WO2009074933A1 - Biodétecteur avec cavité optique - Google Patents

Biodétecteur avec cavité optique Download PDF

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Publication number
WO2009074933A1
WO2009074933A1 PCT/IB2008/055116 IB2008055116W WO2009074933A1 WO 2009074933 A1 WO2009074933 A1 WO 2009074933A1 IB 2008055116 W IB2008055116 W IB 2008055116W WO 2009074933 A1 WO2009074933 A1 WO 2009074933A1
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WO
WIPO (PCT)
Prior art keywords
light
optical cavity
sensor surface
total internal
internal reflection
Prior art date
Application number
PCT/IB2008/055116
Other languages
English (en)
Inventor
Coen A. Verschuren
Original Assignee
Koninklijke Philips Electronics N. V.
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 Koninklijke Philips Electronics N. V. filed Critical Koninklijke Philips Electronics N. V.
Publication of WO2009074933A1 publication Critical patent/WO2009074933A1/fr

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Classifications

    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles

Definitions

  • biosensors allow for the detection of a given specific molecule within an analyte, wherein the amount or concentration of said target molecule is typically small.
  • the amount of drugs or cardiac markers within saliva or blood may be measured. Therefore, label particles, for example paramagnetic label beads, are used which bind to a specific binding site or spot only, if the molecule to be detected is present within the analyte.
  • a magnetic field (gradient) below the well can be used to pull the beads towards the bottom of the well.
  • the magnetic field is removed, and another magnetic field above the well may be applied to pull the non-bonded beads away from the well bottom. Subsequently, the presence of beads at the binding spots at the bottom of the well may be detected.
  • the detection of the beads may be done using for example magneto- resistive techniques.
  • a further known technique is to optically detect the magnetic label beads bound to the binding spots using FTIR.
  • Such a FTIR magnetic biosensor may have a geometry as schematically shown in Fig. l(a).
  • the biosensor device has a hemispherical bottom with a radius R.
  • Light emitted from a light source for example a laser or a LED, is coupled into the sample at an angle of total internal reflection, that is, an angle which is larger than ⁇ c . If no particles are present close to the sample surface, the light is completely reflected.
  • a way to increase the sensitivity of a magneto-optical FTIR biosensor is to allow the light beam emitted by the light source to undergo multiple FTIR reflections on the sample surface, before detecting the intensity in the photo-detector.
  • This may be achieved by providing, for example, a dove-tail configuration as shown in Fig. l(b) with a highly reflective surface on one side of the dove-tail configuration.
  • the light beam reflected from the sensor surface may again be re-directed to the sensor surface by the reflection on the highly reflecting surface and may then be detected after a further FTIR reflection from the sensor surface.
  • multiple highly reflective surfaces multiple-pass reflection on the sensor surface may be possible.
  • the maximum number n of reflections, and thus the gain in sensitivity is limited to about 10 for a typical configuration.
  • the FTIR biosensor device comprises an optical cavity wherein the optical path through the optical cavity comprises a total internal reflection on a sensor surface of the FTIR biosensor device.
  • Light emitted from a light source coupled into the optical cavity is directed multiple times through the cavity, including the total internal reflection on the sensor surface of the biosensor device.
  • the light path through the cavity further includes a light entrance and a light exit.
  • a light redirecting means redirects a predetermined portion of the light beam directed from the sensor surface towards the light exit back to the sensor surface and subsequently to the light exit.
  • the light exit may comprise a mirror functioning as light beam redirecting means.
  • the mirror preferably has a high reflectivity to allow a substantial portion of light to be redirected through the optical path to the sensor surface. However, also a small portion of light is coupled out of the optical cavity through the mirror each round-trip inside the cavity. The light coupled out from the cavity is detected by detecting means, for example a fast photo-multiplier or an avalanche photo-diode.
  • Signal detection methods may be similar to those used in cavity ring- down spectroscopy and related fields.
  • the intensity decay time or ring-down time of the cavity which is determined by using the change of the intensity of the light detected by the detecting means, is used to characterize the intensity loss at the detection interface.
  • the measured intensity decay time depends on the frustration of the total internal reflection on the sensor surface, for example due to the presence of magnetic beads close to the sensor surface.
  • the optical cavity comprises two or more high-reflective mirrors acting as light beam redirecting means with appropriate spacing and radii of curvature to form a stable resonator.
  • the optical cavity may have the shape of a dove-tail prism, as shown in Fig. l(b), where high-reflective mirrors are arranged on the inclined surfaces of the prism.
  • the high-reflective mirrors should have a reflectivity of at least 90% so that sufficient light is redirected through the cavity to the sensor surface.
  • the mirrors should have a transmission which may be 5% or smaller in order to allow the light to be coupled in and out of the optical cavity through the mirrors.
  • the optical cavity may include multiple facets, the optical path through the cavity comprising total internal reflections on some or on all of these facets.
  • Light may be coupled in and out of such a cavity by using a prism-like structure in very close proximity to the entrance and exit facets.
  • One single facet may act as entrance and exit facet, the entrance and exit facets may alternatively also be different facets of the optical cavity.
