WO2013053930A1

WO2013053930A1 - Resonant biosensor

Info

Publication number: WO2013053930A1
Application number: PCT/EP2012/070351
Authority: WO
Inventors: Peter Bienstman; Tom Claes; Wim Bogaerts
Original assignee: Universiteit Gent; Imec
Priority date: 2011-10-12
Filing date: 2012-10-12
Publication date: 2013-04-18
Also published as: GB201117649D0

Abstract

A photonic sensor (100) for detecting a biological, chemical or biochemical target analyte in a medium is described. The sensor (100) is adapted for sensing an effect of the presence of the medium on both a first periodic transfer spectrum and a second periodic transfer spectrum by which radiation is modulated in a optical filter element (103, 104, 204), allowing taking into account environmental changes in the medium. It furthermore is adapted for sensing a difference in the first periodic transfer spectrum and the second periodic transfer spectrum by which radiation is modulated in the optical filter element (103, 104, 204) dependent on the presence of target analytes in the medium, thus allowing accurate determination of the target analytes.

Description

Resonant biosensor

Field of the invention

The invention relates to the field of photonic biosensors. More specifically it relates to an evanescent wave sensor for detection and/or quantification of chemical, biological or biochemical targets and methods for detection or quantification of chemical, biological or biochemical targets.

Background of the invention

Label-free photonic biosensors can perform sensitive and quantitative multiparameter measurements on biological systems and can therefore contribute to major advances in medical analyses, food quality control, drug development and environmental monitoring. Additionally they offer the prospect of being incorporated in laboratories-on-a-chip that are capable of doing measurements at the point-of-care at an affordable cost.

A crucial component in most of these photonic biosensors is a transducer that can transform a refractive index change in its environment to a measurable change in its optical behaviour. Silicon-on-insulator may be a material system with many assets for such transducers. First, it has a high refractive index contrast permitting very compact sensors of which many can be incorporated on a single chip, enabling multiplexed sensing. Second, silicon-on-insulator photonic chips can be made with CMOS-compatible process steps, allowing for a strong reduction of the chip cost for high volume fabrication. These sensor chips can therefore be disposable, meaning that the chip is only used once, avoiding complex cleaning of the sensor surface after use. Often, a spectral shift of the transmission spectrum of the transducer is used to quantify the measured refractive index change. This method can be extended to the parallel read-out of multiple sensors in a sensor matrix.

For biosensors, the detection limit is an important figure of merit. The detection limit for resonant-based sensors is defined here as the ratio of the smallest detectable spectral shift and the sensitivity of the sensor. The latter is a measure for how much the spectrum shifts for a given change of the refractive index. There exist different types of transducers on silicon-on-insulator that use a variety of methods to achieve a low limit of detection. By using resonant sensors with high quality factors that have very narrow resonance peaks, the smallest detectable spectral shift can be minimized. These sensors use a resonator, e.g. a ring resonator, which is exposed to a medium containing an analyte of interest. Such sensors may have a surface which is adapted for the targeted analyte, e.g. which may comprise surface receptors for interacting with the target analyte, e.g. temporarily or permanently binding to it. This interaction causes a local change in refractive index, which may influence the transmission spectrum of the resonator through the evanescent field, e.g. causing a wavelength offset in this spectrum.

Ring resonator sensors are known in the art that are made with mass fabrication compatible technology and that may have a detection limit as low as 7.6 10^~7 RIU. Such sensors may have a bulk sensitivity of 163nm/RIU, which is not exceptionally high. However they may accomplish a smallest detectable wavelength shift as small as 0.22pm with an optimized sensor design and a very noise resistant optical setup and data analysis. Slot waveguides with enhanced light-matter interaction may be applied to improve the sensitivity of ring resonator sensors with a factor two to four, but increased optical losses may prevented these sensors from achieving better detection limits than normal ring resonator sensors. Integrated interferometers with large interaction lengths may also have proved to be promising, with detection limits in the order of 10^~6 RIU.

Furthermore, sensors are known in the art which consist of multiple ring resonators, for example arranged in cascade such that a high sensitivity may be achievable due to the Vernier-principle. The Vernier-scale is a method to enhance the accuracy of measurement instruments. It consists of two scales with different periods, of which one slides along the other one. The overlap between measurement marks on the two scales is used to perform the measurement. This scale is commonly used in callipers and barometers, and it has also found previous application in photonic devices, e.g. in the design of integrated lasers and tuneable filters. In D. Dai, "Highly sensitive digital optical sensor based on cascaded high-Q ring-resonators", Optics Express 2009 17 (26), such a Vernier-based sensor is disclosed. Referring to FIG. 1, such a Vernier-based sensor 1 may be implemented in Silicon-On-lnsulator, for example comprising components patterned in silicon on an insulator layer 2 such as a silica layer. This sensor 1 comprises two ring resonators 3,4 with different optical roundtrip lengths, which are cascaded such that the drop signal of the first ring resonator is 3 coupled via a interconnecting waveguide 5 to the input of the second ring resonator 4, as illustrated in FIG. 1. The entire chip typically is covered with a thick cladding 6, except for a region 7 in close proximity to one of the resonators, further referred to as the sensor ring resonator 4, where an opening is provided in the cladding so as to enable contacting the sensor ring resonator 4 to a test medium, for example this region 7 may be shaped such as to form a sample reservoir. This sensor ring resonator 4 will act as the sliding part of the Vernier-scale, as its evanescent field can interact with the refractive index in the environment of the sensor, where a change will cause a wavelength shift of the resonance spectrum. The other resonator, further referred to as the filter ring resonator 3, is shielded from these refractive index changes by the cladding and will act as the fixed part of the Vernier-scale. The cascade of both resonators can be designed such that a small shift of the resonance wavelengths of the sensor ring resonator will result in a much larger shift of the transmission spectrum of the cascade. Light may be coupled into the resonator cascade via an input waveguide 8, and collected from an output waveguide 9.

