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

A compact guided mode resonance sensor for high-precision sensing using angle, spectrum, mode and polarization diversity

[0001] This application is that the application date is September 7, 2007, the application number is 200780041644. 3, the title of the invention is "Compact guided mode for high-precision sensing using angle, spectrum, modal and polarization diversity Divisional application of the application of "Resonance Sensor".

[0002] Priority

[0003] This application claims the priority of the provisional patent application serial number 60/163,705 filed on November 5, 1999, the complete content of which is expressly incorporated herein by reference without waiver.

[0004] This application also claims the priority of the provisional patent application serial number 60/164,089 filed on November 6, 1999, the complete content of which is expressly incorporated herein by reference without waiver.

[0005] This application also claims the priority of the provisional patent application serial number 60/825, 066 filed on September 8, 2006, the complete content of which is expressly incorporated herein by reference without waiver.

[0006] This application also claims priority to the U.S. Patent Application Serial No. 09/707, 435 filed on November 6, 2000, which requires provisional patent application serial numbers 60/163, 705 and 60/164, The priority of 089, its complete content is expressly incorporated into this article by reference without waiver.

Field of invention

[0007] The present disclosure provides an optical sensor operating in a resonant leaky mode with a periodic structure, wherein angular diversity, spectral diversity, modal diversity, and polarization diversity are advantageously applied to high-precision sensing in the form of a compact system . The cross-referenced data set fitted to the numerical model thus obtained provides increased precision and accuracy to enhance the quality of the sensing operation in a variety of applications.

[0008] Description of related knowledge

[0009] A variety of optical sensors for biological and chemical detection have been developed commercially and found in research literature. Example devices include surface plasmon resonance sensors, MEMS-based cantilever sensors, resonant mirrors, Bragg grating sensors, waveguide sensors, waveguide interferometric sensors, ellipsometry and grating coupled sensors. Although there are great differences in concept, function, and performance, the surface plasmon resonance (SPR) sensor among these devices is the closest to the guided mode resonance (GMR) sensor that is the subject of the present disclosure. Both the GMR sensor and the SPR sensor provide label-free biochemical detection capabilities.

[0010] The term surface plasmon (SP) refers to charge density oscillations induced by an electromagnetic field that can occur at the interface between a conductor and a dielectric (eg, a gold/glass interface). An SP mode can be generated by resonance excitation of parallel-polarized TM polarized light (TM polarization refers to the light whose electric field vector is in the plane of incidence), rather than TE polarized light (TE polarization refers to the light whose TE vector is orthogonal to the plane of incidence). Phase matching is produced by the following methods: using a metalized diffraction grating; or, as in prism coupling, by using total internal reflection obtained from a high-refractive-index material; or an evanescent field obtained by a guided wave. When the SPR surface wave is excited, the absorption minimum appears in a specific waveband. Although for these sensors, the angular sensitivity and spectral sensitivity are very high, the resolution is limited by the signal-to-noise ratio of the sensor response and the wide resonance spectral line width (about 50nm). In addition, when the dynamic range of the sensor is increased, the sensitivity of the sensor generally decreases. Since physically only a single polarization (TM) can be used for detection, the changes in refractive index and thickness cannot be determined simultaneously in one measurement. This is

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It is very important in chemical sensor applications, where binding kinetics include changes in the thickness of the sensor surface, and the background refractive index can vary according to the concentration of the analyte. The present disclosure provided here can improve some of the limitations of the prior art.

[0011] Magnusson et al. discovered a guided-mode resonant filter, which is adjustable to changes in resonance structural parameters. Therefore, spectral changes or angular changes caused by changes in layer thickness or changes in refractive index in the surrounding medium or device layers can be used to sense these changes. Wawro et al. discovered new implementations of GMR sensors and new possibilities for applying these GMR sensors when integrated with optical fibers. There are additional aspects of GMR sensors in different application scenarios.

[0012] Content overview

[0013] The present disclosure provides a label-less resonance sensor that works in a reflection mode (that is, a band stop filter) or works in a transmission mode (that is, a band pass filter), in which the GMR sensor is illuminated by a shaped angular spectrum element. These spectra are used to directly illuminate the linear detector array, or CCD matrix, or other detectors with the received signal while covering the range of incident angles of interest. When biomolecules are attached, or other changes of interest occur in the sensing area, these relatively narrow reflection or transmission angle spectra change their position on the detector matrix, resulting in a response to the molecular event of interest. Quantitative measurement. In addition, when the resonance comes from different TE and TM polarization responses, by acquiring dual TE/TM resonance data, switching the input light polarization state can be used to improve the quality of the sensing operation, or to measure additional parameters. In addition, if necessary, the spectrum of the input light can be tuned to pass through a set of discrete wavelengths, thereby spatially moving the position of the measured spectrum on the detector, providing the possibility of additional measurement accuracy. Finally, due to the existence of multiple leaky waveguide modes, sensor operation with multiple resonance peaks can further increase measurement accuracy.

