WO2008139356A1

WO2008139356A1 - A cartridge for sample investigations

Info

Publication number: WO2008139356A1
Application number: PCT/IB2008/051728
Authority: WO
Inventors: Coen Adrianus Verschuren; Albert Hendrik Jan Immink; Michel Gerardus Pardoel; Hubertus Adrianus Hendrikus Kelders
Original assignee: Koninklijke Philips Electronics N. V.
Priority date: 2007-05-09
Filing date: 2008-05-05
Publication date: 2008-11-20

Abstract

The invention relates to a cartridge(100) for providing optical access to a sample chamber(2), said cartridge(100) having a carrier(110) with a binding surface(112) and with at least one optical window(121, 121'). Moreover, the cartridge(100) comprises a protection element(122, 123, 124, 122', 123') for shielding the optical window(121, 121') of the carrier(110) from a contact to external objects, thus avoiding a contamination of the optical window with dirt etc. The protection element can for example comprise an adhesive foil(124) attached to the optical window(121) prior to its use, or comprise constructive measures like an arrangement of the optical window(121, 121') in a recess.

Description

A cartridge for sample investigations

The invention relates to a cartridge for providing optical access to a sample chamber in which a sample can be provided. Moreover, it relates to a microelectronic sensor device comprising such a cartridge.

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 quantitative measurements in this and similar setups is that they require a precise knowledge of the amount of light that reaches the surface of total internal reflection.

Based on this situation it was an object of the present invention to provide means for optical investigations or manipulations of a sample that allow for well-defined operating conditions.

This object is achieved by a cartridge according to claim 1 and a microelectronic sensor device according to claim 12. Preferred embodiments are disclosed in the dependent claims.

The term "cartridge" is used in the context of the present application in a very broad and general sense as a name for a device, element or unit that provides optical access to a sample chamber, i.e. to some space in which a sample to be manipulated or investigated can be provided. The cartridge comprises two principal components: a) A carrier that may optionally be constructed as a one-piece element from a homogeneous material, for example from glass or from transparent plastics. The carrier comprises:

A "binding surface" with an "investigation region" that is or that can be disposed adjacent to the sample chamber. The term "binding surface" is chosen here primarily as a unique reference to a particular part of the surface of the carrier, and though target components of a sample will in many applications actually bind to said surface, this does not necessarily need to be the case. The "investigation region" may be a sub-region of the binding surface or comprise the complete binding surface; it will typically have the shape of a substantially circular spot.

At least one optical window through which a light beam can pass, i.e. enter or leave the carrier.

A transparent light path optically connecting the aforementioned optical window and the investigation region; a light beam can therefore propagate within the carrier from the optical window to the investigation region or vice versa along said light path. Typically the light path will be realized by a straight channel between the optical window and the investigation region that is made from a transparent material with homogeneous refraction index. b) A "protection element" for a shielding the optical window of the carrier from contacts to external objects, i.e. objects that are separate and different from the cartridge. The shielding function is typically not perfect, i.e. there may exist particular external objects or particular ways to move external objects for which a contact to the optical window can occur. The probability that external objects can contact the optical window should however be significantly reduced, particularly for practically relevant objects and for the typical application scenario of the cartridge.

Due to the provision of a protection element, the described cartridge has a considerably reduced risk of a contamination or even damage of the optical window by external objects, for example by dust, fingerprints, rain (in case of an outdoor use) etc. This helps to ensure well-defined and reproducible conditions for light beams passing through the optical window and to avoid uncontrollable and unknown effects, e.g. a scattering or absorption of light by dust particles on the optical window. Thus the cartridge allows for more accurate measurements.

In the general case, the sample chamber in contact to which the binding surface of the carrier can be brought may be of arbitrary design. The sample chamber may for example be open to the surroundings for detecting target components (molecules etc.) in e.g. the ambient atmosphere and/or for applying such target components to the binding surface by spraying or painting. Typically, the sample chamber is an empty cavity or a cavity filled with some substance like a gel that may absorb a sample substance; it may be an open cavity, a closed cavity, or a cavity connected to other cavities by fluid connection channels. The sample chamber may further be a part of the cartridge or not. The cartridge may be used in combination with many different devices and methods. For a practically important special application in an investigation procedure, the carrier of the cartridge comprises two optical windows of the kind described above (with corresponding light paths and protection elements), wherein an "incident light beam" can enter the carrier through a first one of the two optical windows such that this light beam is totally internally reflected in the investigation region at the binding surface; moreover, a light beam that is called "reflected light beam" here and that originates in the investigation region shall be able to leave the carrier through a second one of the optical windows. The reflected light beam will typically comprise or totally consist of light of the incident light beam that was totally internally reflected at the binding surface; it may however also comprise light from other sources like a fluorescence stimulated in the investigation region. Moreover, it should be noted that the occurrence of total internal reflection requires that the refractive index of the carrier is larger than the refractive index of the material adjacent to the binding surface. This is for example the case if the carrier is made from glass (n = 2) and the adjacent material is water (n = 1.3). It should further be noted that the term "total internal reflection" shall include the case called "frustrated total internal reflection", where some of the incident light is lost (absorbed, scattered etc.) during the reflection process.

