WO2009004538A1

WO2009004538A1 - Microelectronic sensor device for examinations in a carrier

Info

Publication number: WO2009004538A1
Application number: PCT/IB2008/052566
Authority: WO
Inventors: Coen A. Verschuren; Albert H. J. Immink
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2007-06-29
Filing date: 2008-06-26
Publication date: 2009-01-08

Abstract

The invention relates to a microelectronic sensor device and a method for making optical examinations in an investigation region (13) of a carrier (10), wherein an input light beam (L1) is sent from a light source (20) towards the investigation region (13) and an output light beam (L2) comes from the investigation region (13). A deviation detector (30) is used to detect deviations of the output light beam (L2) from a nominal output light configuration, for example from a nominal path. Thus disturbances like a misalignment of the carrier (10) with respect to the device can be detected and optionally be corrected. The deviation detector (30) may comprise a light sensitive area (34) that is partitioned into several sensor units or pixels to detect for example an off-centre position of the output light beam (L2).

Description

MICROELECTRONIC SENSOR DEVICE FOR EXAMINATIONS IN A CARRIER

The invention relates to a microelectronic sensor device and a method for optical examinations in an investigation region of a carrier, comprising the emission of light into the investigation region and the observation of light coming from the investigation region. Moreover, it relates to the use of such a device. 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 measurement principles is that they are very sensitive to disturbances and variations in the light paths. This is particularly an issue if there are disposable parts like a sample carrier in the light paths that are prone to misalignment, production tolerances, or contamination with dirt.

Based on this situation it was an object of the present invention to provide means for optical examinations in an investigation region that comprises for example a biological sample. In particular, it is desirable that these means are robust with respect to variations and disturbances introduced by the use of exchangeable parts like sample carriers.

This object is achieved by a microelectronic sensor device according to claim 1, a method according to claim 15, and a use according to claim 16. Preferred embodiments are disclosed in the dependent claims.

The microelectronic sensor device according to the present invention is intended for making optical examinations in an investigation region of a carrier (wherein the investigation region and the carrier do not necessarily belong to the device). In this context, the term "examination" is to be understood in a broad sense, comprising any kind of manipulation and/or interaction of light with some entity in the investigation region, for example with biological molecules to be detected. The investigation region will typically be a small volume at the surface of the (preferably transparent) carrier in which material of a sample to be examined can be provided. The microelectronic sensor device comprises the following components: a) A light source for emitting a light beam, called "input light beam" in the following, towards the investigation region. 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. b) A "deviation detector" for detecting the deviation of a light beam, which comes from the investigation region and which will be called "output light beam" in the following, from a nominal (or reference) output light configuration. The output light beam will usually comprise light that is related to the input light beam, for example fluorescence light stimulated by the input light beam or reflected input light, wherein this component often carries some information one is interested in.

While known optical examination apparatuses usually base their measurements on the assumption that all (optical) components are perfectly aligned, the described microelectronic sensor device has the advantage to provide an explicit control of the configuration of the output light beam by detecting deviations from a nominal situation. As will be described in the following, the detection result can be used for preventing or reducing the negative effects of undesired disturbances.

There are many possibilities to define the "nominal output light configuration" of the output light beam. One practically important example of a nominal output light configuration is a target or reference path of the output light beam. Another important example is a target or reference cross- sectional light distribution of the output light beam. These examples have for certain application the advantage that they are related to parameters of the output light beam which are not affected by processes one is interested in. If the output light beam is for example generated by frustrated total internal reflection of the input light beam in the investigation region and if the degree of frustration carries the desired information, the path of the output light beam is not affected by the processes of interest and the cross-sectional light distribution should in the ideal case be homogeneous.