[0014] These operational modality (angle, spectrum, mode and polarization) can be used in various combinations as needed. The sensor can be deployed in a compact, high-density platform that requires a minimum amount of reagents. Therefore, as explained in this disclosure, the method has multiple advantageous uses in actual sensor systems for high-precision measurement applications.

[0015] The present disclosure provides a GMR sensor assembly, including:

[0016] A waveguide structure configured to operate at or near one or more leaky modes;

[0017] A receiving device for receiving input light from a light source onto the waveguide structure to generate one or more leakage TE resonance modes and TM resonance modes;

[0018] A detection device for detecting one or more changes in the phase, waveform, and/or amplitude of each of the TE resonance and the TM resonance to allow the waveguide structure or its direct environment to be distinguished The physical state and the second physical state.

[0019] In the GMR sensor assembly provided in the present disclosure, the GMR sensor assembly may also be configured to work in a band stop mode.

[0020] The GMR sensor assembly may also be configured to operate in a bandpass mode.

[0021] The GMR sensor assembly may be configured to work in situations where the input light includes divergent light.

[0022] The GMR sensor assembly may be configured to work in situations where the input light includes concentrated light.

[0023] The GMR sensor assembly may further include a beam shaping element for forming an input wavefront of input light having known amplitude and phase characteristics.

[0024] The illumination source that generates the input wavefront of the input light can be selected from the group consisting of: light emitting diodes, laser diodes, vertical cavity surface emitting lasers, and filtered broadband light sources.

[0025] The waveguide structure may be configured to operate with substantially unpolarized input light.

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[0026] The GMR sensor assembly may also include means for applying a first known polarization state at a first known time and a second known polarization state at a second known time.

[0027] The GMR sensor assembly may further include means for selectively inputting input light of different wavelengths into the waveguide structure.

[0028] The detection device may be arranged such that the TE resonance and the TM resonance to be detected are resonances reflected from the waveguide structure onto the detection device.

[0029] The detection device may be arranged such that the TE resonance and the TM resonance to be detected are resonances transmitted to the detection device through the plane of the waveguide structure.

[0030] The detection device may be a matrix of photodetector elements.

[0031] The GMR sensor assembly can be configured to operate with more than one resonant leaky mode.

[0032] The GMR sensor assembly may also include a holographic diffractive element for diffracting input light.

[0033] The input light may be able to be incident at any angle, and the detection device may receive the TE resonance and

TM resonance.

[0034] The present disclosure also provides a GMR sensor assembly, including:

[0035] A waveguide structure configured to operate at or near one or more leaky modes of input light, and

[0036] The detector, which is used for TE resonance and TM resonance, includes a sensor array having at least NXM sensor elements.

[0037] In the GMR sensor assembly also provided in the present disclosure, the waveguide structure may be configured to receive a divergent beam of input light.

[0038] The detector may be arranged on a side of the plane passing through the waveguide structure opposite to the input light in order to receive the resonance signal transmitted through the plane of the waveguide structure.

[0039] The input light may have known amplitude and phase characteristics.

[0040] The waveguide structure may be configured to receive a condensed beam of input light.

[0041] The detector may be arranged on the same side of the plane passing through the waveguide structure as the input light in order to receive the resonance signal reflected from the waveguide structure.

[0042] Each sensor element can be illuminated by an input light source, which is taken from the group of a light emitting diode, a laser diode, and a vertical cavity surface emitting laser.

[0043] NXM sensor elements may be configured to be illuminated by a single light source input through the light shaping port.

Description of the drawings

[0044] In order to help those skilled in the art to understand the use and implementation of the present disclosure, for the sake of clarity and convenience, reference is made to the attached drawings.

[0045] FIG. 1 shows an example of a biomolecule binding event on the surface of a biosensor.

[0046] FIG. 2 provides a schematic diagram of an exemplary bacterial detection.

[0047] FIG. 3 gives an explanation of the diffraction of the resonant photonic-crystal waveguide structure, where the zero-order state and the leakage mode resonance excitation are clearly defined.

