US20060205058A1 - Spatially scanned optical reader system and method for using same - Google Patents
Spatially scanned optical reader system and method for using same Download PDFInfo
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- US20060205058A1 US20060205058A1 US11/437,477 US43747706A US2006205058A1 US 20060205058 A1 US20060205058 A1 US 20060205058A1 US 43747706 A US43747706 A US 43747706A US 2006205058 A1 US2006205058 A1 US 2006205058A1
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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
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/251—Colorimeters; Construction thereof
- G01N21/253—Colorimeters; Construction thereof for batch operation, i.e. multisample apparatus
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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
- G01N21/554—Attenuated total reflection and using surface plasmons detecting the surface plasmon resonance of nanostructured metals, e.g. localised surface plasmon resonance
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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
- G01N21/75—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
- G01N21/774—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 reagent being on a grating or periodic structure
- G01N21/7743—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 reagent being on a grating or periodic structure the reagent-coated grating coupling light in or out of the waveguide
Definitions
- the present invention relates to an optical reader system that uses a scanned optical beam to interrogate one or more biosensors.
- the biosensors are incorporated within the wells of a microplate.
- optical reader systems are always trying to design a new and improved optical reader system that can be used to interrogate a resonant waveguide grating biosensor to determine if a biomolecular binding event (e.g., binding of a drug to a protein) occurred on a surface of the biosensor.
- a biomolecular binding event e.g., binding of a drug to a protein
- One such new and improved optical reader system is the subject of the present invention.
- the present invention includes an optical reader system that uses a scanned optical beam to interrogate a resonant waveguide grating biosensor to determine if a biomolecular binding event occurred on a surface of the biosensor.
- the optical reader system includes a light source, a detector and a processor (e.g., computer, DSP).
- the light source outputs an optical beam which is scanned across a moving biosensor and while this is happening the detector collects the optical beam which is reflected from the biosensor.
- the computer processes the collected optical beam and records the resulting raw spectral or angle data which is a function of a position (and possibly time) on the biosensor.
- the processor can then analyze the raw data to create a spatial map of resonant wavelength (peak position) or resonant angle which indicates whether or not a biomolecular binding event occurred on the biosensor.
- Several other uses of the raw data are also described herein.
- FIGS. 1A and 1B respectively illustrate a block diagram of the optical reader system and a flowchart of the method for using the optical reader system in accordance with one embodiment of the present invention
- FIGS. 2-4 are graphs used to help describe how the resonant waveguide grating biosensor can be interrogated by the optical reader system in order to determine whether or not a biomolecular binding event occurred on the biosensor;
- FIGS. 5 and 6 are block diagrams used to describe how the optical reader system can be configured so it can interrogate multiple biosensors that are located in a microplate in accordance with another embodiment of the present invention
- FIGS. 7-15 are graphs and diagrams that are used to illustrate the results of several experiments which where conducted to show how the raw spectral data obtained from the optical reader system can be used to detect a biomolecular binding event in accordance with the present invention
- FIGS. 16-17 are graphs that are used to illustrate the results of an experiment which was conducted to show how the raw spectral data obtained from the optical reader system can be used to characterize a biosensor in accordance with the present invention
- FIGS. 18-20 are graphs and diagrams that are used to illustrate the results of an experiment which was conducted to show how the raw spectral data obtained from the optical reader system can be used to register the position of a biosensor in accordance with the present invention
- FIGS. 21-23 are graphs that are used to illustrate the results of an experiment which was conducted to show how the raw spectral data obtained from the optical reader system can be used to minimize angular dependent effects of the optical reader system in accordance with the present invention
- FIGS. 24-35 are graphs that are used to illustrate the results of an experiment which was conducted to further test the capabilities of the optical reader system to minimize angular and translational sensitivities when interrogating the resonant waveguide grating biosensor in accordance with the present invention.
- FIGS. 36-37 are graphs that are used to illustrate the results of an experiment which was conducted to test the 2-dimensional scan capabilities of the optical reader system in accordance with the present invention.
- the optical reader system 100 is preferably used to interrogate a biosensor 102 (e.g., resonant waveguide grating (RWG) biosensor 102 , a surface plasmon resonance (SPR) biosensor 102 ) to determine if a biomolecular binding event occurred on the biosensor 102 .
- a biosensor 102 e.g., resonant waveguide grating (RWG) biosensor 102 , a surface plasmon resonance (SPR) biosensor 102
- RWG resonant waveguide grating
- SPR surface plasmon resonance
- the optical reader system 100 includes a light source 106 (e.g., lamp, laser, diode) that outputs (step 102 b ) an optical beam 104 which is scanned (step 104 b ) across the biosensor 102 .
- a light source 106 e.g., lamp, laser, diode
- step 104 b an optical beam 104 which is scanned across the biosensor 102 .
- the biosensor 102 is moved so the optical beam 104 can be scanned across the biosensor 102 .
- the optical beam 104 itself may be scanned with a mirror, galvanometer, electro-optic or acousto-optic scanner or other suitable adjustable optical element, across a stationary biosensor 102 .
- a detector 108 e.g., spectrometer, CCD camera or other optical detector collects (step 106 b ) an optical beam 112 which is reflected from the biosensor 102 .
- a processor 110 e.g., DSP 110 , computer 110 ) then processes (step 108 b ) the collected optical beam 112 to obtain and record (step 110 b ) raw spectral data 114 which is a function of a position (and possibly time) on the biosensor 102 . Thereafter, the processor 110 analyzes the raw spectral data 114 to create a spatial map of resonant wavelength (peak position) data which indicates if a biomolecular binding event occurred on the biosensor 102 .
- the computer 110 can analyze the raw spectral data 114 to perform a wide range of tasks in addition to detecting a biomolecular binding event on the biosensor 102 .
- the processor 110 can analyze the raw spectral data 114 to create a spatial map of reflected power that can be used to locate an edge of a grating in the biosensor 102 so that biosensor 102 can be properly re-located after being removed and reinserted into a path of the optical beam 104 .
- the processor 110 can analyze the raw spectral data 114 to create a spatial map of reflected power and reflected wavelength which can be used to evaluate the locations, quantities and sizes of defects on the biosensor 102 .
- the processor 110 can analyze the raw spectral data 114 to create a spatial map of reflected wavelength data that can be used to ameliorate undesirable effects on changes in measured wavelengths that arise from drifts of the detector 108 and other sources of error including waveguide coating drift, source spectra variations overtime, or bulk index error. More details about the optical reader system 100 and the uses of the raw spectral data 114 are described below after a brief description is provided about the structure of the biosensor 102 and about the different ways the biosensor 102 can be used to detect a biomolecular binding event.
- the biosensor 102 includes a thin ( ⁇ 100 nm) layer of material 116 (e.g., waveguide film 116 ) deposited on a substrate 118 either before or after the fabrication of a diffraction grating 120 which together form a waveguide 122 .
- the diffraction grating 120 is formed within the substrate 118 or waveguide film 116 by embossing, holography, or other methods. The diffraction grating 120 can thereby be located above, below, or even within the waveguide film 116 .
- the waveguide film 116 is preferably made of a metal-oxide based material such as Ta 2 O 5 , TiO 2 , TiO 2 ⁇ SiO 2 , HfO 2 , ZrO 2 , Al 2 O 3 , Si 3 N 4 , HfON, SiON, scandium oxides or mixtures thereof.
- the diffraction grating 120 was formed within a substrate 118 and then the thin waveguide film 116 having a higher refractive index was coated on top of the diffraction grating 120 .
- the biosensor 102 makes use of changes in the refractive index at the sensor surface that affect the waveguide coupling properties of the optical beam 104 emitted from the light source 106 and the optical beam 112 reflected back into the detector 108 to enable label-free detection of a biological substance 124 (e.g., cell, molecule, protein, drug, chemical compound, nucleic acid, peptide, carbohydrate) on the superstrate 103 (sensing region) of the biosensor 102 .
- a biological substance 124 e.g., cell, molecule, protein, drug, chemical compound, nucleic acid, peptide, carbohydrate
- the biological substance 124 may be located within a bulk fluid that is deposited on the superstrate 103 (sensing region) of the biosensor 102 and it is the presence of this biological substance 124 that alters the index of refraction at the surface 126 of the biosensor 102 .
- the biosensor 102 needs to be at least probed with an optical beam 104 and then a reflected optical beam 112 received at the detector 108 is analyzed to determine if there are any changes ( ⁇ 1 part per million) in the refractive index caused by the presence of the biological substance 124 .
- the top surface 126 may be coated with biochemical compounds (not shown) that only allow surface attachment of specific complementary biological substances 124 which enables a biosensor 102 to be created that is both highly sensitive and highly specific.
- biochemical compounds not shown
- the optical reader system 100 and biosensor 102 may be used to detect a wide variety of biological substances 124 .
