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WO2014118068A1 - Dispositif biocapteur - Google Patents

Dispositif biocapteur Download PDF

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Publication number
WO2014118068A1
WO2014118068A1 PCT/EP2014/051285 EP2014051285W WO2014118068A1 WO 2014118068 A1 WO2014118068 A1 WO 2014118068A1 EP 2014051285 W EP2014051285 W EP 2014051285W WO 2014118068 A1 WO2014118068 A1 WO 2014118068A1
Authority
WO
WIPO (PCT)
Prior art keywords
container
flow
sensor
medium
sensing device
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2014/051285
Other languages
English (en)
Inventor
Peter Bienstman
Cristina LERMA ARCE
Elewout Hallynck
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universiteit Gent
Interuniversitair Microelektronica Centrum vzw IMEC
Original Assignee
Universiteit Gent
Interuniversitair Microelektronica Centrum vzw IMEC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universiteit Gent, Interuniversitair Microelektronica Centrum vzw IMEC filed Critical Universiteit Gent
Publication of WO2014118068A1 publication Critical patent/WO2014118068A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G01N21/7746—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides the waveguide coupled to a cavity resonator
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0848—Specific forms of parts of containers
    • B01L2300/0851—Bottom walls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B01L2400/049—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics vacuum
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5082—Test tubes per se
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/05—Flow-through cuvettes

Definitions

  • the present invention relates to methods and systems for biological, biochemical or chemical sensing and/or detecting of particles. More particularly, the present invention relates to methods for label-free detection of particles using flow in a container and to corresponding devices and systems.
  • Label-free techniques such as silicon photonic microring resonator sensors attempt to overcome the stability and reliability problems of biosensors relying on the detection of labeled molecules. While labeled detection methods can be sensitive down to a single molecule, labels can structurally and functionally alter the assay and the labeling process is labor intensive and costly. Quantification is difficult since the bias label intensity level is dependent on all working conditions. Moreover a labeled assay can only be performed in an 'end-point' fashion so that no kinetic information on the biomolecular interaction can be obtained. In practice, label-based assays require a high degree of development to assure that the label does not block an important active site on the tagged molecule or modify the molecular conformation.
  • Label-free detection is a solution to this and involves a transducer element that directly measures some physical property of the biological compound.
  • a transducer element may comprise an affinity-based biosensor whereby a so-called 'receptor' or 'ligand' is attached to the surface of the sensor, which responds to the affinity interaction of the receptor with the analyte of interest.
  • the receptor molecule can be an antibody, receptor protein or DNA. The formation of complexes can thus be monitored continuously and many interactions can be followed simultaneously. This real-time data results in information on the kinetics of the reaction as well as on the concentration of the antibodies in the sample.
  • optical label-free biosensors have received considerable attention over the past years.
  • the key behind optical biosensors' ability to detect biological analytes is that they are able to translate changes in the propagation speed of light into a quantifiable signal proportional to the amount of biological material present on the sensor surface.
  • a method and device can be provided that can be used in a lab-compatible reaction tube platform, such as a reaction tube or micro titer plate.
  • embodiments of the present invention relate to a sensing device for sensing a biological, chemical, biomimic or biochemical target analyte in a medium.
  • the sensing device comprises a container for holding the medium and a sensor attached to at least part of the container in such a way that there is a contact interface between the inside of the container and at least part of the sensor, when the medium is held in the container.
  • the at least part of the sensor being in contact with the inside of the container comprises a transducer element having at least one characteristic parameter.
  • the sensing device further comprises flow creating means for creating a flow of the medium over the transducer element, thereby creating a change of the characteristic parameter upon occurrence or variation, e.g. presence, of the target analyte in the medium.
  • the flow creating means may be a flow through means allowing the medium to flow through the container.
  • the flow creating means may comprises - besides a filling opening - at least one container hole in the container. The latter will allow that the medium easily can flow through the container.
  • At least part of the sensor may be in contact with the opening of the container hole.
  • the at least part of the sensor being in contact with the opening of the container hole may comprise at least one sensor hole.
