OPTOELECTRONIC CHIP

Abstract

The present invention relates to an optoelectronic chip for receiving a sample for optical examination, having a carrier layer, a thin-film lightguide having an active region, in which the sample interacts with a guided mode of the thin-film lightguide, wherein at least one scattering structure is arranged in the active region, which scatters a part of the light guided in the thin-film lightguide, whereby a reference light field is produced. The invention further relates to an optical system having such a chip. The system is used for the marker-free analysis of particles, particularly biomolecules in their natural environment.

Claims

1. Optoelectronic chip for receiving a sample for optical examination, having a carrier layer, a thin-film lightguide having an active region, in which the sample interacts with a guided mode of the thin-film lightguide, wherein at least one scattering structure is arranged in the active region, which scatters the light guided in the thin-film lightguide, whereby a reference light field is produced.

2. Optoelectronic chip according to claim 1, wherein the scattering structure is formed regularly or irregularly and extends partially or completely over the active region.

3. Optoelectronic chip according to claim 1 or 2, wherein the scattering structure comprises local variations in the effective refractive index of the thin-film lightguide or a layer interacting with the guided mode.

4. Optoelectronic chip according to any one of the preceding claims, wherein the reference light field is produced by light-scattering particles interacting with the mode guided in the lightguide layer.

5. Optoelectronic chip according to any one of the preceding claims, characterized in that the thin-film waveguide further has a structure for mode purification which, preferably by means of at least one adiabatic transition, limits the light guided in the thin-film waveguide to a single mode, at least in sections.

6. Optoelectronic chip according to any one of the preceding claims, having at least two coupling regions; one for coupling in the mode guided in the thin-film lightguide and one for coupling out a part of the mode guided in the thin-film lightguide from the thin-film lightguide for monitoring the intensity of the guided mode.

7. Optoelectronic chip according to claim 6, characterized in that the coupling region for coupling out a part of the mode guided in the thin-film lightguide from the thin-film lightguide for monitoring the intensity of the guided mode runs at least in sections adjacent to the structure for mode purification, such that light can preferably be transferred from the thin-film lightguide into a reference lightguide for monitoring the intensity of the guided mode in the thin-film lightguide by means of a preferably evanescent coupling.

8. Optoelectronic chip according to any one of the preceding claims, which contains an optically transparent thin-film heating element in addition to the thin-film waveguide.

9. Use of an optoelectronic chip according to any one of the preceding claims for receiving a sample for optical examination, wherein a sample, preferably an at least partially liquid, solid or gel-like sample is applied to the optoelectronic chip in such a way that the sample partially or completely surrounds the active region of the thin-film lightguide.

10. Use according to claim 9, characterized in that the sample contains at least one or a plurality of particle(s) that is/are capable of and/or designed to interact with a guided mode of the thin-film lightguide.

11. Optical system which is designed to be used with an optoelectronic chip according to any one of the preceding claims 1 to 8, and designed to generate interference between a scattered light of a particle located in the sample space and a reference light generated by the scattering structure.

12. Optical system according to claim 11, which is further designed to detect the interference generated by means of a detector.

13. Optical system according to claim 12, characterized in that the detector is an array detector and/or the optical system is a microscope.

14. Optical system according to any one of the preceding claims 11 to 13, which is designed to introduce light into a thin-film lightguide of an optoelectronic chip, such that a sample received in an active region of the thin-film lightguide can interact with the light.

15. Use of an optoelectronic chip according to any one of claims 1 to 8 and/or an optical system according to any one of claims 1 to 14 for determining the antigen-antibody binding affinity, examining an antibody-antibody cross-linking and/or multi-site binding processes, to analyze protein-protein interactions, to estimate protein sizes, in the context of investigations on protein degradation and denaturation properties, and to optimize and characterize formulations.

