HK1138066B - Guided-mode resonance sensors employing angular, spectral modal, and polarization diversity for high-precision sensing in compact formats - Google Patents

Abstract

A guided mode resonance (GMR) sensor assembly and system are provided. The GMR sensor includes a waveguide structure configured for operation at or near one or more leaky modes, a receiver for input light from a source of light onto the waveguide structure to cause one or more leaky TE and TM resonant modes and a detector for changes in one or more of the phase, waveshape and/or magnitude of each of a TE resonance and a TM resonance to permit distinguishing between first and second physical states of said waveguide structure or its immediate environment.

Description

Compact form guided mode resonance sensor for high precision sensing with angular, spectral, modal and polarization diversity

Priority

This application claims priority to provisional patent application serial No. 60/163,705 filed on 5.11.1999, the entire contents of which are expressly incorporated herein by reference without loss of authority. This application also claims priority to provisional patent application serial No. 60/164,089 filed on 6.11.1999, the entire contents of which are expressly incorporated herein by reference without disclaimer. This application also claims priority to provisional patent application serial No. 60/825,066 filed on 8.9.2006, the entire contents of which are expressly incorporated herein by reference without loss of authority. This application is also entitled to priority from U.S. patent application serial No. 09/707,435 filed on 6.11.2000, which claims priority from provisional patent application serial nos. 60/163,705 and 60/164,089, the entire contents of which are expressly incorporated herein by reference without loss of authority.

Technical Field

The present disclosure provides optical sensors operating in a periodic structure at resonant leaky modes, where angular diversity, spectral diversity, modal (modal) diversity and polarization diversity are advantageously applied for high precision sensing in a compact system form. The cross-reference data set thus obtained, fitted to a numerical model, provides increased accuracy and precision to enhance the quality of the sensing operation in a wide variety of applications.

Description of related knowledge

A variety of optical sensors for biological and chemical detection have been developed commercially and are found in the research literature. Example devices include surface plasmon resonance sensors, MEMS-based cantilever sensors, resonant mirrors, bragg grating sensors, waveguide interferometric sensors, ellipsometry (ellipsometry), and grating coupled sensors. Although greatly different in concept, function, and performance, Surface Plasmon Resonance (SPR) sensors are closest to the guided-mode resonance (GMR) sensors that are the subject of the present disclosure among these devices. Both GMR and SPR sensors provide label-free biochemical detection capability.

The term Surface Plasmon (SP) refers to an electromagnetic field induced charge density oscillation that can occur at the interface between a conductor and a dielectric (e.g., gold/glass interface). One SP mode can be generated by resonance excitation of parallel polarized TM polarized light (TM polarization refers to light with the electric field vector in the plane of incidence) rather than TE polarized light (TE polarization refers to light with the TE vector orthogonal to the plane of incidence). The phase matching is generated by: adopting a metallized diffraction grating; or by using total internal reflection obtained from high index materials, as in prism coupling; or an evanescent field obtained from one guided wave. When an SPR surface wave is excited, an absorption minimum occurs in a specific wavelength band. Although the angular and spectral sensitivity is very high for these sensors, the resolution is limited by the signal-to-noise ratio of the sensor response and the wide resonance line width (about 50 nm). Furthermore, as the sensor operating dynamic range increases, the sensor sensitivity typically decreases. Since only a single polarization (TM) can be physically used for detection, the changes in refractive index and thickness cannot be determined simultaneously in one measurement. This is important in chemical sensor applications, where binding kinetics (binding kinetics) involve changes in the thickness of the sensor surface, while background (background) refractive index can vary depending on analyte concentration. The disclosure provided herein can ameliorate some of the limitations of the prior art.

Magnusson et al have found guided mode resonance filters that are tunable to changes in the parameters of the resonant structure. Thus, spectral or angular changes caused by changes in layer thickness or changes in refractive index in the surrounding medium or device layer can be used to sense these changes. Wawro et al have discovered new GMR sensor implementations and new possibilities to apply these GMR sensors when integrated with optical fibers. There are additional aspects of GMR sensors in different application scenarios.

Summary of the contents

The present disclosure provides a tagless resonant sensor that operates in reflection (i.e., a band stop filter) or in transmission (i.e., a band pass filter) with a shaped angular spectrum illuminating the GMR sensor element. These spectra cover the range of incidence angles of interest simultaneously with the received signal directly illuminating a linear detector array, or CCD matrix or other detector. These relatively narrow reflection or transmission angular spectra change their position on the detector matrix when biomolecule attachment occurs, or other changes of interest occur within the sensing region, thereby producing a quantitative measurement of molecular events of interest. Furthermore, by acquiring dual TE/TM resonance data, switching the input light polarization state may be used to improve the quality of the sensing operation, or to measure additional parameters, when the resonances are from different TE and TM polarization responses. In addition, if desired, the spectrum of the input light can be tuned through a set of discrete wavelengths, thereby spatially shifting the position of the measured spectrum on the detector, providing the possibility of additional increasing the measurement accuracy. Finally, sensor operation with multiple resonant peaks can further increase measurement accuracy due to the presence of multiple waveguide leaky modes (leaky waveguide modes).

These operational modalities (angular, spectral, modal and polarization) can be used in various combinations as desired. The sensors can be arranged into a compact high density platform requiring a minimum amount of reagent. Thus, as illustrated in the present disclosure, the present method has a number of advantageous uses in practical sensor systems for high precision measurement applications.

The present disclosure provides a GMR sensor assembly comprising:

a waveguide structure configured to operate at or near one or more leaky modes;

receiving means for receiving input light from a light source onto the waveguide structure to produce one or more leaky TE and TM resonant modes;

a detection arrangement for detecting a change in one or more of the phase, waveform and/or amplitude of each of the TE and TM resonances to allow discrimination between a first physical state and a second physical state of the waveguide structure or its immediate environment.

