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WO2018141070A1 - Puce de biocapteur combinant plasmon de surface et détection électrochimique - Google Patents

Puce de biocapteur combinant plasmon de surface et détection électrochimique Download PDF

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Publication number
WO2018141070A1
WO2018141070A1 PCT/CA2018/050130 CA2018050130W WO2018141070A1 WO 2018141070 A1 WO2018141070 A1 WO 2018141070A1 CA 2018050130 W CA2018050130 W CA 2018050130W WO 2018141070 A1 WO2018141070 A1 WO 2018141070A1
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WIPO (PCT)
Prior art keywords
waveguide
biosensor
sample
dielectric
optical radiation
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Application number
PCT/CA2018/050130
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English (en)
Inventor
Pierre Simon Joseph Berini
Original Assignee
University Of Ottawa
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Publication of WO2018141070A1 publication Critical patent/WO2018141070A1/fr

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    • 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
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection
    • G01N21/553—Attenuated total reflection and using surface plasmons
    • 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
    • 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
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/1717—Systems in which incident light is modified in accordance with the properties of the material investigated with a modulation of one or more physical properties of the sample during the optical investigation, e.g. electro-reflectance
    • G01N2021/1731—Temperature modulation
    • 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
    • G01N2021/7706—Reagent provision
    • G01N2021/7709—Distributed reagent, e.g. over length of guide
    • 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
    • G01N2021/7756—Sensor type
    • G01N2021/7763—Sample through flow
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/49—Systems involving the determination of the current at a single specific value, or small range of values, of applied voltage for producing selective measurement of one or more particular ionic species

Definitions

  • the present invention relates to long-range surface plasmon- polariton sensors and electrochemical sensors, and in particular, systems, apparatus and methods using long-range surface plasmon-polariton biosensors and electrochemical biosensors for detecting one or more analytes in a sample.
  • SPPs Surface plasmon polaritons
  • TM transverse magnetic
  • a single-interface SPP exhibits interesting and useful properties such as an energy asymptote in its dispersion curve, high surface and bulk sensitivities, and subwavelength confinement near its energy asymptote.
  • LRSPP long-range SPP
  • LRSPPs Long-range surface plasmon polaritons
  • TM-polarized (p-polarised) incident light propagating along a thin metal strip or slab bounded on all sides by the same dielectric cladding.
  • LRSPP attenuation is at least a factor of 2 to 3 lower than that of the single- interface SPP, resulting in propagation over a longer distance.
  • attenuation reduction factors, or equivalently, range extension factors, greater than 100 can be achieved with the LRSPP.
  • the range extension mitigates an important limitation of the single-interface SPP and the increased propagation length of LRSPPs enables a better overall sensitivity due to increased optical interaction length with the sensing medium.
  • biosensors and in particular, systems, apparatus and methods for detecting one or more analytes in a biological sample using both optical and electrochemical detection.
  • a surface plasmon-polariton (SPP) biosensor there is provided a surface plasmon-polariton (SPP) biosensor.
  • the biosensors of the present invention can be applied to various sensing applications such as medical diagnostics, environmental monitoring, and food safety and security.
  • biosensors of the present invention are readily adaptable for and are particularly suitable for performing a plurality of different forms of simultaneous detection by using different waveguides in combination with different fluidic channel designs.
  • a system and a method of label-free optical sensing that has high sensitivity, overcomes the need for tagging and unnecessary chemical manipulation of the analyte (and/or receptor molecules), requires very low working volumes, does not have electromagnetic interference, can determine kinetic, specificity, affinity and concentration in one step, and provides real time and simultaneous detection of a plurality of biomolecules.
  • a system and a method which combines SPP biosensors and electrochemical detection to provide complementary information on a biological sample.
  • a system and a method which integrates polymer chain reaction (PCR) on chip to provide an integrated solution.
  • PCR polymer chain reaction
  • electrophoresis and dielectrophoresis capabilities are provided.
  • a system and a method which improves the signal-to-noise ratio at the detector by allowing for a weak optical modulation to the signal.
  • the detection strategies discussed below illustrate generally examples of analyte detection that can be done using the biosensors according to various embodiments described herein .
  • the biosensors of the present invention may be useful for the detection of various diseases which require at least two combination tests for reliable diagnosis.
  • the present disclosure provides for a biosensor comprising surface plasmon and electrochemical detection
  • the biosensor comprises a grating coupling means for optical I/O, an electrical access to the waveguide strip, an extra metal strip integrated into the same fluidic channel enabling electrochemistry, and a multilayer lower cladding.
  • the biosensor comprises a multilayer lower cladding, a grating coupler, an electrical contact, and an
  • the multilayer lower cladding is configured for optical and electrochemical sensing on the same biosensor.
  • the present disclosure provides a biosensor for detecting a plurality of analytes in a sample, the biosensor comprising a waveguide including a plurality of branches. At least one of the branches being a sensing branch capable of having an reagent deposited thereon for immobilizing a ligand for binding to at least one of the analytes to be detected. At least one of the branches being a reference branch.
  • the waveguide is bounded by dielectric claddings. Etched in a dielectric cladding is at least one microfluidic channel, the channel configured to move fluids towards and away from the sensing branch.
  • the present invention relates to a waveguide for receiving and propagating an optical radiation along the length of the waveguide as a surface plasmon-polariton (SPP) wave with its transverse electric field substantially perpendicular to the width of the waveguide, the waveguide comprising : an input region for receiving the optical radiation at one end; an output region at an opposed end for emitting the propagated optical radiation away from the waveguide and towards a detector; and a sensing region between the input and output region .
  • SPP surface plasmon-polariton
  • the waveguide further comprises : an input grating coupler in the input region, for coupling perpendicularly incident light into LRSPP waves propagating along the waveguide.