- multiple biosensors 102 are arranged in array an like in a microplate then they may be used to enable high throughput drug or chemical screening studies (see FIG. 5 ).
- FIG. 5 A more detailed discussion about the structure of the preferred biosensor 102 is provided in the following documents:
- the sensitivity of the biosensor 102 may be best understood by analyzing the structure of the diffraction grating 120 and the waveguide 122 .
- the grating vector ⁇ is defined as a vector having a direction perpendicular to the lines of the diffraction grating 120 and a magnitude given by 2 ⁇ / ⁇ where ⁇ is the grating period (pitch) (see FIG. 1A ). This expression may also be written in terms of wavelength ⁇ and incident angle ⁇ as shown in equation no.
- n inc 2 ⁇ ⁇ ⁇ ⁇ n eff ⁇ - 2 ⁇ ⁇ ⁇ [ 2 ]
- ⁇ is the angle of incidence of the optical beam 104
- n inc is the index of refraction of the incident medium
- ⁇ is the wavelength of the optical beam 104
- n eff is the effective index of refraction of the waveguide 122 .
- the effective index of the waveguide 122 is a weighted average of the indices of refraction that the optical waveguide mode field “sees” as it propagates through the waveguide 122 .
- the optical waveguide mode preferably has a spatial extent that is much wider than the waveguide 122 itself, the extent depending on the refractive index of the substrate 118 .
- the optical waveguide mode has an evanescent wave/tail that extends into the superstrate 103 (sensing region) which “sees” any surface changes created when the biological substance 124 approaches or comes in contact with the top surface 126 of the biosensor 102 .
- n inc has been set to 1 so that it could be removed from this expression. This approximation is used since air (n ⁇ 1.0003) is the most common incident medium. This relation is pictured in the graph shown in FIG. 2 .
- the effective index of the waveguide 122 is altered which leads to the shifting the resonant wavelength or resonant angle of the biosensor 102 .
- This shifting can be seen as a shift of the x-intercept in the line shown in FIG. 2 .
- the resonant condition (e.g., resonant wavelength or resonant angle) of such a biosensor 102 may be interrogated to determine refractive index changes by observing the optical beam 112 reflected from the biosensor 102 (see FIG. 1A ).
- angular interrogation a nominally single wavelength optical beam 104 is focused to create a range of illumination angles and directed into the biosensor 102 .
- the reflected optical beam 112 is monitored with a CCD camera or other optical detector 108 .
- the angular interrogation concept is graphically represented in the graph shown in FIG. 3 .
- spectral interrogation a nominally collimated, broadband optical beam 104 is sent into the biosensor 102 and the reflected optical beam 112 is collected and monitored with a spectrometer 108 (for example).
- spectrometer 108 for example.
- the spectral interrogation concept is graphically represented in the graph shown in FIG. 4 .
- the focus of the description is on the method of spectral interrogation even though the present invention can utilize both interrogation methods.
- the spatially scanned optical reader system 100 is shown where an optical beam 104 strikes the biosensor 102 and the reflected optical beam 112 is collected and interrogated by the spectral method.
- the optical beam 104 is translated across the moving biosensor 102 , and spectral data 114 is recorded as a function of position on the biosensor 102 .
- the optical beam 104 may be swept in a line, raster scanned across two dimensions of the biosensor 102 , or made to move in an arbitrary pattern across the biosensor 102 .
- the raw spectral data 114 may also be obtained and recorded as a function of time by performing repetitive scans across the biosensor 102 .
- the raw spectral data 114 may be processed to produce a spatial map of resonant wavelength data (peak position) that indicates whether or not a biological binding event occurred on the biosensor 102 .
- the surface refractive index of the biosensor 102 can be spatially and temporally mapped.
- the optical beam 104 needs to be smaller than the biosensor 102 .
- a focusing optic may be needed to alter the shape and size of the optical beam 104 so that it is smaller than the biosensor 102 (see focusing lens 514 in FIG. 5 ).
- FIG. 5 there is shown a schematic of an embodiment of an optical reader system 100 ′ which is configured so it can interrogate multiple biosensors 102 that are located in a microplate 516 .
- a super-luminescent diode (SLD) 502 emits an optical beam 104 that is sent through a variable optical attenuator (VOA) 504 and a polarization scrambler 506 and is then split into 8 channels using a series of two splitters 508 and 510 .
- the optical beams 104 are then sent through eight fibers 512 and eight focusing lenses 514 which create a series of nominally 100 ⁇ m diameter optical beams 104 .
- VOA variable optical attenuator
- FIG. 6 shows a schematic of the optics used to create each interrogating beam 104 .
- the single mode fiber 512 and pigtailed lens 514 forms the nominally 100 ⁇ m diameter optical beam 104 on one of the RWG biosensors 102 .
- the reflected light 112 is collected by the same fiber 512 and lens 514 and passed back into the fiber splitters 510 and 508 and then routed to a series of eight spectrometers 108 which are read out by a processor 110 (see FIG. 5 ).
- a combination of a linear polarizer 602 and a quarter wave plate 604 can be placed near the end of the fiber 512 to reject Fresnel and other parasitic reflections while passing the resonantly reflected light 112 .
- the microplate 516 is moved across the optical reader system 100 ′ and the raw spectral data 114 in the reflected optical beam 112 is recorded as a function of plate (sensor) position.
- the raw spectral data 114 can be analyzed by the processor 110 to enable a wide range of tasks to be performed.
- the raw data 114 can be used to: (1) detect biomolecular binding event(s); (2) characterize the biosensor 102 ; (3) register the biosensor 102 ; and (4) mitigate optical system artifacts. Each of these tasks is described in greater detail below with respect to FIGS. 7-36 .
- the optical reader system 100 and 100 ′ can use a scanned optical beam 104 to interrogate one or more biosensors 104 has been described above with respect to FIGS. 1-6 .
- a problem that can affect the accuracy of any optical reader system occurs when there is a change in the resonant wavelength (or angle) which is caused by things like the environment rather than the specific binding event of interest.
- anything that changes the refractive index of the biosensor 102 may cause false or spurious signals.
- the things that can affect the biosensor 102 include temperature changes, the introduction of fluids with different bulk refractive indices, pressure changes and non-specific binding of molecules to the sensor's surface 126 .
- FIG. 7 shows an example of this type of biosensor 102 ′ where the reference (non-binding) region 702 is designed to respond to the same local environmental changes, but not to the biochemical binding event of interest that occurs in the sample (binding) region 704 . If the biosensor 102 ′ is designed so that the non-binding region 702 and binding region 704 are in close proximity to one another, then one may remove the environmental effects from the signal by subtracting the non-binding region's wavelength change from the binding region's wavelength change. However, this leads to the problem of how to interrogate the closely spaced non-binding region 702 and binding region 704 .
- optical reader system 100 and 100 ′ of the present invention where the optical beam 104 is scanned across both the non-binding and binding regions 702 and 704 as shown in FIG. 7 .
- the traditional optical reader systems would have difficulty in solving this problem since they do not use a scanned optical beam 104 .
- FIG. 8 is a graph that shows the results of an experiment in which the wavelengths of each half (left and right) of a RWG sensor 102 ′ were tracked as a function of time while the temperature of the well, containing water, was changed by adding hot water to the well.
- this experiment there was a ⁇ 5° C. temperature change upon the first addition of water, and a ⁇ 20° C. change on the second addition of water to the well.
- each half of the biosensor 102 ′ responded similarly to the temperature perturbation, so that, when subtracted, the effect of temperature is removed.
- FIG. 9 is a graph that shows the results of an experiment that is similar to the previous experiment except where the water was replaced by a solution of 0.5% glycerol.
- the refractive index of the solution changed because of the glycerol concentration, and each half of the biosensor 102 ′ exhibited a wavelength change.
- the wavelength changes of each half of the biosensor 102 ′ are subtracted it can be seen that the impact of the bulk refractive index change is removed.
- FIG. 10 is a graph that shows the results of an experiment where a RWG biosensor 102 ′ covered with water was monitored as a function of time by the optical reader system 100 ′.
- the graph shows the wavelengths of each of the halves of the biosensor 102 , and also shows the signal difference between each of those wavelengths. As can be seen, the slowly changing environmental effects are removed after the subtraction of the wavelengths associated with each half of the biosensor 102 .
- FIGS. 11-14 are used to show the results of experiments that were conducted using the optical reader system 100 ′ and well plates 516 containing 3 mm square RWG biosensors 102 ′ which were prepared by blocking half of the sensor surface with O,O′-Bis(2-aminopropyl)polyethyleneglycol 1900 (PEG).
- the blocking agent was applied using a pin-printer, and details on how this can be done are provided in the aforementioned U.S. patent application Ser. No. 11/027,509.