[0048] FIG. 4 provides a comparison between experiment and theory of the dielectric resonance element.

[0049] FIG. 5 shows the electric field distribution of the leakage mode when the element in FIG. 4 resonates.

[0050] FIG. 6 shows the calculated instantaneous electromagnetic standing wave diagram associated with the leakage mode at the maximum value in FIG. 5

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"Snapshot".

[0051] FIG. 7 shows a guided mode resonant refractive index sensor using TE and TM polarization diversity, and describes the structure that produces the calculated response.

[0052] FIG. 8 shows the corresponding TE polarization resonance wavelength shift for the large dynamic range sensing of the example in FIG. 7.

[0053] FIG. 9 shows thickness sensing in air.

[0054] FIG. 10 provides the measured spectral response of the GMR sensor on the surface of the TE polarization (top left) device in the air, and the surface of the device is modified with a silane chemical connector (bottom left). It also shows a scanning electron micrograph (SEM) (top right) and a device model (bottom right).

[0055] FIG. 11 depicts a submicron grating contact printing technique and an electron microscopic image of a grating with a period of 520-nm that is contact-printed in an optical adhesive medium.

[0056] FIG. 12 shows the calculated TE polarization angle response of the GMR sensor for different additional thicknesses (dbio) of the biological material, and FIG. 13 shows the corresponding TM-polarization response.

[0057] FIG. 14 is a schematic diagram of the proposed resonant sensor system with dual polarization detection. From a light source, such as LED or

The divergent beams of LD or VCSEL are incident on the sensor at different angles at the same time.

[0058] FIG. 15 shows an exemplary GMR sensor implementation with a divergent input beam and an associated detector using polarization diversity detection.

[0059] FIG. 16 is a schematic diagram of an NXM microwell array of any size, which integrates a GMR sensor/detector unit as shown in detail in FIG. 15.

[0060] FIG. 17 explains polarization sensing in transmission mode, in which the peak value (or minimum) of TE and the peak value (or minimum) of TM are guided to the detector array by means of reflections at the walls of the micropores.

[0061] FIG. 18 is an illustration of the experimental use of GMR sensor polarization diversity to quantify the binding of biotin to a silane-coated sensor surface. The molecular attachment event is monitored as a function of time. The results for TE and TM polarization are shown.

[0062] FIG. 19 shows an exemplary element structure that achieves the characteristics of a band-pass filter, and thus realizes a GMR sensor that works in a transmission mode. This component can be implemented in a silicon-on-insulator (S0I) material system.

[0063] FIG. 20 provides calculated transmission-type SOI resonance sensor spectra for different thicknesses of increased biological materials. The sensor works in the air and has incident waves, reflected waves (R), and transmitted waves (T) as shown in FIG. 19. In this example, the incident wave is TM polarized. The sensor design is shown in Figure 19.

[0064] FIG. 21 depicts a sensor/detector structure related to a sensing operation in a direct transmission manner.

[0065] FIG. 22 shows the calculated TE angle response for the different thicknesses of the biological material added, for example, in relation to the GMR sensor design shown in FIG. 21.

[0066] FIG. 23 shows the calculated TE angle response of the GMR sensor structure in FIG. 21 for varying input wavelengths to show wavelength diversity. In this calculation, dbio = 100nm divergent input beam automatically covers the angle range of interest.

[0067] FIG. 24 shows the calculated TM angular response of the GMR bandpass sensor shown schematically in FIG. 19 for different biological layer thicknesses. The divergent incident beam automatically covers the angular range of interest. In this example, the parameters are the same as in Figure 19, and the input wavelength is set to λ = 1. 5436 μ m_o

[0068] FIG. 25 shows the related sensor/detector architecture for sensing operations with direct, polarization-enhanced detection in a compact layout. The TE and TM resonance zero (or peak) position on the detector array passes through the virtual

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The line arrows indicate schematically.

[0069] FIG. 26 shows a related sensor/detector architecture for sensing operations with a flow channel in a biological or chemical sensing system that directly transmits through a microfluid. Figure 27 shows an HTS platform with a single-source plane wave input and a wavefront shaped with a lens array to realize an angularly addressable GMR sensor array without moving parts.

[0070] FIG. 28 belongs to an HTS platform, which has a single source input and a wavefront shaped by a lens array to realize an angularly addressable GMR sensor array in a microfluidic environment. Figure 29 shows a GMR sensor manufactured in a plastic or glass medium by imprinting and molding.