Description

[0109] Further advantages, features and effects of the present invention are shown in the following description of preferred exemplary embodiments with reference to the figures, in which the same or similar components are designated by the same reference numerals. In the figures:

[0110] FIG. 1 shows a schematic representation of the layer construction of a chip according to the invention;

[0111] FIG. 2 shows an optoelectronic chip according to the invention with a representation of the light coupling interfaces as well as the interfaces in the waveguide required for light intensity measurement;

[0112] FIG. 2a shows an optoelectronic chip according to the invention with a structure for mode purification;

[0113] FIG. 3 shows the principle of on-chip interferometric detection as performed in the context of the present invention,

[0114] FIG. 3a additionally shows a scattering structure for producing a reference light field; and

[0115] FIG. 3 shows the construction of an optical system according to the invention, in particular a microscope.

[0116] FIG. 1 shows an optoelectronic chip 1, which has up to seven layers (L1-L7). In this embodiment, all layers preferably have a surface roughness of less than 5 nm rms. All layers can be structured independently in the substrate plane, e.g. with grating couplers for diffraction of the incident free beam into one of the guided modes. The waveguide layer L5 can be chemically functionalized, e.g. for the specific binding of biomolecules.

[0117] The layer L1 has or consists of a carrier material, in particular a transparent glass substrate (e.g. borosilicate, quartz glass, etc.) with a thickness between 50 and 1000 m and a refractive index of n.sub.sup or a semiconductor material (e.g. Si) in combination with a transparent separating layer.

[0118] Optionally, a transparent layer L2 can be provided as a separating layer, wherein the layer L2 has a refractive index of n.sub.sp1, where preferably n.sub.sp1<n.sub.wg. The layer L2 can be made up of several sub-layers.

[0119] Alternatively or additionally, an optionally transparent layer L3 can be provided as a separating layer, wherein the layer L3 has a refractive index of n.sub.sp2, where n.sub.sp2<n.sub.wg. The layer L3 can be made up of several sub-layers.

[0120] For the integration of a thin-film resistance temperature sensor, an additional layer L4, preferably a metal layer, can be applied either on the separating layer L2, the separating layer L3 or on the carrier material of the carrier layer L1. The layer L4 can consist of metal lower layers. The layer L4 preferably only extends over a partial region of the adjacent layers; in this example the layers L1 and L4.

[0121] The layer L5 has or consists of a waveguide. The layer L5 is used as a highly refractive, non-absorbing layer with a refractive index of preferably n.sub.wg>n.sub.sup. The layer thickness is preferably between 30 and 600 nm. The layer L5 preferably comprises or consists of materials such as TiO.sub.2, Ta.sub.2O.sub.5, Al.sub.2O.sub.3, Nb.sub.2O.sub.5, Si.sub.3N.sub.4, GaP, ZrO.sub.2, SiO.sub.2, etc. The layer L5 can consists of several sub-layers of different materials.

[0122] Optionally, a layer L6 can be provided as a heating element. The layer L6 is preferably a transparent conductive layer with a thickness of 1 nm-100 nm and is designed as a resistance heater, i.e. it preferably has materials such as ITO, carbon nanotubes, etc. for resistance heating.

[0123] The layer L7 reflects the sample volume. This volume contains particles that interact with the guided mode of the waveguide layer. The sample can be liquid, solid or gel-like and preferably partially or completely surrounds the waveguide.

[0124] The functionality of an optoelectronic chip according to the invention is explained below with reference to the representation in FIG. 2.

[0125] FIG. 2 shows a top view of an optoelectronic chip 1 according to the invention, in which a waveguide structure 2 and an active region 3 of the chip 1 are visible.

[0126] In the chip shown in FIG. 2, a substrate is coated on one side with a patterned waveguide layer that supports single or multiple waveguide modes with significant power ratio outside the waveguide layer itself (>1%). Within the active region 3 of the waveguide 2, the guided light can be scattered, absorbed or/and re-emitted by particles within the sample volume. A reference light field is generated within the active region 3 of the waveguide 2 by selectively or non-selectively coupling out parts of the guided mode in the direction of the collection lens (also referred to as detection lens). The waveguide (lightguide) 2 corresponds to a measuring waveguide (measuring lightguide).