In the GMR sensor assemblies provided by the present disclosure, the GMR sensor assemblies may also be configured to operate in a band-stop mode.

The GMR sensor assembly is also configurable to operate in a bandpass mode.

The GMR sensor assembly may be configured to operate in situations where the input light comprises diverging light.

The GMR sensor assembly may be configured to operate in situations where the input light comprises converging light.

The GMR sensor assembly may further comprise a beam shaping element for forming an input wavefront of the input light having known amplitude and phase characteristics.

The illumination source that generates the input wavefront of the input light may be selected from the group consisting of: light emitting diodes, laser diodes, vertical cavity surface emitting lasers, and filtered broadband light sources.

The waveguide structure may be configured to operate with substantially unpolarized input light.

The GMR sensor assembly may further comprise means for applying the first known polarization state at a first known time and applying the second known polarization state at a second known time.

The GMR sensor assembly may further comprise means for selectively inputting different wavelengths of input light to the waveguide structure.

The detection means may be arranged such that the TE and TM resonances to be detected are those reflected from the waveguide structure onto the detection means.

The detection means may be arranged such that the TE and TM resonances to be detected are those transmitted through the plane of the waveguide structure onto the detection means.

The detection means may be a matrix of photodetector elements.

The GMR sensor assembly may be configured to operate with more than one resonant leaky mode.

The GMR sensor assembly may further comprise a holographic diffractive element for diffracting the input light.

The input light may be capable of being incident at any angle and the detection means may receive the TE resonance and the TM resonance at any angle.

The present disclosure also provides a GMR sensor assembly comprising:

a waveguide structure configured to operate at or near one or more leaky modes of input light, an

A detector for TE and TM resonance comprising a sensor array having at least NxM sensor elements.

In GMR sensor assemblies also provided by the present disclosure, the waveguide structure may be configured to receive a diverging beam of input light.

The detector may be arranged on the opposite side of the plane through the waveguide structure from the input light in order to receive the resonance signal transmitted through the plane of the waveguide structure.

The input light may have known amplitude and phase characteristics.

The waveguide structure may be configured to receive a diverging beam of input light.

The detector may be arranged on the same side of the plane through the waveguide structure as the input light in order to receive the resonance signal reflected from the waveguide structure.

Each sensor element may be illuminated by an input light source taken from the group of a light emitting diode, a laser diode and a vertical cavity surface emitting laser.

The NxM sensor elements can be configured to be illuminated by a single light source input through the light shaping port.

Drawings

For clarity and convenience, reference is made to the various drawings attached hereto in order to assist those skilled in the art in understanding the use and practice of the present disclosure.

FIG. 1 shows an example of a biomolecule binding event on a biosensor surface.

FIG. 2 provides a schematic illustration of an exemplary bacterial assay.

An explanation of the diffraction of the resonant photonic-crystal waveguide structure is given in fig. 3, where the zero order state and the leakage mode resonance excitation are clearly defined.

Fig. 4 provides a comparison between experiments and theory of dielectric resonant elements.

Fig. 5 shows the electric field distribution of the leaky modes at resonance with respect to the element in fig. 4.

Fig. 6 shows a calculated instantaneous "snapshot" of the electromagnetic standing wave pattern associated with the leaky mode at the maximum in fig. 5.

FIG. 7 shows a guided mode resonant index sensor using TE and TM polarization diversity and depicts the structure that produces the calculated response.

Figure 8 shows the corresponding TE polarization resonance wavelength shift for the large dynamic range sensing of the example of figure 7.

Fig. 9 shows thickness sensing in air.

Fig. 10 provides measured GMR sensor spectral responses in air for TE polarized (top left) device surfaces modified with silane chemical connectors (bottom left). Also shown is a Scanning Electron Micrograph (SEM) (top right) and a device model (bottom right).

Figure 11 depicts an electron microscope image of a submicron grating contact printing technique and a grating of 520-nm period contact printed in an optical adhesive medium.

FIG. 12 shows the calculated TE polarization angular response of the GMR sensor for different additional thicknesses (dbio) of the biological material, while FIG. 13 shows the corresponding TM-polarization response.

Fig. 14 is a schematic diagram of a proposed resonant sensor system with dual polarization detection. Divergent beams from a light source, such as an LED or LD or VCSEL, are incident on the sensor at different angles simultaneously.

FIG. 15 shows an exemplary GMR sensor implementation with a diverging input beam and an associated detector using polarization diversity detection.

FIG. 16 is a schematic diagram of an arbitrary sized NxM micro-well array incorporating a GMR sensor/detector unit as shown in detail in FIG. 15.

FIG. 17 illustrates polarization sensing in transmission mode, where the TE peak (or minimum) and TM peak (or minimum) are directed to the detector array by reflection at the walls of the microwells.

FIG. 18 is a diagram of GMR sensor polarization diversity experimentally used to quantify biotin binding to silane coated sensor surfaces. Molecular attachment events are monitored as a function of time. The results for TE and TM polarizations are shown.

Fig. 19 shows an exemplary element structure which achieves the characteristics of a band-pass filter and thus realizes a GMR sensor operating in transmission. This element can be implemented in a silicon-on-insulator (SOI) material system.

Fig. 20 provides transmission type SOI resonant sensor spectra calculated for different thicknesses of added biological material. The sensor operates in air with incident waves, reflected waves (R), and transmitted waves (T) as shown in fig. 19. In this example, the incident wave is TM polarized. The design of the sensor is shown in fig. 19.