[0071] FIG. 30 belongs to a GMR sensor array fabricated in a silicon-on-insulator material system.

[0072] FIG. 31 provides the calculated TE-reflection coefficient angular response of the GMR multi-mode sensor for different thicknesses (dbio) of increased biomaterials.

[0073] FIG. 32 provides the calculated angular transmittance spectrum of the multimode sensor corresponding to FIG. 31.

[0074] FIG. 33 shows the calculated transmittance spectrum corresponding to the device parameters in FIG. 31, where the incident is normal and θ=0, showing multimode resonance characteristics. In the wavelength range shown, this multi-mode biosensor works with leaky modes TEO, TEI and TE2. In this exemplary case, the highest sensitivity is provided by the TE2 mode.

[0075] FIG. 34 shows a single-source system using a splitter and optical fiber transmission.

[0076] FIG. 35 shows a single-channel schematic diagram of a label-free guided mode resonance sensor system for detecting chemical or biological analytes bound to antibodies.

[0077] FIG. 36 shows a reflective architecture that uses an optical fiber array for optical transmission. Figure 37 shows a reflective sensor system that uses a scan line source.

[0078] Detailed Description of Exemplary Embodiments

[0079]

[0080] The inventors have proposed that by changing the refractive index and/or thickness of the resonant waveguide grating, its resonant frequency can be changed or tuned. The inventors have discovered that this idea can be applied to biosensors, because by tracking the shift of the corresponding resonance wavelength with a spectrometer, the accumulation of the attached biological layer can be monitored in real time without the use of chemical tags. Therefore, the rate of binding between the analyte and its designated receptor can be determined; 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 waveguide grating layer can be measured. Therefore, a new class of highly sensitive biological and chemical sensors can be realized. This sensor technology is widely used in medical diagnosis, drug development, industrial process control, genomics, environmental monitoring, and homeland security.

[0081] To state the application of an 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 method is very useful because this sensor technology can provide improved 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 specific proteins or inhibit target reactions. The purpose of high-throughput screening (HTS) is to exclude compounds with no prospects before further development costs are incurred. The current HTS technology usually uses fluorescent chemical tags or radioactive chemical tags as indicators of biological activity. Due to the complexity of indicator-compound combination, it is sometimes necessary to use new indicator technology or reaction chemistry to carefully design a completely new assay. There are more and more requirements for novel sensor technologies, which do not require labels, and allow for minimal laboratory development (using easily accessible antibodies-antigens, nucleic acids, and other highly selective biological materials) to perform real-time processing of a variety of materials Selectively screen. Reduce errors from screening variables (such as temperature, and background fluid changes)

The ability, and the ability to monitor binding dynamics 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 requirements for high-throughput screening applications.

[0082] The sensor includes a periodic dielectric waveguide (also called a photonic crystal) in which a resonant leaky mode is excited by incident light waves. The incident broadband light is effectively reflected in a narrow spectral band, and the center wavelength of the narrow spectral band is very sensitive to the chemical reaction that occurs on the surface of the sensor element. The interaction of the target analyte with the biochemical layer on the sensor surface produces a measurable spectral shift that directly recognizes the binding event without additional processing or foreign tags. A bioselective layer (such as an antibody) can be bound to the sensor surface to give specificity during operation, as shown in Figure 1. With the right from the nanometer level (< 0. 1 Angstrom) The sensor design with sensitivity to thickness changes as large as a few microns has been analyzed. Therefore, the same sensor technology can be used to detect the binding events of small molecule drugs (< lnm) and proteins (< 10nm) and larger bacterial analytes (> lum), as shown in Figure 2. High resolution (obtained by narrow, well-defined resonance peaks) and high sensitivity (related to surface local mode leakage) provide high possibilities for accurately detecting an event. In addition, the two main polarization states have independent resonance peaks to accurately sense the binding events of biomaterials. This feature makes possible the ability to distinguish between average thickness changes and average density changes that occur on the sensor surface. Therefore, the sensor resonance response to the target chemical binding event (which includes the molecular conformation change) can be distinguished from the sensor resonance response of the non-binding material staying on the sensor surface, thereby reducing the occurrence of false positive readings. .