Each individual ring resonator has a comb-like transmission spectrum with peaks at its resonance wavelengths. The spectral distance between these peaks, the free spectral range, is inversely proportional to the optical roundtrip of the resonator. Therefore, each resonator in the cascade will have a different free spectral range, as illustrated by the transmission spectra of the filter ring resonator (dashed line) and of the sensor ring resonator (full line) shown in FIG. 2. As the transmission spectrum of the cascade of the two ring resonators, illustrated in FIG. 3, is the product of the transmission spectra of the individual resonators, it will only exhibit peaks at wavelengths for which two resonance peaks of the respective ring resonators at least partially overlap, and the height of each of these peaks will be determined by the amount of overlap. Thus, the cascade will have a spectral response with major peaks locating at the common resonant wavelengths of the cascaded rings.

However, the wavelength shift induced in the resonance spectrum of the sensor ring resonator 4 is not only dependent on presence of the analyte of interest, for example when bonding with purposefully designed receptors 10 on the sensor ring resonator surface which is exposed to the medium carrying the analyte of interest. Other factors, such as temperature or non-specific binding of undesired biomolecules, may influence the refraction index of the medium introduced into the region 7, and hence may cause a resonance spectrum shift and contribute to noise in the measurement process.

Summary of the invention

It is an object of the present invention to provide good and sensitive photonic detection and/or quantification of biological, chemical or biochemical targets in a medium, as well as good corresponding detection devices and the use thereof.

It is an advantage of embodiments according to the present invention that methods and systems are provided allowing to take into account the effect of environmental effects, resulting in a low detection limit for refractive index changes due to biological, chemical or biochemical targets.

It is an advantage of embodiments according to the present invention that methods and systems are provided that allow for taking into account both environmental effects as well as variations in the optical source used for optically characterizing biological, chemical or biochemical targets in the medium.

It is an advantage of at least some embodiments according to the present invention that methods and systems are provided wherein the conditions wherein reference information is obtained are identical to the conditions wherein the biological, chemical or biochemical target information is obtained, as interaction with the environment, including e.g. passage of the sample, can be identical. It is an advantage of embodiments according to the present invention that a good signal to noise ratio may be obtained. It is an advantage that noise due to temperature, pH of the medium, targets not binding to the surface but passing the surface, targets binding in an a-specific manner to the surface, etc. can be suppressed or compensated for.

It is an advantage of embodiments according to the present invention that analytes such as for example bio-analytes may be characterized by analyzing changes of refractive index in a medium.

It is an advantage of embodiments according to the present invention that an integrated biosensor may be provided having few components and a small area footprint.

It is an advantage of embodiments according to the present invention that a disposable integrated biosensor may be provided that is cheap and easy to manufacture.

It is an advantage of embodiments according to the present invention that the smallest detectable wavelength shift, and thus the resolution, may be substantially lower than achievable by known discrete sensing techniques.

It is an advantage of embodiments according to the present invention that a large sensitivity may be achieved. It is a further advantage that embodiments of the present invention may be well suited for integration with on-chip dispersive elements such as arrayed waveguide gratings or planar concave gratings.

It is an advantage of embodiments according to the present invention that a cheap and portable sensor read-out may be provided.

The above objective is accomplished by a method and device according to the present invention.

The present invention relates to a photonic sensor for detecting a biological, chemical, biomimic or biochemical target analyte in a medium, the sensor comprising at least one optical filter element adapted for receiving a first electromagnetic wave component and for modulating by interference the first electromagnetic wave component propagating in the at least one optical filter element with a first periodic transfer spectrum having a first free spectral range,

at least one optical filter element adapted for receiving a second electromagnetic wave component and for modulating by interference said second electromagnetic wave component propagating in said at least one optical filter element with a second periodic transfer spectrum having a second free spectral range being different from the first free spectral range,

an output means for outputting a signal representative for a combination of said first electromagnetic wave component and said second electromagnetic wave component out of the photonic sensor, e.g. a combined radiation signal,

the sensor also comprising

an surface interface providing an interface between the at least one optical filter element adapted for receiving the first electromagnetic wave component and the at least one optical filter element adapted for receiving the second electromagnetic wave component and the medium when introduced in the sensor, wherein the difference between the first free spectral range and the second free spectral range is smaller than or equal to a largest full width at half maximum of the peaks in the first and second periodic transfer spectrum.

The surface interface, the at least one optical filter element adapted for receiving the first electromagnetic wave component and the at least one optical filter element adapted for receiving the second electromagnetic wave component also are arranged for inducing an effect of the presence of the medium on the first periodic transfer spectrum as well as on the second periodic transfer spectrum and, upon presence of target analytes in the medium, a different effect is induced on the first and second periodic transfer spectrum. It is an advantage of embodiments according to the present invention that noise contributions may be eliminated which are due to differences in the local environment of multiple optical filter elements, e.g. temperature gradients, or due to differences in structure of multiple optical filter elements, e.g. surface roughness or geometric aberrations. It is a further advantage that a high resolution and good detection limit may be achieved. The at least one optical filter element adapted for receiving and modulating a first electromagnetic wave component and the at least one optical filter element adapted for receiving and modulating the second electromagnetic wave component may be a single optical filter element. Alternatively, the at least one optical filter element adapted for receiving and modulating a first electromagnetic wave component and the at least one optical filter element adapted for receiving and modulating the second electromagnetic wave component may be different optical filter elements (204) arranged in cascade. The first and/or second optical filter element may be any of a resonator or an interferometer.

The same or different samples can in principle be used in the first and the second optical filter element. According to at least some embodiments, the measurement can be performed simultaneously, on the same sample or even on different samples, e.g. with a specific reference sample for one optical filter element, and a measurement sample for another optical filter element.

The at least one optical filter element adapted for receiving the first electromagnetic wave component and the second optical filter element adapted for receiving the second electromagnetic wave component may be arranged for receiving electromagnetic wave components substantially simultaneously from the same emitting radiation source. This can be obtained by using one optical resonator acting both as first optical filter element and second optical filter element simultaneously, or by putting both optical filter elements in cascade, thereby taking into account that the speed of variations in the radiation source are negligible compared to the speed of radiation in the structure.