- the biosensor 102 ′ that was created was one where target molecules and subsequent analyte molecules would bind only to the unblocked portion (sample region 704 ).
- FIG. 11 is a graph that shows the results of an assay where streptavidin (SA) was immobilized on the binding region 704 of the biosensor 102 ′, and then a solution containing fluorescein-biotin was added to the wells.
- SA streptavidin
- the difference signal displays the binding process itself without showing many of the environmental drifts present in the signals from the reference region 702 and the binding region 704 .
- FIG. 12 is a graph that shows the results of an assay where several intra-well referenced biosensors 102 ′ were interrogated by the optical reader system 100 ′.
- biotin-labeled bovine serum albumin BSA
- SA streptavidin
- the response of the half blocked biosensor 102 ′ in the region without the PEG blocker was the same as the unblocked biosensor 102 ′.
- the blocked (non-binding) regions 702 of the half blocked biosensor 102 ′ did exhibit a small amount of wavelength change, which may be attributed to non-specific binding of the SA.
- this non-specific binding is nearly identical on both regions 702 and 704 of the half blocked biosensor 102 ′, and hence may be referenced out when the two signals are subtracted.
- FIG. 13 is a graph that shows the high spatial frequency patterning of non-binding and binding regions 702 and 704 of a biosensor 102 ′.
- the PEG blocking agent used created a sufficiently thick layer so as to cause a resonant wavelength shift of ⁇ 1 nm in the region 702 where it was present.
- the optical reader system 100 ′ produced transitions between blocked and unblocked regions 702 and 704 that were sharp and well defined, with each region being approximately 150 ⁇ m wide.
- FIG. 14 is a graph that shows the net wavelength change that occurred during the assay associated with FIG. 13 .
- the same reference regions 702 that were blocked exhibited little wavelength change, whereas the sample regions 704 that were unblocked exhibited binding signals.
- the use of such a high spatial frequency pattern can be used to reject any perturbations that vary rapidly as a function of position. These include effects such as large temperature gradients, sensitivity variations across the biosensor 102 ′, and binding variations across the biosensor 102 ′.
- FIGS. 15A and 15B are two diagrams that show different examples of patterning techniques that may be used on an intra-well referenced biosensor 102 ′. These patterning techniques may be employed with binding/non-binding areas only, or they may be employed in situations where different target molecules are immobilized in each distinct binding region 704 , which allows the multiplexing of assays with a single RWG biosensor 102 ′. This technique is described in more detail in a related U.S. patent application Ser. No. 11/027,509 entitled “Method for Creating a Reference Region and a Sample Region on a Biosensor and the Resulting Biosensor”.
- the optical reader system 100 can use a scanned optical beam 104 and the resulting raw spectral data 114 to perform a variety of tasks like create a spatial map of sensor resonant wavelength, reflectivity, peak width, local angle, wavelength interrogation slope (WIS), and other parameters.
- Some of these spatial maps can be used to characterize a biosensor 102 and 102 ′. For instance, an example of a spatial map of reflectivity that was obtained from a group of biosensors 102 using small optical beams 104 ( ⁇ 100 micron diameter) is shown in the graph of FIG. 16 .
- FIG. 17 is a graph that shows the resonant wavelength data from the same scan used in FIG. 16 .
- the optical reader system 100 can also use a scanned optical beam 104 and the resulting raw spectral data 114 to create a spatial map of reflected power that enables one to precisely locate the edge of the biosensor's gratings 120 (or similar fiducial markings).
- An advantage of knowing this information is that it enables one to properly re-locate or “register” a biosensor 102 after it is removed and reinserted into the optical path 104 . Such registration can be critical as the observed resonant wavelength can vary rapidly with position.
- the resonance wavelength is a function of the position of the interrogating beam 104 over the grating 120 . So, when the sensor plate 102 is removed from and re-inserted into the reader 100 , one can generate some measurement errors because the interrogation is at a slightly different area of the grating 120 . So, being able to register the position of the sensor 102 is an important aspect for high throughput readers 100 .
- a second problem associated with repositioning the sensor plate 102 is the angular dependence of the resonance wavelength.
- single mode fibers can be used which should, at first order, be angularly insensitive, some angular dependence can be observed which depends on the lens aberration and on the position of the beam over the grating 120 . So, to minimize this error contribution, the same lens should be used for interrogating both the reference and the measurement channels. Also, by scanning the sensor length, one can average the contribution associated with the sensor non-homogeneity so that one can get very repeatable angular sensitivity curves.
- FIG. 21 is a series of plots that show the results of an experiment where a 96 well microplate, with each well containing a RWG biosensor 102 , was scanned at a varying set of incident beam angles.
- Each plot shows a family of 12 curves that were associated with the 12 biosensors 102 of one row in the microplate 516 that were scanned at a variety of angles by the fibers/lens array 512 / 514 .
- the resonance wavelength was calculated as the average of the wavelength measured during the scan of every single sensor 102 .
- the plots clearly indicate that the wavelength change with angle is a function of the optic 514 used, which is common for all biosensors within a given row, and not the biosensor 102 being illuminated.
- the binding and reference regions 702 and 704 of a biosensor 102 ′ are illuminated with the same optic 514 , then they will see similar changes if the angle is altered.
- FIG. 22 is a graph that shows the results of an experiment where the average wavelength was tracked on each half of one RWG biosensor 102 as that biosensor 102 was tilted. Again, here, the wavelength was averaged over the scan. As can be seen, by subtracting the wavelength changes in each of the reference and binding regions 702 and 704 , the net change from angular tilts may be removed.
- FIG. 23 is a graph that shows the angular sensitivity (in pm/mRad) of this system when the binding and reference signals are subtracted. Angular tilts and misalignment can easily occur if a biosensor 102 ′ is removed and reinserted into the optical reader system 100 and 100 ′. As such, the mitigation of the impact of angular changes on RWG signal is important for an optical reader system.
- this experiment was performed to determine if there was an advantage of using small interrogating beam sizes and scanning methods to reduce the angular and lateral sensitivities of the measurements.
- FIG. 24 is a graph that shows the typical shape of the resonance wavelength that was measured across a 3 mm biosensor 102 with a 500 microns diameter interrogating beam 104 at normal incidence. Each of the curves corresponds to a different angular misalignment. The “solid line” curves are for positive angles while the “dashed line” curves are for negative angles. It can be observed from this graph that the angular dependence of the wavelength was a function of the position across the biosensor 102 . In this case, for instance, the d ⁇ /d ⁇ was very small around the middle of the biosensor 102 and was much bigger everywhere else.
- the curve 2502 indicates the average sensitivity across the biosensor 102 .
- the curves 2504 and 2506 respectively indicate the MAX and MIN sensitivities across the biosensor 102 .
- d ⁇ /d ⁇ At the “measurement” location and at the “reference” location of a sensor. Sometimes, one may be lucky and d ⁇ /d ⁇ may be equal at both spatial locations but this is not guaranteed. The worst case corresponds to the case where d ⁇ /d ⁇ is maximum for one and minimum for the other. So, although the average d ⁇ /d ⁇ is close to 15 pm/mRd, the impact on the measurement accuracy might be up to 100 pm/mRd at 0 mRd incidence. Moreover, although the average curve appears to be quite repeatable from one biosensor 102 to another one, the MAX and MIN values can significantly change making the results even worse.
- the angular sensitivity remained relatively constant over a range of +/ ⁇ 1 mRd. And, the average sensitivity around normal incidence was around 7 pm/mRd and, in the worst case, the measurement sensitivity in static conditions to angular misalignments was around 30 pm/mRd.
- An advantage of scanning the biosensor 102 is that, by averaging the data over large areas, all variations that have spatial periods less than the scanning range can be averaged. So, the problem of the difference between d ⁇ /d ⁇ at the reference position and at the measurement position drastically decrease.
- FIG. 28 is a graph that shows the evolution of resonances calculated as the spatial average over the first half (PAD 1 ) and the second half (PAD 2 ) of the biosensor 102 . All measurements were obtained using 3 mm long biosensors 102 . As can be seen, both signals have some angular dependence. However, both curves are very similar which means that there is likely to be some kind of systematic angular variations associated with the aberrations of the fibers to sensor imaging lens.
- FIG. 29 is a graph that shows a global measurement angular sensitivity curve which was obtained after subtracting the signals associated with PAD 1 and PAD 2 . As can be seen, the angular sensitivity that is below 1 pm/mRd over an angular range of +/ ⁇ 2 mRd.
- the problem with this case is that the period of the variations are of the same order of magnitude than the length of the scan so that the impact of averaging over half of the biosensor 102 does not work as well as in the previous case as can be seen in FIG. 30 .
- FIG. 31 shows the d ⁇ /dx that was measured at normal incidence as a function of the angular misalignment of the microplate 516 .