The amount of light in the reflected light beam will typically be measured by some light detector to provide quantitative information about the conditions in the investigation region, particularly about the concentration of target components (e.g. biomolecules, complexes, cell fractions or cells) in the investigation region that may be the cause of a frustrated total internal reflection. In such a setup, light of the incident light beam that is deflected (e.g. due to scattering by dirt particles) on its way from the light source to the investigation region and/or light of the reflected light beam that is deflected on its way from the investigation region to a detector may wrongly be attributed to effects of target components in the investigation region. The accuracy of the measurements can therefore considerably be increased if such effects are minimized, which is achieved inter alia by protecting the optical windows from contaminations etc. with the protection elements. According to a first particular embodiment of the protection element, this element comprises a movable cover that can assume a first position, in which it shields the optical window from the ambience, and a second position, in which it provides (optical) access to the optical window. During the time from the fabrication to the application of the cartridge, such a protection element will usually be in its first position in which it protects the optical window; once the cartridge is ready for use, the protection element can be transferred to the second position to provide free optical access to the optical window, e.g. for irradiating the investigation region with an incident light beam. The transition of the cover from the first to the second position may both be reversible or irreversible, wherein the latter is typically the case for disposable cartridges. The cover may further be designed such that it is automatically moved from the first to the second position if the cartridge is inserted into some examination apparatus.

In a first particular realization of the aforementioned cover, this cover (completely or partially) encloses the carrier when it is in its first position. With other words, the cover is designed as a container for the carrier, thus shielding the carrier and allowing its safe handling during transportation and storage. The cover may optionally be disconnected from the carrier in its second position. One example of such a cover is a container of the aforementioned kind which is typically a separate element independent of the carrier. Another example is a removable cap that (only) protects the optical window. In another embodiment, the cover is fixed to the optical window in its first position by adhesive forces. Such a cover may for example be realized by a flexible plastic foil that is glued to the optical window by an intermediate adhesive layer, wherein the adhesion to the optical window should be weak enough that the cover can readily and without remains be torn off once the cartridge shall be used. In still another embodiment, the cover is connected to the carrier by a joint, for example a hinge that allows translational and/or rotational movements. In this case the cover is always connected to the carrier and will therefore not be lost or have to be separately stored if it is in its second position.

Furthermore, the cover may comprise a plastic portion, e.g. a section of a flexible metal foil. Such a plastic portion can provide a similar function as a hinge, allowing a movement of the cover from the first to the second position while keeping the connection to the carrier. Moreover, the plastic portion will usually hold the cover in the first or second position as long as no forces act on it.

In another variant of the invention, the protection element comprises at least one protrusion projecting from the optical window in such a way that objects with a bending radius larger than a given threshold radius cannot touch the optical window. The optical window may particularly be located in a recess of the carrier, the walls of this recess serving as protrusions of the aforementioned kind. The protrusions provide a constructive protection of the optical window, which is practically complete for objects which are not too tapered. By prescription of an appropriate threshold radius, the practically very important protection from fingerprints can thus be achieved.

Up to now the description of the cartridge included the case that only a single investigation region is present on the binding surface. In many practically relevant embodiments of the cartridge, the binding surface will however comprise a plurality of investigation regions at which different incident light beams can be totally internally reflected. One carrier then allows the processing of several investigation regions and thus for example the search for different target components, the observation of the same target components under different conditions and/or the sampling of several measurements for statistical purposes. The "different incident light beams" may optionally be components of one broad light beam that is homogeneously generated by one light source, they may be individual separate light beams entering the carrier simultaneously (optionally through the same or through different optical windows), and/or they may be temporally different (i.e. be generated by one generic light beam scanning the investigation regions). While it is in principle possible that the carrier has some dedicated structure with multiple components of different materials, it is preferred that the carrier is homogenously fabricated from a transparent material, for example from glass or a transparent plastic. The carrier can thus readily be produced for example by injection moulding. The investigation region of the carrier may optionally be covered with at least one type of capture element that can bind one or more target components contained in the sample. A typical example of such a capture element is an antibody to which corresponding antigens can specifically bind. By providing the investigation region with capture elements that are specific to certain target components, it is possible to selectively enrich these target components in the investigation region. Moreover, undesired target components can optionally be removed from the binding surface by suitable (e.g. magnetic or hydrodynamic) repelling forces (that do not break the bindings between desired target components and capture elements). The investigation region may preferably be provided with several types of capture elements that are specific for different target components. In a carrier with a plurality of investigation regions, there are preferably at least two investigation regions having different capture elements such that these regions are specific for different target components.