  • the waveguide further comprises : an output grating coupler in the output region, for coupling LRSPP waves propagating along the waveguide input perpendicularly emerging light.
  • the biosensor further comprising a reagent configured to be adsorbed onto the sensing region, the adsorbed reagent forming an adlayer for immobilizing a ligand.
  • the waveguide comprises a plurality of units along the length of the waveguide, the units optically coupled and arranged in an end-to-end relationship with adjacent units.
  • At least one branch further comprises a reference branch optically coupled thereto.
  • Optically non-invasive electrical contacting means are provided to the waveguide.
  • the waveguide comprises a metallic strip, the strip comprising gold, silver, copper, aluminum, chromium, titanium, platinum or palladium, or combinations thereof.
  • Metal nitrides can also be used, particularly formed from group 4, 5 and 6 transition metals, such as titanium nitride, zirconium nitride, tungsten nitride, vanadium nitride, tantalum nitride, and niobium nitride.
  • a particularly good choice is Au due to its good optical performance and its chemical stability.
  • a thin layer of Cr or Ti, for example, can be used as an adhesion metal, if necessary, to adhere the strip to the lower cladding.
  • the claddings are glass, quartz, or a low-index UV or thermal curing polymer.
  • the waveguide has a thickness from about 20 to about 60 nm, preferably about 35 nm and a width from about 1 to about 12 ⁇ , preferably about 5 ⁇ .
  • the sensing region is from about 0.5 to about 4 mm in length.
  • the fluidic channels comprise curved portions.
  • the index of refraction of the claddings is substantially similar to the index of refraction of the fluid.
  • the lower cladding is formed from a multilayer dielectric stack operating as a truncated 1-D photonic crystal with a stopband overlapping with the operating wavelength.
  • a metal electrode is integrated near the waveguide within the same fluidic channel.
  • the metal electrode is shaped into a strip, the strip comprising gold, silver, copper, aluminum, chromium, titanium, platinum or palladium, or combinations thereof.
  • Metal nitrides can also be used, particularly formed from group 4, 5 and 6 transition metals, such as titanium nitride, zirconium nitride, tungsten nitride, vanadium nitride, tantalum nitride, and niobium nitride.
  • a particularly good choice is Pt due to its good electrochemical performance.
  • a thin layer of Cr or Ti, for example, can be used as an adhesion metal, if necessary, to adhere the strip to the lower cladding.
  • electrical contacting means are provided to the LRSPP waveguide and to the metal electrode.
  • the sensing fluid comprises an electrolyte
  • the waveguide acts as a working electrode and the metal electrode acts as a counter electrode;
  • a potential reference is provided, for example, by a Ag/AgCI cell in contact with the electrolyte.
  • the biosensor further comprising : a substrate for supporting the biosensor thereon and a lid secured over the biosensor.
  • the lid comprises : a fluid inlet in fluid communication with the fluidic channel for directing fluid downwards and towards the sensing region and a fluid outlet for removing fluid from the fluidic channel upwards and away from the fluidic channel.
  • the biosensor chip comprises : a facet bounding at least a portion of the dielectric cladding; a fluid inlet formed in the facet, the inlet in fluid communication with the fluidic channel for directing fluids laterally and towards the sensing region; and a fluid outlet formed in the facet, the outlet for removing fluid from the fluidic channel laterally and away from the sensing region.
  • the reagent is configured to for an adlayer on the waveguide.
  • the adlayer is a self- assembled monolayer.
  • the ligand is an antibody or an antigen and the biological sample is blood.
  • a biosensor for detecting one or more analytes in a sample, the biosensor comprising : a waveguide configured to receive an optical radiation, and to
  • SPP surface plasmon-polariton
  • the waveguide comprising a sensing region configured to form an adlayer thereon configured for binding to one or more analytes in a sample; a dielectric cladding surrounding the waveguide; at least one fluidic channel formed in the dielectric cladding for
  • a system for detecting one or more analytes in a sample comprising : a biosensor comprising : a waveguide configured to receive an optical radiation, and to propagate the optical radiation along the length of the waveguide as a surface plasmon-polariton
  • the waveguide comprising a sensing region configured to form an adlayer thereon for binding to one or more analytes in a sample; a light source for transmitting the optical radiation into the waveguide; and a detector configured for receiving the propagated optical radiation.
  • a method of manufacturing a biosensor for detecting one or more analytes in a sample comprising : forming an adlayer on a biosensor, the adlayer configured to immobilize one or more analytes in a sample thereon, the biosensor comprising : at least one waveguide configured to receive an optical radiation, and to propagate the optical radiation along the length of the waveguide as a surface plasmon-polariton (SPP) wave with its transverse electric field substantially perpendicular to the width of the waveguide, and to emit the propagated optical radiation away from the waveguide and towards a detector, the at least one waveguide comprising a sensing region configured to form an adiayer thereon; a dielectric cladding surrounding the at least one waveguide; at least one fluidic channel formed in the dielectric cladding for directing a fluid towards and away from the sensing region ; and at least one counter-electrode in communication with the at least one fluidic channel,
  • SPP surface plasmon-polariton
  • the biosensor further comprises at least another pair of a waveguide and a counter-electrode
  • the method of manufacturing further comprises the steps of: applying an electrical potential to a first pair of a waveguide and a counter-electrode to desorb the adiayer formed on the waveguide of the first pair; and forming a different adiayer on the waveguide of the first pair, wherein the step of forming a different adiayer comprises flowing another reagent through the fluidic channel to the sensing region of the waveguide of the first pair to deposit the another reagent as an another adlayer to form a different adlayer on the waveguide of the first pair.