  • the at least one sensor hole and the at least one container hole may be arranged, e.g. aligned, in such a way that they form at least one flow through channel, also referred to as perforation extending from top to bottom, through the sensing device through which the medium can exit or enter, e.g. thereby flowing over an area of the sensor around the sensor hole and flowing through the sensor and exiting or entering the container.
  • the container hole and the sensor hole may in this way drain the medium out of the container and form the flow creating means, creating a flow over the transducer element.
  • the transducer element may be positioned in the area around the sensor hole where the flow is created.
  • the transducer element may be positioned such that the distance of the at least one transducer element and at least one sensor hole is less than 5 times the diameter of the sensor hole, e.g. less than 3 times the diameter of the sensor hole or e.g. less than 2 times the diameter of the sensor hole.
  • the diameter of the sensor hole may be defined as the average diameter of the at least one sensor hole closest to the at least one transducer element.
  • the senor and/or the transducer element may be part of a photonic integrated circuit.
  • the transducer element may be a photonic filter element, but is not limited thereto.
  • the container may be any of a reaction tube or a micro titer plate.
  • the transducer element may comprise a functionalized sensing surface for binding with the target analyte. Functionalisation is well known in the art and is therefore not described in more detail in the present application.
  • the sensing device may thus be a flow through system.
  • the sensing device may be a label-free sensing device, allowing sensing under dynamic conditions of the medium in a label-free manner.
  • the flow creating means may also comprise or may co-operate with a flow inducing means such as any of a pumping system or an electrophoresis system or any other suitable system allowing to induce flow of the medium, i.e. to induce dynamic conditions of the medium.
  • a flow inducing means such as any of a pumping system or an electrophoresis system or any other suitable system allowing to induce flow of the medium, i.e. to induce dynamic conditions of the medium.
  • Such flow inducing means thus also may be integrated in the sensor and/or the container.
  • the flow creating means thus may refer to the sensor holes and/or container holes allowing the flow, whereas the flow inducing means may refer to the flow inducing means.
  • the flow inducing means may be considered as part of the flow creating means.
  • the flow creating means can in some embodiments be adapted for internally creating flow in the container without providing a flow through system.
  • the flow in the container may thus create a flow of the medium over the transducer element.
  • the flow creating means may be a stirring or mixing means positioned in the container.
  • the sensing device may be a consumable, e.g. a one-time-use only device, having the advantage of avoiding cross-contamination and/or avoiding the need for cleaning of the device.
  • the present invention also relates to a detection system for detecting a biological, chemical, biomimic or biochemical target analyte in a medium, the detection system comprising
  • sensing device holder for holding a sensing device as described above
  • an excitation source and/or detector configured with respect to the sensing device holder for coupling with the transducer element of the sensor in the container of the sensing device, when the sensing device is positioned in the sensing device holder.
  • the excitation source and/or the detector may be configured such that radiation is coupled to the sensing device in the sensor in the container and/or may be configured such that radiation is coupled from the sensing device after interaction with the medium for detecting and analyzing signals.
  • the detection system furthermore may comprise a flow inducing means - in some embodiments not integrated in the sensing device but in the detection system - co-operating with the flow creating means of the sensing device for inducing a flow of the medium over the transducer element.
  • the flow inducing means may be a pumping means arranged for pumping the medium through the container of the sensing device.
  • the sensing device holder may comprise a chuck for positioning and holding the sensing device accurately with respect to the remaining components of the detection system.
  • the chuck may be vacuum based.
  • the holder may be adapted for aligning the sensing device with the flow inducing means as well as with other components of the detection system, such as for example the excitation source and/or the detector.
  • the present invention relates to a method for sensing a biological, chemical, biomimic or biochemical target analyte in a medium. It comprises the steps of
  • a sensing device comprising a container for holding the medium and a sensor attached to at least part of the container, at least part of the sensor comprising a transducer element having at least one characteristic parameter
  • the obtained sensing device may be a consumable.
  • the method may in addition or alternatively comprise the steps of:
  • Creating a flow of the medium over the transducer element may comprise the steps of creating at least one container hole in the container, creating at least one sensor hole in the sensor, attaching the sensor to the container in such a way that at least one perforation is formed by the at least one container hole and sensor hole through which the medium can exit or enter both the container and the sensor.
  • the at least one perforation may in this way create a flow in an area around the sensor hole.