- FIG. 32 represents the same data measured with a beam size of 500 microns. As can be seen, the sensitivities were lower by a factor of approximately 2 with an average of 0.2 pm/microns and a worst case of around 1 pm/micron.
- FIG. 33 is a graph which shows the resonance as a function of a scan position that was measured with a 115 microns spot size.
- the collimator focusing optic
- the different curves correspond to the curves when translating the collimator by 2.5 microns in a direction perpendicular to the scanning. As can be seen, even though the curves have the same shape, the translation over a 25 microns full range, quantitatively impacts the measurement result.
- FIGS. 36 and 37 contain 2D images from this experiment, obtained for reflected power and reflected wavelength, respectively. It should be noted how the 2D scan adds clarity to how a “picture” can be assembled, and to how binding and non-binding regions 702 and 704 may be identified on a biosensor 102 ′.
Abstract
An optical reader system is described herein that uses a scanned optical beam to interrogate a biosensor to determine if a biomolecular binding event occurred on a surface of the biosensor. In one embodiment, the optical reader system includes a light source, a detector and a processor (e.g., computer, DSP). The light source outputs an optical beam which is scanned across a moving biosensor and while this is happening the detector collects the optical beam which is reflected from the biosensor. The computer processes the collected optical beam and records the resulting raw spectral or angle data which is a function of a position (and possibly time) on the biosensor. The processor can then analyze the raw data to create a spatial map of resonant wavelength (peak position) or resonant angle which indicates whether or not a biomolecular binding event occurred on the biosensor. Several other uses of the raw data are also described herein.
Description
- This application is a divisional application of United States patent application Ser. No. 11/027,547, filed Dec. 29, 2004, now pending.
- This application is related to U.S. patent application Ser. No. 11/027,509 filed concurrently herewith and entitled “Method for Creating a Reference Region and a Sample Region on a Biosensor and the Resulting Biosensor” the contents of which are hereby incorporated by reference herein.
- 1. Field of the Invention
- The present invention relates to an optical reader system that uses a scanned optical beam to interrogate one or more biosensors. In one embodiment, the biosensors are incorporated within the wells of a microplate.
- 2. Description of Related Art
- Manufacturers of optical reader systems are always trying to design a new and improved optical reader system that can be used to interrogate a resonant waveguide grating biosensor to determine if a biomolecular binding event (e.g., binding of a drug to a protein) occurred on a surface of the biosensor. One such new and improved optical reader system is the subject of the present invention.
- The present invention includes an optical reader system that uses a scanned optical beam to interrogate a resonant waveguide grating biosensor to determine if a biomolecular binding event occurred on a surface of the biosensor. In one embodiment, the optical reader system includes a light source, a detector and a processor (e.g., computer, DSP). The light source outputs an optical beam which is scanned across a moving biosensor and while this is happening the detector collects the optical beam which is reflected from the biosensor. The computer processes the collected optical beam and records the resulting raw spectral or angle data which is a function of a position (and possibly time) on the biosensor. The processor can then analyze the raw data to create a spatial map of resonant wavelength (peak position) or resonant angle which indicates whether or not a biomolecular binding event occurred on the biosensor. Several other uses of the raw data are also described herein.
- A more complete understanding of the present invention may be had by reference to the following detailed description when taken in conjunction with the accompanying drawings wherein:
-
FIGS. 1A and 1B respectively illustrate a block diagram of the optical reader system and a flowchart of the method for using the optical reader system in accordance with one embodiment of the present invention; -
FIGS. 2-4 are graphs used to help describe how the resonant waveguide grating biosensor can be interrogated by the optical reader system in order to determine whether or not a biomolecular binding event occurred on the biosensor; -
FIGS. 5 and 6 are block diagrams used to describe how the optical reader system can be configured so it can interrogate multiple biosensors that are located in a microplate in accordance with another embodiment of the present invention; -
FIGS. 7-15 are graphs and diagrams that are used to illustrate the results of several experiments which where conducted to show how the raw spectral data obtained from the optical reader system can be used to detect a biomolecular binding event in accordance with the present invention; -
FIGS. 16-17 are graphs that are used to illustrate the results of an experiment which was conducted to show how the raw spectral data obtained from the optical reader system can be used to characterize a biosensor in accordance with the present invention; -
FIGS. 18-20 are graphs and diagrams that are used to illustrate the results of an experiment which was conducted to show how the raw spectral data obtained from the optical reader system can be used to register the position of a biosensor in accordance with the present invention; -
FIGS. 21-23 are graphs that are used to illustrate the results of an experiment which was conducted to show how the raw spectral data obtained from the optical reader system can be used to minimize angular dependent effects of the optical reader system in accordance with the present invention; -
FIGS. 24-35 are graphs that are used to illustrate the results of an experiment which was conducted to further test the capabilities of the optical reader system to minimize angular and translational sensitivities when interrogating the resonant waveguide grating biosensor in accordance with the present invention; and -
FIGS. 36-37 are graphs that are used to illustrate the results of an experiment which was conducted to test the 2-dimensional scan capabilities of the optical reader system in accordance with the present invention. - Referring to
FIGS. 1-37 , there are disclosed several diagrams, photos and graphs which are used to help describe theoptical reader system 100 and method 100 b of the present invention. As shown inFIGS. 1A and 1B , theoptical reader system 100 is preferably used to interrogate a biosensor 102 (e.g., resonant waveguide grating (RWG)biosensor 102, a surface plasmon resonance (SPR) biosensor 102) to determine if a biomolecular binding event occurred on thebiosensor 102. Theoptical reader system 100 includes a light source 106 (e.g., lamp, laser, diode) that outputs (step 102 b) anoptical beam 104 which is scanned (step 104 b) across thebiosensor 102. Typically, thebiosensor 102 is moved so theoptical beam 104 can be scanned across thebiosensor 102. Alternatively, theoptical beam 104 itself may be scanned with a mirror, galvanometer, electro-optic or acousto-optic scanner or other suitable adjustable optical element, across astationary biosensor 102. While theoptical beam 104 is scanned across thebiosensor 102, a detector 108 (e.g., spectrometer, CCD camera or other optical detector) collects (step 106 b) anoptical beam 112 which is reflected from thebiosensor 102. A processor 110 (e.g., DSP 110, computer 110) then processes (step 108 b) the collectedoptical beam 112 to obtain and record (step 110 b) rawspectral data 114 which is a function of a position (and possibly time) on thebiosensor 102. Thereafter, theprocessor 110 analyzes the rawspectral data 114 to create a spatial map of resonant wavelength (peak position) data which indicates if a biomolecular binding event occurred on thebiosensor 102. - In other aspects of the present invention, the
computer 110 can analyze the rawspectral data 114 to perform a wide range of tasks in addition to detecting a biomolecular binding event on thebiosensor 102. For instance, theprocessor 110 can analyze the rawspectral data 114 to create a spatial map of reflected power that can be used to locate an edge of a grating in thebiosensor 102 so thatbiosensor 102 can be properly re-located after being removed and reinserted into a path of theoptical beam 104. And, theprocessor 110 can analyze the rawspectral data 114 to create a spatial map of reflected power and reflected wavelength which can be used to evaluate the locations, quantities and sizes of defects on thebiosensor 102. Moreover, theprocessor 110 can analyze the rawspectral data 114 to create a spatial map of reflected wavelength data that can be used to ameliorate undesirable effects on changes in measured wavelengths that arise from drifts of thedetector 108 and other sources of error including waveguide coating drift, source spectra variations overtime, or bulk index error. More details about theoptical reader system 100 and the uses of the rawspectral data 114 are described below after a brief description is provided about the structure of thebiosensor 102 and about the different ways thebiosensor 102 can be used to detect a biomolecular binding event. - As shown in
FIG. 1A , thebiosensor 102 includes a thin (˜100 nm) layer of material 116 (e.g., waveguide film 116) deposited on asubstrate 118 either before or after the fabrication of a diffraction grating 120 which together form awaveguide 122. The diffraction grating 120 is formed within thesubstrate 118 orwaveguide film 116 by embossing, holography, or other methods. The diffraction grating 120 can thereby be located above, below, or even within thewaveguide film 116. Thewaveguide film 116 is preferably made of a metal-oxide based material such as Ta2O5, TiO2, TiO2−SiO2, HfO2, ZrO2, Al2O3, Si3N4, HfON, SiON, scandium oxides or mixtures thereof. As shown, the diffraction grating 120 was formed within asubstrate 118 and then thethin waveguide film 116 having a higher refractive index was coated on top of the diffraction grating 120. - The
biosensor 102 makes use of changes in the refractive index at the sensor surface that affect the waveguide coupling properties of theoptical beam 104 emitted from thelight source 106 and theoptical beam 112 reflected back into thedetector 108 to enable label-free detection of a biological substance 124 (e.g., cell, molecule, protein, drug, chemical compound, nucleic acid, peptide, carbohydrate) on the superstrate 103 (sensing region) of thebiosensor 102. Thebiological substance 124 may be located within a bulk fluid that is deposited on the superstrate 103 (sensing region) of thebiosensor 102 and it is the presence of thisbiological substance 124 that alters the index of refraction at thesurface 126 of thebiosensor 102. Thus, to detect thebiological substance 124, thebiosensor 102 needs to be at least probed with anoptical beam 104 and then a reflectedoptical beam 112 received at thedetector 108 is analyzed to determine if there are any changes (˜1 part per million) in the refractive index caused by the presence of thebiological substance 124. In one embodiment, thetop surface 126 may be coated with biochemical compounds (not shown) that only allow surface attachment of specific complementarybiological substances 124 which enables abiosensor 102 to be created that is both highly sensitive and highly specific. In this way, theoptical reader system 100 andbiosensor 102 may be used to detect a wide variety ofbiological substances 124. And, ifmultiple biosensors 102 are arranged in array an like in a microplate then they may be used to enable high throughput drug or chemical screening studies (seeFIG. 5 ). A more detailed discussion about the structure of thepreferred biosensor 102 is provided in the following documents: -
- U.S. Pat. No. 4,815,843 entitled “Optical Sensor for Selective Detection of Substances and/or for the Detection of Refractive Index Changes in Gaseous, Liquid, Solid and Porous Samples”.