FIG. 21 depicts a sensor/detector configuration associated with sensing operations in direct transmission.

FIG. 22 shows the TE angular response calculated for different added thicknesses of biological material in relation to a GMR sensor design such as that shown in FIG. 21.

FIG. 23 shows the TE angle response of the GMR sensor structure of FIG. 21 calculated for varying input wavelengths to illustrate wavelength diversity. In this calculation, dbio is 100 nm. The diverging input beam automatically covers the angular range of interest.

FIG. 24 shows the calculated TM angular response of the GMR band-pass sensor schematically shown in FIG. 19 for different bio-layer thicknesses. The diverging incident beam automatically covers the angular range of interest. In this example, the parameters are the same as in fig. 19, and the input wavelength is set to λ 1.5436 μm.

FIG. 25 shows an associated sensor/detector architecture for sensing operation with direct, polarization enhanced detection in a compact layout. The locations of the TE and TM resonance nulls (or peaks) on the detector array are indicated schematically by dashed arrows.

Fig. 26 represents a related sensor/detector architecture for sensing operations with direct transmission through a flow channel in a microfluidic biological or chemical sensing system. Fig. 27 shows an HTS platform with a single source plane wave input and wavefront shaping with a lens array to achieve an angularly addressable GMR sensor array without moving parts.

Fig. 28 pertains to an HTS platform with a single source input and wavefront shaping with a lens array to achieve an angularly addressable GMR sensor array in a microfluidic environment. FIG. 29 shows GMR sensors fabricated in plastic or glass media by imprinting and molding.

FIG. 30 pertains to a GMR sensor array fabricated in a silicon-on-insulator material system.

FIG. 31 provides the calculated TE-reflectance angular response of the GMR multimode sensor for different thicknesses (dbio) of the added biomaterial.

Fig. 32 provides a calculated angular transmittance spectrum for the multimode sensor corresponding to fig. 31.

Fig. 33 shows the calculated transmittance spectrum corresponding to the device parameter of fig. 31, where θ is 0 at normal incidence, exhibiting multimode resonance characteristics. In the wavelength range shown, this multimode biosensor operates with leaky modes TE0, TE1, and TE 2. In this exemplary case, the highest sensitivity is provided by the TE2 mode.

Fig. 34 shows a single source system using a splitter and fiber optic transmission.

FIG. 35 shows a single channel schematic of a label-free guided-mode resonance sensor system for detecting chemical or biological analytes bound to antibodies.

Fig. 36 shows a reflective architecture that employs an array of optical fibers for light transmission. Figure 37 shows a reflective sensor system employing a scanning line source.

Detailed description of exemplary embodiments

Background

The inventors have proposed that by varying the refractive index and/or thickness of the resonant waveguide grating, its resonant frequency can be varied, or tuned. The inventors have found that this idea can be applied to biosensors, since the accumulation of attached bio-layers can be monitored in real time without the use of chemical labels by tracking the shift of the corresponding resonance wavelength with a spectrometer. Thus, the rate of binding between an analyte and its designated receptor can be quantified; in fact, the characteristics of the entire binding cycle, including binding, dissociation, and regeneration, can be recorded. Similarly, small changes in the refractive index in the surrounding medium, or in any of the waveguide grating layers, can be measured. Thus enabling a new class of high sensitivity biological and chemical sensors. This sensor technology is widely used in medical diagnostics, drug development, industrial process control, genomics, environmental monitoring, and homeland security.

Stating the application of one embodiment in more detail, a high performance, label-free photonic crystal GMR sensor is very attractive for improved process control in drug development applications. This approach is very useful because this sensor technology can provide an increase in detection accuracy to advance the process of drug development and screening. In this industry, millions of distinct chemical compounds need to be screened quickly and accurately to determine which compounds bind to a particular protein or inhibit a target reaction. The goal of High Throughput Screening (HTS) is to eliminate compounds that are not promising before further development costs arise. Current HTS technologies typically use fluorescent or radioactive chemical tags as indicators of biological activity. Due to the complexity of indicator-compound binding, it is sometimes necessary to carefully design entirely new assays using new indicator technologies or reaction chemistries. There is an increasing demand for novel sensor technologies that do not require tags and allow for the selective screening of multiple materials in real time with minimal assay development (using readily available antibodies-antigens, nucleic acids and other highly selective biological materials). The ability to reduce errors from screening variables such as temperature, and background (background) fluid variations, and to monitor binding kinetics in real time with a simple array architecture are other desirable characteristics. High precision GMR sensor methods, such as those disclosed herein, can meet these needs for high throughput screening applications.

The sensor includes a periodic dielectric waveguide (also known as a photonic crystal) in which a resonant leaky mode (leaky mode) is excited by an incident light wave. Incident broadband light is efficiently reflected within a narrow spectral band whose center wavelength is very sensitive to chemical reactions taking place at the sensor element surface. The interaction of the target analyte with the biochemical layer of the sensor surface produces a measurable spectral shift that directly identifies the binding event without additional processing or extraneous labels. A bio-selective layer (such as an antibody) can be bound to the sensor surface to confer specificity in operation, as shown in figure 1. Sensor designs with sensitivity to thickness variations from the nanometer scale (< 0.1 angstroms) to several microns have been analyzed. Thus, the same sensor technology can be used to detect binding events for small molecule drugs (< 1nm) and proteins (< 10nm) as well as larger bacterial analytes (> 1 μm), as shown in FIG. 2. High resolution (obtained by narrow, well-defined formants) and high sensitivity (associated with surface local leaky modes) provide a high probability for accurately detecting an event. Furthermore, the two dominant polarization states have independent resonance peaks to accurately sense biomaterial binding events. This property enables the ability to distinguish between the average thickness variation and the average density variation occurring at the sensor surface. Thus, the sensor resonance response to a target chemical binding event (which includes a change in the conformation of the molecule) is distinguishable from the sensor resonance response of unbound material residing on the sensor surface, thereby reducing the occurrence of false positive readings.