  • the flow may induce a change of the characteristic parameter of the transducer element upon sensing of target analytes in the medium by the transducer element, for instance upon binding of target analytes to the transducer element.
  • the present invention also comprises a method for manufacturing a sensing device, the method comprising
  • the method also may comprise attaching the sensor to the container.
  • Creating at least one sensor hole comprises inducing the sensor hole in the sensor through laser processing, such as for example laser ablation.
  • FIG. 1 illustrates a chip layout as can be used according to an embodiment of the present invention.
  • a chip layout top view is shown, whereas at the bottom side a side view is shown in relationship to the irradiation beam and the detector.
  • FIG. 2 schematically illustrates a three dimensional representation of an example of a device according to an embodiment of the present invention, as well as a layout indicating the sensor holes.
  • FIG. 3 shows a simulation of a water-based fluid flow in an exemplary device structure, as can be obtained in an embodiment of the present invention.
  • Streamlines in black in the middle confirm the existence of a flow in the vicinity of the apertures.
  • FIG. 4 illustrates a microscope picture of the array of photonic sensors accompanied by an array of perforations next to them, as can be used in an embodiment of the present invention. Each perforation will create a flow in its closest sensor.
  • FIG. 5 illustrates a silicon photonic chip with the array of sensors and the embedded microfluidic system incorporated in the bottom of a reaction tube, according to an embodiment of the present invention.
  • FIG. 6. and FIG. 7 illustrate an elevated side view and a cross-sectional view of a sensing device mounted in a sensing system according to an embodiment of the present invention.
  • FIG. 8. illustrates the optical registration of three different steps of a bioassay, thus illustrating features of an embodiment according to the present invention.
  • PIC photonics integrated circuit
  • this may refer to a variety of forms and material systems such as for example low-index contrast waveguide platforms (e.g. polymer waveguides, glass/silica waveguides, Al x Gaj. x As waveguides, xGaj.xAS y Pj. y waveguides), high-index contrast waveguides (e.g. Silicon-on-lnsulator, semiconductor membranes), plasmonic waveguides (e.g. metal nano-particle arrays, metal layers), also called Photonic Lightwave circuits (PLC).
  • low-index contrast waveguide platforms e.g. polymer waveguides, glass/silica waveguides, Al x Gaj. x As waveguides, xGaj.xAS y Pj. y waveguides
  • high-index contrast waveguides e.g. Silicon-on-lnsulator, semiconductor membranes
  • plasmonic waveguides e.g. metal nano-particle arrays, metal layers
  • a photonic integrated circuit comprises at least one integrated optical component, such as for example but not limiting to an integrated optical cavity, an 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 source or a combination thereof.
  • the optical components can be active or passive.
  • the components can be integrated for example monolithically, heterogeneously or hybridly.
  • Monolithical integration is the integration technology that uses a single processing flow to process the diverse components potentially using different materials, e.g. integrated germanium detectors in silicon photonics IC.
  • Heterogeneous integration is the integration technology for which the components are processed in separate process flows, which are then integrated at die or wafer level, e.g. BCB bonding, wafer bonding, and other bonding schemes, 3D integration.
  • Hybrid integration is the integration of components or materials on processed photonic integrated platforms, e.g. flip-chipping of detectors, bumping, gluing, wire bonding, co-packaging, etc.
  • the PIC may be an SOI (Silicon-on-lnsulator) material system, also referred to as silicon photonics system.
  • SOI Silicon-on-lnsulator
  • the devices and methods of the present invention can be based on other material systems, such as for example ll l-V material systems, metallic layers, low index contrast material systems or a combination thereof.
  • the present invention relates to a sensing device for detecting a biological, chemical, biomimic or biochemical target analyte in a medium.
  • the sensing device may comprise a container for holding the medium and a sensor attached to at least a part of the container in such a way that there is a contact interface between the medium and at least part of the sensor.
  • the container may for instance comprise or be a reaction tube or microtiter plate, but is not limited thereto.
  • the sensor is attached to at least part of the container.
  • the sensor may be provided partly or entirely to the inside of the container.
  • the sensor may be provided partly or entirely to the outside of the container.