  • a method for detecting one or more analytes in a sample comprising the steps of: positioning a sample on a biosensor comprising : a waveguide configured to receive an optical radiation, and to propagate the optical radiation along the length of the waveguide as a surface plasmon- polariton (SPP) wave with its transverse electric field substantially perpendicular to the width of the waveguide, and to emit the propagated optical radiation away from the waveguide and towards a detector, the waveguide comprising a sensing region configured to form an adlayer thereon for binding to one or more analytes in a sample; flowing the sample through the fluidic channel to immobilize the analyte to the ligand; and detecting the presence of the immobilized analyte.
  • SPP surface plasmon- polariton
  • the step of detecting comprises: transmitting an optical radiation into the waveguide; and monitoring the changes in the power levels of the propagated optical radiation emitted from the waveguide using the detector, wherein a change in the power levels of the propagated optical radiation is indicative of the presence of the analyte in the sample through the binding of the analyte to the adlayer.
  • the step of detecting comprises : transmitting an optical radiation into the waveguide; and monitoring the changes using a camera, wherein a change in the image is indicative of the presence of the analyte in the sample through the binding of the analyte to the adlayer.
  • the step of detecting further comprises : controlling a potential difference between the reference electrode and the waveguide while measuring a current flowing through the waveguide, wherein the potential is controlled so as to cause a redox reaction between a redox ion species in the fluid and the waveguide, and the current through the waveguide is balanced by a current through the counter electrode; and employing the measured current to detect the presence of the analyte in the sample through the binding of the analyte to the adlayer.
  • the method detecting one or more analytes in a sample further comprises: applying an electrical potential to the waveguide and the counter- electrode to desorb the adlayer from the sensing region.
  • FIG. 1 is a schematic diagram in top view of a biosensor chip, according to an aspect of the present invention.
  • FIG. 2 is a schematic diagram in top view of a biosensor chip, according to another aspect of the present invention ;
  • Fig. 3 is a cross-sectional view along line 3-3 of the biosensor chip of Figs. 1 or 2;
  • Fig. 4 is a cross-sectional view along line 4-4 of the biosensor chip of Figs. 1 or 2;
  • Fig. 5 is a cross-sectional view along line 5-5 of the biosensor chip of Fig. 2;
  • FIG. 6 is a schematic diagram in top view of a biosensor chip including a multilayer lower cladding, according to another aspect of the present invention.
  • Fig. 7 is an cross-sectional view along line 7-7 of the biosensor chip of Fig. 6;
  • Fig. 8(a) is an image of the LRSPP mode output emitted from a waveguide according to an embodiment
  • Fig. 8(b) is an image of the LRSPP mode output emitted from a waveguide according to another embodiment.
  • LRSPPs Long-range surface plasmon polaritons
  • TM polarized p-polarised incident light propagating along a thin metal strip or slab bounded on all sides by dielectric claddings of similar refractive index.
  • LRSPP attenuation is at least a factor of 2 to 3 lower than that of the single-interface SPP, resulting in propagation over a longer distance.
  • attenuation reduction factors, or equivalently, range extension factors, greater than 100 can be achieved with the LRSPP.
  • the range extension mitigates an important limitation of the single-interface SPP and the increased propagation length of LRSPPs enables a better overall sensitivity due to increased optical interaction length.
  • LRSPP waveguides are sensitive to bulk and surface changes because the mode is bound to the surface of the metal, has fields that peak thereon, and propagates mostly in the background dielectric. Any minor change along the metal surface will affect the mode, changing the
  • LRSPPs may, in certain environments, be less confined and less surface sensitive than single-interface SPPs, they propagate much farther so long-interaction length sensors make it possible to achieve greater adlayer sensitivity and lower limits of detection. Also, the sensing depth is greater ( ⁇ 1 ⁇ vs. ⁇ 200 nm) so greater protein loading along the perpendicular to the strip area (width x length) is possible using, for example, a hydrogel matrix. LRSPPs may also be useful for sensing large biological entities such as cells which cause strong scattering of loosely bound LRSPPs into radiative modes.
  • Biosensor chip 10 in accordance with one embodiment of the present invention for detecting one or more analytes 2 in a sample of fluid 4.
  • Biosensor chip 10 has a top 12, a bottom 14, side A 16, side B 18, side C 20, and side D 22.
  • Biosensor chip 10 comprises at least one or a plurality of waveguides 100.
  • the waveguides 100 according to the present invention are polarization sensitive in that the plasmon-polariton wave is highly linearly polarized in the vertical direction, i.e. perpendicular to the plane of the metallic strip (out of the page).
  • the waveguides of the present invention are configured for receiving and propagating an optical radiation along the length of the waveguide as a surface plasmon-polariton (SPP) or a long range surface plasmon-polariton (LRSPP) wave with its transverse electric field
  • SPP surface plasmon-polariton
  • LRSPP long range surface plasmon-polariton
  • Waveguide 100 comprises an input region 102 for receiving optical radiation at one end and an output region 104 at an opposed end for emitting perpendicularly optical radiation away from waveguide 100 and towards a detector (e.g. a power sensor or a camera, not shown).
  • a sensing region 106 may be located between input end 102 and output end 104 for reasons to be discussed below.
  • Fig. 3 shows a longitudinal cross-sectional along the line 3-3 shown in Fig. 1.
  • Fig. 4 shows a longitudinal cross- sectional sketch along line 4-4 shown in Fig. 1.
  • Waveguide 100 may comprise a metallic strip of thickness t, width w, and permittivity ⁇ 2.
  • the thickness and the width of the strip may be selected such that the waveguide 100 can support a long-range surface plasmon-polariton (LRSPP) mode at the free-space operating wavelength of interest.
  • Suitable materials for the waveguide strip 100 include (but are not limited to) gold, silver, copper, aluminum, chromium, titanium, platinum or palladium, or combinations thereof.