GMR sensor technology is very versatile. The biomolecular reactions associated with a single sensor, or sensor elements in an array, can be measured simultaneously using a variety of properties including angular spectrum, wavelength spectrum and polarization. Furthermore, the GMR element itself may be designed to be in a single leaky mode (referred to as TE)₀Fundamental mode) in a single peak, or in multiple leaky modes (e.g. TE)₀，TE₁And TE₂Mode), a different polarization resonance is exhibited. With proper sensor design, such multiple modes will be excited in the angular and wavelength spectrum regions of interest. The electromagnetic field structure of the resonant mode can be configured to cause the sensor to operate with an evanescent tail in the sensing region, orAlternatively, it is made to operate as a bulk mode sensor (bulk mode sensor), in which the leaky mode completely contains the sensing region. In fact, a particular working leaky mode can be chosen to maximize the light-analyte (measurand) interaction to improve detection sensitivity. For example, in a particular design, at TE₂Operation in the mode may yield advantages over TE₀The result of the modulus. The detection schemes summarized herein increase the amount and reliability of information collected about molecular events compared to those collected by other means.

This sensor is envisaged to be capable of a wide range of applications depending on the material, operating wavelength and design configuration. It is multifunctional in that only the sensitizing surface layer needs to be chemically altered to detect different species. Operation in both air and liquid environments is possible. Due to the flexibility of material selection, environmentally friendly dielectrics can be selected for the fabrication of the sensor element. Applicable materials include polymers, semiconductors, glasses, metals, and dielectrics.

Guided mode resonance effect

Fig. 3 shows the interaction of a thin film waveguide grating (photonic crystal slab) and an incident plane wave. As the period Λ decreases, the higher-order propagating wave is cut off more and more until a zero-order state (zero-order region) in fig. 3(b) is obtained. If the structure comprises a suitable waveguide, the first order wave, which now is evanescent or cut off, can be brought into resonance by coupling into a leaky mode. In practice, the zeroth order state is generally preferred because no energy is wasted in transmitting the higher order diffracted waves as shown in fig. 3 (a).

Such a thin-film structure comprising a waveguide layer and periodic elements (photonic crystals) exhibits a Guided Mode Resonance (GMR) effect under the correct conditions. When an incident wave is phase matched by the periodic element with the leaky mode of the waveguide as shown in fig. 3(c), it is re-radiated in the specular direction with a reflection coefficient R as it propagates along the waveguide and constructively interferes with the directly reflected wave, as shown in fig. 3 (c). Conversely, equivalently, the phase of the re-radiated leaky mode in the forward, directly transmitted wave (transmissivity T) direction in FIG. 3(c) is π radians out of phase with the direct unguided T wave, thus eliminating the transmitted light.

Experimental bandstop Filter example

Fig. 4 shows the measured and calculated spectral reflectivities of the dielectric guided mode resonance device. This device acts as a band stop filter in which the spectrum of interest is reflected in a narrow band with relatively small sidebands. Although theoretical calculations predict a peak efficiency of a plane incident wave of 100%, in practice, the peak efficiency is reduced due to various factors, such as material and scattering losses, incident beam divergence, and lateral device size; the peak efficiency of the experiment here is 90%. The resonant element was fabricated by depositing an HfO on a fused silica substrate (1 inch diameter)₂Layer (about 210nm) and one SiO₂Layer (about 135 nm). SiO 2₂The grating was obtained by a series of processes including holographic recording of a photoresist mask grating (period Λ 446nm) with an Ar + UV laser (λ 364nm) in a Lloyd mirror interference (Lloyd mirror interference) setup, growing, depositing an approximately 10nm Cr mask layer on the photoresist grating, stripping the photoresist grating, and then subjecting the SiO to a process of CF4₂The layer is subjected to reactive ion etching. The apparent surface roughness in the SEM contributes to a reduction in peak efficiency.

Leaky mode field structure

In addition to the reflection/transmission characteristics of propagating electromagnetic waves, the near-field characteristics of periodic lattice (lattice), including localization and field strength enhancement, are of interest in sensor applications. The calculated near field pattern associated with the fabricated example structure shown in fig. 4 is shown in fig. 5. Numerical results are obtained with Rigorous Coupled Wave Analysis (RCWA) to provide quantitative information about the relative field strength and spatial extent (spatial extent) associated with the near field. As shown in fig. 5, zero order S₀Wave (S)₀Electric field representing the zeroth order) Propagating at a reflected amplitude close to unit 1, produces the standing wave pattern shown by interference with the unit amplitude input wave. Thus, at resonance, most of the energy is reflected back. At the same time, S₁And S_-1The first-order evanescent diffracted wave shown constitutes in this example a counter-propagating leaky mode. In this particular sensor, the maximum field value is located in the homogenous layer and the evanescent tail gradually penetrates into the substrate and the top layer, as is clearly shown in FIG. 5. FIG. 6 shows S propagating from opposite directions at a certain time_-1And S₊₁Standing wave patterns of wave formation. Due to S_±1Spatial harmonics correspond to local waves, which can be very strong at resonance. According to the level of the grating modulation (Δ ∈ ═ n)_H ²-n_L ²) The field amplitude may be about 10-1000 times the amplitude of the incident wave in a layer, which represents the zone intensities I-S²Is increased greatly. S₁Is approximately inversely proportional to the modulation intensity. In general, small frequency offset modulation (small modulation) means a narrow spectral line width Δ λ and a large resonator Q factor Q ═ λ/Δ λ.