The surface of the optical window of the carrier is preferably substantially perpendicular to a light beam that enters or leaves the carrier in a typical application of the carrier, i.e. the angle of incidence lies in a range of about ±5° around 90°. In this case the direction of the light beam will not or only minimally change during the transition from a surrounding medium into the carrier or vice versa. Moreover, reflection will be minimized. Additionally or alternatively, the corresponding regions may also have an anti-reflection coating. To prevent feedback into the light source (e.g. a laser), it may be preferable to have an incident beam (at most) a few degrees off-perpendicular.

The optical window of the carrier may optionally have a flat or a curved surface, particularly a surface with a form similar or identical to a hemisphere or a truncated pyramid. Such forms may function like lenses and/or prisms and thus provide a favorable guidance of passing light beams. In case of a curved surface, the bending radius may preferably range between 10% and 200%, most preferably around 100% of the distance between the optical window and the investigation region (i.e. of the length of the associated light path).

The carrier may further optionally comprise a cavity in which a (magnetic or electrical) field generator can at least partially be disposed. Thus a field source can be positioned as close as possible to the binding surface, allowing to generate high field strengths in the investigation region with minimal effort (e.g. electrical currents) and with minimal disturbances for other regions (e.g. neighboring investigation regions). Moreover, such a cavity can be used to center the carrier with respect to the field generator and/or other components (e.g. a light source, a light detector). Field generators are particularly useful if the sample comprises field-sensitive "label particles".

The carrier is preferably designed as an exchangeable component of an investigation device, for example as a well-plate. Thus it may be used as a low-cost disposable part, which is particularly useful if it comes into contact with biological samples and/or if its coating (e.g. with antibodies) is used up during one measurement process.

The invention further relates to a microelectronic sensor device that serves for 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 term "label particle" shall denote a particle (atom, molecule, complex, nanoparticle, microparticle etc.) that has some property (e.g. optical density, magnetic susceptibility, electrical charge, fluorescence, radioactivity, etc.) which can be detected, thus indirectly revealing the presence of the associated target component. The "target component" and the "label particle" may optionally also be identical. The microelectronic sensor device comprises the following components: a) A cartridge of the kind described above, i.e. with a carrier and a protective element, wherein the carrier has a binding surface at which target components can collect (typically in concentrations determined by parameters associated to the target components, to their interaction with the binding surface, to their mobility and the like). The carrier preferably has two optical windows with associated protective elements through which the light beams that will be described next can pass. b) A light source for emitting a light beam, called "incident light beam" in the following, into the aforementioned carrier such that it is totally internally reflected in the investigation region at the binding surface of the carrier. 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 incident light beam. c) A light detector for determining the amount of light in a reflected light beam, wherein the term "reflected light beam" shall both be a unique reference to the light that is caught by the detector and imply that this beam comprises light that stems from the aforementioned total internal reflection of the incident light beam. It is however not necessary that the "reflected light beam" comprises all the totally internally reflected light (though this will preferably be the case), as some of this light may for example be used for other purposes or simply be lost.

The 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.

The described microelectronic sensor device allows a sensitive and precise quantitative or qualitative detection of target components in an investigation region at the binding surface, which is not affected by contaminations at the optical windows of the carrier as these are shielded by a protective element. For more information on details, advantages and further developments of the microelectronic sensor device, reference is made to the above description of the cartridge.

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 shows the general setup of a microelectronic sensor device in which a cartridge according to the present invention can be used; Figure 2 shows a perspective of the bottom surface of the carrier of

Figure 1.

Figure 3 illustrates design parameters of a recess for an optical window;

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

Figure 1 shows the general setup of a microelectronic sensor device with a cartridge 100 according to the present invention. A central component of the cartridge 100 is a carrier 110 that may for example be made from glass or transparent plastic like poly-styrene. The carrier 110 is, during its application, 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 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 Figure). 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 110 and the sample chamber 2 is formed by a surface called "binding surface" 112. This binding surface 112 may optionally be coated with capture elements, e.g. antibodies, which can specifically bind the target components.