  • Metal nitrides can also be used, particularly formed from group 4, 5 and 6 transition metals, such as titanium nitride, zirconium nitride, tungsten nitride, vanadium nitride, tantalum nitride, and niobium nitride.
  • a particularly good choice is Au due to its good optical performance and its chemical stability.
  • the sensing region 106 of waveguide 100 is suitable for depositing a reagent thereon (not shown) as an adlayer.
  • the adlayer is configured to be immobilized onto the waveguide 100 and is configured to bind a ligand for one or more analytes in a biological sample to be analyzed.
  • various biomolecules can be attached to the surface of the waveguide strip 100 in the sensing region 106 using various methods including, but not limited to, physisorption; binding using a protein A or protein G linker; binding using a streptavidin or avidin-biotin linker; binding using appropriately terminated alkanethiols; or binding using covalent attachment.
  • the sensing region 106 is prepared by forming a suitable self-assembled monolayer (SAM) thereon.
  • SAM self-assembled monolayer
  • Alkanethiols where a thiol is covalently linked to a longer hydrocarbon chain, are commonly used SAM molecules.
  • a suitable alkanethiol is 16- Mercaptohexadecanioc acid (16-MHA).
  • the SAM is assembled by incubation of the alkanethiol in an appropriate solvent over the metallic surface of the waveguide strip 100, for example Au.
  • the SAM can then be functionalised as desired.
  • One functionalization method is using carbodiimide coupling (i.e. using l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N- Hydroxysuccinimide (NHS) chemistry for protein coupling) of the
  • biomolecules to the carboxylated metallic surface may also be used.
  • Other methods of forming an adlayer at the sensing region of the waveguide suitable for detecting other biomolecules e.g. deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), etc ..) known to those of ordinary skill in the art may also be used.
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • An input grating coupler 108 can be provided at the input region 102 and an output grating coupler 110 can be provided at output region 104. According to one embodiment, use of the grating couplers 108 and 110 may obviate the need for a high-quality end facets and simplify the optical alignment.
  • the input grating coupler 108 is configured to couple
  • the resultant LRSPP wave may be configured to propagate in two longitudinal directions , a forward direction and a reverse direction along waveguide 100 (indicated by black arrows on Fig. 1). In the reverse direction, one LRSPP wave will emerge longitudinally from the end facet along side 16, thereby producing a reference signal. In the forward direction, the other LRSPP wave is allowed to propagate through to the sensing region 106 and towards the output region 104.
  • the output grating coupler 110 may be of similar design to the input grating coupler 108, but is configured for coupling the LRSPP wave emerging from the sensing region 106 to perpendicularly emerging light.
  • Grating couplers 108 and 110 may be configured as a series of protrusions 112 extending outwards having thickness H R and length L R arranged in period ⁇ .
  • Suitable materials for the protrusions 112 include any of the metals (or combinations thereof) as used for the waveguide 100.
  • a particularly suitable material is Au because of its optical performance.
  • Suitable dimensions for the grating couplers 108 and 110 at a free-space operating wavelength of 1310 nm are about 1000 nm for the period ⁇ , 50 to 300 nm for the protrusion thickness H R and about ⁇ /2 for the protrusion length L R . About 15 periods (15 protrusions arranged periodically) are sufficient.
  • the width of the grating WG can be approximately the same as the width w of the waveguide 100.
  • the grating couplers 108 and 110 are formed of 16 Au protrusions arranged in a period ( ⁇ ) of about 1000 nm, each protrusion having a thickness (H R ) of about 150 nm and a length (L R ) of about 400 nm.
  • the input grating coupler 108 could be removed, and TM-polarized light butt-coupled to waveguide 100 in the input region of the biosensor chip 10 through its facet along edge A, thereby exciting LRSPP waves along waveguide 100.
  • the output grating coupler 110 could be removed, and the LRSPP wave allowed to propagate through the output region 104 and its facet along edge B, thereby producing freely propagating output radiation.
  • Dielectric claddings 200 may surround waveguide 100.
  • cladding 200 comprises an upper cladding 202 and a lower cladding 204.
  • the upper 202 and lower cladding 204 can surround all the sides of waveguide 100 and at least partially along the length of the waveguide 100.
  • Cladding 200 may be comprised of a homogenous dielectric of permittivity ⁇ 3. Suitable materials for the dielectric include (but are not limited to) glasses, quartz, and polymers. Particularly suitable combinations of materials for sensing applications include Au for the waveguide 100 and low-index UV or thermal curing optical polymer, CytopTM or TeflonTM for the upper and/or lower claddings 202 and 204.
  • the lower cladding 204 comprises a multilayer stack 1204 of dielectric material as will be described in detail further below.
  • An adhesion metal (not shown) of a thin layer of Cr or Ti, for example, can be used, if necessary, to secure the waveguide 100 to the lower cladding 204.
  • the waveguide 100 and cladding 200 are supported by a substrate 300.
  • the substrate 300 may be any material that is flat and mechanically rigid. Suitable substrates include semiconductor materials, such as silicon wafers or glass wafers.
  • a lid 400 is secured to the top of the upper cladding 202 in order enclose the biosensor chip 10.
  • the lid 400 may be removably secured or permanently secured by wafer bonding, for example, either directly to cladding 200 or through an intervening bonding layer 402.
  • Suitable materials for the lid 400 include glasses such as fused silica, borosilicate,
  • borophosphosilicate BorofloatTM, and PyrexTM and polymers such as PMMA (Poly(methyl methacrylate)) and polyimide.
  • Suitable materials for the bonding layer 402 include Cytop, Teflon, SU-8 and BCB (benzocyclobutane).
  • biosensor chip 10 comprises at least one fluidic channel 500 dimensioned to contain a sensing solution 502 of refractive index n c .