Exemplary sensor response and sensitivity

The calculated spectral response for a single layer sensor designed for use in a liquid environment is given in fig. 7. This sensor may be of Si₃N₄Fabricated and patterned by plasma etching, resulting in a diffractive layer. One-dimensional resonant guided wave grating structures have different reflection coefficient peaks for TE (electric vector orthogonal to plane) and TM polarized incident waves. Calculations show that the design can resolve 3x10 assuming a spectrometer resolution of 0.01nm^-5Average refractive index variation of Refractive Index Unit (RIU). For and grating structure (n)_C＝n_L1.3 to 1.8), a near linear wavelength shift can be maintained (fig. 8), making this a versatile sensor with a large dynamic range. The sensitivity of a biosensor is defined as: the measured response (e.g., peak wavelength shift) for a particular amount of material being tested. This represents the maximum achievable sensitivity to the analyte being detected. Conveying applianceSensor resolution includes practical component limitations such as resolution of the spectroscopic equipment, power meter accuracy, bio-selective reagent response, and peak shape or linewidth. The spectral line width is the full width at half maximum (FWHM) of the reflection peak response. It affects the accuracy of the spectral sensor, since narrow spectral lines can generally improve resolution of wavelength shifts; resonant waveguide grating sensors typically have narrow spectral line widths on the order of about 1nm, which can be controlled by design. Although resonant sensors are capable of monitoring small refractive index changes, they can also be used to detect thickness changes at the sensor surface, as represented by the calculation in FIG. 9 for actual materials and wavelengths.

Exemplary sensor results

As shown in fig. 10, GMR sensing technology for biosensing applications has been used to analyze protein binding studies in air, using a 2-layer resonant element illuminated at normal incidence. In this example, a clean grating surface was first chemically modified with amino groups by treatment with a 3% solution of aminopropyltrimethoxysilane (Sigma) in methanol (fig. 10 top left). The device was then rinsed with a solution of bovine serum albumin (BSA, 100mg/ml, Sigma), and the deposited 38nm thick layer of BSA produced a shift in the resonance peak spectrum of the 6.4nm reflection (FIG. 10 bottom left). Note that minimal signal attenuation was produced by the biomaterial layer on the sensor surface, and that the reflectivity remained at about 90% before and after BSA attachment.

Fabrication of resonant sensor elements by contact printing

In addition to the methods described thus far, an economical contact printing process is attractive for imprinting optical polymers in the desired submicron grating pattern. Silicone raster embossing (silicone raster stamp) can be used to imprint the raster onto a thin layer of UV-curable optical adhesive (fig. 11 (a)). By spraying a thin layer of Si₃N₄Or other suitable medium, a waveguide layer is deposited on the top surface of the grating. Optionally, the grating is coated with high index spin coating (high index spin-on)TiO₂Polymer film to produce a high mass resonant sensor element. An example of a contact-printed grating is shown in fig. 11 (b).

Dual-mode TE/TM polarized GMR sensor

The simultaneous detection of TE and TM resonance shifts on the bio-layer attached to the sensor can greatly improve the quality of the sensing operation. This allows accurate determination of overall biolayer properties; namely the refractive index and the thickness. Fig. 12 and 13 show the results of calculations showing resonance shift for the angles of both polarizations. In fact, moderate angle TE/TM resonance separation can be achieved with appropriate element design, which enables simultaneous detection of two signals on a linear detector array when using divergent illumination provided by light emitting diodes (LEDs, possibly filtered to achieve spectral contraction), or Vertical Cavity Surface Emitting Lasers (VCSELs), or Laser Diodes (LDs) with λ 850nm, automatically covering the range of angles of interest, as shown in fig. 14. In this example, the measuring beam (indirect lightbeam) enters through a covering medium, such as fused silica or plastic sheeting (refractive index n)_c). The light distribution of interest appears as a reflection peak on the detector. This example illustrates the use of high index polymer materials as the homogeneous and periodic layers. This can be produced, for example, by: a silicone mold was used to form the grating in a commercial TiO 2-rich, thermally or UV curable polymer medium spun onto a supporting wafer. Alternatively, a high index waveguide layer can be deposited onto the support wafer and the periodic layer molded on top of it.

FIG. 15 illustrates the use of an embodiment of the present invention in a biomolecule sensing environment. Although unpolarized light will provide TE and TM formants on the detector array or matrix, the signal-to-noise ratio (S/N) can be improved by: as shown in fig. 15, the detector is switched between polarization states and scanned in time in synchronism with the polarization switching to obtain independent TE and TM signals. Furthermore, to further improve the signal-to-noise ratio, the light source may be equipped with a beam shaping element to shape the light distribution over the sensor in an optimal way. Indeed, in some applications it may be desirable to use a converging rather than a diverging wavefront. Such beam shaping may be accomplished, for example, by suitable holographic or diffractive optical elements. This allows wavefronts of arbitrary amplitude and phase distribution to be generated. Fig. 16 shows the use of the device of fig. 15 in a porous system. In the pharmaceutical industry, microplates are used for the efficient screening of pharmaceutical compounds, and the application of the present system may find advantageous use therein. Fig. 17 shows an additional architecture in which the detector matrix is now mounted on top of the aperture and the transmission nulls (or peaks) associated with the TE and TM resonances are measured. When a bio-layer is added to the sensor, the zero position on the detector shifts, allowing quantification of the binding event. In this example, the incident wave is incident at an angle and the signal is restored by reflection off the walls of the microwells.