- K. Tiefenthaler et al. “Integrated Optical Switches and Gas Sensors” Opt. Lett. 10, No. 4, April 1984, pp. 137-139.
The contents of these documents are incorporated by reference herein.
- The sensitivity of the
biosensor 102 may be best understood by analyzing the structure of thediffraction grating 120 and thewaveguide 122. Theoptical beam 104 shone on thediffraction grating 120 can only be coupled into thewaveguide 122 if its wave vector satisfies the following resonant condition as shown in equation no. 1:
k x ′=k x−κ [1]
where kx′ is the x-component of the incident wave vector, kx is the guided mode wave vector, and κ is the grating vector. The grating vector κ is defined as a vector having a direction perpendicular to the lines of thediffraction grating 120 and a magnitude given by 2π/Λ where Λ is the grating period (pitch) (seeFIG. 1A ). This expression may also be written in terms of wavelength λ and incident angle θ as shown in equation no. 2:
Where θ is the angle of incidence of theoptical beam 104, ninc is the index of refraction of the incident medium, λ is the wavelength of theoptical beam 104, and neff is the effective index of refraction of thewaveguide 122. The effective index of thewaveguide 122 is a weighted average of the indices of refraction that the optical waveguide mode field “sees” as it propagates through thewaveguide 122. The optical waveguide mode preferably has a spatial extent that is much wider than thewaveguide 122 itself, the extent depending on the refractive index of thesubstrate 118. In particular, the optical waveguide mode has an evanescent wave/tail that extends into the superstrate 103 (sensing region) which “sees” any surface changes created when thebiological substance 124 approaches or comes in contact with thetop surface 126 of thebiosensor 102. - The previous expression shown in equation no. 2 may be rewritten in the more convenient form shown in equation no. 3:
which is the equation of a line where sin θ being the y axis, λ being the x-axis, Λneff the x-intercept, and −1/Λ the slope. To obtain equation no. 3, ninc has been set to 1 so that it could be removed from this expression. This approximation is used since air (n˜1.0003) is the most common incident medium. This relation is pictured in the graph shown inFIG. 2 . When abiological substance 124 binds to thesurface 126, the effective index of thewaveguide 122 is altered which leads to the shifting the resonant wavelength or resonant angle of thebiosensor 102. This shifting can be seen as a shift of the x-intercept in the line shown inFIG. 2 . - The resonant condition (e.g., resonant wavelength or resonant angle) of such a
biosensor 102 may be interrogated to determine refractive index changes by observing theoptical beam 112 reflected from the biosensor 102 (seeFIG. 1A ). There are two different modes of operation for monitoring refractive index changes from such a resonant waveguide grating biosensor—angular interrogation or spectral interrogation. In angular interrogation, a nominally single wavelengthoptical beam 104 is focused to create a range of illumination angles and directed into thebiosensor 102. The reflectedoptical beam 112 is monitored with a CCD camera or otheroptical detector 108. By monitoring the position of the resonant angle reflected by thebiosensor 102, one can monitor binding or refractive index changes on or near thesurface 126 of thebiosensor 102. The angular interrogation concept is graphically represented in the graph shown inFIG. 3 . In spectral interrogation, a nominally collimated, broadbandoptical beam 104 is sent into thebiosensor 102 and the reflectedoptical beam 112 is collected and monitored with a spectrometer 108 (for example). By observing the spectral location of the resonant wavelength (peak), one can monitor binding or refractive index changes on or near thesurface 126 of thebiosensor 102. The spectral interrogation concept is graphically represented in the graph shown inFIG. 4 . In the present invention, the focus of the description is on the method of spectral interrogation even though the present invention can utilize both interrogation methods. - Referring again to
FIG. 1A , the spatially scannedoptical reader system 100 is shown where anoptical beam 104 strikes thebiosensor 102 and the reflectedoptical beam 112 is collected and interrogated by the spectral method. As can be seen, theoptical beam 104 is translated across the movingbiosensor 102, andspectral data 114 is recorded as a function of position on thebiosensor 102. Theoptical beam 104 may be swept in a line, raster scanned across two dimensions of thebiosensor 102, or made to move in an arbitrary pattern across thebiosensor 102. The rawspectral data 114 may also be obtained and recorded as a function of time by performing repetitive scans across thebiosensor 102. Once the rawspectral data 114 is obtained as a function of position and possibly time, it may be processed to produce a spatial map of resonant wavelength data (peak position) that indicates whether or not a biological binding event occurred on thebiosensor 102. In this way, the surface refractive index of thebiosensor 102 can be spatially and temporally mapped. Of course, for this to work theoptical beam 104 needs to be smaller than thebiosensor 102. As such, a focusing optic may be needed to alter the shape and size of theoptical beam 104 so that it is smaller than the biosensor 102 (see focusinglens 514 inFIG. 5 ). - Referring to
FIG. 5 , there is shown a schematic of an embodiment of anoptical reader system 100′ which is configured so it can interrogatemultiple biosensors 102 that are located in amicroplate 516. As shown, a super-luminescent diode (SLD) 502 emits anoptical beam 104 that is sent through a variable optical attenuator (VOA) 504 and a polarization scrambler 506 and is then split into 8 channels using a series of twosplitters optical beams 104 are then sent through eightfibers 512 and eight focusinglenses 514 which create a series of nominally 100 μm diameteroptical beams 104. These spots illuminate from below one column (8 wells) of amicroplate 516 where each well contains an ˜3 mmsquare RWG biosensor 102.FIG. 6 shows a schematic of the optics used to create each interrogatingbeam 104. As can be seen, thesingle mode fiber 512 andpigtailed lens 514 forms the nominally 100 μm diameteroptical beam 104 on one of theRWG biosensors 102. The reflectedlight 112 is collected by thesame fiber 512 andlens 514 and passed back into thefiber splitters spectrometers 108 which are read out by a processor 110 (seeFIG. 5 ). A combination of alinear polarizer 602 and aquarter wave plate 604 can be placed near the end of thefiber 512 to reject Fresnel and other parasitic reflections while passing the resonantly reflected light 112. As shown, themicroplate 516 is moved across theoptical reader system 100′ and the rawspectral data 114 in the reflectedoptical beam 112 is recorded as a function of plate (sensor) position. - As mentioned above, the raw
spectral data 114 can be analyzed by theprocessor 110 to enable a wide range of tasks to be performed. For instance, theraw data 114 can be used to: (1) detect biomolecular binding event(s); (2) characterize thebiosensor 102; (3) register thebiosensor 102; and (4) mitigate optical system artifacts. Each of these tasks is described in greater detail below with respect toFIGS. 7-36 . - Detect Biomolecular Binding Event(s)
- How the
optical reader system optical beam 104 to interrogate one ormore biosensors 104 has been described above with respect toFIGS. 1-6 . However, a problem that can affect the accuracy of any optical reader system occurs when there is a change in the resonant wavelength (or angle) which is caused by things like the environment rather than the specific binding event of interest. In short, anything that changes the refractive index of thebiosensor 102 may cause false or spurious signals. For example, the things that can affect thebiosensor 102 include temperature changes, the introduction of fluids with different bulk refractive indices, pressure changes and non-specific binding of molecules to the sensor'ssurface 126. To combat this problem, optical reader systems have made use of a “reference” biosensor and a “sample” biosensor, where the reference biosensor is exposed to similar environmental conditions and fluids as the sample biosensor, but whose surface is prepared such that no biochemical binding takes place. Reference is made to the following documents for a more detailed discussion about how two biosensors have been used in attempt to solve this problem: -
- J. Dubendorfer et al. “Sensing and Reference Pads for Integrated Optical Immunosensors” J. Biom. Optics, 2(4), 391-400 (October 1997).