  • a container hole is preferably made in the container and the sensor is positioned at least partly over this container hole in order to create a contact interface between the inside of the container and at least part of the sensor.
  • the sensor may also be provided to the inside of the container and positioned at least partly over this container hole.
  • the contact interface may then be formed by the top surface of the sensor or at least part of the top surface.
  • the sensor may be attached to any surface of the container.
  • the attachment can for instance be done to a side surface of the container or to a bottom surface of the container, the surfaces being inner or outer surfaces.
  • the contact interface may be formed by the top surface of the sensor or at least part thereof.
  • the contact interface may be formed by a part of the sensor in contact with the opening of the container hole.
  • the part of the sensor being in contact with the medium in the container, i.e. the part of the sensor having a contact interface with the container comprises at least one transducer element having at least one characteristic parameter.
  • the transducer element may for instance be a mechanical, electrical or optical transducer element, with a corresponding characteristic parameter being for instance a resonance frequency, capacitance or resonance wavelength, but is not limited thereto.
  • the transducer element may for instance be an optical filter element, such as for instance an optical resonator element, such as for instance an optical ring resonator, but is not limited thereto.
  • the sensing device further comprises flow creating means for creating a flow of the medium over the transducer element.
  • the flow may create a change of the characteristic parameter upon presence of the target analyte in the medium.
  • the flow creating means may for instance take the form of mechanical stirring means which are able to stir the medium inside the container, thereby creating a flow of the medium in the vicinity of the transducer element.
  • the flow creating means also may be at least one sensor hole in the part of the sensor being in contact with the medium in the container, i.e. the part of the sensor having a contact interface with the inside of the container, as such at least one sensor hole may allow the medium to flow through the sensor and may allow flow over the sensor, e.g. over the at least one transducer element.
  • the sensor hole may be extending from top to bottom of the sensor.
  • the perforation may create a flow of the medium in an area around the at least one sensor hole.
  • the sensor hole may act as flow creating means creating a flow of the medium over the transducer element.
  • the at least one container hole and/or sensor hole may have any shape considered suitable by the person skilled in the art, such as for instance, but not limited to circular, elliptical or rectangular shape.
  • the dimensions of the container hole may have the same dimensions as those of the sensor hole, or may be larger or smaller.
  • the at least one container hole and/or the at least one sensor hole may have dimensions in the micrometer range, millimeter or centimeter range. In case the sensor is a photonic integrated circuit, the at least one sensor hole may have dimensions in the micrometer range, but is not limited thereto. Positioning the transducer element in an area around the sensor hole, may mean positioning the transducer element on a distance in the micrometer range away from the sensor hole, but is not limited thereto.
  • the sensing device may comprise multiple transducer elements, each of the transducer elements having one or more corresponding sensor holes. One or more of the sensor holes may be aligned with the same container hole or with different container holes.
  • the position of the at least one transducer element is preferably chosen in such a way that the flow of the medium is created in the vicinity or in an area around the transducer element.
  • the distance between the at least one transducer element and a sensor hole advantageously is less than 5 times, e.g. less than 3 times or less than 2 times the diameter of the sensor hole.
  • the flow of the medium over the transducer element may create, upon presence of a target analyte in the medium, a change of the characteristic parameter of the transducer element.
  • a change of the characteristic parameter may for instance be achieved because the transducer element comprises a sensor layer that binds with the target analyte, creating a shift of the characteristic parameter of the transducer element upon binding.
  • the optical resonator element may comprise a sensing layer that binds with the target analyte, thereby creating a shift of the resonance frequency of the optical resonator element upon binding.
  • Functionalisation of sensor surfaces is well known to the person skilled in the art and is therefore not discussed in detail in the present description.
  • the device according to the present invention may further comprise a detection element for detecting a shift of the characteristic parameter, for instance upon binding of the target analyte onto a sensing surface of the transducer element.
  • the device may further comprise a processor for deriving information on the target analyte, said deriving being based on a detected shift of the characteristic parameter of the transducer element, for instance a shift of the resonance wavelength upon binding of target analytes onto a sensing surface of the transducer element.
  • information about the target analyte may for instance include, but is not limited to information on the affinities and kinetics of the reaction as well as on the concentration of the antibodies in the sample.