  • Fluidic channel 500 is etched into the upper cladding 202 and includes an inlet 504 for introducing the sensing solution 502 which may also contain the biological sample 4 containing one or more analytes 2 to be detected.
  • Fluidic channel also includes an outlet 506 for removing liquids away from the fluidic channel 500.
  • Fluidic channel 500 includes one or more sensing chambers 510 configured to receive a sensing region 106 of respective a waveguide 100 therein .
  • Fluidic channel 500 therefore serves as a conduit for the sensing solution 502 and is configured to expose at least a portion of the sensing region 106 of waveguide 100 to any sensing solutions 502 and/or any biological sample 4 that may be directed into and contained in fluidic channel 500 in the area of the sensing chamber 510.
  • Fluidic channel 500 therefore is configured for directing sensing solution 502 towards and away from sensing region 106 of the waveguide 100.
  • Fluidic channel 500 may be configured to span the width of a plurality of waveguides 100 or be dedicated to one waveguide as shown in Fig. 1.
  • the width W s and the length Lf of the sensing chamber 510, and the overall shape and numbers may be adapted as required.
  • fluidic channel 500 may branch out to create a fluidic network comprising, for example, several parallel sensing chambers 510a and 510b and etc., and the dimensions of the chambers 510 adjusted, for example, to equalize flow rates in each sensing chamber 510.
  • the channel 500 may also incorporate rounded corners to avoid dead volumes.
  • Fluidic channel 500 may open to edge fluidic inlets 520 and outlets 522 along a facet of the biosensor chip 10, for instance along side 20 as shown in Fig. 1. Edge fluidic inlets 520 and outlets 522 may be
  • edge-access because the edge fluidic inlets 520 and outlets 522 are formed along the edges of biosensor chip 10.
  • the edge inlets 520 and outlets 522 are provided by dicing through a perpendicular fluidic channel 500.
  • Biosensor chip 10 may be configured so that one biosensor chip
  • biosensor chip 10 may include a plurality of waveguides 100 and separate fluidic channels 500 to enable the performance of a plurality of independent assays either simultaneously or sequentially.
  • biosensor chip 10 comprises two fluidic channels 500.
  • Each fluidic channel 500 comprises two sensing chambers 510a and 510b, wherein each sensing chamber 510a and 510b has its own associated waveguide 100. Therefore, in this example, biosensor chip 10 comprises 4 waveguides 100 arranged symmetrically about an axis bisecting the biosensor chip 10 where one pair of waveguides 100 is in fluid communication with one fluidic channel 500 and the another pair of waveguides 100 is in fluid communication with a separate fluidic channel 500.
  • a different fluid 502 can be injected into the edge inlet along side 22 relative to the edge inlet along side 20, and/or the waveguides 100 interfaced along side 22 may be chemically functionalized differently than the waveguides interfaced along side 20.
  • FIG. 2 Shown in Fig. 2 is an alternative arrangement of fluidic channels 500.
  • upper cladding 202 and lid 400 define fluidic inlets 530 and outlets 532, respectively for fluidic channel 500.
  • Fluidic inlets lid 400 may be operatively connected sealing means (for instance O-rings), tubing, a pump and vials or reservoirs (not shown).
  • Fig. 5 shows a longitudinal cross-sectional sketch along the line 5-5 shown in Fig. 2 by the dash-dot line running through fluidic inlet 530 and outlet 532.
  • the two sensing chambers 510a and 510b are exposed to same sensing solution 502.
  • This configuration may be termed "top-access” because a fluidic inlet 530 and a fluidic outlet 532 are formed in lid 400 where fluidic inlet 530 and outlet 532 are in fluid communication with fluidic channels 500 such that fluid inlet 530 directs fluid downwards and towards sensing region 106 and fluid outlet 532 directs fluid upwards and away from sensing region 106.
  • a design can be mirrored about the chip bisector producing independent duplicate sensors with top access fluidic inlets and outlets, as sketched in Fig. 2.
  • a different fluid 502 can be injected into inlet 530 relative to inlet 534, and/or the biosensors interfaced with inlets
  • the biosensor chip 10 may be configured so that one biosensor chip 10 may include a plurality of sensors and separate fluidic channels to enable the performance of a plurality of independent assays either simultaneously or sequentially, as described above.
  • Biosensor chip 10 can comprise one or more reference waveguides (not shown) which are not exposed to fluidic channel 500. While these reference waveguides would not have sensing region 106, they may be useful for any noise cancellation, and to provide input and output optical coupling means.
  • the present invention is directed a system and a method which uses an optical arrangement for power attenuation based sensing of one or more analytes in a biological sample.
  • incident TM-polarized (p-polarised) light may be aligned to impinge perpendicularly onto the input grating coupler 108 of the waveguide 100, as shown in Figs. 1, 2, 3, 6, and 7, or
  • a polarized laser diode may be butt- coupled via a polarization-maintaining single-mode optical fiber (PM-SMF) to the input region 102 of the waveguide 100.
  • the polarization of the light emitted by the LD may be aligned with the PM-SMF to ensure that the light incident onto the biosensor 10 is TM-polarized (p-polarized).
  • a broad range of suitable free-space operating wavelength may be used. In some embodiments, free-space operating wavelengths of 850, 1310, or 1550 nm, or therebetween can be used. In one preferred embodiment, the free-space operating wavelength is 1310 nm.
  • Optical radiation is received by the waveguide 100 and propagated downstream and along the length of a waveguide 100.
  • the output of the waveguide along side 18 may be collimated by a microscope objective lens and passed through an aperture to reduce the background light, then detected using a power sensor or a camera (not shown).
  • the output of the optical biosensor emanating perpendicularly from output grating coupler 110 may be collimated by a microscope objective lens and passed through an aperture to reduce the background light, then detected using a power sensor or a camera (not shown).