- M. Wiki et al. “Wavelength-Interrogated Optical Sensor for Biochemical Applications,” Optics Letters 25, No. 7, 463-465 (2000).
- K. Cottier et al. “Label-Free Highly Sensitive Detection of (Small) Molecules by Wavelength Interrogation of Integrated Optical Chips” Sensors and Actuators B 91 (2003) 241-251.
- K. Tiefenthaler et al. “Sensitivity of Grating Couplers as Integrated-Optical Chemical Sensors” J. Opt. Soc.
Am. B 6, No. 2, February 1989, pp. 209-220. - W. Lukosz et al. “Integrated Optical Chemical and Direct Biochemical Sensors” Sensors and Actuators B 29, 1995, pp. 37-50.
- M. Wiki et al. “Novel Integrated Optical Sensor Based on a Grating Coupler Triplet,” Biosensors and Bioelectronics 13 (1998) 1181-1185.
The contents of these documents are incorporated by reference herein.
- However such referencing techniques are imperfect, since any two
biosensors 102 may see different signals due to pipetting errors, temperature gradients, or other well-to-well (sensor-to-sensor) changes. An improved strategy has been developed in which a sample (binding) region and reference (non-binding) region are formed on thesame biosensor 102. How this can be done was described in detail in a related U.S. patent application Ser. No. 11/027,509 entitled “Method for Creating a Reference Region and a Sample Region on a Biosensor and the Resulting Biosensor”. -
FIG. 7 shows an example of this type ofbiosensor 102′ where the reference (non-binding)region 702 is designed to respond to the same local environmental changes, but not to the biochemical binding event of interest that occurs in the sample (binding)region 704. If thebiosensor 102′ is designed so that thenon-binding region 702 andbinding region 704 are in close proximity to one another, then one may remove the environmental effects from the signal by subtracting the non-binding region's wavelength change from the binding region's wavelength change. However, this leads to the problem of how to interrogate the closely spacednon-binding region 702 andbinding region 704. This problem can be solved with theoptical reader system optical beam 104 is scanned across both the non-binding andbinding regions FIG. 7 . The traditional optical reader systems would have difficulty in solving this problem since they do not use a scannedoptical beam 104. - Following are descriptions about the results of several experiments that were conducted to show how one can better detect a biomolecular binding event in the presence of undesired environmental noise using the
optical reader system 100′ andmicroplate 516 shown inFIGS. 5 and 6 and thebiosensor 102′ shown inFIG. 7 . -
FIG. 8 is a graph that shows the results of an experiment in which the wavelengths of each half (left and right) of aRWG sensor 102′ were tracked as a function of time while the temperature of the well, containing water, was changed by adding hot water to the well. In this experiment, there was a ˜5° C. temperature change upon the first addition of water, and a ˜20° C. change on the second addition of water to the well. As can be seen, each half of thebiosensor 102′ responded similarly to the temperature perturbation, so that, when subtracted, the effect of temperature is removed. -
FIG. 9 is a graph that shows the results of an experiment that is similar to the previous experiment except where the water was replaced by a solution of 0.5% glycerol. Here the refractive index of the solution changed because of the glycerol concentration, and each half of thebiosensor 102′ exhibited a wavelength change. However, once again when the wavelength changes of each half of thebiosensor 102′ are subtracted it can be seen that the impact of the bulk refractive index change is removed. -
FIG. 10 is a graph that shows the results of an experiment where aRWG biosensor 102′ covered with water was monitored as a function of time by theoptical reader system 100′. The graph shows the wavelengths of each of the halves of thebiosensor 102, and also shows the signal difference between each of those wavelengths. As can be seen, the slowly changing environmental effects are removed after the subtraction of the wavelengths associated with each half of thebiosensor 102. -
FIGS. 11-14 are used to show the results of experiments that were conducted using theoptical reader system 100′ andwell plates 516 containing 3 mmsquare RWG biosensors 102′ which were prepared by blocking half of the sensor surface with O,O′-Bis(2-aminopropyl)polyethyleneglycol 1900 (PEG). The blocking agent was applied using a pin-printer, and details on how this can be done are provided in the aforementioned U.S. patent application Ser. No. 11/027,509. Thebiosensor 102′ that was created was one where target molecules and subsequent analyte molecules would bind only to the unblocked portion (sample region 704). -
FIG. 11 is a graph that shows the results of an assay where streptavidin (SA) was immobilized on thebinding region 704 of thebiosensor 102′, and then a solution containing fluorescein-biotin was added to the wells. As can be seen, the difference signal displays the binding process itself without showing many of the environmental drifts present in the signals from thereference region 702 and thebinding region 704. -
FIG. 12 is a graph that shows the results of an assay where several intra-well referencedbiosensors 102′ were interrogated by theoptical reader system 100′. In this assay, biotin-labeled bovine serum albumin (BSA) was immobilized on some but not all of the bindingregions 704 of thebiosensors 102′. A solution of streptavidin (SA) was introduced into each well and the amount of wavelength shift during this binding assay was recorded as a function of position across the sensor. InFIG. 12 , one trace shows abiosensor 102′ with no blocking agent, another trace shows abiosensor 102′ that was entirely blocked, and the third trace shows abiosensor 102′ that was half blocked. As can be seen, the response of the half blockedbiosensor 102′ in the region without the PEG blocker was the same as theunblocked biosensor 102′. The blocked (non-binding)regions 702 of the half blockedbiosensor 102′ did exhibit a small amount of wavelength change, which may be attributed to non-specific binding of the SA. However, this non-specific binding is nearly identical on bothregions biosensor 102′, and hence may be referenced out when the two signals are subtracted. -
FIG. 13 is a graph that shows the high spatial frequency patterning of non-binding andbinding regions biosensor 102′. The PEG blocking agent used created a sufficiently thick layer so as to cause a resonant wavelength shift of ˜1 nm in theregion 702 where it was present. Theoptical reader system 100′ produced transitions between blocked and unblockedregions -
FIG. 14 is a graph that shows the net wavelength change that occurred during the assay associated withFIG. 13 . As can be seen, thesame reference regions 702 that were blocked exhibited little wavelength change, whereas thesample regions 704 that were unblocked exhibited binding signals. The use of such a high spatial frequency pattern can be used to reject any perturbations that vary rapidly as a function of position. These include effects such as large temperature gradients, sensitivity variations across thebiosensor 102′, and binding variations across thebiosensor 102′. -
FIGS. 15A and 15B are two diagrams that show different examples of patterning techniques that may be used on an intra-well referencedbiosensor 102′. These patterning techniques may be employed with binding/non-binding areas only, or they may be employed in situations where different target molecules are immobilized in each distinctbinding region 704, which allows the multiplexing of assays with asingle RWG biosensor 102′. This technique is described in more detail in a related U.S. patent application Ser. No. 11/027,509 entitled “Method for Creating a Reference Region and a Sample Region on a Biosensor and the Resulting Biosensor”. - Characterization of
Biosensor 102 - As briefly mentioned above, the
optical reader system 100 can use a scannedoptical beam 104 and the resulting rawspectral data 114 to perform a variety of tasks like create a spatial map of sensor resonant wavelength, reflectivity, peak width, local angle, wavelength interrogation slope (WIS), and other parameters. Some of these spatial maps can be used to characterize abiosensor biosensors 102 using small optical beams 104 (˜100 micron diameter) is shown in the graph ofFIG. 16 . And,FIG. 17 is a graph that shows the resonant wavelength data from the same scan used inFIG. 16 . In these graphs, it can be seen how reflectivity and wavelength varies as a function of position, and one may use this data to characterize thebiosensor 102′ by evaluating the coating uniformity, the locations, the quantities and sizes of defects. This spatial information can also be used to exclude regions with obvious defects from use in calculations. In addition, one may use this scanned data and take the average of the wavelength across specified regions of abiosensor 102 to reduce or ameliorate the effects of spatial non-uniformities. - Register the
Biosensor 102 - The
optical reader system 100 can also use a scannedoptical beam 104 and the resulting rawspectral data 114 to create a spatial map of reflected power that enables one to precisely locate the edge of the biosensor's gratings 120 (or similar fiducial markings). One can obtain this information by taking the derivative of the power vs. position data and then using the minimum and maximum derivative values to locate the edges of thebiosensor 102 as is shown in the graph illustrated inFIG. 18 . An advantage of knowing this information is that it enables one to properly re-locate or “register” abiosensor 102 after it is removed and reinserted into theoptical path 104. Such registration can be critical as the observed resonant wavelength can vary rapidly with position. In addition this is important because the resonance wavelength is a function of the position of the interrogatingbeam 104 over thegrating 120. So, when thesensor plate 102 is removed from and re-inserted into thereader 100, one can generate some measurement errors because the interrogation is at a slightly different area of thegrating 120. So, being able to register the position of thesensor 102 is an important aspect forhigh throughput readers 100. - The results of several experiments where the edges of biosensor's
