manipulate them into the space between the wires 15 of the wire-grid, i.e. into the space where the detection occurs. One could of course think of using the wires 15 of the wire-grid as electrodes for generating the magnetic field gradient, however without proper shielding of the wires with an isolating material (such as an oxide) the risk of short circuiting between the wires and electrolysis due to high current flowing through the fluid on top of the wires is high. One could try to solve this problem by covering the wires 15 with an isolating material of typically a few 100 nm thickness. But proper operation of the wire-grid sensor device requires that the space between the wires 15 is accessible for the magnetic particles 1. In a microelectronic sensor device with a wire-grid of the aforementioned kind it is therefore a problem to find a configuration with low risk of short-circuiting between the wires 15 of the wire-grid and electrolysis in the sample fluid on top of the wire-grid.

This problem is solved in the microelectronic sensor device of Figure 2 by the electrode structure with the embedded conductor wires 14 underneath the wires 15 of the wire-grid, and by the use of these conductor wires 14 for magnetic actuation

and/or as an optically transparent structure for temperature control. The conductor wires 14 are covered with an electrically isolating and substantially optically transparent layer 17. The pitch between the conductor wires 14 is substantially above the diffraction limit to enable that the incident light of the input light beam Ll can reach the wire- grid 15 that is defined on top of the isolating layer.

The preferred orientation of the embedded conductor wires 14 is the same as in Figure 1, i.e. such that the blocking of the incident input light beam Ll and related shadowing and diffraction effects are minimized, which can be achieved by arranging the conductor wires 14 parallel to the plane of incidence of the input light beam Ll . Typical dimensions and parameters of the microelectronic sensor devices of Figures 1 and 2 are:

Wires 15 of wire-grid: Period: 150 nm; duty cycle: 50 % (i.e. the spaces or apertures between two wires 15 are as broad as the wires, yielding a first dimension in y-direction parallel to the plane of the contact surface of 50%- 150 nm = 75 nm); height of wires: 150 nm; materials: aluminum, gold.

Conductor wires 14: width: a few micrometers; height: 100 nm; material: aluminum, gold, chromium, silver, copper and alloys.

Typical currents through the conductor wires 14 are 100-500 mA (time averaged) and up to 1.5 A peak at low duty cycle (10-20%). These currents allow magnetic beads with sizes in the order of a few 100 nanometers (e.g. Ademtech 300 nm and 500 nm beads) to be attracted over a distance of a few 100 μms within 1 minute.

Isolation layer 17 above conductor wires 14: Typical thickness 100 nm, up to a few microns. The layer should be sufficiently thick to avoid strong currents (0.1 A or more) in the fluid on top that could result in electrolysis. Preferably, the isolating layer 17 has an index of refraction that is similar to the substrate below in order to avoid parasitic reflections. Suitable candidates for the isolating layer are oxides which have an extraordinarily high resistivity (e.g. gold: 2.4-10 "8 ω-m; SiC^: MO 13 ω-m) and index of refraction similar to the (glass) substrate. Preferably one uses a material that can be spun

over the conductor wires 14, because this results in the desired planarization of the isolating layer (e.g. spin-on-glass, sol-gel, but also UV-curable polymers).

The configuration of Figure 2 can also be used for temperature control by flowing a current through the conductor wires 14 and the resulting Joule heating. Temperature control is especially relevant for applications involving DNA, where increasing the initial concentration of DNA by a Polymerase Chain Reaction requires accurate control of the temperature of the sample fluid. An important requirement is a uniform temperature throughout the chamber. A method to achieve this is by combining the conductor wires 14 that are embedded in the carrier 11 with a second top-electrode, called "complementary-electrode" 16 in the following. Though Figure 2 shows a uniform complementary-electrode 16, this might also be a structured electrode.

Both the conductor wires 14 and the complementary-electrode 16 are fed with a current that results in Joule heating. For a single heating wire, it is well known that the temperature decreases away from the wire resulting in a non-uniform temperature. Uniformity can however be improved by using two heating wires, such as the conductor wires 14 and the complementary-electrode 16. This can be easily understood for a material between two identical uniform wires with a length and width substantially larger than the distance between the wires and with identical currents flowing through them, where the upper wire generates a heat flux in the downwards direction and the lower wire generates a heat flux of the same magnitude in the upwards direction resulting in a canceling net flux. Because the temperature gradient is proportional to the flux, this results in a uniform temperature distribution.

While the invention was described above with reference to particular embodiments, various modifications and extensions are possible, for example: - Alternatively or additionally to the means described above, the device may comprise any suitable sensor to detect the presence of particles on or near to a sensor surface, based on any property of the particles, e.g. it can detect via magnetic methods, optical methods (e.g. imaging, fluorescence, chemiluminescence, absorption, scattering, surface plasmon resonance, Raman, etc.), sonic detection (e.g. surface acoustic wave, bulk acoustic wave, cantilever, quartz crystal etc), electrical detection (e.g. conduction, impedance, amperometric, redox cycling), etc.

In addition to molecular assays, also larger moieties can be detected with sensor devices according to the invention, e.g. cells, viruses, or fractions of cells or viruses, tissue extract, etc.

The detection can occur with or without scanning of the sensor element with respect to the sensor surface.

Measurement data can be derived as an end-point measurement, as well as by recording signals kinetically or intermittently.

The particles serving as labels can be detected directly by the sensing method. As well, the particles can be further processed prior to detection. An example of further processing is that materials are added or that the (bio)chemical or physical properties of the label are modified to facilitate detection.

The device and method can be used with several biochemical assay types, e.g. binding/unbinding assay, sandwich assay, competition assay, displacement assay, enzymatic assay, etc. It is especially suitable for DNA detection because large scale multiplexing is easily possible and different oligos can be spotted via ink-jet printing on the optical substrate.

The device and method are suited for sensor multiplexing (i.e. the parallel use of different sensors and sensor surfaces), label multiplexing (i.e. the parallel use of different types of labels) and chamber multiplexing (i.e. the parallel use of different reaction chambers).

The device and method can be used as rapid, robust, and easy to use point-of-care biosensors for small sample volumes. The reaction chamber can be a disposable item to be used with a compact reader, containing the one or more field generating means and one or more detection means. Also, the device, methods and systems of the present invention can be used in automated high-throughput testing. In this case, the reaction chamber is e.g. a well-plate or cuvette, fitting into an automated instrument.

Finally it is pointed out that in the present application the term

"comprising" does not exclude other elements or steps, that "a" or "an" does not exclude a plurality, and that a single processor or other unit may fulfill the functions of several means. The invention resides in each and every novel characteristic feature and each and

every combination of characteristic features. Moreover, reference signs in the claims shall not be construed as limiting their scope.