The surface interface may comprise receptors adapted for interacting with said target analyte and arranged for inducing the dependency on the presence of targets of the effect on the first periodic transfer spectrum and of the effect on the second periodic transfer spectrum. It is an advantage of embodiments of the present invention that the Vernier-based sensors can be made specific to one or more target analytes.

The arrangement of the surface interface and the optical filter element adapted for receiving the first electromagnetic wave component on the one hand and the arrangement of the surface interface and the optical filter element adapted for receiving the second electromagnetic wave component may be the same. The optical filter element adapted for receiving the first electromagnetic wave component and the optical filter element adapted for receiving the second electromagnetic wave component both may - except for receptors - be uncovered or may be covered in the same manner.

The surface interface may comprises a microfluidic channel for transporting the medium. It is an advantage of embodiments of the present invention that for the sensor use can be made of microfluidic devices, which typically allow easy detection. The at least one optical filter element adapted for receiving a first electromagnetic wave component and the at least one optical filter element adapted for receiving a second electromagnetic wave component may be the same optical filter element. It is an advantage of embodiments according to the present invention that a compact photonic sensor can be obtained making use of the Vernier principle.

The one and the same optical filter element may be adapted for both conducting the first electromagnetic wave component in a first photonic mode and the second electromagnetic wave component in a second photonic mode. It is an advantage of embodiments according to the present invention that a single optical filter element can be used supporting two photonic modes, whereby a different sensitivity of the two photonic modes can be used for using a Vernier effect. The first photonic mode is a TM mode and the second photonic mode is a TE mode.

The output means adapted for outputting a combined signal may be adapted for outputting a signal representative for a linear combination of the first electromagnetic wave component and the second electromagnetic wave component. The linear combination may be a superposition of the first electromagnetic wave component and the second electromagnetic wave component.

The one and the same optical filter element may comprise a first input waveguide for inputting the first electromagnetic wave component and a second input waveguide, different from the first input waveguide, for inputting the second electromagnetic wave component. The one and the same optical filter element may comprise a single input waveguide for inputting the first electromagnetic wave component and the second electromagnetic wave component.

The at least one optical filter element may comprise a first optical filter element adapted for conducting the first electromagnetic wave component, and a second optical filter element, different from the first optical filter element, adapted for conducting the second electromagnetic wave component.

The second optical filter element may be optically coupled in sequence to the first optical filter element, and wherein the second electromagnetic wave component corresponds with a modulated version of the first electromagnetic wave component. The output means may be adapted for outputting a signal representative for a multiplicative combination of the first electromagnetic wave component and the second electromagnetic wave component.

Receptors on the surface interface may be positioned in proximity to only one of the optical filter elements. In proximity may mean that binding on the receptors can be felt in only one of the optical filter elements.

The one or more optical filter elements in the sensor may comprise at least one micro-ring optical filter element.

The one or more optical filter elements in the sensor may comprise a first micro-ring optical filter element enclosed in a second micro-ring optical filter element.

The optical roundtrip of the first optical filter element and the second optical filter element differs by less than 50% from each other, advantageously less than 20%. The surface interface and the at least one optical filter element may be arranged so that the presence of a medium induces a change in refractive index sensed by the electromagnetic radiation in the at least one optical filter element.

The surface interface may be arranged such that the evanescent field of the first and second electromagnetic wave component extends beyond the surface interface, such that refractive index changes in the medium, when contacting the photonic sensor at said surface interface, influence the evanescent fields and therefore the propagation of electromagnetic radiation through the at least one optical filter element. The output means may be an output waveguide for coupling out the combined radiation signal out of the photonic sensor and wherein the combined radiation signal is a combined wave being a combination of said first electromagnetic wave component and said second electromagnetic wave component.

The output means may be a detector for detecting a combined radiation signal, the combined radiation signal being radiation leaking out of the second optical filter element.

The present invention also relates to a system for detecting a biological, chemical or biochemical target analyte in a medium, the system comprising a photonic sensor as described above, a radiation source for coupling radiation into the photonic sensor, a radiation detector for coupling to an output means of the photonic sensor, and a processing unit for determining a property related to the presence of said target analyte taking into account a measurement obtained from the radiation detector detector.

The present invention also relates to a method for detecting a biological, chemical or biochemical target analyte in a test medium, the method comprising the steps of coupling radiation into a photonic sensor as described above,

providing a contact between a medium and the surface interface of the photonic sensor, and

measuring a property of the radiation received from the output waveguide of the photonic sensor.

The method furthermore may comprise determining a property related to the presence of a target analyte in the medium taking into account the property of the radiation.

Particular and preferred aspects of the invention are set out in the accompanying independent and dependent claims. Features from the dependent claims may be combined with features of the independent claims and with features of other dependent claims as appropriate and not merely as explicitly set out in the claims. These and other aspects of the invention will be apparent from and elucidated with reference to the embodiment(s) described hereinafter.

Brief description of the drawings

FIG. 1 - prior art illustrates a prior art photonic sensor comprising two cascaded ring resonators.

FIG. 2 - prior art shows exemplary transmission spectra, for the two ring resonators, in isolation, of the sensor shown in FIG. 1, wherein transmission values are presented on a peak-normalized scale.

FIG. 3 - prior art shows a transmission spectrum corresponding to the two ring resonators, in cascade, of the sensor shown in FIG. 1, wherein transmission values are presented on a peak-normalized scale.

FIG. 4 shows a schematic representation of a first embodiment of a double-ring based photonic sensor based on the Vernier principle according to the first aspect of the present invention.

FIG. 5 shows a schematic representation of a second embodiment of a single-ring photonic sensor based on the Vernier principle according to the first aspect of the present invention.