[0083] GMR sensor technology is very versatile. Biomolecular reactions related to an independent sensor or sensor elements in an array can be simultaneously measured using multiple characteristics of light, including angular spectrum, wavelength spectrum, and polarization. In addition, the GMR element itself can be designed to be in a single peak generated by a single leakage mode (called TEo fundamental mode), or in multiple leakage modes (such as TE₀, ΤΕι and TE2 modes) produced multiple peaks, showing different polarization resonance. Through correct sensor design, such multiple modes can be excited in the area of the angular spectrum and wavelength spectrum of interest. The electromagnetic field structure of the resonant mode can be constructed so that the sensor works in the evanescent tail of the sensing area, or, alternatively, it works as a bulk mode sensor, in which the leakage mode is completely Contains the sensing area. In fact, a specific working leakage mode can be selected to maximize the light-measurand interaction to improve detection sensitivity. For example, in a specific design, the operation in TE? mode can produce better than TE₀The result of the model. Compared with the information about molecular events collected by other means, the detection scheme summarized here increases the quantity and reliability of information about molecular events collected.

[0084] This sensor concept can be widely used according to materials, operating wavelengths and design structures. It is versatile because only the sensitizing surface layer needs to be chemically altered to detect different species. It is possible to work in both air and liquid environments. Due to the flexibility of material selection, environmentally friendly dielectrics can be selected for the manufacture of sensor elements. Applicable materials include polymers, semiconductors, glass, metals and dielectrics.

[0085] Guided mode resonance effect

[0086] Figure 3 shows the interaction of a thin film waveguide grating (photonic crystal plate) and an incident plane wave. As period A decreases, higher-order transmission waves are increasingly cut off until the zero-order regime in Figure 3(b) is obtained._oIf the structure contains a suitable waveguide, the first-order wave evanescent or cut off at the moment can cause resonance by coupling to the leakage mode. In fact, the zero-order state is usually preferred because there is no energy wasted in transmitting the high-order diffracted waves as shown in Figure 3(a).

[0087] This thin film structure including a waveguide layer and periodic elements (photonic crystals) exhibits a guided mode resonance (GMR) effect under the correct conditions. When the incident wave passes through the periodic element and matches the phase of the leakage mode of the waveguide as shown in Figure 3(c), when it propagates along the waveguide and interferes constructively with the directly reflected wave, it is reflected in the specular reflection direction with a reflection coefficient R Up and then radiate,

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As shown in Figure 3(c). On the contrary, equivalently, the phase of the re-radiation leakage mode in the forward direction and the direct transmission wave (transmittance Τ) direction in Figure 3(c) is out of phase with the direct unguided T wave by π radians, thus eliminating Transmitted light.

[0088] Experimental band stop filter example

[0089] FIG. 4 shows the measured and calculated spectral reflectance of the dielectric guided mode resonant 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 that the peak efficiency of a plane incident wave is 100%, in practice, the peak efficiency is reduced due to different factors, such as material and scattering loss, incident beam divergence, and lateral device size; here is the experiment The peak efficiency is 90%. This kind of resonance element is made by depositing a Hf0 on a fused silica substrate (1 inch diameter).₂Layer (about 210nm) and a SiO? layer (about 135nm) manufacturing. The SiO? grating is obtained through a series of processing, including the holographic recording of the photoresist mask grating (period A = 446nm) with Ar+UV laser (human = 364nm) in the Lloyd mirror interference setting, Grow and deposit about 10nm Cr mask layer on the photoresist grating, peel off the photoresist grating, and then use CF4 to Si0₂The layer undergoes reactive ion etching. The apparent surface roughness in the SEM contributes to the reduction of peak efficiency.

[0090] Leaky Mode Field Structure

[0091] In addition to the reflection/transmission characteristics of the propagating electromagnetic waves, the near-field characteristics of the resonant periodic lattice, including localization and field strength enhancement, are all concerns in sensor applications. The calculated near field pattern associated with the manufactured example structure shown in FIG. 4 is shown in FIG. 5. A rigorous coupled wave analysis (RCWA) is used to obtain numerical results to provide quantitative information about the relative field strength and spatial extent related to the near field. As shown in Figure 5, the zero order S. The wave (S. represents the zero-order electric field) propagates with a reflected wave amplitude close to unit 1, and through interference with the input wave of unit amplitude, the standing wave diagram shown is generated. Therefore, at resonance, most of the energy is reflected back. At the same time, the first-order evanescent diffracted waves denoted by S] and J constitute a counter-propagating leaky mode in this example. In this particular sensor, the maximum field value is located in the homogeneous layer, and the evanescent tail gradually penetrates into the substrate and surface layer, as clearly shown in Figure 5. Figure 6 shows St and S propagated from opposite directions at a certain moment₊₁A graph of standing waves formed by waves. Since the S±i spatial harmonics correspond to local waves, they can be very strong at resonance. According to the level of grating modulation (Δ ε = n_H²-nL²), the field amplitude in the layer can be about 10-1000 times the amplitude of the incident wave, which represents a large increase in the area intensity 1-8. The maximum amplitude of S] is approximately inversely proportional to the modulation intensity. Generally, small modulation means narrow spectral line width λ and large resonator Q factor Q = λ / Δ λ ο [0092] Sample sensor response and sensitivity