  • the emerging light may be collected in a multimode or singlemode optical fiber then detected using a power sensor or a camera.
  • the signal output may be split using a beam splitter into two portions : one portion may be directed to a camera to visually monitor the emerging mode for ease of alignment, and another portion may be directed to a photodetector which is connected to a power meter to record real-time changes in the output power.
  • the output signals may be sent directly to a camera where the mode images are recorded and post- processed using analysis software.
  • An intervening material instead of air could be inserted between optical fibers and the waveguide 100, such as an optical bonding material, or such an intervening material could be placed in physical contact with the sensor (not shown).
  • Optical input and output configurations may include generally- available apparatus and techniques used in the optical technical domain to manage confined light, such as, for example, optical fibers, or free-space beams such as coupled to or from the sensors described herein using lenses or beamsplitters.
  • a Gaussian beam, emerging from a lens system or from an optical fiber, for example, is suitable for use as an input.
  • the changes in the power levels of the propagated optical radiation emitted from the output port is monitored using the detector, wherein a change in the power levels of the propagated optical radiation is indicative of the presence of the analyte(s) in the biological sample through the binding of the analyte to the ligand on the surface of the sensing branch of the waveguide.
  • the power levels from the sensing branch may be compared to the power levels from the reference branch to minimize noise.
  • the present invention is directed a system and a method which uses the principles of
  • electrochemistry to provide for, among other things, electrochemical detection of one or more analytes in a biological sample to provide complementary information on a biological sample.
  • biosensor chip 10 further comprise electrical contact pads 600 and contact arms 602.
  • Contact arms 602 are optically non-invasive (i.e., substantially non-disruptive to the LRSPP wave propagating along the waveguides 100) and connect each end of the waveguides 100 to the electrical contact pads 600 contact arms 602.
  • the contact pads 600 are accessible from the top through holes 604.
  • the holes 604 can be formed, for example, by patterning a mask and etching through the lid 400The dimensions of holes 604 can be slightly larger or smaller than the contact pads 600.
  • the contact pads can have an area and a thickness t c large enough to facilitate probing by electrical probes (needles), for example, an area of about 50 ⁇ by 50 ⁇ and a thickness t c of about 200 to 1000 nm, and may be formed from any of the metals (or combinations thereof) as used for the waveguide 100.
  • the contact arms 602 may be defined and formed at the same time as the waveguide 100, using the same materials and the same thickness t as the strip.
  • the width of the contact arms 602 may be in the range of about 1 ⁇ to 10 ⁇ in order to remain optically non-invasive -.
  • the length of the contact arms 602 can be sufficient to ensure that the contact pads 600 are positioned a sufficient distance from the waveguide 100 to not disrupt the propagation of the LRSPP thereon .
  • a suitable length for the contact arm 602 is from about 10 ⁇ to 50 ⁇ .
  • Access to the contact pads 600 may achieved from the top through holes 604.
  • the holes 604 can be formed, for example, by patterning a mask and etching through the lid 400 and upper cladding 202 down to the contact pad 600 and the lower cladding 204.
  • a metal element 700 is provided within the same fluidic channel 500 as waveguide 100.
  • the metal element 700 is an elongate metal element and is located in proximity to and parallel to waveguide 100.
  • the metal element 700 is similarly contacted electrically through contact pads 800, contact arms 802 and via holes 804, as shown in Fig. 1.
  • the element 700 is positioned a sufficient distance away from the waveguide 100 to avoid optical coupling to the LRSPP propagating thereon .
  • the cladding 200 is Cytop
  • the waveguide 100 is a 35 nm thick, 5 ⁇ wide, Au strip, at a free-space operating wavelength of 1310 nm and a suitable length for the element 700 is from about 50 ⁇ to 200 ⁇ .
  • Suitable materials for the element 700 include any of the metals (or combinations thereof) as used for the waveguide strip 100. A particularly good choice is Pt due to its good electrochemical performance.
  • the sensing fluid 502 includes an electrolyte
  • the waveguide 100 may act as a working electrode 100
  • the metal element 700 may act as a counter-electrode 700, forming an electrochemical cell since waveguide 100 and counter-electrode 700 can be electrically connected and configured to complete an electrical circuit.
  • a potential reference electrode may be provided, for example, by an external Ag/AgCI cell in fluidic contact with the electrolyte 114.
  • the reference electrode serves as the voltage potential reference of the working electrode when a selected potential is placed on the working electrode by a voltage source (not shown). This potential is measured by a voltage measuring device (not shown) which can additionally include conventional circuitry for maintaining the potential at a selected voltage.
  • the reference electrode and a counter-electrode 700 are in electrical conductive contact with working electrode 100.
  • the fluid/electrolyte solution 502 is present in the fluidic channel 500, this completes an electrical circuit and any changes owing to the binding of any analytes 2 at the waveguide 100 in the sensing region 106 will alter the electron transfer properties at the waveguide/working electrode 100 thereby providing a change in the electrochemical response at the waveguide/working electrode 100.
  • the biosensor chip 10 is an electrochemical biosensor where the binding of an analyte is effective to measurably alter current flow between the working electrode 100 and the counter-electrode 700 mediated by a redox (reduction-oxidation) ion species in the solution 502, relative to the current flow observed in the absence of the binding of the analyte.
  • the electrochemical response can be measured upon binding of an analyte 2 to the working electrodelOO is as follows: controlling a potential difference between the reference electrode and the working electrode 100 while measuring a current flowing through the working electrode 100, wherein the potential is controlled so as to cause a redox reaction between a component (i.e.
  • the measurement of the electrochemical response, for example, increased electrical resistance, at the working electrode 100 can be accomplished using a voltmeter, ohmmeter, ammeter, multimeter, potentiostat, or a cyclic voltmeter.