FIG. 6 illustrates a schematic overview of a detection system according to the second aspect of the present invention.

FIG. 7 shows an exemplary method of a detection/sensing method according to an embodiment of a third aspect of the present invention.

The drawings are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes.

Any reference signs in the claims shall not be construed as limiting the scope. In the different drawings, the same reference signs refer to the same or analogous elements.

Detailed description of illustrative embodiments The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes. The dimensions and the relative dimensions do not correspond to actual reductions to practice of the invention.

Furthermore, the terms first, second and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequence, either temporally, spatially, in ranking or in any other manner. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

Moreover, the terms top, under and the like in the description and the claims are used for descriptive purposes and not necessarily for describing relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other orientations than described or illustrated herein.

It is to be noticed that the term "comprising", used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. It is thus to be interpreted as specifying the presence of the stated features, integers, steps or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps or components, or groups thereof. Thus, the scope of the expression "a device comprising means A and B" should not be limited to devices consisting only of components A and B. It means that with respect to the present invention, the only relevant components of the device are A and B.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments.

Similarly it should be appreciated that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of this invention.

Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

In the description provided herein, numerous specific details are set forth. However, it is understood that embodiments of the invention may be practiced without these specific details. In other instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure an understanding of this description.

Where in embodiments of the present invention reference is made to radiation, reference is made to electromagnetic radiation. The radiation envisaged is in principle not limited and may be any useful wavelength or wavelength range for detection or sensing applications envisaged. Some examples of radiation ranges that are envisaged, embodiments of the present invention not being limited thereto, are visual radiation, infrared radiation, near infrared radiation and mid infrared radiation.

Where in embodiments of the present invention reference is made to a photonics integrated circuit, reference is made to a variety of forms and material systems such as for example low-index contrast waveguide platforms, e.g. polymer waveguides, glass/silica waveguides, AlxGal-xAs waveguides, InxGal-xAsyPl-y waveguides or SiN waveguides, high-index contrast waveguide platforms, e.g. Silicon- on-lnsulator or semiconductor membranes, or plasmonic waveguides, or waveguides based on silicon, germanium, silicon germanium, silicon nitride, silicon carbide, etc. Silicon-on-lnsulator, is a very interesting material system for highly integrated photonic circuits. The high refractive index contrast allows photonic waveguides and waveguide components with submicron dimensions to guide, bend and control light on a very small scale so that various functions can be integrated on a chip. Such waveguides allow a high level of miniaturization, which is advantageous. Furthermore for such waveguide types radiation can be efficiently coupled in and out the photonics integrated circuit. Using Silicon-on-insulator also has some technological advantages. Due to the CMOS industry, silicon technology has reached a level of maturity that outperforms any other planar chip manufacturing technique by several orders of magnitude in terms of performance, reproducibility and throughput. Nano-photonic ICs can be fabricated with wafer scale-processes, which means that a wafer can contain a large number of photonic integrated circuits.

When in embodiments of the present invention reference is made to a photonics integrated circuit, reference is made to an optical circuit comprising at least one optical filter element, e.g. an integrated optical component, being for example an optical resonator, like a ring resonator or disc resonator, a Fabry-Perot resonator, a photonic crystal resonator, an interferometer such as a Mach-Zehnder interferometer, etc. . Further components also may be integrated such as an integrated optical cavity, a further integrated optical resonator, an integrated optical interferometer, an integrated optical coupler, a waveguide, a taper, a tuneable filter, a phase-shifter, a grating, a modulator, a detector, a light source or a combination thereof.

Where in embodiments of the present invention reference is made to the detection limit of a refractive index sensor, reference is made to the smallest change of the refractive index that can be detected, i.e. can be calculated as the ratio between the smallest detectable spectral shift of the transmission spectrum of the sensor, as such referred to spectral resolution, and the sensitivity of the sensor. The sensitivity is indicative of the amount of shift in the transmission spectrum in the sensor for a given amount of targets to be sensed.

Whereas embodiments of the present invention have been and will be further discussed mainly with reference to resonators, it should be understood that this equally applies to other type of filter elements, such as interferometers.

In a first aspect, the present invention relates to a photonic sensor 100 for detecting a biological, chemical, biomimic or biochemical target. In particular, such a photonic sensor 100 may be implemented on a photonics integrated circuit, for example in a silicon-on-insulator substrate, e.g. a circuit comprising photonic components patterned in a silicon layer on top of an insulator layer 102, e.g. a silica carrier, embodiments not being limited thereto as indicated above.

The sensor is adapted for detecting a compound or analyte of interest, e.g. a protein, for example dissolved or suspended in a fluid. The latter may be a liquid or a gas. Such a sensor may be referred to as a label-free sensor, as detection is not based on labels attached to the analytes of interest. The sensor according to embodiments of the present invention may comprise purposefully selected biological or chemical receptors 110 to interact with a specific analyte of interest, e.g. to bind such analytes to the sensor 100.

A photonic sensor 100 according to embodiments of the first aspect of the present invention comprises at least one resonator 103, 104, 204. The at least one resonator is adapted for receiving a first electromagnetic wave component and for modulating by interference the first electromagnetic wave component propagating in the at least one resonator with a first periodic transfer spectrum having a first free spectral range. The sensor 100 also comprises at least one resonator 103, 104, 204 adapted for receiving a second electromagnetic wave component and for modulating by interference said second electromagnetic wave component propagating in said at least one resonator with a second periodic transfer spectrum having a second free spectral range being different from the first free spectral range. In one embodiment, the resonator for receiving the first electromagnetic wave component may be different from the resonator for receiving the second electromagnetic wave component. The second electromagnetic wave component may be a modulated version of the first electromagnetic wave component. The resonator for receiving the first component and the resonator for receiving the second component may be optically coupled in sequence. The resonators may be positioned in cascade. The resonator(s) thus may comprise an integrated waveguide or combination of waveguides for enabling a first electromagnetic wave component to propagate through the at least one resonator, and an integrated waveguide or combination of waveguides for enabling a second electromagnetic wave component to propagate through the at least one resonator. In another embodiment the resonator for receiving the first electromagnetic wave component and the resonator for receiving the second electromagnetic wave component may be one and the same resonator. The at least one resonator thus may comprise a single integrated waveguide structure adapted for enabling both the first and the second electromagnetic wave component to propagate through the at least one resonator, e.g. the first electromagnetic wave component in a first optical mode of such single integrated waveguide structure and the second electromagnetic wave component in a second optical mode of the single integrated waveguide structure.