[0093] The calculated spectral response of a single-layer sensor designed for use in a liquid environment is given in FIG. 7. This sensor can be made of SisNg and patterned by plasma etching to produce a diffractive layer. The one-dimensional resonant guided wave grating structure has different reflection coefficient peaks for TE (electric vector orthogonal to the plane) and TM polarized incident waves. Calculations show that, assuming that the resolution of the spectrometer is 0.01nm, the design can resolve the average refractive index change of 3xl0 "5 refractive index units (RIU). For the grating structure (n_c = n_L = 1. 3 to 1.8) The wide refractive index change of the contacting medium, and the nearly linear wavelength shift can be maintained (Figure 8), making this a general-purpose sensor with a large dynamic range. The sensitivity of a biosensor is defined as the measured response (such as peak wavelength shift) for a specific amount of material being detected. This represents the maximum achievable sensitivity to the analyte being detected. The sensor resolution includes the limitations of the actual components, such as the resolution of the spectroscopic device, the accuracy of the power meter, the response of the biological selection reagent, and the peak shape or spectral line width. 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, because a narrow spectral line can generally improve the resolution of the wavelength shift; a resonant waveguide grating sensor usually has a narrowness on the order of 1 nm. Spectral line width, which can be controlled by design. Although resonant sensors can monitor small changes in refractive index, they can also be used to detect the thickness of the sensor surface

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The change, for the actual material and wavelength, is represented by the calculation result in Figure 9.

[0094] Sample sensor results

[0095] As shown in FIG. 10, GMR sensing technology for biosensing applications has been used to analyze protein binding in the air, in which a 2-layer resonant element illuminated with normal incidence is used. In this example, the clean grating surface was first treated with a 3% solution of aminopropyltrimethoxysilane (Sigma) in methanol, and then chemically modified with amino groups (Figure 10, upper left). The device was then rinsed with a solution of bovine serum albumin (BSA, 100 mg/ml, Sigma), and the deposited 38 nm thick BSA layer produced a 6.4 nm reflected resonance peak spectral shift (Figure 10 bottom left). Note that the smallest signal attenuation is caused by the biomaterial layer on the sensor surface, and the reflectivity remains at about 90% before and after the BSA is attached.

[0096] Manufacturing Resonant Sensing Elements by Contact Printing

[0097] In addition to the methods described so far, an economical contact printing method is attractive for imprinting optical polymers with the desired submicron grating pattern. Silicone grating stamps can be used to imprint gratings onto a thin layer of UV-curable optical adhesive (Figure 11(a)). By spraying a thin layer of Sis% or other suitable medium, the waveguide layer is deposited on the top surface of the grating. Optionally, the grating is coated with high index spin-on Ti0₂Polymer film to produce high-quality resonant sensing elements. An example of a contact-printed grating is shown in Figure 11 (b).

[0098] Dual-mode TE/TM polarization GMR sensor

[0099] Simultaneous detection of TE and TM resonance shifts attached to the biological layer of the sensor can greatly improve the quality of the sensing operation. This allows accurate determination of all biological layer properties; that is, refractive index and thickness. Figures 12 and 13 show the calculation results showing the resonance shift for the angles of the two polarizations. In fact, appropriate element design can be used to achieve moderate angular TE/TM resonance separation, which makes it possible to use light-emitting diodes (LEDs, which may be filtered to achieve spectral contraction), or vertical cavity surface emitting lasers (VCSEL), or λ = When the 850nm laser diode (LD) provides divergent illumination that automatically covers the range of the angle of interest, it can simultaneously detect two signals on the linear detector array, as shown in Figure 14. In this example, the interrogating light beam enters through the covering medium, such as fused silica or plastic sheet (refractive index rabbit). The light distribution of interest appears as a reflection peak on the detector. This example illustrates the use of high refractive index polymer materials as homogeneous and periodic layers. This can be made, for example, by using a silicone mold to form the grating in a commercial TiO2 rich, thermally curable or UV-curable polymer medium spin-coated on a support wafer. Alternatively, the high refractive index waveguide layer can be deposited on the support wafer, and the periodic layer is molded on top of it.