  • the sensor may be part of a photonic integrated circuit, but is not limited thereto.
  • the detection element and/or processor may comprise a photonic integrated circuit compatible, integrated detection element and/or processor. It is an advantage of embodiments according to the present invention that integration of the sensor may result in a small footprint of the sensor.
  • detection elements, processing components and excitation sources may also be part of a detection system, e.g. a read-out system for reading out sensing devices.
  • the sensing devices may only comprise passive components.
  • the sensing devices can in some embodiments advantageously be used as consumables.
  • the present invention relates to a detection system for detecting a biological, chemical, biomimic or biochemical target analyte in a medium. The detection system thereby can be advantageously used for reading out sensing devices according to the first aspect.
  • the active components for using and reading out sensing devices are comprised in the detection system, such that the sensing devices can be used as low price consumables.
  • the detection system comprises a sensing device holder for holding a sensing device as described in the first aspect, and an excitation source and/or detector configured with respect to the sensing device holder for coupling with the transducer element of the sensor in the container of the sensing device, when the sensing device is positioned in the sensing device holder.
  • an excitation source and/or detector configured with respect to the sensing device holder for coupling with the transducer element of the sensor in the container of the sensing device, when the sensing device is positioned in the sensing device holder.
  • the detection system furthermore may comprise a flow inducing means - in some embodiments not integrated in the sensing device but in the detection system - co-operating with the flow creating means of the sensing device for inducing a flow of the medium over the transducer element.
  • the flow inducing means may be a pumping means arranged for pumping the medium through the container of the sensing device or any other means for inducing a flow.
  • the flow inducing means when part of the detection system, may be configured, e.g. using appropriate connection channels, with respect to the sensing device holder such that flow can be induced in the sensing device, when it is positioned in the sensing device holder.
  • the sensing device holder may also comprise a chuck or table for positioning and holding the sensing device, which may have the shape of a reaction tube or a micro titer plate, accurately with respect to the remaining components of the detection system. Further features of the detection system may be partly or completely as described elsewhere in the description.
  • a photonic chip 100 was fabricated in SOI with 2- ⁇ buried oxide and a 220-nm silicon top layer with CMOS compatible 193-nm optical lithography and dry etching. The process was described by Selvaraja et al. in J. Lightwave Technol. 27 (2009) p 4076 - 4083.
  • the resonators consist of 450-nm- wide single-mode waveguides, with 5- ⁇ bend radius, 2 ⁇ m-long directional couplers, and a gap of 180 nm between the waveguides.
  • the layout of the chip 100 is illustrated in Fig. 1, the upper drawing showing a chip layout top view and the lower drawing showing an elevated side view of the chip in relation to the incident irradiation beam and the detector.
  • rings 110 are connected to one common input waveguide, each of them having a dedicated drop signal port. Three of these four ring series are placed independently next to the other.
  • the three input waveguides are simultaneously addressed through vertical grating couplers 120 with a 2-mm-wide collimated beam, irradiation beam 130, from a tunable laser source.
  • the output signals of the ring resonators 110 are near-vertically coupled to free space by means of integrated grating couplers 140 and are imaged with a detector 150, e.g. an infrared camera.
  • the shallow-etched gratings are, in the present example, part of the chip design and have a maximum coupling efficiency of 31 % at a wavelength of 1.55 ⁇ (40-nm 1-dB bandwidth) for a 10° off-vertical coupling angle. Because the bandwidth of the grating couplers is larger than the free spectral range of the resonators, the grating couplers do not limit the number of resonators placed in series. This optical setup allows very high alignment tolerances, measures the spectrum of all the ring resonators in parallel, and therefore presents no limitation for high-throughput sensing.
  • a TSL-510 tunable laser was in the present example used as a light source.
  • the transmitted light was in the present example detected by an infrared camera.
  • the input power was chosen so that the intensity of the resonance peaks corresponds to the pixel saturation level to obtain a maximum signal- to-noise ratio.
  • An image is captured for every wavelength step and stores the maximum intensity values within each dedicated area that overlaps with an output grating coupler spot.
  • Post processing consists of fitting the spectra to their theoretical shape and tracking these resonance peaks over time, but other post processing techniques also may be performed.