This at least one resonator 103,104,204 is adapted for causing interference in the electromagnetic wave components, for example being in form and composition configured for creating wavelength-dependent constructive and destructive interference in the electromagnetic wave components, e.g. such a wave component coupled by an input coupler into a photonic mode of the at least one resonator. In this way, the first electromagnetic wave component is modulated with a first periodic transfer spectrum having a first free spectral range. Particularly, the first periodic transfer spectrum, e.g. a transmission as function of wavelength, may have a plurality of peaks, corresponding to wavelengths of the first electromagnetic wave component for which constructive interference occurs in the at least one resonator, which are regularly interspaced by a substantially constant period, i.e. the first free spectral range. The second electromagnetic wave component thus is modulated by a second periodic transfer spectrum having a second free spectral range. Particularly, the second periodic transfer spectrum, e.g. a transmission as function of wavelength, may have a plurality of peaks, corresponding to wavelengths of the second electromagnetic wave component for which constructive interference occurs in the at least one resonator, which are regularly interspaced by a substantially constant period, i.e. said second free spectral range. This second free spectral range is in embodiments of the present invention different from the first free spectral range. One example of free spectral ranges that can be used is 220pm for the first spectral range and 211pm for the second spectral range.

The at least one resonator may be selected such that the difference between free spectral ranges is small. The difference in the free spectral ranges may be smaller than the largest full width at half maximum of the peaks in the periodic transfer spectra, i.e. the largest full width at half maximum (of the peaks) in the first periodic transfer spectrum and the second periodic transfer spectrum.

The at least one resonator may be a resonant microcavity, a ring resonator, a disc resonator, a Fabry Perot resonator, a photonic crystal resonator or another optical resonator. Alternatively, also interferometers may be used, such as for example a Mach-Zehnder interferometer. In particular embodiments of the present invention this at least one resonator may comprise one or more ring resonators, e.g. micro ring resonators. Such a ring resonator may comprise a waveguide formed in a closed loop coupled to one or more waveguides 105,108,109 for coupling electromagnetic radiation into and out of the closed loop. Over a plurality of roundtrips, the electromagnetic wave component coupled into a ring resonator may build up intensity or extinguish, depending on the wavelength of the electromagnetic wave component. While reference is made to a ring resonator, it will be clear to the skilled person that a ring resonator may comprise any kind of closed loop waveguide structure, i.e. that the ring resonator may have be folded in a convenient way so as to obtain a small area footprint for a large loop length. The condition of small differences in the free spectral ranges can e.g. be obtained by selecting resonators wherein the optical roundtrip of the resonators differs less than 50% with respect to each other, advantageously less than 20%.

The photonic sensor 100 also comprises an output means 109 for outputting a signal representative for a combination of the first electromagnetic wave component and the second electromagnetic wave component. Such an output means 109 may in a number of embodiments be an output waveguide, but may for example also be a detector for detecting leakage of radiation in the last resonator wherein the radiation is present. The output means may for example be an output waveguide 109 which is coupled to the at least one resonator 103,104,204 so as to enable propagation of a combination of the first electromagnetic wave component and the said second electromagnetic wave component out of the photonic sensor, e.g. collecting a combination of these wave components and out-coupling this combined wave for example by means of a tapered grating. The combination for which the signal that is outputted by the output means is representative, may for example be a linear combination of the first electromagnetic wave component and the second electromagnetic wave component, but may also for example be multiplicative in nature, e.g. as may be obtained by a cascade in which the first periodic transfer spectrum and the second periodic transfer spectrum are applied in series to an input electromagnetic wave. The combination may for example be a superposition.

In other embodiments, the output means also may for example be an output means wherein an electrical signal representative for the first electromagnetic wave component and for the second electromagnetic wave component is determined, whereby the combination is a combination of electrical signals, being a combination of originally radiative signals that were converted into electrical signals. Whereas the output means thus is not limited to an output waveguide, particular embodiments of the present invention will be described with reference to an output waveguide, embodiments of the present invention not being limited thereto.

The photonic sensor 100 also comprises a surface interface 107. The surface interface provides an interface between the at least one resonator adapted for receiving the first electromagnetic wave component and the at least one resonator 104, 204 adapted for receiving the second electromagnetic wave component on the one hand and the medium on the other hand when the medium is introduced in the sensor. The surface interface, the at least one resonator 103, 204 adapted for receiving the first electromagnetic wave component and the at least one resonator 104, 204 adapted for receiving the second electromagnetic wave component are arranged for inducing an effect of the presence of the medium on the first periodic transfer spectrum as well as on the second periodic transfer spectrum. The effect may be an interaction effect between at least one optical property, e.g. a local distribution of the refractive index, of the test medium and a first wavelength offset of the first periodic transfer spectrum, and an interaction effect between at least one optical property of the test medium and a second wavelength offset of the second periodic transfer spectrum. The first wavelength offset obtained by this interaction effect is substantially different from the second wavelength offset obtained by this interaction effect in the presence of a target analyte in the test medium. This can be obtained in a plurality of ways, e.g. through positioning of specific receptors 110 at one resonator where the first periodic transfer spectrum is influenced and not on the second resonator where the second periodic transfer spectrum is influenced, e.g. by the relative position of where modes in the resonator propagate as a resonator may be adapted for propagating an electromagnetic wave mode of a first type closer to the interface than an electromagnetic wave mode of a second type, so that the corresponding periodic transfer spectrum is influenced in a different manner, .... For example, locally a greater refractive index change may be obtained by specific receptors 110 for the target analyte, which by specific spatial design influences this first wavelength offset to a greater extent than the second wavelength offset. The receptors on the surface interface may be obtained by modification through provision of a coating which is designed to attract certain molecules or by attaching molecules to it, which are suitable to bind the target molecules which are present in the sample fluid. Such molecules are know to the skilled person and include complementary DNA, antibodies, antisense RNA, aptmers, etc. Such molecules may be attached to the surface by means of spacer or linker molecules. The surface interface of the sensor device can also be provided with molecules in the form of organisms (e.g. viruses or cells) or fractions of organisms (e.g. tissue fractions, cell fractions, membranes). Alternatively, use may be made of a system allowing to contact one resonator by a reference sample, e.g. a medium for which it is known that no targets are present, and to contact the other resonator with the test medium to be characterised.