  • One example of a multi-facet shape of the optical cavity is a regular octagon.
  • Fig. 1 schematically shows a FTIR biosensor with (a) a hemispherical bottom and (b) a dove-tail prism shaped bottom for FTIR detection;
  • Fig. 2 schematically shows the lay-out of a biosensor including an optical cavity according to an embodiment of the invention
  • Fig. 3 shows diagrams of the ring-down time versus the light loss
  • Fig. 4 schematically shows an optical cavity in the form of a regular octagon according to another embodiment of the invention.
  • Fig. 2 schematically illustrates the layout of a FTIR biosensor device comprising an optical cavity 10 according to an embodiment of the present invention.
  • a structure for sample application similar to the one shown in Fig. l(a) and l(b) may be added on top of the optical cavity 10 shown in Fig. 2.
  • the general shape of the optical cavity 10 is a dove-tail prism as the one shown in Fig. l(b).
  • the inclined surfaces of the prism are high-reflectivity mirrors 4 as an example of light beam redirecting means, by the reflections on these mirrors 4 and the reflection on the sensor surface 2 the optical cavity 10 is formed.
  • a laser source 1 which represents in this example the light source 1 is coupled into the optical cavity 10 through one of the high-reflectivity mirrors 4.
  • a short laser pulse is coupled into the optical cavity 10.
  • the intensity of light coupled out of the optical cavity 10 through the other high-reflectivity mirror 4 at the right side of Fig. 2 is measured by detector 3.
  • the intensity detected by detector 3 exponentially decreases with time.
  • the measured intensity may be digitized using a digitizer 6.
  • a trigger signal 5 may be supplied to the digitizer 6 from the laser light source 1.
  • the digitized signal output from the digitizer 6 may be used to extract the decay time, for example in a computer 7.
  • the extraction of the decay time can be done by fitting the natural logarithm of the digitized data to a straight line, using a weighted least squares fitting algorithm.
  • the absolute intensity loss can be determined.
  • the intensity decay rate is thus a direct measure for the number of label particles on the sample surface.
  • Fig. 3(a) and (b) show the light loss for the ring-down time and ⁇ - ⁇ o, respectively, for the above numbers.
  • the lOps resolution just allows to distinguish the nominal ring-down time from a ring-down time for a light loss which is related to the presence of magnetic particles close to the sensor surface 2, as small as 2xlO ⁇ 5 , that is L 0 xl0ps / ⁇ o, which is orders of magnitude better than previous methods which may achieve a sensitivity of 10 ⁇ 2 .
  • ring-down times go down rapidly, ultimately to values which are too small for the current detectors to capture.
  • these small ring-down time fall outside the interesting range.
  • the photo detectors do not need to be very fast.
  • the ring-down time is in the order of 10ns or larger. Therefore, low noise is more important in order to extract the decay time with high accuracy.
  • time-averaging can be used, that is, an average of multiple decay time measurements may be calculated.
  • a photodetector with a high sensitivity is required.
  • a fast photo -multiplier tube (PMT) or an avalanche photo-diode arrangement may be used.
  • a time- integration of the detector signal can be used with a fixed or calibrated laser intensity to extract the decay time, even when the decay time itself can no longer be measured directly.
  • the laser power intensity is no problem since the decay time is measured and not the intensity itself.
  • pulsed lasers also continuous lasers can be used.
  • the light emitted by the continuous laser is rapidly scanned through a small wavelength range.
  • the wavelength corresponds to one of the resonance frequencies of the optical cavity 10
  • the detected intensity will show a peak.
  • the total intensity of this peak is also a direct measure of the decay time, and thus a measure for the light loss at the detection surface.
  • total internal reflection mirrors 4 with high optical grade, ultra-smooth polished surfaces may be used in the optical cavity. With such surfaces, 1-R values of 10 "6 have been achieved, allowing orders of magnitude improvements in sensitivity.
  • a regular octagon configuration is shown in Fig. 4.
  • a prism- like structure 12 in very close proximity to an entrance facet 8 and an exit facet 9 can be used.
  • the entrance facet 8 for coupling in light is at the bottom side of the octagon next to the light source 1
  • the exit facet 9 for coupling out light is at the right side of the octagon next to the detector 3.
  • the sensor surface 2 is arranged.
  • the five residual facets of the optical cavity 10 formed as an octagon are means for redirecting the light, in this example mirrors 4.
  • the exact distance from the facet determines the efficiency of evanescent coupling from the light source 1 to the optical cavity 10 and from the optical cavity 10 to the detector 3, respectively.
  • This distance can be tuned using piezo-actuators, and also by applying a low-refractive index transparent dielectric with the correct thickness on the mentioned facets may be used. In the latter case, the prisms may simply be pushed in contact with the coated facets.
  • the course of light inside the cavity 10 is described in the following.
  • the light from the light source 1 enters the cavity 10, is reflected by the facets of the octagon in a direction anticlockwise. Small losses of light occur at the sensor surface 2, at the entrance facet 8, and at the exit facet 9. The main part of light is reflected at the facets and keeps going round inside the cavity 10 as indicated by the arrows showing the course of light.
  • the sensor surface 2 at the top the light looses relatively much intensity, depending on the amount of label beads in the analyte which is correlated to the molecule or substance to be detected by the biosensor. As described the label beads are detected by the detector means or detector 3.
  • an assay is a procedure and a substrate at which a property or concentration of a substance is measured.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