gratings 120 were located from such power vs. position data are shown in the graph ofFIG. 19 . This edge detection technique can be used to register the position of eachbiosensor 102 to <1 μm. In an alternative embodiment, one may also use specifically designed fiducial markings to refine this registration technique. An example of such a design is shown inFIG. 20 where adiagonal cut 2000 was made across thebiosensor 102. Thediagonal cut 2000 allows one to estimate both the x and y location of thebiosensor 102 with a 1-dimensional beam scan. The rising edge of a power vs. position trace is used to determine the x-position and the difference between the rising and falling edges is used to determine the y-position. - Mitigate Optical System Effects
- A second problem associated with repositioning the
sensor plate 102 is the angular dependence of the resonance wavelength. Although single mode fibers can be used which should, at first order, be angularly insensitive, some angular dependence can be observed which depends on the lens aberration and on the position of the beam over thegrating 120. So, to minimize this error contribution, the same lens should be used for interrogating both the reference and the measurement channels. Also, by scanning the sensor length, one can average the contribution associated with the sensor non-homogeneity so that one can get very repeatable angular sensitivity curves. -
FIG. 21 is a series of plots that show the results of an experiment where a 96 well microplate, with each well containing aRWG biosensor 102, was scanned at a varying set of incident beam angles. Each plot shows a family of 12 curves that were associated with the 12biosensors 102 of one row in themicroplate 516 that were scanned at a variety of angles by the fibers/lens array 512/514. For each curve, the resonance wavelength was calculated as the average of the wavelength measured during the scan of everysingle sensor 102. As can be seen, the plots clearly indicate that the wavelength change with angle is a function of the optic 514 used, which is common for all biosensors within a given row, and not thebiosensor 102 being illuminated. Thus, if the binding andreference regions biosensor 102′ are illuminated with thesame optic 514, then they will see similar changes if the angle is altered. -
FIG. 22 is a graph that shows the results of an experiment where the average wavelength was tracked on each half of oneRWG biosensor 102 as thatbiosensor 102 was tilted. Again, here, the wavelength was averaged over the scan. As can be seen, by subtracting the wavelength changes in each of the reference andbinding regions -
FIG. 23 is a graph that shows the angular sensitivity (in pm/mRad) of this system when the binding and reference signals are subtracted. Angular tilts and misalignment can easily occur if abiosensor 102′ is removed and reinserted into theoptical reader system - Additional Experiment
- Following is a description about another experiment that was performed to evaluate the capabilities of the scanned
optical reader system 100. Basically, this experiment was performed to determine if there was an advantage of using small interrogating beam sizes and scanning methods to reduce the angular and lateral sensitivities of the measurements. - Two different instrument configurations were analyzed and are referred hereinafter as static configuration and dynamic configuration. In the static configuration, the reference and the measurement areas of the
same biosensor 102 were sequentially interrogated by an optical reader system that did not scan theoptical beam 104 across thebiosensor 102. And, in the dynamic configuration, the reference and the measurement areas of thesame biosensor 102 were interrogated by anoptical reader system 100 that continuously scanned anoptical beam 104 over grating sub-areas called “pads” on thebiosensors 102. In the dynamic condition, the resonance wavelength is calculated as the average over the ‘pad’ length. Thebiosensors 102 in this experiment used a waveguide made from Nb2O5. - 1. Angular Sensitivity in Static Conditions
- 1.1 Large Beam Diameter & Normal Incidence
-
FIG. 24 is a graph that shows the typical shape of the resonance wavelength that was measured across a 3mm biosensor 102 with a 500 micronsdiameter interrogating beam 104 at normal incidence. Each of the curves corresponds to a different angular misalignment. The “solid line” curves are for positive angles while the “dashed line” curves are for negative angles. It can be observed from this graph that the angular dependence of the wavelength was a function of the position across thebiosensor 102. In this case, for instance, the dλ/dθ was very small around the middle of thebiosensor 102 and was much bigger everywhere else. From this data, one can calculate the angular sensitivity expressed in pm/mRd as a function of the position across thebiosensor 102 as shown inFIG. 25 . In this graph, thecurve 2502 indicates the average sensitivity across thebiosensor 102. And, thecurves biosensor 102. - To calculate the impact of an angular misalignment upon the measurement, one must determine dλ/dθ at the “measurement” location and at the “reference” location of a sensor. Sometimes, one may be lucky and dλ/dθ may be equal at both spatial locations but this is not guaranteed. The worst case corresponds to the case where dλ/dθ is maximum for one and minimum for the other. So, although the average dλ/dθ is close to 15 pm/mRd, the impact on the measurement accuracy might be up to 100 pm/mRd at 0 mRd incidence. Moreover, although the average curve appears to be quite repeatable from one
biosensor 102 to another one, the MAX and MIN values can significantly change making the results even worse. - 1.2 Small Beam Diameter & Normal Incidence
- Next, a
smaller beam 104 was used where “small” means much smaller than the distance over which thebeam 104 is scanned. And, the following curves shown inFIG. 26 illustrate the resonance wavelength across thebiosensor 102. The “solid line” curves are the positive angles and the “dashed line” curves are the negative angles. Again, it can be seen in this graph that dλ/dθ is also dependent on the location where theoptical beam 104 hits thebiosensor 102. The major difference is that those variations happened at much higher spatial frequencies when compared toFIG. 24 . Then, as shown inFIG. 27 , the average 2702,MAX 2704 andMIN 2706 of the angular dependence over thebiosensor 102 can be calculated. As one can see, the angular sensitivity remained relatively constant over a range of +/−1 mRd. And, the average sensitivity around normal incidence was around 7 pm/mRd and, in the worst case, the measurement sensitivity in static conditions to angular misalignments was around 30 pm/mRd. - 2.0 Angular Sensitivity in Dynamic Conditions
- 2.1 Small Beam Diameter & Normal Incidence
- An advantage of scanning the
biosensor 102 is that, by averaging the data over large areas, all variations that have spatial periods less than the scanning range can be averaged. So, the problem of the difference between dλ/dθ at the reference position and at the measurement position drastically decrease. -
FIG. 28 is a graph that shows the evolution of resonances calculated as the spatial average over the first half (PAD1) and the second half (PAD2) of thebiosensor 102. All measurements were obtained using 3 mmlong biosensors 102. As can be seen, both signals have some angular dependence. However, both curves are very similar which means that there is likely to be some kind of systematic angular variations associated with the aberrations of the fibers to sensor imaging lens.FIG. 29 is a graph that shows a global measurement angular sensitivity curve which was obtained after subtracting the signals associated with PAD1 and PAD2. As can be seen, the angular sensitivity that is below 1 pm/mRd over an angular range of +/−2 mRd. - 2.2 Large Beam Diameter & Normal Incidence
- One can apply the same logic to the case of a 500 microns beam diameter. The problem with this case is that the period of the variations are of the same order of magnitude than the length of the scan so that the impact of averaging over half of the
biosensor 102 does not work as well as in the previous case as can be seen inFIG. 30 . - 3.0 Lateral Sensitivity in Static Conditions
- One can use the same curves as above to determine the sensitivity to lateral displacement. In this case, the angle was fixed and we calculated for each angle the amplitude of dλ/dx.
FIG. 31 shows the dλ/dx that was measured at normal incidence as a function of the angular misalignment of themicroplate 516. As can be seen, there is an average dλ/dx of around 0.4 pm/microns close to normal incidence and, in the worst case, the impact on the measurement accuracy was up to 2.4 pm/microns. These sensitivities remained relatively constant over an angular range of +/−1 mRd but became worst for higher misalignments. -
FIG. 32 represents the same data measured with a beam size of 500 microns. As can be seen, the sensitivities were lower by a factor of approximately 2 with an average of 0.2 pm/microns and a worst case of around 1 pm/micron. - 4. Lateral Sensitivity in Dynamic Conditions
- For angular sensitivity, the idea is that by integrating the signal over relatively large sub-areas (
PADS 1 & 2) of thebiosensor 102, one can then average the dλ/dθ.FIG. 33 is a graph which shows the resonance as a function of a scan position that was measured with a 115 microns spot size. During the measurement, the collimator (focusing optic) was intentionally misaligned by 2 mRd. The different curves correspond to the curves when translating the collimator by 2.5 microns in a direction perpendicular to the scanning. As can be seen, even though the curves have the same shape, the translation over a 25 microns full range, quantitatively impacts the measurement result. From these curves, we calculated the integral of the signal on PAD1 and PAD2 as a function of the lateral motion as shown inFIG. 34 . And, then by calculating the difference between PAD1 and PAD2, we determined the measurement lateral sensitivity as shown inFIG. 35 . In this case, the lateral sensitivities were in the range of 0.2 to 0.3 pm/micron which is much lower than one can get with static measurement methods. - 5. Conclusion
- In this experiment, the static configuration and the dynamic configuration were tested. And, for each of these configurations, two different beam sizes were investigated.