The surface interface 107 may furthermore be shaped such that it forms a microfluidic channel, a microwell, a reservoir, or at least part thereof. Alternatively, the medium also may merely flow over the surface interface, without a well, channel or reservoir being present. Microfluidics design is well known by the person skilled in the art, and is therefore not further discussed in detail.

In the following, a number of particular embodiments will be discussed by way of example, embodiments of the present invention not being limited thereto. While further embodiments of the first aspect of the present invention will be presented using ring resonators, it will be understood by the person skilled in the art that the present invention may be reduced to practice using any kind of waveguide structure which creates a resonant spectrum, i.e. a periodic response as function of wavelength, such as, but not limited to, resonant cavities or disc resonators, Fabry- Perot resonators, photonic crystal resonators, interferometers etc. The first optical filter element thereby may be the same optical filter element as the second optical filter element, or it may be two separate separate optical filter elements, positioned in cascade so that they receive the electromagnetic wave components substantially simultaneously from the same radiation source. In a first particular embodiment of the first aspect of the present invention, illustrated in FIG. 4, the photonic sensor 100 comprises two ring resonators 103,104. An input waveguide 108 may be coupled to a means for coupling light into the photonic sensor, e.g. a tapered grating (not shown), from an external source, e.g. a laser diode. Such an input waveguide 108 may be adapted for coupling light into a first ring resonator 103, for example into a TE optical mode of the ring resonator 103. An interconnecting waveguide structure 105 may furthermore couple light from this first ring resonator 103 into the second ring resonator 104. This second ring resonator may have a substantially different loop length compared to the first ring resonator, e.g. this difference in loop length being similar as in a prior art device introduced in the background section hereinabove. In contrast to prior art devices, both the first ring resonator 103 and the second ring resonator 104 are exposable to a medium, e.g. the sensor 100 may be covered with a cladding 106, except for a region in which a surface interface 107 exposes at least partially the first ring resonator 103 and the second ring resonator 104, such that a test medium, when brought into contact with the photonic sensor 100 in this region may influence the evanescent field of a first electromagnetic wave component propagating in the first ring resonator 103, as well as the evanescent field of a second electromagnetic wave component propagating in the second ring resonator 104. While the resonance spectra of both the first and second ring resonator may shift under the influence of refractive index changes in a test medium, when brought into contact with the sensor 100 at this surface interface 107, one resonator, e.g. the second ring resonator 104, may be adapted for a higher sensitivity to a particular target analyte in the test medium. For example, the second ring resonator 104 may comprise receptors 110 exposed at the surface interface 107 which may interact with the particular target analytes in the test medium, e.g. bind such analytes, in order to locally change refractive index when such analytes are present. The other resonator, e.g. the first ring resonator 103, may preferably lack such receptors 110, or at least have a different density or type of such receptors, in order to obtain a differential wavelength shift in the transmission spectra of the first and second ring resonator when exposed to these target analytes, while obtaining a similar or congruent wavelength shift in these spectra in response to refractive index changes of the test medium, e.g. induced by temperature, pH value of the medium, unspecific binding of undesired analytes, etc.

In a second embodiment of the first aspect of the present invention, illustrated in FIG. 5, the photonic sensor 100 may comprise one ring resonator 204. An input waveguide 108 may be coupled to a means for coupling light into the photonic sensor, e.g. a tapered grating (not shown), from an external source, e.g. a laser diode. Such an input waveguide 108 may be adapted for coupling light into the ring resonator 204 as a first electromagnetic wave component, for example into a quasi-TE optical mode of the ring resonator 204, while also being adapted for coupling light into the ring resonator 204 as a second electromagnetic wave component, for example into a quasi-TM mode of the ring resonator 204. For coupling in both modes using the same waveguide, the input waveguide may be designed whereby the coupling section between the waveguide and the ring are such that radiation from one mode in the access waveguide couples to both modes in the ring waveguide e.g. by choosing the width of the access waveguide so that the effective refractive index of the TE-mode is close to that of the effective refractive index of the TM mode of the resonator. The same power fraction from the TE mode of the input waveguide can then be coupled to both the TE mode and the TM mode of the resonator. Alternatively, both a first input waveguide and a second input waveguide are present for coupling in the two modes. The first and second electromagnetic wave component, being coupled into different modes of the resonator, will experience different roundtrip lengths, and will therefore each pass through a spectral comb filter characterized by different free spectral ranges. In this embodiment, the output waveguide 109 may collect light not coupled into the resonator 204, such that a drop signal of the ring resonator 204 may be measured. For example, the coupling may be designed such that the first electromagnetic wave component in a first mode of the resonator and the second electromagnetic wave component in a second mode of the resonator are individually undercoupled, giving rise to shallow sharp dips in the transmission spectrum of the ring resonator. However, the ring resonator may be designed such that critical coupling occurs when two resonances of these two modes overlap, giving rise to a very deep dip, e.g. deeper than obtained by additive superposition of the individual spectra, in the combined transmission spectrum. Such a critical coupling dip may be easy to distinguish and to track, i.e. may be used in discrete measurement techniques. The processing of the optical signal to derive information may be similar to the processing of the optical signal in the prior art Vernier twin ring resonator sensor discussed in the background section hereabove.