The cartridge 100 further comprises some lid-element 130 (only partially depicted in the Figure) that is located above the binding surface 112 and forms, in combination with the carrier 110, a fluidic system comprising the sample chamber 2.

The sensor device comprises a magnetic field generator 41, for example an electromagnet with a coil and a core, for controllably generating a magnetic field (not shown) at the binding surface 112 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 112 in order to accelerate the binding of the associated target component to said surface.

The sensor device further comprises a light source 21, for example a laser or an LED, that generates an incident light beam Ll which enters the carrier 110 through a first optical window 121 and then propagates within the carrier 110 via a first light path. The incident light beam Ll arrives in an investigation region 113 at the binding surface 12 at an angle larger than the critical angle θ_c of total internal reflection (TIR) and is therefore totally internally reflected as a "reflected light beam" L2. The reflected light beam L2 leaves the carrier 110 via a second light path and through a second optical window 121' and is detected by a light detector 31, e.g. a photodiode. The light detector 31 determines the amount of light of the reflected 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 measurement results are evaluated and optionally monitored over an observation period by an evaluation and recording module (not shown) that is coupled to the detector 31.

A further light detector (not shown) can alternatively or additionally be used to detect fluorescence light emitted by fluorescent particles which were stimulated by the evanescent wave of the incident light beam Ll . As this fluorescence light is usually emitted isotropically to all sides, the corresponding detector can in principle be disposed anywhere, e.g. also above the binding surface 112. Moreover, it is of course possible to use the detector 31, too, for the sampling of fluorescence light, wherein the latter may for example spectrally be discriminated from reflected light L2. Though the following description concentrates on the measurement of reflected light, the principles discussed here can mutatis mutandis be applied to the detection of fluorescence, too. 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 propagates (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 in the setup of Figure 1, part of the incident 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 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 110 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 110 and its lid-element 130 can consist of a relatively simple, injection-molded piece of polymer material that may also contain fiuidic channels 111.

Large multiplexing possibilities for multi-analyte testing: The binding surface 112 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. To achieve the last item, i.e. a low-noise read-out and reliable measurements, the detected drop in the intensity of the reflected light beam L2 should accurately correspond to the amount of light which is scattered and/or absorbed in the investigation region 113. However, source light Ll being scattered from contamination or damage of the optical windows 121, 121' (in particular the entrance window 121) can reach the detector 31 without being reflected in the investigation region 113. This part of the light therefore gives a constant, but a-priori unknown offset to the detector signal, affecting the accuracy of the measurement.

To prevent the aforementioned effects from occurring, and thus to improve the reliability and robustness of the measurement method, the optical windows 121, 121' of the carrier 110 should be clean and smooth to start with. In fabrication, this can be easily achieved. For use in a practical situation, particular measures are however needed to make the cartridge robust against contamination or damage. It is therefore proposed here to add a "protection element" to the cartridge for shielding the optical windows 121, 121' of the carrier 110 from a contact to external objects. To this end, a number of options are available which can be used separately or in combination, for example:

Adding a cover in the form of a small container (not shown) to the cartridge for storing the carrier 110, wherein the container may partly or completely enclose the carrier before its use and (at least) protect the optical windows 121, 121' against dust and fingerprints.

Adding a cover in the form of an adhesive foil to the cartridge 100 to protect the optical windows 121, 121', said foil being removed shortly prior to use. In Figure 1, such a foil 124 is still present on the entrance window 121 while it has already been removed (and disposed) from the output window 121'.

Adding a cover in the form of a sliding door (not shown) to the cartridge 100 to protect the optical windows, e.g. a folded metal sheet, which is e.g. pushed aside to provide optical access to the optical windows 121, 121' when the cartridge is inserted into a reader device. Rotating or folding options can be used for such a cover as well. Providing a passive protection, notably against fingerprints by the user, by positioning the optical windows 121, 121' in an area which is recessed from the exterior surface of the carrier 110.

The last option of an arrangement of the optical windows in recesses will now be explained in more detail. For a practical implementation with injection molded plastic carriers 110, additional requirements on the design and location of the optical windows 121, 121' are necessary in order to prevent undesired effects like bending, shrinking and internal stress. To achieve this, it is beneficial to keep the material thickness over the structure as uniform as possible. Moreover, due to limitations in mold manufacturing, in particular polishing steps for optically smooth surfaces, it is highly beneficial to keep the recess depth d limited to a fraction of the material thickness. In addition, for magnetic actuation, the material thickness at the investigation region 113 should be less than about 1 mm, in order to achieve sufficient magnetic field strength at moderate currents. Generally, the smallest window-dimension w (height or width, but most preferably the height) and the recess depth d should be chosen such that they prevent contact on the window area for an object with a (mean or minimal) radius of curvature R, for example a human finger. Figure 3 shows a principal sketch of the associated geometry, from which it can be derived that for a given radius R and window-height w, the minimum required recess depth d is given by d > R - (R² -w²/4)^1/2.