  • the photonic chip is integrated at the bottom of the reaction tube.
  • the photonic chip comprises apertures that perforate the chip from the top to the bottom.
  • the solution inserted in the tube will flow through these openings that work as exit channels, creating a flow, which will accelerate the detection process.
  • FIG. 2 shows a schematic illustration of an exemplary device with the embedded microfluidic system, wherein the sensor chip 100, is shown as well as a container 160.
  • the sensor chip 100 flow creation means being sensor holes 210 in the present case are indicated
  • the sensor chip may be a silicon-on-insulator chip with the photonic biosensors and the embedded microfluidic system.
  • the chip is incorporated at the bottom of the reaction tube.
  • the chip may be incorporated in a well of a micro titer plate or a plurality of chips may be incorporated in a plurality of wells of a micro titer plate.
  • the solution inserted in the tube will flow through these openings that work as exit channels, creating a flow, which will accelerate the detection process.
  • the lay-out of the chip is such that an array of ring resonator sensors accompanied by an array of sensor holes, also referred to as perforations, next to them can be seen.
  • the perforations of the silicon-on-insulator chip are advantageously achieved by means of laser ablation.
  • a Duetto laser source (Time-Bandwidth) was used to perform the perforations. 1000 ps- duration pulses were applied with a repetition rate of 50kHz at 355nm. The size of the openings and their position can be easily optimized by editing some parameters in the laser.
  • FIG. 3 shows the streamlines of a water-based fluid that goes through holes of 40 ⁇ diameter which simulate the perforations of the chip for one particular example. It can be seen that the sensor holes create a flow over the transducers. The position of the perforations may be in the near vicinity of the sensors to warrantee enough flow on their surface. In one example, the sensor hole may be positioned at 5 times the diameter of the hole or less, advantageously 3 times the diameter of the hole or less, for example 2 times the diameter of the hole or less. The diameter may for example be ⁇ or less or for example 50 ⁇ or less.
  • FIG. 4 shows the perforations made in the chip. The array of sensors is accompanied by an array of perforations. Each perforation will create a flow for its closest sensor.
  • the photonic chip with the array of sensors and the embedded microfluidic system (being the number of perforations) described above is in some embodiments incorporated to the bottom of the reaction tube, once its original bottom is mechanically removed.
  • FIG. 5 shows the picture of the final device.
  • the device was fixed on a tiny chuck by means of vacuum.
  • This chuck also has a connection to a pump, where pressure can be applied positively or negatively, pushing or sucking any gas or fluid applied in a specific area of this chuck.
  • the reaction tube with the photonic chip integrated at its bottom was carefully aligned, so the perforations of the chip coincide with this area. Any fluid in contact with the chip will flow through the holes and be sucked or pushed up again by the pump.
  • FIG. 6 shows the device fixed on this chuck in elevated side view.
  • grating couplers were used to couple the light from a tunable laser into the chip and couple it out to be detected by an infrared camera.
  • Light is coupled in and out from the bottom of the chip, i.e. through the 750- ⁇ thick silicon substrate. The latter can be seen in the cross- sectional view of the sensing device mounted on the sensing system in FIG. 7. Silicon is considered practically transparent for the wavelength used (1.55 ⁇ ).
  • the silicon substrate was thinned down to 300 ⁇ by chemical mechanical grinding and afterwards a chemical mechanical polishing step was performed in order to attain a smooth surface.
  • the time to perform each of these steps was less than one hour.
  • Fig. 8 shows three different graphs corresponding to each one of the steps of the assay. They show the evolution in time of the resonance wavelength shift of the ring resonators during the measurements with different solutions. The different lines each correspond to one sensor.
  • FIG. 8 at the top shows the silanization of the surface with APTES resulting in ethanol-APTES- ethanol.
  • FIG. 8 center shows the binding of biotin after flowing 3mg/ml solution of biotin in PBS and its disassociation when it is rinsed with PBS, resulting in immobilization of the biotin with formation of PBS-biotin-PBS .
  • a shift of 30pm is measured when streptavidin in flowed through the chip proving the binding of this to the biotin.
  • FIG. 8 at the bottom graph illustrates the binding of streptavidin to biotin resulting in the formation of PBS-streptavidin-PBS.