The ring resonator 204 may be exposable to a test medium, e.g. the sensor 100 may be covered with a cladding 106, except for a surface interface 107 exposing at least partially the ring resonator 204, such that a test medium, when brought into contact with the photonic sensor 100 at the surface interface 107 may influence the evanescent field of the first and second electromagnetic wave component propagating in the ring resonator 204. While the resonance spectra of both the first and second electromagnetic wave component propagating in the ring resonator 204 may shift under the influence of refractive index changes in a test medium, when brought into contact with the sensor 100 at the region 107, the ring resonator 204 may be adapted for a higher sensitivity of the second electromagnetic wave component relative to the first electromagnetic wave component to a particular target analyte in the test medium. For example, the ring resonator 204 may comprise receptors 110 exposed at the region 107 which may interact with the particular ta get analytes in the test medium, e.g. bind such analytes, in order to locally change refractive index when such analytes are present. The first and second electromagnetic wave components, coupled respectively into a first and second mode of the resonator, have a different spatial evanescent field distribution, so that the first electromagnetic wave component, for example coupled into a quasi-TM mode with a broad profile extending relatively far out of the resonator, has a higher relative sensitivity to changes in the test medium than the second electromagnetic wave component, for example coupled into a quasi-TE mode with a profile more closely confined near the resonator. Therefore a differential wavelength shift and/or intensity change in the transmission spectra of the first and second mode of the ring resonator 204 are obtained when exposed to target analytes, for example causing a local change near the resonator surface at receptor sites 110, while obtaining a similar or congruent wavelength shift in these spectra in response to refractive index changes of the test medium, e.g. induced by temperature, pH, a-specific binding of targets to the surface. Where sensing by monitoring the wavelength change typically is referred to as wavelength interrogation, monitoring the intensity change typically is referred to as intensity interrogation.

In some embodiments of the present invention more than two resonators are used, providing for example the possibility of using different receptors and therefore to detect different target analytes of interest.

In some embodiments of the present invention, the resonators may be positioned on the photonics device, such that one resonator is positioned completely within the other resonator.

In some embodiments of the present invention the sensor is a gas sensor, whereby the targets to be detected are present in a gas, for example flowing over the surface interface. The targets in the sample may be bound to receptors, which for gas sensors typically may be in the form of a porous film, which may be chemically active. In a second aspect, the present invention relates to a system 300 for detecting a biological, chemical or biochemical target analyte in a medium. An example of such a system is illustrated in FIG. 6, embodiments of the present invention not being limited thereto. This system 300 comprises a photonic sensor 100 according to an embodiment of the first aspect of the present invention. The system 300 also comprises a radiation source 310 for coupling radiation into the photonic sensor 100. The radiation source 310 may be integrated in the photonics substrate, although embodiments of the present invention are not limited thereto and a separate radiation source 310 also may be used. The system 300 furthermore comprises a radiation detector 320 for detecting the radiation after it has passed through the photonic sensor 100. The radiation may be detected with the radiation detector 320 by collecting it from the output waveguide 109 of the photonic sensor 100. Optionally, the system 300 also comprises a processing unit 330 for determining a property related to the presence of said target analyte taking into account a measurement obtained from said radiation detector 32. The processing unit 330 may be programmed for processing the detected optical signals. The processing of the obtained combined signal may be performed in any suitable manner, e.g. by the method as described by Claes et al. in Optics Express, Vol. 18, no. 22, page 22747.

In a third aspect, the present invention relates to a method 400, such as the exemplary method 400 illustrated in FIG. 7, for detecting a biological, chemical or biochemical target analyte in a test medium. The method 400 is especially suitable for use with a photonic sensor as described in the first aspect. The method 400 according to embodiments of the present invention comprises coupling 410 radiation into a photonic sensor 100 according to embodiments of the first aspect of the present invention. It furthermore comprises providing a contact 420 between a medium to be tested and a surface interface 107 of the photonic sensor 100. The latter may for example be performed by passing the medium in liquid format through a channel running in or over the surface interface 107. The method 400 also comprises measuring 430 a property of the radiation received from the output waveguide 19 of the photonic sensor 11. The measured property of the radiation may be a transmission intensity, e.g. an intensity of the radiation as function of wavelength. The method also comprises calculating 44 a property related to the presence of a target analyte in the test medium taking into account this property of light. The foregoing description details certain embodiments of the invention. It will be appreciated, however, that no matter how detailed the foregoing appears in text, the invention may be practiced in many ways, and is therefore not limited to the embodiments disclosed.

Claims

1.- A photonic sensor (100) for detecting a biological, chemical, biomimic or biochemical target analyte in a medium, the sensor (100) comprising

at least one optical filter element (103,204) adapted for receiving a first electromagnetic wave component and for modulating by interference the first electromagnetic wave component propagating in the at least one optical filter element (103, 204) with a first periodic transfer spectrum having a first free spectral range,

at least one optical filter element (104, 204) adapted for receiving a second electromagnetic wave component and for modulating by interference said second electromagnetic wave component propagating in said at least one optical filter element (104, 204) with a second periodic transfer spectrum having a second free spectral range being different from the first free spectral range,

- an output means (109) for outputting a signal representative for a combination of said first electromagnetic wave component and said second electromagnetic wave component out of the photonic sensor (100), the sensor (100) also comprising

a surface interface providing (107) an interface between the at least one optical filter element (103,204) adapted for receiving the first electromagnetic wave component and the at least one optical filter element (104,204) adapted for receiving the second electromagnetic wave component and the medium when introduced in the sensor,

wherein the difference between the first free spectral range and the second free spectral range is smaller than or equal to a largest full width at half maximum of the peaks in the first and second periodic transfer spectrum, and

wherein the surface interface, the at least one optical filter element (103,204) adapted for receiving the first electromagnetic wave component and the at least one optical filter element (104,204) adapted for receiving the second electromagnetic wave component are arranged for inducing an effect of the presence of the medium on the first periodic transfer spectrum as well as on the second periodic transfer spectrum and wherein, upon presence of target analytes in the medium, a different effect is induced on the first and second periodic transfer spectrum.