In another embodiment of the microelectronic sensor device, the deviation detector comprises a plurality of light sensitive sensor units that are distributed over the cross section of the output light beam. Thus, a spatially resolved measurement of the output light beam is possible which allows to detect for example the aforementioned deviations of the output light beam from its target path and/or from its target light distribution. In a preferred embodiment of the aforementioned design, the sensor units cover different sectors of the cross-sectional area of the output light beam, wherein a "sector" shall denote an area that is bounded by two radii originating in the same point (and a third arbitrary border line, for example an arc of a circle around the origin), and wherein the origin of all sectors shall be the same point. In a preferred case, the sectors correspond to quadrants that partition a plane into four equally sized parts, which allows to obtain a maximal amount of information with a minimal number of sectors. In another realization of a deviation detector with a plurality of sensor units, these sensor units constitute an array of light sensitive picture element or "pixels". Sensor devices with pixel arrays are widely used in imaging devices, e.g. digital cameras, and can for example be realized by comparatively cheap charge coupled devices (CCD) or CMOS devices. With a suitable pixel size, these devices can provide very detailed and spatially highly resolved information about the output light beam.

The deviation detector with a plurality of sensor units may further optionally be combined with an evaluation unit that is adapted to determine differences in the illumination of different sensor units. The evaluation unit can for example be realized by analog or digital data processing hardware together with appropriate software. It can for example detect if the output light beam has no homogeneous or no symmetrical distribution of light over its cross section and/or if it is not aligned in a predetermined way with the sensor units. Preferably, the evaluation unit is adapted to determine relative differences, which may for example be achieved by normalizing the measured illumination of the sensor units with the total illumination measured by all sensor units. The detected differences can thus be made independent of the actual amount of output light. In another variant, the evaluation unit may be adapted to determine the location of a characteristic parameter of the output light beam, for example the location of an intensity peak of the beam with respect to its cross section. In case of a perfect optical alignment, the characteristic beam parameter should be found at a certain location, the intensity peak for example in the centre of the sensor units. Deviations from this location will therefore indicate disturbances in the output light beam. The microelectronic sensor device may optionally comprise an optical unit (e.g. a diaphragm, an aperture, a lens, or a filter) for shaping the input light beam such that deviations from the nominal output light configuration can more readily be detected. In the context of the aforementioned embodiment, the diameter of the input light beam may for example be restricted such that the output light beam illuminates approximately only a point. Thus the location of the intensity peak may readily be found without a complicated evaluation of light profiles.

The microelectronic sensor device may optionally comprise a light detector for determining the amount of light in the output light beam. This light detector may comprise any suitable sensor or plurality of sensors by which light of a given spectrum can be detected, for example a photodiode, a photo resistor, a photocell, or a photo multiplier tube. It may preferably be identical with the deviation detector comprising a plurality of sensor units as described above. In many applications, the amount of light in the output light beam comprises the information one is interested in, for example about the concentration of target components (e.g. biomolecules) in the investigation region.

The microelectronic sensor device may further comprise a "measurement unit" for determining a quantitative measure for the detected deviation of the output light beam from a nominal output light configuration. Thus there is not only a binary "yes/no" detection of the presence/absence of such deviations, but also a quantification of the degree of the deviation. The measurement unit may favorably be integrated into an evaluation unit of the kind described above. A microelectronic sensor device with both the aforementioned measurement unit and a light detector for determining the (total) amount of light in the output light beam may optionally further comprise a "correction unit" for correcting the determined amount of light with respect to the measured deviation degree. The correction unit may for example apply formulae derived from a model of the examination process/apparatus which allow to estimate the "genuine" amount of light in the output light beam (i.e. without deviations) from a quantitatively measured deviation. If the intensity peak of the output light beam is for example a measured distance off- centre and if the (nominal) distribution of light over the cross section of the output light beam is known, the correct amount of light in the output light beam can be calculated based on the measurement of the off-centre beam.

In another embodiment of the invention, the microelectronic sensor device comprises centering elements for mechanically aligning a carrier with respect to the light source and/or the deviation detector. The centering elements may for example comprise mechanical springs that push a carrier to a reference position. In a more elaborate embodiment, the centering elements may be coupled to a controller that receives information from the deviation detector, preferably from a measurement unit of the kind described above. Such centering elements might for example comprise a pushing rod that is driven by an electrical motor. In this case, a feedback control loop can be realized that tends to move the carrier towards its nominal position in which no more deviation is detected.