This formula can alternatively be rewritten for given R and d, yielding the maximal allowable window-height w, or for given w and d, yielding the minimal allowable value of R. The carrier 110 of Figure 1 is designed according to the above principles.

In order to provide a uniform magnetic field, the material thickness around the investigation region 113 is generally kept to 1 mm or less. Due to the large angle of incidence, this also limits the height w of the optical windows 121, 121' to approximately 1 mm (for other reasons, the width L of the windows is chosen as 8 mm, cf. Figure 2). Moreover, protrusions or shoulders 122, 123 and 122', 123' are located next to the entrance window 121 and output window 121', respectively, thus arranging these windows in recesses with a depth d of about 0.1 mm. This provides protection against objects with a radius larger than 1.3 mm. As fingers have a typical radius of curvature of more than 5 mm, this is a safe choice. In order to meet and combine all requirements mentioned above, including protection against fingerprints, it is preferable to provide optical windows with a height w of 1 mm, a width L between 1 and 10 mm, and a recess depth d of about 0.1 mm.

It should be noted that in the drawings the recessed optical windows have a flat surface. The reason is that for a relatively large beam diameter (e.g. 0.5 mm) a curved surface would lead to aberration of the spot at the sensing surface. On the other hand a carrier with a flat surface needs accurate angular alignment with respect to the reader to avoid refraction at the entrance surface. In case a curvature is chosen with a radius equal to the distance from sensing spot in the investigation region 113 to the surface of the entrance window 121, the angular dependency is eliminated to a large extent.

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

The sensor can comprise any suitable sensor to detect the presence of magnetic 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.

Claims

CLAIMS:

1. A cartridge (100) for providing optical access to a sample chamber (2), comprising a) a carrier (110) having a binding surface (112) with an investigation region (113) that is or that can be disposed adjacent to the sample chamber (2); at least one optical window (121, 121') through which a light beam (L1,L2) can pass; a transparent light path connecting the optical window (121, 121') and the investigation region (113); b) a protection element (122, 123, 124, 122', 123') for shielding the optical window (121, 121') of the carrier (110) from a contact to external objects.

2. The cartridge (100) according to claim 1, characterized in that the carrier (110) comprises a first and a second optical window (121, 121'), wherein an incident light beam (Ll) can enter the carrier (110) through the first optical window (121) such that it is totally internally reflected in the investigation region (113) at the binding surface (112), and wherein a reflected light beam (L2) originating in the investigation region (113) can leave the carrier (110) through the second optical window (121').

3. The cartridge (100) according to claim 1, characterized in that the protection element comprises a movable cover (124) that can assume a first position, in which it shields the optical window (121) from the ambience, and a second position, in which it provides access to the optical window (121).

4. The cartridge (100) according to claim 3, characterized in that the cover encloses the carrier (110) in the first position.

5. The cartridge (100) according to claim 3, characterized in that the cover (124) is disconnected from the carrier (110) in the second position.

6. The cartridge (100) according to claim 3, characterized in that the cover (124) is fixed to the optical window (121) by adhesive forces in the first position.

7. The cartridge (100) according to claim 3, characterized in that the cover is connected to the carrier (110) via a joint.

8. The cartridge (100) according to claim 1, characterized in that the cover comprises a plastic portion.

9. The cartridge (100) according to claim 1, characterized in that the protection element comprises at least one protrusion (122, 123, 122', 123') projecting from the optical window (121, 121') such that objects with a bending radius (R) larger than a given threshold value cannot contact the optical window (121, 121').

10. The cartridge (100) according to claim 1, characterized in that the optical window (121, 121') is located in a recess of the carrier (110).

11. The cartridge (100) according to claim 1 , characterized in that the optical window of the carrier has a curved surface, particularly a surface with a bending radius that lies between 10% and 200%, most preferably around 100%, of the distance between the optical window and the investigation region (113).

12. A microelectronic sensor device for the detection of target components comprising label-particles (1), comprising a) a cartridge (100) according to claim 1; b) a light source (21) for emitting an incident light beam (Ll) into the carrier (110) of the cartridge such that it is totally internally reflected in the investigation region (113) at the binding surface (112) of the carrier; c) a light detector (31) for determining the amount of light in a reflected light beam (L2).