  • the biosensor chip 10 of the present invention for the detection one or more analytes in a sample using both optical and electrochemical detection.
  • sensing region 106 of waveguide 100 may operate as an optical biosensor where the SPP wave senses the formation of an adlayer thereon, or as an electrochemical sensor with integrated working electrode 100 and counter-electrode 700.
  • the biosensor chip 10 may function in sequential or simultaneous operation as an optical biosensor and as an electrochemical sensor.
  • the (bio)chemical adlayer formed on the waveguide strip 100 can be desorbed electrochemically, enabling in-situ regeneration down to the metal surface of the strip 100.
  • the waveguide 100 can then be chemically re-functionalized in-situ and re-used for biosensing .
  • biosensor chip 10 comprises two fluidic channels 500.
  • Each fluidic channel 500 comprises two sensing chambers 510a and 510b, wherein each sensing chamber is associated with its own waveguide 100 and counter- electrode 700.
  • a first functionalization chemistry for example, a first solution of alkanethiol having a high affinity to the target analyte
  • a step of electrochemical desorption of said first functionalization chemistry can be injected into the fluidic channel 500, leading to a disposition of the first adlayer on the sensing region 106 of each of the waveguides 100.
  • a functionalization chemistry can then be carried out selectively on waveguide 100 in sensing chamber 510a using the associated electrical contacts 600 and 800 to waveguide 100 and counter-electrode 700, respectively, leaving said first functionalization chemistry on strip 100 in sensing chamber 510b intact.
  • a second functionalization chemistry (for example, a second solution of alkanethiol having a low affinity to the target analyte or having an affinity to a different analyte) can then be injected into the fluidic channel 500 leading to a deposition of a second adlayer, different from the first adlayer on waveguide 100 in sensing chamber 510a.
  • the respective waveguide 100 within each sensing chamber 510a and 510b would have different functionalization chemistries with a different affinity to the target analyte.
  • the contacts 600 and 800 can be used to apply a potential difference to waveguide 100 and counter-electrode 700, thereby establishing an electric field (e.g. a DC electric field) between them within the sensing solution 502, thus enabling the techniques of electrophoresis and dielectrophoresis to be incorporated into optical biosensing protocols.
  • a potential difference can be applied simultaneously as optical biosensing is carried out.
  • the contacts 600 can be used to transmit a current along the waveguide 100 thereby heating the waveguide 100 and the surrounding sensing fluid 502. Heat can be applied in this manner simultaneously or sequentially with optical biosensing may be useful for a variety of applications, including, but not limited to thermally stabilizing the sensing region 106, thermally desorbing a (bio)chemical adlayer from a waveguide strip 100 (for re-generation and re-use or to chemically differentiate sensing regions 106 of a plurality of waveguides 100), thermal cycling enabling chemical amplification via polymerase chain reactions (PCR). Additionally, it would be possible to to improve the signal-to-noise ratio performing thermo-optic modulation to of the SPP wave by
  • the contacts 800 can be used to inject a current along the strip 700 to achieve similar ends.
  • the biosensor chip 10 are readily adaptable for and are particularly suitable for performing a plurality of different forms of simultaneous detection by using different waveguides and electrodes in combination with different fluidic channel designs.
  • Top fluidic access as shown in Figs. 2 and 5 may be advantageous as more fluidic inlets/outlets can be accommodated over the area of the lid compared to inlets and outlets located along the edges of a biosensor chip 16, as in Fig. 1.
  • Figs. 6 and 7 shows a biosensor chip 1010 according to another embodiment of the present invention comprising a lower cladding 1204 which includes a plurality of layers of different dielectric material. This embodiment is distinct from the embodiment of the biosensor chip 10 shown in Figs. 3, 4 and 5 where the same dielectric is used to form the upper and lower claddings 202 and 204.
  • the multilayer lower cladding 1204 comprises a periodic arrangement of N unit cells 1206, each unit cell formed of a first layer of thickness tA of first dielectric (e.g. dielectric A) and a second layer of thickness te of a second dielectric (e.g. dielectric B).
  • each layer of dielectric A and dielectric B can be chosen to tailor the field decay in the stack, minimize the losses due to light tunneling into the substrate, and act as a suitable replacement for uniform substrate medium 204.
  • the multilayer lower cladding 1204 may further comprise a matching layer 1208 between the periodic arrangement of N unit cells and the metal waveguide 100.
  • Matching layer 1208 of thickness ti2os can comprise dielectric A or another dielectric material.
  • the thickness ti2oe of matching layer 1208 is selected such that an LRSPP propagates along the waveguide 100 at the operating wavelength of interest.
  • the purpose of the multilayer lower cladding 1204 is to optically mimic the properties of the lower cladding material 204 for LRSPP waves propagating along the strip 100.
  • a wide class of materials can be used for the multilayer stack 1204.
  • dielectrics with a sufficient refractive index contrast can be used as dielectrics A and B.
  • a wide class of manufacturing methods and techniques can be used.
  • the multilayer stack may be termed a truncated ID photonic crystal.
  • the LRSPP wave propagating along waveguide 100 in this system may be termed a Bloch LRSPP or a Tamm LRSPP, and except for an oscillatory distribution through the multilayer stack, has substantially the same characteristics (e.g. mode size, attenuation, range, and surface and bulk sensitivities along the sensing channel) as LRSPPs in a corresponding system comprising a uniform lower cladding .
  • any suitable dielectrics can be chosen as dielectrics A and B.
  • the materials can be selected from the following categories of materials: semiconductors (operating as a dielectric, below the electronic bandgap of the semiconductor), glasses, oxides, nitrides, chalcogenides, fluorides, and polymers.