The microelectronic sensor device may further comprise a "monitoring unit" for providing an information signal to a user that indicates the detected beam deviation. The user is thus informed if the setup deviates from optimum and can then for example try to correct the alignment of the carrier, treat the measurement results with a smaller degree of confidence, and/or repeat the whole procedure. Preferably, the monitoring unit provides information about the degree of the deviation, for example if it is coupled to a measurement unit of the kind described above. In this case the user can adapt the measures to be taken to the degree of deviation. Moreover, the monitoring unit may internally realize a threshold and provide an error signal only if the deviation exceeds this threshold and the measurement results can no longer be used. The described microelectronic sensor device can be applied in a variety of setups and apparatuses. In a particular example, the output light beam comprises light of the input light beam that was totally internally reflected in the investigation region. To this end, the investigation region must comprise an interface between two media, e.g. glass and water, at which total internal reflection (TIR) can take place if the incident light beam hits the interface at an appropriate angle (larger than the associated critical angle of TIR). Such a setup is often used to examine small volumes of a sample at the TIR- interface which are reached by exponentially decaying evanescent waves of the totally internally reflected beam. Target components - e.g. atoms, ions, (bio- )molecules, cells, viruses, or fractions of cells or viruses, tissue extract, etc. - that are present in the investigation region can then scatter the light of the evanescent waves which will accordingly miss in the reflected light beam. In this scenario of a "frustrated total internal reflection", the output light beam of the sensor device will consist of the reflected light of the input light beam, wherein the small amount of light missing due to scattering of evanescent waves contains the desired information about the target components in the investigation region. Thus the signal one is interested in (missing light) is very small and prone to disturbances by misalignments of the output light beam and the associated detector. Moreover, the penetration depth of evanescent waves depends critically on the angle of incidence, making these measurements also sensible to misalignments of the input light beam. The proposed use of a deviation detector helps in this situation to minimize the negative effects of misalignments.

In another embodiment of the invention, the deviation detector is adapted to restrict its detection activity to points in time and/or in space in which the nominal output light configuration is not affected by processes in the investigation region. Such an affection of the output light beam may for example occur in the aforementioned embodiment when target components are specifically bound in the investigation region. To avoid a misinterpretation of this binding as a deviation from a nominal output light configuration, the detection process of the deviation detector can be restricted to times before binding occurs and/or to locations of the carrier where no binding takes place. The invention further relates to a method for optical examinations in an investigation region of a carrier, said method comprising the following steps: a) Emitting an input light beam towards the investigation region, wherein this emission may preferably be done with a light source of the kind described above. b) Detecting deviations of an output light beam, which comes from the investigation region, from a nominal output light configuration, wherein this detection may preferably be done with a deviation detector of the kind described above.

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 sensor device 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 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 schematically illustrates the design of a microelectronic sensor device according to the present invention; Figure 2 shows the microelectronic sensor device of Figure 1 when the carrier is tilted;

Figure 3 shows four perspective views of a particular realization of a microelectronic sensor device with an inserted carrier, wherein increasingly more components are omitted from the left to the right drawing to reveal the inner design of the device; Figure 4 is a diagram indicating the distance at which the evanescent wave intensity is decayed to about 37% in dependence on the angle of incidence of the associated totally internally reflected beam; Figure 5 illustrates a deviation detector with sensor units in four quadrants under central or nominal illumination (left) and off-centre illumination (right).

Like reference numbers or numbers differing by integer multiples of 100 refer in the Figures to identical or similar components.

Though the present invention will in the following be described with respect to a particular setup (using magnetic particles and frustrated total internal reflection as measurement principle), it is not limited to such an approach and can favorably be used in many different applications and setups.

The microelectronic sensor device shown in Figures 1 and 2 comprises a light source 20 for emitting an "input light beam" Ll and a light detector 31 for detecting and measuring an "output light beam" L2. The input light beam Ll is emitted into a (disposable) carrier 10 that may for example be made from glass or transparent plastic like poly-styrene. The carrier 10 is located in a casing 40 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 1, for example superparamagnetic beads, wherein these particles 1 are usually bound as labels to the aforementioned target components (for simplicity only the magnetic particles 1 are shown in the Figures). It should be noted that instead of magnetic particles other label particles, for example electrically charged of fluorescent particles, could be used as well.