L'invention concerne un dispositif de biodétecteur en spectométrie infrarouge à transformée de Fourrier (FTIR) qui comprend une cavité optique. Selon l'invention, de la lumière est couplée à l'intérieur de la cavité optique à partir d'une source de lumière, par exemple un laser pulsé. A l'intérieur de la cavité optique, la lumière est dirigée de multiples fois le long d'un trajet optique qui comprend une entrée de lumière, une réflexion sur la surface de détection du biodétecteur FTIR à un angle satisfaisant à la condition de réflexion interne totale, et une sortie de lumière. Une partie prédéterminée du faisceau lumineux dirigé de la surface de détection vers la sortie de lumière est redirigée à nouveau vers la surface de détection et ultérieurement vers la sortie de lumière. La perte d'intensité due à la réflexion interne totale sur la surface de détection est une mesure de la présence de particules de marqueur proches de la surface de détection. L'intensité de la lumière couplée hors de la cavité optique est détectée par des moyens de détection.
PCT/IB2008/055116 2007-12-13 2008-12-05 Biodétecteur avec cavité optique WO2009074933A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07123152 2007-12-13
EP07123152.6 2007-12-13

Publications (1)

Publication Number Publication Date
WO2009074933A1 true WO2009074933A1 (fr) 2009-06-18

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103512654A (zh) * 2013-09-13 2014-01-15 中国水产科学研究院东海水产研究所 一种全方位环境光采集装置以及鱼类放流标志
EP2478367B1 (fr) 2009-09-14 2015-05-13 Koninklijke Philips N.V. Dosage immunologique haute sensibilité à marqueurs à grosses particules
EP3074756A4 (fr) * 2013-11-27 2017-06-28 Baker Hughes Incorporated Estimation de caractéristiques de matériau faisant intervenir une spectroscopie de réflectance interne
US9863863B2 (en) 2011-11-14 2018-01-09 Koninklijke Philips N.V. Apparatus for cluster detection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5835231A (en) * 1997-10-31 1998-11-10 The United States Of America As Represented By The Secretary Of Commerce Broad band intra-cavity total reflection chemical sensor
US5986768A (en) * 1997-10-31 1999-11-16 The United States Of America, As Represented By The Secretary Of Commerce Intra-cavity total reflection for high sensitivity measurement of optical properties
EP1528389A1 (fr) * 2003-10-31 2005-05-04 Agilent Technologies, Inc. Méthode et dispositif pour détection optique à ultra-haute sensibilité d'agents chimiques et biologiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5835231A (en) * 1997-10-31 1998-11-10 The United States Of America As Represented By The Secretary Of Commerce Broad band intra-cavity total reflection chemical sensor
US5986768A (en) * 1997-10-31 1999-11-16 The United States Of America, As Represented By The Secretary Of Commerce Intra-cavity total reflection for high sensitivity measurement of optical properties
EP1528389A1 (fr) * 2003-10-31 2005-05-04 Agilent Technologies, Inc. Méthode et dispositif pour détection optique à ultra-haute sensibilité d'agents chimiques et biologiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PIPINO A C R AND HODGES J T: "Evanescent wave cavity ring-down spectroscopy for trace water detection", PROC. SPIE, vol. 4205, 2001, pages 1 - 11, XP002524282 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2478367B1 (fr) 2009-09-14 2015-05-13 Koninklijke Philips N.V. Dosage immunologique haute sensibilité à marqueurs à grosses particules
EP2478367B2 (fr) † 2009-09-14 2018-04-04 Koninklijke Philips N.V. Dosage immunologique haute sensibilité à marqueurs à grosses particules
US11493507B2 (en) 2009-09-14 2022-11-08 Siemens Healthineers Nederland B.V. Highly sensitive immunoassay with large particle labels
US9863863B2 (en) 2011-11-14 2018-01-09 Koninklijke Philips N.V. Apparatus for cluster detection
CN103512654A (zh) * 2013-09-13 2014-01-15 中国水产科学研究院东海水产研究所 一种全方位环境光采集装置以及鱼类放流标志
EP3074756A4 (fr) * 2013-11-27 2017-06-28 Baker Hughes Incorporated Estimation de caractéristiques de matériau faisant intervenir une spectroscopie de réflectance interne

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