Preliminary experiments have demonstrated the polarization diversity properties of this technique, which provides independent formant shifts for each polarization (TE and TM), thereby providing a method to achieve high detection accuracy as described above. FIG. 18 shows example results for GMR biosensor applications.

Band-pass GMR sensor

The transmission resonance sensor element, or the bandpass resonance sensor element, can be fabricated from a variety of media, including silicon-on-insulator (SOI), silicon-on-sapphire (SOS), and directly imprintable thermally or UV curable polymers. The formation of the periodic layer can be accomplished by conventional methods including electron beam writing (e-beam writing) and etching with a pre-master, holographic interferometry, and nanoimprint lithography. To illustrate this embodiment, fig. 19 shows a transmission sensor designed with an exemplary SOI structure. FIG. 20 shows a sensor pair having a thickness d_bioIncreases the response of the sensor surface. The transmission peak changes its spectral position in a sensitive way. This diagram should be contrasted with the sensor of fig. 12-14, for example, which operates in a reflective state. When the biological material is attachedThe rate of shift of the resonant wavelength as it approaches the sensor surface is essentially a spectral shift of about 1.6nm for each 1nm increase in material. Note the unique profile design that achieves this performance in this example.

Flat compact GMR sensor and array sensor system

For ease of manufacture and reduced cost we now disclose the implementation of embodiments of the invention in the form of the flat system set out above. The sensor operates in transmission. Thus, light enters the sensor, which is in contact with the medium whose interaction with the sensor is of interest. The light is transmitted through the medium to the detector, where the transmission intensity minima (band stop filter) or intensity maxima (band pass filter) are measured. These spatial shifts in light distribution position allow quantification of the main properties of the biomolecular binding reaction.

Fig. 21 illustrates this concept for a single sensor that performs assays with divergent beams from Laser Diodes (LDs), Light Emitting Diodes (LEDs), or Vertical Cavity Surface Emitting Lasers (VCSELs). The polarization, beam shaping or line narrowing functions may be integrated into the light source as desired. The detectors are located on opposite sides of the sensing body as shown. Fig. 22 shows the calculated intensity distribution (signal) over the detector matrix for a GMR sensor operating in bandstop mode, thus producing a peak in reflection and an accompanying minimum in transmission. In this example, the input wavelength is 850 nm. The two minima occur at angular positions that are symmetric with respect to the normal to the sensor, since the resonance wavelength at normal incidence differs from the resonance wavelength at non-normal incidence. These two simultaneous minima can be used to enhance the accuracy of the sensing operation, since two angular offsets are acquired. In the present example of fig. 22, for increased bio-layer thickness d_bio0, the minimum occurs at θ to 6 °, and for d_bioThe resonance is at an angle of 100nm from θ to 5 °. FIG. 23 illustrates wavelength diversity; that is, by tuning the input wavelength to a discrete set of wavelengths, additional numbers can be collectedTo improve the accuracy of the data analysis and fitting to the numerical model. As the wavelength changes, the resonance angle and the light distribution of the sensor also change. In addition, the wavelength controls the location of the minimum on the detector, which provides flexibility in specifying a dedicated detector area usage for each GMR sensor pixel in the sensor array.

As explained in connection with fig. 20, we have designed a number of resonator filters that operate at the transmission peak, i.e. as band pass filters. In this example for a design such as that of fig. 21, an intensity maximum (rather than a minimum) will appear across the detector array. Such a transmissive element can be very efficiently designed with a high refractive index medium such as silicon. Fig. 24 shows biosensing with angular diversity using a band-pass filter. By setting the wavelength such that the device maintains a transmission peak for an undisturbed surface, an ultra-high sensitivity arrangement is obtained. The fastest change in the transmission angle spectrum occurs when detuning (detuning) by bio-layer accumulation transitions the sensor from the band-pass state to the band-stop state at normal incidence, as shown in fig. 24. Thus, the increase in sub-nanometer biofilm will be directly measurable by a simple intensity change on the output side at the detector. The shape of the forward transmitted light distribution received by the detector matrix is a sensitive function of the thickness of the biological layer, as clearly shown in fig. 24.

Yet another polarization diversity embodiment is schematically illustrated in fig. 25, where four simultaneous minima (or peaks) are monitored for high accuracy biosensing. FIG. 26 provides an embodiment that can be used for sensing in a microfluidic system.

In the face of the growing number of biological and pharmaceutical objects, there is an increasing need to invent new methods to profile chemical activity in a massively parallel manner. At the same time, there is a need to reduce HTS costs by dispensing a minimum amount of reagents for the assay. Thus, there is a trend in the industry towards the dispensing of liquids of nanoliter (nanoliter) grade. The GMR sensor technology proposed herein can be used to meet these needs. The flat transmission format proposed and explained above enables the development of multi-channel sensor systems. Existing and developing CCD and CMOS detector matrix technologies with pixels down to the order of 5-10 μm make possible precise measurements of intensity distributions and their variations. Nano-imprint technology and precision thin-film methods enable the fabrication of the required GMR sensor arrays. Molding can be applied to the formatting and assembling of larger parts in these arrays.

FIG. 27 shows a system capable of parallel biosensing according to embodiments of the invention described in this disclosure. GMR sensors mounted to the microplate are addressed by the angular spectrum generated by converting an incident plane wave to a spherical or cylindrical wave with an appropriately designed array of diffractive or refractive microlenses, as shown. An overhead mounted detector array receives the signals to achieve accurate biosensing. FIG. 28 shows a similar operation in which the sensor is excited by a directed flow within a flow channel in the microfluidic assembly; fig. 28 omits the complex channel structure and details associated with an actual microfluidic device.