The interface between the carrier 10 and the sample chamber 2 is formed by a surface called "binding surface" 12. This binding surface 12 may optionally be coated with capture elements, e.g. antibodies, which can specifically bind the target components. The sensor device optionally comprises a magnetic field generator (not shown), for example an electromagnet with a coil and a core, for controllably generating a magnetic field at the binding surface 12 and in the adjacent space of the sample chamber 2. With the help of this magnetic field, the magnetic 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 magnetic particles 1 to the binding surface 12 in order to accelerate the binding of the associated target component to said surface.

The light source 20 comprises for example a laser or an LED 21 that generates the input light beam Ll which is transmitted into the carrier 10 through an entrance window 14. The input light beam Ll arrives at the binding surface 12 at an angle larger than the critical angle of total internal reflection (TIR) and is therefore totally internally reflected as the output light beam L2. The output light beam L2 leaves the carrier 10 through an exit window 11 and is detected by a light sensitive area 34 (e.g. an array of photodiodes) in the light detector 31. The light detector 31 thus 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).

It is optionally possible to use the detector 31 (or a separate detector) for detecting fluorescence light emitted by fluorescent particles 1 which were stimulated by the evanescent wave of the input light beam Ll .

The described microelectronic sensor device applies optical means for the detection of magnetic particles 1 and the target components one is actually interested in. 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 magnetic 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 magnetic beads 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 magnetic beads 1, and therefore for the concentration of target molecules. When the mentioned interaction distance of the evanescent wave of about 200 nm is compared with the typical dimensions of anti-bodies, 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. Another reason for the low background is that most biological materials have relatively low refractive indices near to the refractive index of water, i.e. n=1.3. The magnetic beads consist of a matrix material that has a significantly higher refractive index (n=1.6) causing the outcoupling of the signal. Furthermore, the magnetic bead contains potentially light scattering magnetic or magnetizable grains. 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 10 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 Π_A = 1.52, nβ is allowed up to a maximum of 1.43). Higher values of nβ would require a larger Π_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 10 can consist of a relatively simple, injection-molded piece of polymer material. - Large multiplexing possibilities for multi-analyte testing: The binding 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 magnetic 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 electrical 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. A problem of the described sensor device is that misalignment of the

(disposable) carrier 10 in the sensor device can lead to erroneous measurements: depending on the design and implementation, small values of the misalignment are acceptable. However, too large tilt can cause the light beam(s) to partly miss the investigation region 13 and/or the optical entrance window 14 and exit window 11, and/or the detector area 34.

This is schematically illustrated in Figure 2, which shows the same setup as Figure 1 but with a slightly tilted carrier 10. This tilting causes the output light beam L2' to hit the light sensitive area 34 of the detector 31 off-centre (it should be noted that disturbances of the optical light path by refractions at the optical windows 14, 11 have been neglected in the drawing for simplicity). The detector 31 will therefore measure less output light than is actually available in the output light beam L2'.

Figures 1 and 2 illustrate the use of mechanical springs 41, 42 that are fixed to the casing 40 of the microelectronic sensor device and that press against the carrier 10 to keep it in a well aligned, central position. Similar small springs 141 can be seen in the four perspective views of Figure 3 showing an actual design of a microelectronic sensor device with a casing 140 and an inserted carrier 110. By using such mechanical guiding means, the misalignment and tilt angle can be minimized. However, still small residual errors may remain.

Moreover, large tilt values will have a significant effect on the penetration depth of the evanescent wave into the sample fluid, and therefore on the amplitude of the response to the magnetic beads. This dependence is illustrated in Figure 4, depicting the distance d at which the intensity of the evanescent wave is decayed to e^"1 (about 37%) as a function of the incident angle α of the input light beam and for two different wavelengths λo of this beam. For the typical refraction indices n_l5 n₂ indicated in the Figure legend, the critical angle of TIR is 59.1°. As can be seen from the diagram, a change in incident angle by 1 degree already gives rise to a change in decay distance of several percent.