  • the present invention also relates to a method for sensing a biological, chemical, biomimic or biochemical target analyte in a medium. It comprises the steps of obtaining a sensing device comprising a container for holding the medium and a sensor attached to at least part of the container, at least part of the sensor comprising a transducer element having at least one characteristic parameter
  • the method also may encompass method steps expressing the functionality of features and/or components of a sensing device according to the first aspect or a detection system according to the second aspect.
  • the present invention also relates to a method for manufacturing a sensing device, advantageously a sensing device according to an embodiments according to the first aspect.
  • the manufacturing method thereby comprises obtaining a container for holding the medium and obtaining a sensor comprising a transducer element having at least one characteristic parameter.
  • Obtaining a container and obtaining a sensor may comprise obtaining these components off the shelf. Alternatively, such components may be obtained by constructing them.
  • Constructing a container such as a reaction tube or a micro titer plate, may be performed according to techniques well known in the art. Constructing a sensor, e.g. a photonics sensor, also is known in the art and therefore not discussed in detail anymore.
  • the method also comprises creating at least one sensor hole in the sensor and creating at least one container hole in the container so that, upon attaching the sensor to the container, at least one flow through channel is created allowing flow of the medium through the container.
  • the at least one sensor hole in the sensor is being positioned with respect to the transducer element such that the flow of the medium through the container induces a flow of the medium over the transducer element.
  • the latter can be obtained by limiting the distance between the transducer element and at least one sensor hole formed.
  • the sensor hole(s) may be formed at a distance from transducer less than 5 times, e.g. less than 3 times or less than 2 times the sensor hole diameter.
  • the method also may comprise attaching the sensor to the container.
  • the sensor hole(s) are generated through laser processing, e.g. laser ablation.

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Abstract

La présente invention concerne un dispositif capteur pour la détection d'un analyte biologique, chimique, biomimétique ou biochimique cible dans un fluide. Le dispositif de détection comporte un récipient pour contenir le fluide et un capteur fixé à au moins une partie du récipient. Le capteur comporte un élément transducteur ayant au moins un paramètre caractéristique. Le dispositif capteur comporte également un moyen de création d'écoulement pour la création d'un écoulement du fluide sur l'élément transducteur, permettant ainsi la création d'une modification du paramètre caractéristique lors de l'apparition ou de la variation de l'analyte cible dans le fluide.
PCT/EP2014/051285 2013-01-29 2014-01-23 Dispositif biocapteur Ceased WO2014118068A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090320622A1 (en) * 2006-06-28 2009-12-31 Carsten Mueller Microreactor array, Device Comprising a Microreactor array, and Method for Using a Microreactor Array

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090320622A1 (en) * 2006-06-28 2009-12-31 Carsten Mueller Microreactor array, Device Comprising a Microreactor array, and Method for Using a Microreactor Array

Non-Patent Citations (4)

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Title
CRISTINA LERMA ARCE ET AL: "Silicon photonic sensors incorporated in a digital microfluidic system", ANALYTICAL AND BIOANALYTICAL CHEMISTRY, SPRINGER, BERLIN, DE, vol. 404, no. 10, 29 August 2012 (2012-08-29), pages 2887 - 2894, XP035140588, ISSN: 1618-2650, DOI: 10.1007/S00216-012-6319-6 *
FLUECKIGER JONAS ET AL: "Cascaded silicon-on-insulator microring resonators for the detection of biomolecules in PDMS microfluidic channels", MICROFLUIDICS, BIOMEMS, AND MEDICAL MICROSYSTEMS IX, SPIE, 1000 20TH ST. BELLINGHAM WA 98225-6705 USA, vol. 7929, no. 1, 10 February 2011 (2011-02-10), pages 1 - 10, XP060011002, DOI: 10.1117/12.873974 *
KSENDZOV A ET AL: "INTEGRATED OPTICS RING-RESONATOR SENSORS FOR PROTEIN DETECTION", OPTICS LETTERS, OPTICAL SOCIETY OF AMERICA, US, vol. 30, no. 24, 15 December 2005 (2005-12-15), pages 3344 - 3346, XP001237542, ISSN: 0146-9592, DOI: 10.1364/OL.30.003344 *
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