[0127] This can be achieved, for example, by introducing a certain surface roughness or a periodic structure (e.g. a grid) within the active region 3, preferably within the layers L1, L2 and/or L5, which are used as a scattering structure and create a reference light field.

[0128] The scattering structure preferably overlaps spatially with the active region, in particular when viewed along the light used as a reference beam.

[0129] The amount of light injected into the reference beam path is preferably selected in such a way that the interference signal of the nanoparticles on the detector is optimized in terms of contrast, signal-to-noise ratio and visual noise for a given integration time of the detector.

[0130] The width of a waveguide of an optoelectronic chip according to the invention (for example, the dimension from the upper edge of the waveguide 2 or 9 to the lower edge of the waveguide 2 or 9 in FIG. 2) 2 is preferably between 100 nm and 1000 m.

[0131] The dimension of a chip 1 according to the invention is preferably 3020 mm. It has been found advantageous if a chip 1 according to the invention is smaller than 50 mm50 mm and larger than 5 mm5 mm.

[0132] The on/off coupling of waveguide modes in the chip 1 of FIG. 2 according to the invention is preferably performed as follows: Coupling regions 4 enable the coupling in and out of free space modes into or out of the waveguide mode. The chip 1 may contain one or more coupling regions 4 and one or more waveguides 2. A coupling region 4 is preferably provided to couple into a waveguide mode.

[0133] An additional coupling region can be used as a reference coupling region 5 to couple a certain portion of the guided light back into free space modes in order to monitor the light intensity propagating within the guided mode. In other words, the reference coupling region 5 selectively couples light out of the waveguide 2 so as to monitor the light intensity. A reference waveguide (reference lightguide) 9 is provided for this purpose. The outcoupled light can be used to stabilize the intensity within the guided mode either before or after the active region.

[0134] FIG. 2a shows an optoelectronic chip according to the invention with a structure for mode purification. The mode purification can take place via a single mode taper. In this case, the guided mode in the measurement waveguide can be purified by an adiabatic transfer 11 into the single-mode regime, so that multi-mode interference can be avoided and homogeneous sample illumination can be ensured. In FIG. 2a, the reference numeral 10 indicates a single-mode region in which a single mode is present. After the transition to the single-mode regime, the measuring waveguide 2 can again be adiabatically expanded by an adiabatic transition 11, such that a sample range of several 100 m.sup.2 up to several mm.sup.2 can be excited. The single-mode region 10 can be used simultaneously to extract a certain amount of light from the waveguide for intensity monitoring by means of a reference waveguide 9, for example via evanescent coupling.

[0135] The detection of particles in the sample volume is shown schematically in FIG. 3 and is preferably carried out as follows: Particles 3 in the sample volume L7 and in the immediate vicinity of the waveguide 2 (layer L5) of the chip 1, i.e. within the evanescent field 4 of the waveguide 2, can interact with the propagation mode.

[0136] The light 5 scattered by the particles 3 as well as, if applicable, fluorescence signals of the particles in combination with the reference beam or the reference light 6 generated by means of the scattering structure is collected with optical elements (e.g. a lens 7) orthogonally to the propagation direction of the waveguide 2 on one or both sides of the waveguide (for example above and below the chip).

[0137] The signals are then projected onto a detector, e.g. the camera 8, where the coherent signals, in particular the light 5 scattered by the particles and the reference light 6, interfere. The optional fluorescence signal that is still present can be separated with optical filters and simultaneously projected onto another detector (not shown here).

[0138] FIG. 3a also shows a scattering structure 12 which is arranged on the surface of the waveguide 2 (measuring waveguide) and generates the reference light field 6. The scattering structure is embedded in the waveguide 2, for example, and may be produced by a surface etching of the waveguide 2. In principle, the scattering structure can be formed by applying and/or introducing surface modification to or into a surface of the waveguide 2, e.g. in the form of tiny protrusions or recesses.