To solve the above problems, it is proposed here to use a "deviation detector" that can detect deviations of the output light beam L2, L2' from nominal output light configurations, particularly from a nominal output light path and/or a nominal cross-sectional distribution of output light. Thus the correct alignment of the carrier 10 with respect to the casing 40, the light source 20, and the light detector 31 can be checked. Moreover, various other error sources can be detected this way. In the embodiment of Figures 1 and 2, the deviation detector 30 is largely identical with the above described light detector 31, which has a particular design to provide the additional function of a deviation detection. In the following, the light detector 31 will therefore be called "deviation detector" as this functionality is in the focus of the further description.

The light sensitive area 34 of the deviation detector 30 may comprise several spatially distributed sensor units, for example four sensor units 34A, 34B, 34C, 34D that are arranged in the quadrants A, B, C, D of the sensitive area 34 as shown in Figure 5. This Figure further illustrates by dots an exemplary intensity distribution of an output light beam impinging on the sensitive area 34, wherein the left drawing corresponds to a perfectly aligned output light beam L2 (cf. Figure 1), while at the right drawing shows the off-centre deviation of an output light beam L2' due to a tilt of the carrier (cf. Figure 2). The nominal position of the intensity peak of the output light beam L2 corresponds to the centre of the detector in this case.

The measurement signal S of the light sensitive area 34 when working for the light detector 31 is obtained by the sum S = (S_A+S_B+S_C+S_D) of the single measurement signals S_A, S_B, S_C, S_D from all four sensor units 34A, 34B, 34C, 34D. A misalignment of the output light beam L2' follows from the difference signals in both orthogonal directions, e.g. S_x = (S_A+S_B) - (S_C+S_D) and S_y = (S_A+S_C) - (S_B+S_D), respectively. These signals S_x, S_y are zero for the nominal case. Their sign and amplitude are a direct measure of the beam displacement from the centre position. Preferably, the signals S_x, S_y are normalized on the sum signal S to make them independent from the power of the input light beam Ll and independent from the percentage of reflected light that might vary during the actual assay measurement. The described calculations can be done by an evaluation and measurement unit 32 coupled to the light detector 31 / deviation detector 30.

Alternative implementations using multiple sensor units in the sensitive area 34 can be used as well. For example, a pixelated detector with a pixel size (much) smaller than the beam diameter (such as a CCD or CMOS chip) can also provide the necessary information. The centre of the output light beam can be found in such a design for instance by looking for the peak of maximum intensity. Any deviation from a previously stored nominal position of this peak then corresponds to a misalignment. Alternatively a deliberate inhomogeneity may be introduced in the input light beam Ll (e.g. via a diaphragm or via partial shielding of the input light beam) in order to be able to determine the deviation of the output light beam L2 with respect to a previously stored nominal position.

Besides performing the above summations and/or subtractions of sensor signals, the evaluation and measurement unit 32 may comprise a "correction unit" to correct the measurements for detected deviations of the output light beam from its nominal configuration. The correction unit may for example implement a model of the beads 1 bound to the binding surface 12, the carrier 10 and the read-out mechanism of the sensor device. Using this model the measured result (overall intensity of the output light beam) can be corrected for the measured misalignment as long as the misalignment is within a certain window. In this way misalignment compensation is possible. In principle also a mechanical correction is possible, requiring appropriate means like motor driven positioning elements (instead or additionally to the merely passive springs 41, 42) to return a tilted carrier 10 to its correct position.

When the detected misalignment of the output light beam is larger than a pre-defined threshold, an error indication can be given. Thus a signaling unit (e.g. an LED 33) can for example be activated to provide an optical and/or acoustic warning signal to the user. The signal can e.g. be an indication to realign the carrier 10 or to replace the cartridge with the carrier 10. Different pre-defined threshold values can be used for the misalignment in the different orthogonal directions. For example, a 'vertical' misalignment may directly affect the angle of incidence, and may therefore be more critical than a 'horizontal' misalignment.