2. A photonic sensor (100) according to claim 1, wherein the at least one optical filter element (103,204) adapted for receiving and modulating a first electromagnetic wave component and the at least one optical filter element (104, 204) adapted for receiving and modulating the second electromagnetic wave component is a single optical filter element (204) or are different optical filter elements (204) arranged in cascade.

3.- A photonic sensor (100) according to any of the previous claims, in which said surface interface (107) comprises receptors (110) adapted for interacting with said target analyte and arranged for inducing a different effect on the first and the second periodic transfer spectrum.

4.- A photonic sensor (100) according to any of the previous claims, wherein the arrangement of the surface interface and the first optical filter element adapted for receiving the first electromagnetic wave component on the one hand and the arrangement of the surface interface and the second optical filter element adapted for receiving the second electromagnetic wave component is the same.

5.- A photonic sensor (100) according to any of claims 1 to 4, wherein the surface interface (107) comprises a microfluidic channel for transporting the medium.

6. - A photonic sensor (100) according to any of the previous claims, wherein the at least one optical filter element (204) adapted for receiving a first electromagnetic wave component and the at least one optical filter element (204) adapted for receiving a second electromagnetic wave component are one and the same optical filter element (204).

7. - A photonic sensor (100) according to claim 6, wherein the one and the same optical filter element (204) is adapted for both conducting the first electromagnetic wave component in a first photonic mode and the second electromagnetic wave component in a second photonic mode.

8.- A photonic sensor (100) according to any of claims 6 to 7, wherein said output means is adapted for outputting a signal representative for a combination being a linear combination of the first electromagnetic wave component and the second electromagnetic wave component.

9.- A photonic sensor (100) according to any of claims 6 to 8, wherein the one and the same optical filter element (204) comprises a first input waveguide for inputting the first electromagnetic wave component and a second input waveguide, different from the first input waveguide, for inputting the second electromagnetic wave component.

10.- A photonic sensor (100) according to any of claims 6 to 9, wherein the one and the same optical filter element (204) comprises a single input waveguide for inputting the first electromagnetic wave component and the second electromagnetic wave component.

11. - A photonic sensor (100) according to any of claims 1 to 5, wherein the at least one optical filter element comprises a first optical filter element (103) adapted for conducting the first electromagnetic wave component, and a second optical filter element (104), different from the first optical filter element, adapted for conducting the second electromagnetic wave component.

12. - A photonic sensor (100) according to claim 11, wherein the second optical filter element (104) is optically coupled in sequence to the first optical filter element (103), and wherein the second electromagnetic wave component corresponds with a modulated version of the first electromagnetic wave component.

13. - A photonic sensor (100) according to any of claims 11 to 12, in which the output means is adapted for outputting a signal representative of a multiplicative combination of the first electromagnetic wave component and the second electromagnetic wave component.

14. - A photonic sensor according to any of claims 11 to 13, wherein receptors on the surface interface are positioned in proximity to only one of the first optical filter element (103) or the second optical filter element (104).

15. - A photonic sensor (100) according to any of the previous claims, wherein the one or more optical filter elements (103, 104, 204) in the sensor (100) comprises at least one micro-ring optical filter element.

16. - A photonic sensor (100) according to claim 15, wherein the one or more optical filter elements (103, 104) in the sensor (100) comprises a first micro-ring optical filter element enclosed in a second micro-ring optical filter element.

17. - A photonic sensor (100) according to any of the previous claims, wherein the optical roundtrip of the first optical filter element and the second optical filter element differ by less than 50% , advantageously less than 20%.

18.- A photonic sensor (100) according to any of the previous claims, wherein the interface (107) and the at least one optical filter element (103, 104, 204) are arranged so that the presence of a medium induces a change in effective refractive index sensed by the first and second electromagnetic wave component electromagnetic radiation in the at least one optical filter element (103, 104, 204).

19.- A photonic sensor (100) according to claim 18, wherein the surface interface (107) is arranged such that the evanescent field of the first and second electromagnetic wave component extends beyond the surface interface (107), and that, when the photonic sensor (100) is contacted with the medium at said surface interface (107), effective refractive index changes influence the evanescent fields and therefore the propagation of electromagnetic radiation through the at least one optical filter element (103,104,204).

20. - A photonic sensor (100) according to any of claims 1 to 19, wherein the output means is an output waveguide for coupling out the signal out of the photonic sensor (100) and wherein the signal is a combined wave being a combination of said first electromagnetic wave component and said second electromagnetic wave component.

21. - A photonic sensor (100) according to any of claims 1 to 19, wherein the output means is a detector for detecting a combined radiation signal, the combined radiation signal being radiation leaking out of the second optical filter element.

22. - A system (300) for detecting a biological, chemical, biomimic or biochemical target analyte in a medium, the system comprising a photonic sensor (100) according to any of claims 1 to 21, a radiation source (310) for coupling radiation into the photonic sensor (100), a radiation detector (320) for coupling to the output means (109) of the photonic sensor (100), and a processing unit (330) for determining a property related to the presence of said target analyte taking into account a measurement obtained from the radiation detector detector (320).

23. - A method (400) for detecting a biological, chemical, biomimic or biochemical target analyte in a test medium, the method (400) comprising the steps of:

- coupling (410) radiation into a photonic sensor (100) according to any of claims 1 to 21,

providing a contact (420) between a medium and the surface interface (107) of the photonic sensor (100), and

measuring (430) a property of the radiation received from the output means (109) of the photonic sensor (100).

24. - A method (400) according to claim 23, the method furthermore comprising determining (440) a property related to the presence of a target analyte in the medium taking into account the property of the radiation.