[0139] Optionally, an optically transparent heating element can be used to control the temperature of the chip via resistance heating. Furthermore, an additional temperature sensor could be built into the waveguide structure to provide direct temperature feedback. This embodiment is particularly advantageous when temperature-sensitive processes are to be observed.

[0140] The probability of finding particles within the excitation volume can be based on Brownian motion, convection, gravity or determined via a specific or non-specific interaction potential caused by special surface properties (e.g. coatings, functionalizations, etc.) or external optical or electrical forces.

[0141] Preferably, one or more of the following functional elements are arranged on a chip according to the invention:

[0142] Coupling and decoupling structures of the waveguide: The waveguide mode is excited via coupling structures or coupling modules such as grating couplers, prism couplers or direct fiber coupling mechanisms. The waveguide mode is preferably transmitted via the chip including the sample volume. The transmitted mode can be reflected back or coupled out with similar arrangements as the coupling module. A waveguide mode propagating simultaneously or separated in time in another direction can be coupled in with additional coupling modules.

[0143] In the waveguide, a special decoupling structure is preferably implemented for the intensity measurement of the guided light, which allows the light intensity guided in the waveguide to be monitored in interaction with the sample volume. This intensity reference can be detected via a light-sensitive element and used to actively stabilize the intensity.

[0144] The intensity of the measuring waveguide can also be detected in transmission and used for auto-correlation measurements similar to dynamic light scattering (DLS).

[0145] In the active region of the chip, the sample volume comes close to the waveguide. Particles within the sample volume that interact with the guided light (evanescent field) produce fluorescent and/or scattered light. A certain structure within this area generates a reference light field that can also be detected by the detection system and that allows interference with the light scattered by the nanoparticles in the sample volume.

[0146] Furthermore, a heating element may be provided in a chip according to the invention. The heating element preferably consists of or comprises an optically transparent, conductive thin film (e.g. ITO). For example, by applying a direct current, heat is generated which is transported through the carrier material into the sample volume. The heating element is preferably locally limited to the sample volume. Metallic electrodes, for example, allow connection to an external electronic heating circuit.

[0147] A temperature sensor can also be provided. Temperature detection for the heating circuit can be realized in particular with a thin-film resistance temperature sensor (e.g. Pt sensor) integrated on the chip. The temperature sensor is preferably read out via a four-point measurement. The sensor is preferably positioned between the heating element and the sample volume or on the top side or a side of the waveguide layer facing away from the carrier layer (separating layers are required).

[0148] FIG. 4 schematically shows the construction of an optical system according to the invention, in particular a microscope. The microscope has at least one light source 13 which feeds light into a measuring waveguide 2 of the optoelectronic chip 1. The intensity of the light guided into the measuring waveguide 2 is detected by means of two photodetectors 14, for example by coupling the light out of the measuring waveguide 2 via a reference waveguide 9 and feeding it to a photodetector. The optical signals designated with reference 16 in FIG. 4 can be transmitted as free beams and/or e.g. in fibers.

[0149] Both the light source 13 and the photodetectors 14 are connected to a control unit 15 that can control or regulate the light source 13, for example, on the basis of the light intensities detected by means of the photodetectors 14. For this purpose, the control unit 15 is connected to the light source 13 and the photodetectors 14 via bidirectional data lines 17. The camera 8 or imaging lens is also connected to the control unit via bidirectional data lines 17.

[0150] The present invention is particularly useful in the detection of individual particles and the analysis of particle dynamics. Exemplary applications are: the determination of antigen-antibody binding affinity, antibody-antibody cross-linking and multi-site binding processes, the analysis of protein-protein interactions, the estimation of protein sizes (hydrodynamic radius), investigations on protein degradation and denaturation properties, as well as the optimization and characterization of formulations (e.g. vectors of the adeno-associated virus (AAVs), nanoparticles, etc.).