[0100] FIG. 15 illustrates the application of an embodiment of the present invention in a biomolecule sensing environment. Although unpolarized light will provide TE and TM resonance peaks on the detector array or matrix, the signal-to-noise ratio (S/Ν) can be improved in the following ways: As shown in Figure 15, switching between polarization states, and in time The upper scan detector is synchronized with polarization switching to obtain independent TE and TM signals. In addition, in order to further improve the signal-to-noise ratio, the light source can be equipped with a beam shaping element to shape the light distribution on the sensor in the best way. In fact, in some applications, it may be desirable to use convergent rather than divergent wavefronts. Such beam shaping can be done, for example, by suitable holographic or diffractive optical elements. This allows wavefronts of arbitrary amplitude and phase distribution to be generated. Figure 16 shows the use of the device of Figure 15 in a porous system. In the pharmaceutical industry, microplates are used for effective screening of pharmaceutical compounds, and the application of this system can find advantageous use modes in it. Figure 17 shows an additional architecture in which the detector matrix is now mounted to the top of the hole and the transmission zero (or peak) associated with the TE and TM resonance is measured. When the biological layer is added to the sensor, the zero position on the detector shifts, allowing the quantification of binding events. In this example, the incident wave is incident at an angle, and the signal is recovered

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Recovered by reflection away from the wall of the micropore.

[0101] Preliminary experiments have confirmed the polarization diversity characteristics of the technology, which provides independent resonance peak shifts for each polarization (TE and TM), thereby providing a method to obtain high detection accuracy as described above . Figure 18 shows example results for GMR biosensor applications.

[0102] Bandpass GMR sensor

[0103] Transmission resonance sensor elements, or band-pass resonance sensor elements can be manufactured with a variety of media, including silicon-on-insulator (soi), silicon-on-sapphire (sos), and directly imprintable heat-curable or UV-curable polymerization Things. The formation of the periodic layer can be achieved by traditional methods, including e-beam writing and etching with a pre-master, holographic interferometry, and nanoimprint lithography. To clarify this embodiment, Figure 19 shows a transmissive sensor designed with an exemplary SOI structure. Figure 20 shows that the thickness of the sensor pair is cL. The layer of biomolecules increases the response to the sensor surface. The transmission peak changes its spectral position in a sensitive way. This figure should be compared, for example, with the sensors in Figures 12-14 operating in the reflective state. 6nm. When the biological material is attached to the sensor surface, the rate of the resonance wavelength shift is basically that for every 1 nanometer increase in the material, the spectral shift is about 1.6 nm. Note the unique profile design to achieve this in this example.

[0104] Flat and compact GMR sensor and array sensor system

[0105] For ease of manufacturing and cost reduction, we now disclose the implementation of the present invention in the form of the flat system proposed above. The sensor works in transmission mode. Therefore, when light enters the sensor, it is in contact with the medium, and the interaction between the medium and the sensor is of concern. The light travels through the medium and reaches the detector, where the minimum transmission intensity (band stop filter) or the maximum intensity (band pass filter) is measured on the detector. The spatial shift of these light distribution positions allows the quantification of the main characteristics of the biomolecule binding reaction.

[0106] FIG. 21 illustrates this concept for a single sensor that interrogates with a diverging beam, which comes from a laser diode (LD), a light emitting diode (LED), or a vertical cavity surface emitting laser (VCSEL). Polarization, beam shaping or spectral line narrowing functions can be integrated into the light source as required. The detector is located on the opposite side of the sensing body, as shown in the figure. Figure 22 shows the calculated intensity distribution (signal) on the detector matrix for a GMR sensor operating in band-stop mode, resulting in a peak in reflection and an accompanying minimum in transmission. In this example, the input wavelength is 850nm. The two minimums appear at symmetrical angular positions with respect to the sensor's normal line, because the resonant wavelength incident on the normal line is different from the resonant wavelength incident on the illegal line. These two minimum values can be used to enhance the accuracy of the sensing operation because two angular offsets are obtained. In this example of Figure 22, for the increased biological layer thickness d_bi0 = 0, the minimum value appears in θ~6. , And for d_bi0 = 100nm angle resonance at 0~5. . Figure 23 shows wavelength diversity; that is, by tuning the input wavelength to a discrete set of wavelengths, additional data points can be collected to improve the accuracy of data analysis and fitting to a numerical model. As the wavelength changes, the resonance angle and light distribution of the sensor are also changing. In addition, the location of the wavelength control minimum on the detector provides flexibility in designating a dedicated detector area for each GMR sensor pixel in the sensor array.