It should be noted that contamination/damage of any of the optical windows 14, 11 can lead to a non-symmetric light distribution within the cross section of the output light beam L2 which may show the same effects on the deviation detector as a tilt of the carrier 10. When this 'tilt' value is too large, a similar or the same error indication as described above can be given.

Also inhomogeneous binding of (magnetic) labels to the sensor surface can lead to non-symmetric light distribution within the cross section of the output light beam L2 which may show the same effects on the deviation detector as a tilt of the carrier 10. This problem can be circumvented by measuring the tilt in the time between insertion of the cartridge in the reader device and start of the biological assay.

Furthermore, binding of (magnetic) labels on a multiplexed surface, i.e. a surface with at least two binding regions for binding (different type of) labels, may lead to non-symmetric light distribution with the cross section of the output light beam L2. A solution for this issue may be the exclusion of the binding regions from the detector regions used for tilt detection. Especially in case 2D sensor arrays (CMOS imager, CCD sensors) are used this selection can be done electronically.

While the invention was described above with reference to particular embodiments, various modifications and extensions are possible, for example:

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.

Claims

CLAIMS:

1. A microelectronic sensor device for optical examinations in an investigation region (13) of a carrier (10), comprising a) a light source (20) for emitting an "input light beam" (Ll) towards the investigation region (13); b) a deviation detector (30) for detecting the deviation of an "output light beam" (L2), which comes from the investigation region (13), from a nominal output light configuration.

2. The microelectronic sensor device according to claim 1, characterized in that the nominal output light configuration comprises a target path and/or a target cross- sectional light distribution of the output light beam (L2).

3. The microelectronic sensor device according to claim 1, characterized in that the deviation detector (30) comprises a plurality of light sensitive sensor units (34A-34D) distributed over the cross section of the output light beam (L2).

4. The microelectronic sensor device according to claim 3, characterized in that the sensor units (34A-34D) cover sections, preferably quadrants (A, B, C, D), of the cross-sectional area of the output light beam (L2).

5. The microelectronic sensor device according to claim 3, characterized in that the sensor units constitute an array of light sensitive pixels.

6. The microelectronic sensor device according to claim 1, characterized in that it comprises an evaluation unit (32) for determining differences in the illumination of different sensor units (34A-34D) and/or for determining the location of a characteristic parameter, particularly an intensity peak, of the output light beam (L2).

7. The microelectronic sensor device according to claim 1, characterized in that it comprises an optical unit for shaping the input light beam (Ll) such that deviations from the nominal output light configuration can more readily be detected.

8. The microelectronic sensor device according to claim 1, characterized in that it comprises a light detector (31) for determining the amount of light in the output light beam (L2).

9. The microelectronic sensor device according to claim 1, characterized in that it comprises a measurement unit (32) for determining a quantitative measure for the deviation of the output light beam (L2).

10. The microelectronic sensor device according to claim 8 and 9, characterized in that it comprises a correction unit for correcting the determined amount of light with respect to the measured deviation of the output light beam.

11. The microelectronic sensor device according to claim 1 , characterized in that it comprises centering elements (41, 42, 141) for mechanically aligning the carrier (10) with respect to the light source (20) and/or the deviation detector (30) and/or a casing (40, 140).

12. The microelectronic sensor device according to claim 1, characterized in that it comprises a monitoring unit (32, 33) for providing an information signal indicating the detected deviation.

13. The microelectronic sensor device according to claim 1, characterized in that the output light beam (L2) comprises light of the input light beam (Ll) that was totally internally reflected in the investigation region (13).

14. The microelectronic sensor device according to claim 1 , characterized in that the deviation detector (30) is adapted to restrict its detection to points in time and/or space in which the nominal output light configuration is not affected by processes in the investigation region (13).

15. A method for optical examinations in an investigation region (13) of a carrier (10), comprising a) emitting an "input light beam" (Ll) towards the investigation region (13); b) detecting the deviation of an "output light beam" (L2), which comes from the investigation region (13), from a nominal output light configuration.

16. Use of the microelectronic sensor device according to any of the claims 1 to 14 for molecular diagnostics, biological sample analysis, or chemical sample analysis.