Practical cost-effective GMR arrays can be fabricated with glass or plastic media. As an example, an array of diffractive or refractive lenses with a given focal length and diameter on a plastic substrate can be purchased at a cheap price from several manufacturers. Applying high refractive index spin-coated TiO on the blank side of the substrate opposite the lens array₂A polymer film. Next, as shown in FIG. 11, a grating pattern is imprinted with a specially designed silicone stamp (Si-stamp) having an appropriate period, thereby creating a GMR sensor. Next, a flashing wall (spill wall) can be installed by molding to separate the different solutions and avoid cross-contamination. Alternatively, the high index film is first deposited on the substrate, and then the grating pattern is applied on top. The resulting GMR array is shown in fig. 29. Fig. 30 shows a conceptual GMR array fabricated with SOI to take advantage of existing silicon-based micromachining methods.

Multimode GMR sensor

Another way to improve detection reliability is to increase the number of resonant leaky modes of operation and thus apply richer spectra for sensing and precision curve fitting. In this way, multiple formants arising from the presence of multiple waveguide modes can be generated and monitored. These multiple modes provide different spectral characteristics that can be used in precision sensing. Fig. 31 shows the TE polarization response of a dual layer GMR sensor, the parameters of which are graphically illustrated and assumed to have no sidewall attachment. With a fixed input wavelength, the reflection spectrum shows several resonance peaks originating from different leaky modes. As shown in fig. 31, when a bio-layer is added, the spectrum responds with a measurable change in the angular spectrum. This spectrum will be monitored in reflection, for example, using the architecture shown in fig. 16. Fig. 32 gives the corresponding transmission spectrum monitored, for example, in the system of fig. 27. Fig. 33 shows the wavelength spectrum at normal incidence for this sensor, showing three leaky modes in the spectral band shown. Due to the specific distribution of the electromagnetic field in this sensor, in TE₂The operation of the modes gives the highest sensitivity, i.e., produces the largest angle shift and spectral shift per unit thickness increase, as shown in FIGS. 31-33.

Referring now to fig. 34, 35 and 36, and first to fig. 34 thereof, a sensor/detector architecture employing fiber-coupled optical transmission in a GMR sensor platform is described. FIG. 34 shows a single source system using a splitter and fiber optic transmission. A single light source is split (with a beam splitter) into "M" channels and incident on the sensor array through optical fibers. The light exiting each fiber is shaped by an integrated or external lens/DOE and then is incident on the sensor element in free space. Alternatively, the diverging light leaving the optical fiber may be directly incident on the sensor element without using a beam shaping element. As part of the system design, the optical fiber may be selected based on its numerical aperture or other characteristics. A polarization element or polarization maintaining fiber can be used in the system to control the polarization state(s) incident on the sensor element. The incident wavelength may be tunable, thus allowing angular and spectral tuning in a single system.

The system can be constructed as a transmission system, where light transmitted through the sensor array is detected with a detector matrix located on the opposite side of the array from the incident light, as described. The system can also be constructed as a reflective system, where light is incident at an angle to the array and the light beams reflected from the array are detected with a matrix of detectors arranged on the same side as the array from which the light was incident.

Fig. 35 depicts a single channel schematic of a label-free guided-mode resonance sensor system for detecting chemical or biological analytes bound to antibodies. The antibody is represented by "Y" and the analyte is represented by the ball in the cup portion of "Y". The antibody should be selected based on the analyte or analytes being detected. In some embodiments, bovine, camel or alpaca serum antibodies are used, although the invention is not limited to these antibodies.

In operation, a diverging beam from a fiber coupled laser diode is incident on the sensor over a continuous range of angles. When a binding event occurs at the sensor surface (by binding of analyte to antibody), the change in the formants can be tracked as a function of the angle of incidence. The resonances occur at different angles for the TE and TM polarization states of the incident light, which enables high accuracy, cross-reference detection.

FIG. 36 shows a multi-channel array. It has a reflective architecture that employs an array of optical fibers for light transmission. The fiber array may also be scanned across the sensor array (for both reflection and transmission).

For example, to screen an MxN sensor array, an M-fiber array can be scanned across the bottom of N rows of sensor elements. The scanning can be performed by: (a) moving the fiber array + detector matrix across the sensor plate, or (b) moving the sensor plate across the fiber array + detector matrix.

Figure 37 depicts a sensor/detector architecture employing a scanning line source. Although FIG. 37 depicts a reflective sensor, it may also be constructed as a transmissive sensor by placing detector elements on the opposite side of the array plate from the incident light.

The light source may be a single wavelength (or wavelength selectable) source that is shaped with a line focusing element (e.g., a cylindrical lens). Line focus light simultaneously illuminates the M-sensor elements in the MxN sensor array. The reflection response is measured on M rows of the detector matrix (e.g. one row of CCD detector elements). A light line source (light line source) and detector element assembly can be scanned across the bottom of the sensor plate to effectively read the MxN sensor array. Note that: the line focusing element may also act as a beam shaping element (e.g., can be diverging, converging, or any designed wavefront).

The following additional embodiments are also contemplated:

a GMR sensor assembly comprising a waveguide structure configured to operate at or near one or more leaky modes of incident light and a detector for TE and TM resonance comprising a sensor array having at least NxM sensor elements.

The GMR sensor assembly defined above, further comprising a refractive lens to shape the illumination light.

The GMR sensor assembly defined above, further comprising an array of refractive lenses to shape the illumination light.

The GMR sensor assembly defined above, further comprising a diffractive lens to shape the illumination light.

The GMR sensor assembly defined above, further comprising means for determining the polarization state and waveform characteristics of the wavefront of the input light.