- In reviewing, the measurement angular sensitivity data it can be concluded the scanning approach with a small beam in accordance with the present invention resulted in an impressive improvement as can be seen in
TABLE # 1.TABLE # 1Angular sensitivities (pm/mRd) PHI = 115 microns PHI = 500 microns Static (worst case) 30 100 Scanning 1 22 - If the sensitivity to lateral translation is analyzed, then one can conclude that small beam/scanning also achieves better performance as shown in
TABLE # 2.TABLE # 2Lateral sensitivities (pm/microns) PHI = 115 microns PHI = 500 microns Static (worst case) 2.4 1 Scanning 0.3 Not measured
Additional 2-Dimensional Scan Experiment - It was briefly mentioned above how the
optical reader system 100 can be used to perform a 2-D scan of abiosensor 102. To prove the feasibility of this feature an experiment was performed in which theoptical reader system 100′ was in a 2-D scanning mode. In this mode, a linear scan was taken across a biosensor, themicroplate 516 was then stepped over by approximately one optical beam width in a direction perpendicular to the linear scan, and the linear scan was repeated, and so on.FIGS. 36 and 37 contain 2D images from this experiment, obtained for reflected power and reflected wavelength, respectively. It should be noted how the 2D scan adds clarity to how a “picture” can be assembled, and to how binding andnon-binding regions biosensor 102′. - Some additional features and advantages of using the scanned
optical reader system biosensor -
- 1) Scanning a small optical beam across a RWG biosensor allows one to spatially map the reflected power and wavelength (angle) of the sensor in order to better characterize the biosensor. This mapping allows one to find the location of the sensor very accurately, to create a map of sensor response as a function of position, to spatially average the response of the sensor, and to identify and exclude regions of the sensor which are deemed unacceptable.
- 2) The use of a scanned optical beam also allows one to easily interrogate signal and reference regions of a sensor. The use of signal and reference regions of a sensor, located in close proximity, can be used to remove undesired sensor related wavelength changes caused by thermal changes, bulk index of refraction changes, drift, and non-specific binding.
- 3) By scanning the same optical beam across the signal and reference regions of the biosensor, one can separate, via time, the optical signals from the signal and reference regions which may overlap significantly in wavelength. This allows one to utilize a single optical detector to detect both the binding and reference signals, which is not possible if the spectra of the binding and reference signals overlap and the binding and reference regions reflect identical polarization states.
- 4) A scanned optical beam allows one to eliminate a number of optical system related issues that may lead to false wavelength changes. By using the same optical path for interrogating both the signal and reference portions of a biosensor, the system can greatly reduce or cancel out changes in wavelength that arise from angular changes between the biosensor and optics. By using the edges of the sensor or built in fiducial markings on the sensor plate, the scanned optical system can measure the absolute translational position of a biosensor to high accuracy, and hence correct for movements of the plate which can alter wavelength. Additionally, one can greatly reduce or eliminate changes in perceived wavelength that arise from changes in the optical path or drifts of the detector, since the signal and reference share a common path and detector.
- 5) A scanned optical beam may be used to interrogate a patterned array of multiple biochemical targets placed on the same grating, enabling multiplexing of assays using a single RWG biosensor. The use of optical beam scanning allows the different target signals to be separated in time and correlated with a specific position on the biosensor.
- 6) The architecture of the optical reading system can be used even if the wavelengths and polarizations of the binding and reference regions are not precisely controlled, or even if the wavelengths are identical. This scanning technique also has additional benefits of being able to remove false wavelength changes that may arise from the biosensor being physically displaced or altered in its angular orientation, and other undesired wavelength changes that may derive from drift of the optical detector itself.
- 7) In the present invention the spectra collection can be precisely timed based on the position of the scanner. This enables one to collect spectra while moving without requiring an ultra stable scan velocity. Also, one can utilize the amount of time between spectra collections in the algorithm to reject the “velocity jitter” of the scanning stage.
- It should be noted that in most of the drawings herein, were made based on the assumption that the sensor is spectrally interrogated. This means that the sensor is interrogated at a fixed incidence angle with a broad spectral source and that the wavelength is detected in the reflected beam. The source is then a broad spectral source and the detector is a wavelength sensitive detector such as a spectrometer. However, it should be appreciated that the principle of the present invention can also be extended to an angular interrogation approach where the sensor is interrogated with monochromatic light and then a resonant angle is detected in the reflected beam.
- Although multiple embodiments of the present invention have been illustrated in the accompanying Drawings and described in the foregoing Detailed Description, it should be understood that the invention is not limited to the embodiments disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the spirit of the invention as set forth and defined by the following claims.
Claims (20)
1. A method for using an optical reader system, said method comprising the steps of:
generating a first optical beam which has a diameter that is smaller than a biosensor;
scanning the first optical beam across the biosensor;
collecting a second optical beam which is out-coupled from the biosensor;
processing the second optical beam to obtain raw spectral/angular data which is function of a position on the biosensor; and
recording the raw spectral/angular data.
2. The method of claim 1 , further comprising steps of repetitively scanning the first optical beam across the biosensor and collecting the second optical beam out-coupled from the biosensor to obtain raw spectral/angular data which is a function of time and position on the biosensor.
3. The method of claim 1 , wherein said scanning step and said collecting step are both performed while said biosensor is moved.
4. The method of claim 1 , wherein said scanning step and said collecting step are both performed while said biosensor is stationary.
5. The method of claim 1 , wherein said scanning step is performed by scanning the first optical beam on a predefined line across the biosensor.
6. The method of claim 1 , wherein said scanning step is performed by scanning the first optical beam across two-dimensions of the biosensor.
7. The method of claim 1 , wherein said scanning step is performed by scanning the first optical beam in an arbitrary manner across the biosensor.
8. The method of claim 1 , further comprising a step of using the recorded raw spectral/angular data to create a spatial map of one of the following:
resonant wavelength data;
resonant angle data;
reflected power;
reflectivity data;
peak width data;
local angle data; and
wavelength interrogation slope (WIS) data.
9. The method of claim 1 , further comprising a step of using the recorded raw spectral/raw data to create a spatial map of reflected power vs. reflected wavelength/angle which is then used to evaluate locations, quantities and sizes of defects on the biosensor.
10. The method of claim 1 , further comprising a step of using the recorded raw spectral/angular data to create a spatial map of reflected power that is used to locate an edge of a grating in the biosensor so that the biosensor could be properly re-located after being removed and reinserted into a path of the first and second optical beams.
11. The method of claim 1 , further comprising a step of analyzing the recorded raw spectral/angular data to ameliorate undesirable effects in measured wavelengths/angles that arise because of drifts within components on an optical path.
12. The method of claim 1 , wherein the biosensor has a reference region on which a target molecule cannot bind and a sample region on which the target molecule can bind, and wherein the raw spectral/angular data associated with the sample region is used to detect a biomolecular binding event and the raw spectral/angular data associated with the reference region is used to reference out spurious changes that can adversely affect the detection of the biomolecular binding event.
13. The method of claim 1 , further comprising a step of simultaneously interrogating a plurality of biosensors which are located in a plurality of wells in a microplate.
14. The method of claim 1 , wherein said biosensor has at least one predefined patterned reference region on which target molecules cannot bind and at least one predefined patterned sample region on which the target molecules can bind.
15. The method of claim 1 , wherein said scanning step is performed by using the first optical beam to interrogate spatially multiplexed targets on the biosensor which is located within a well of a microplate.
16. The method of claim 1 , wherein said scanning step is performed by using the first optical beam to interrogate spatially patterned sample/reference regions on the biosensor to reduce the undesired effects of spatial gradients on target immobilization, non-specific binding, sensor wavelength interrogation slope (WIS) variation, temperature and/or other environmental perturbations.
17. The method of claim 1 , wherein said scanning step is performed by using the first optical beam to interrogate spatially multiplexed targets.
18. The method of claim 1 , wherein said biosensor is a resonant waveguide grating biosensor.
19. The method of claim 1 , wherein said biosensor is a surface plasmon resonance biosensor.
20. The method of claim 1 , wherein said biosensor includes at least one fiducial marking thereon which is used to determine a position of the biosensor relative to the optical reader system.
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WO2006071992A1 (en) | 2006-07-06 |
US7604984B2 (en) | 2009-10-20 |
US20060141611A1 (en) | 2006-06-29 |
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