  • Other materials which may be easy to deposit using established techniques include sputtered (or evaporated) oxides and nitrides, including S 1O2, Ta20s, S 13N4, T1O2.
  • Transparent conductive oxides such as ITO, ZnO, AZO, ICO can be used.
  • Spin-coated and thermally- and/or UV-cured glasses and polymers can also be used, such as fluorinated and carbonated polymers, Cytop, Teflon, PMMA, BCB, SU-8 and polyimide.
  • the waveguides according to the present disclosure propagate optical radiation along the length of the waveguides 100 from the input region 102 to the output region 104.
  • the waveguides according to the present disclosure can be one continuous strip.
  • the waveguides 100 may comprise a plurality of units aligned along the length of the waveguide 100, the units optically coupled and arranged in an end-to-end relationship with adjacent units, the units being separated from the adjacent units by a gap.
  • the gap distance may be from about 1 ⁇ to about 2 ⁇ .
  • the biosensor chip may include waveguides 100 having a sensing branch (comprising a sensing region 106) and a reference branch (where the reference branch does not have sensing region 106 and is completely surrounded by cladding).
  • An adlayer is formed onto the sensing region 106 of one branch of the waveguide 100 of the biosensor chip 10 or 1010.
  • the adlayer can be configured to immobilize a ligand for a target analyte.
  • the immobilized ligand may be an antibody for an antigen or be an antigen for a target antibody.
  • a sample suspected of containing the target analyte is deposited onto the sensing region 106 of one or more waveguides 100 via one or more fluidic channels 500.
  • Fig. 8(a) shows a mode output emerging from an end facet (side 16) of a biosensor chip, measured using an infrared camera.
  • the LRSPP mode was excited on a waveguide 100 by perpendicularly incident TM-polarized light emerging from a polarization-maintaining single mode fiber aligned with an input grating coupler 108.
  • the biosensor was designed to operate at a wavelength of 1310 nm and was excited at the same wavelength.
  • the width of the grating W G was approximately the same as the width of the waveguide 100 (W G ⁇ 5 ⁇ ).
  • the upper cladding 202 was formed of Cytop and was about 8 ⁇ thick.
  • the lower cladding 204 was also formed of Cytop and was also about 8 ⁇ thick (Fig. 3). The structure was fabricated on a Si wafer. [00131] Example 2 :
  • Fig. 8(b) shows a mode output emerging from an end facet (side 16) of a biosensor chip, measured using an infrared camera.
  • the LRSPP mode was excited on a waveguide 100 by perpendicularly incident TM-polarized light emerging from a polarization-maintaining single mode fiber aligned with an input grating coupler 108.
  • the biosensor was designed to operate at wavelengths near 1310 - 1370 nm and was excited at 1360 nm.
  • the width of the grating W G was approximately the same as the width of the waveguide 100 (W G ⁇ 5 ⁇ ).
  • the upper cladding 202 was formed of Cytop and was about 8 ⁇ thick.
  • the lower cladding 1204 was formed as a multilayer stack (Fig. 6).
  • the structure was fabricated on a Si wafer.

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Abstract

L'invention concerne un biocapteur et un procédé de détection d'un ou plusieurs analytes dans un échantillon. Le biocapteur comprend un guide d'ondes servant à recevoir un rayonnement optique, et à propager le rayonnement optique sur la longueur du guide d'ondes en tant qu'onde de plasmon-polariton de surface (SPP) dont le champ électrique transversal est sensiblement perpendiculaire à la largeur du guide d'ondes, et à émettre le rayonnement optique propagé loin du guide d'ondes et vers un détecteur, le guide d'ondes comprenant une zone de détection servant à former dessus une couche d'addition servant à la liaison d'un ou de plusieurs analytes dans un échantillon ; un revêtement diélectrique entourant le guide d'ondes ; au moins un canal fluidique formé dans le revêtement diélectrique pour la réception et le rapprochement ou l'éloignement de l'échantillon de la zone de détection ; et une contrélectrode en communication avec le canal ou les canaux fluidiques, le guide d'ondes et la contrélectrode étant conçus pour réaliser un circuit électrique lorsque le canal ou les canaux fluidiques sont remplis d'un fluide. Par ailleurs, la présence de l'analyte ou des analytes dans l'échantillon par la liaison de l'analyte au guide d'ondes change les niveaux de puissance du rayonnement optique propagé émis par le guide d'ondes, change de l'image telle qu'elle est capturée par une caméra, et/ou modifie de manière mesurable la circulation du courant entre l'électrode de guide d'ondes et la contrélectrode réalisé par une espèce d'ions redox (oxydoréduction) dans le fluide.
PCT/CA2018/050130 2017-02-06 2018-02-06 Puce de biocapteur combinant plasmon de surface et détection électrochimique WO2018141070A1 (fr)

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EP4227667A1 (fr) * 2022-02-10 2023-08-16 Infineon Technologies AG Système de capteur de fluide monolithique et procédé de fabrication du système de capteur de fluide monolithique

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Title
KRUPIN, O. ET AL.: "Long-Range Surface Plasmon-Polariton Waveguide Biosensors for Disease Detection", JOURNAL OF LIGHTWAVE TECHNOLOGY, vol. 34, no. 20, 15 October 2016 (2016-10-15), pages 4673 - 4681, XP055533504 *
WONG, W. R. ET AL.: "Surface Sensitivity of Straight Long-Range Surface Plasmon Waveguides fc Attenuation-Based Biosensing", APPLIED PHYSICS A, vol. 117, no. 2, November 2014 (2014-11-01), pages 527 - 535, XP035404771 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4227667A1 (fr) * 2022-02-10 2023-08-16 Infineon Technologies AG Système de capteur de fluide monolithique et procédé de fabrication du système de capteur de fluide monolithique

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