The GMR sensor assembly defined above further comprising means for providing input light having at least two different wavelengths.

The GMR sensor assembly defined above further comprising means for providing input light having at least a first polarization characteristic and a second polarization characteristic.

The GMR sensor assembly defined above, further comprising means for detecting at least two resonance modes.

The GMR sensor assembly defined above, further comprising an integrated microfluidic flow channel adjacent to the waveguide structure.

The GMR sensor assembly defined above further comprising a substrate, a light conditioning element and a microvia (micro) tube integrated into the transparent medium.

The GMR sensor assembly defined above wherein the array is disposed on an integrated medium selected from the group of semiconductors, semiconductor/dielectric hybrids, semiconductor/dielectric/metal hybrids and dielectrics.

The GMR sensor assembly defined above wherein the array sensor element is physically separated from the illumination source.

The GMR sensor assembly defined above wherein the array sensor elements are integrated with the illumination input light source.

The GMR sensor assembly defined above, further comprising a read-out detector in the form of a compact biochip or micro-bench top (micro bench).

A guided mode resonance sensor in which the illumination source is a coupled optical fibre or waveguide.

A guided mode resonance sensor in which a waveguide or optical fiber is selected by design to have a particular numerical aperture, polarization maintaining properties or material specifications.

A guided mode resonance sensor in which an illumination source is focused to a line with a line focusing element.

A guided mode resonance sensor, wherein the illumination source is focused to a line with a line focusing element comprising a cylindrical lens.

A guided mode resonance sensor, wherein the illumination source and detector elements are scanned across the sensor array.

A guided mode resonance sensor in which a single light source is divided into several channels by a beam splitter.

A guided mode resonance sensor has an optical fiber/waveguide array that is used to transmit light to an array of sensor elements.

It will be further understood from the foregoing description that various modifications and changes may be made in the preferred embodiments of the present invention without departing from its true spirit. This description is intended for purposes of illustration only and should not be construed in a limiting sense. The scope of the invention should be limited only by the language of the following claims.

Claims (22)

1. A GMR sensor assembly comprising:

a waveguide structure configured to operate at or near one or more leaky modes;

receiving means for receiving non-planar input light from a light source onto the waveguide structure to produce one or more leaky TE and TM resonant modes;

a detection arrangement for detecting a change in one or more of the phase, waveform and/or amplitude of each of the TE and TM resonances to allow discrimination between a first physical state and a second physical state of the waveguide structure or its immediate environment.

2. The GMR sensor assembly defined in claim 1, wherein the GMR sensor assembly is further configured to operate in a band-stop mode.

3. The GMR sensor assembly defined in claim 1, wherein the GMR sensor assembly is further configured to operate in a bandpass mode.

4. The GMR sensor assembly defined in claim 1, wherein the GMR sensor assembly is configured for operation in which the input light comprises diverging light.

5. The GMR sensor assembly defined in claim 1, wherein the GMR sensor assembly is configured to operate where the input light comprises converging light.

6. The GMR sensor assembly defined in claim 1, further comprising a beam shaping element for shaping an input wavefront of input light having known amplitude and phase characteristics.

7. The GMR sensor assembly defined in claim 1, wherein an illumination source that generates the input wavefront of the input light is selected from the group consisting of: light emitting diodes, laser diodes, vertical cavity surface emitting lasers, and filtered broadband light sources.

8. The GMR sensor assembly defined in claim 1, wherein the waveguide structure is configured to operate with substantially unpolarized input light.

9. The GMR sensor assembly defined in claim 1, further comprising means for applying a first known polarization state at a first known time and a second known polarization state at a second known time.

10. The GMR sensor assembly defined in claim 1, further comprising means for selectively inputting different wavelengths of input light to the waveguide structure.

11. The GMR sensor assembly defined in claim 1, wherein the detection means is arranged such that the TE and TM resonances to be detected are resonances reflected from the waveguide structure onto the detection means.

12. The GMR sensor assembly defined in claim 1, wherein the detection means is arranged such that the TE and TM resonances to be detected are those transmitted through a plane passing through the waveguide structure onto the detection means.

13. The GMR sensor assembly defined in claim 1, wherein the detection means is a matrix of photodetector elements.

14. The GMR sensor assembly defined in claim 1, wherein the GMR sensor assembly is configured to operate with more than one resonant leaky mode.

15. The GMR sensor assembly defined in claim 1, further comprising a holographic diffraction element for diffracting the input light.

16. The GMR sensor assembly defined in claim 1, wherein the input light is capable of being incident at any angle and the detection means receives the TE resonance and the TM resonance at any angle.

17. A GMR sensor assembly comprising:

a waveguide structure configured to operate at or near one or more leaky modes of non-planar input light, an

A detector for TE and TM resonance comprising a sensor array having at least NxM sensor elements;

wherein the detector is arranged on the opposite side or the same side of a plane through the waveguide structure as the input light in order to receive a resonance signal transmitted or reflected through the plane of the waveguide structure.

18. The GMR sensor assembly defined in claim 17, wherein the waveguide structure is configured to receive a diverging beam of input light.

19. The GMR sensor assembly defined in claim 17, wherein the input light has known amplitude and phase characteristics.

20. The GMR sensor assembly defined in claim 17, wherein the waveguide structure is configured to receive a converging beam of input light.

21. The GMR sensor assembly defined in claim 17, wherein each sensor element is illuminated by an input light source taken from the group of a light emitting diode, a laser diode, and a vertical cavity surface emitting laser.

22. The GMR sensor assembly defined in claim 17, wherein the NxM sensor elements are configured to be illuminated by a single light source input through the light shaping port.