[0107] As explained in conjunction with FIG. 20, we have designed many resonant filters that work at the transmission peak, that is, as a band-pass filter. In this example, for the design shown in Figure 21, the maximum intensity (instead of the minimum) will appear on the detector array. Such transmissive elements can be designed very effectively with high refractive index media such as silicon. Fig. 24 shows the angular diversity biosensing performed with a band-pass filter. By setting the wavelength so that the device maintains the transmission peak for the undisturbed surface, an ultra-high sensitivity arrangement is obtained. When the detuning caused by the accumulation of the biological layer changes the sensor from the band pass state to the band stop state at normal incidence, the transmission angle spectrum changes the fastest, as shown in Figure 24. Therefore, the increase of the sub-nano biofilm will be directly measured by a simple intensity change on the output side of the detector. by

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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 Figure 24.

[0108] Another implementation of polarization diversity is schematically shown in FIG. 25, in which four simultaneous minimums (or peaks) are monitored for high-precision biosensing. Figure 26 provides an embodiment that can be used for sensing in a microfluidic system.

[0109] Due to the growing number of biological and pharmaceutical objects, there is an increasing need to invent new methods to describe chemical activities in a massively parallel manner. At the same time, it is necessary to reduce the cost of HTS by allocating the minimum amount of reagents for the test. Therefore, there is a trend toward nanoliter liquid distribution in the industry. The GMR sensor technology proposed here can be used to meet these needs. The flat transmission form proposed and explained above enables the development of multi-channel sensor systems. Existing and developing CCD and CMOS detector matrix technologies with pixels as low as 5-10 μm make it possible to accurately measure the intensity distribution and its changes. Nanoimprint technology and precision thin film methods make it possible to manufacture the required GMR sensor array. Molding methods can be applied to formatting and imposition of larger components in these arrays.

[0110] FIG. 27 shows a system capable of parallel biosensing according to the embodiment of the present invention described in the present disclosure. The GMR sensor mounted to the microplate is addressed by the angular spectrum, which is generated by converting the incident plane wave into a spherical or cylindrical wave with a suitably designed diffractive or refractive micro lens array, as shown in the figure. An array of detectors mounted above receives signals for accurate biological sensing. Figure 28 shows a similar operation, in which the sensor is excited by the directional flow in the flow channel in the microfluidic component; Figure 28 omits the complicated channel structure and details related to the actual microfluidic device.

[0111] Practical cost-effective GMR arrays can be manufactured with glass or plastic media. As an example, a diffractive or refractive lens array with a given focal length and diameter on a plastic substrate can be purchased from several manufacturers at low prices. On the blank side of the substrate opposite to the lens array, a high refractive index spin-coated TiO2 polymer film is applied. Next, as shown in FIG. 11, a specially designed silicone stamp with an appropriate period is used to imprint the grating pattern to produce a GMR sensor. Then, a spill wall that separates different solutions and avoids cross-contamination can be installed by molding. Alternatively, the high refractive index film is first deposited on the substrate, and then the grating pattern is applied to the top. The resulting GMR array is shown in Figure 29. Figure 30 shows a conceptual GMR array fabricated with SOI to take advantage of existing silicon-based micromachining methods.

[0112] Multimode GMR sensor

[0113] Another method to improve detection reliability is to increase the number of resonant leaky modes of operation and thus apply a richer spectrum for sensing and precise curve fitting. In this way, multiple resonance peaks due to the existence of multiple waveguide modes can be generated and monitored. These multiple modes provide different spectral features, which can be used in precision sensing. Figure 31 shows the TE polarization response of a dual-layer GMR sensor. Its parameters are described in the text and it is assumed that there is no sidewall attached. With a fixed input wavelength, the reflection spectrum shows several resonance peaks originating from different leakage modes. As shown in Figure 31, when a biological layer is added, the spectrum responds with a measurable change in the angular spectrum. This spectrum will be monitored in reflection using the architecture shown in Figure 16, for example. Fig. 32 shows the corresponding transmission spectra as monitored in the system of Fig. 27, for example. Figure 33 shows the wavelength spectrum of this sensor at normal incidence, showing three leaked modes in the spectrum band shown. Due to the specific distribution of the electromagnetic field in this sensor, the TE₂The operation of the mode gives the highest sensitivity, that is, each increase in the unit thickness produces the maximum angular shift and spectral shift, as shown in Figure 31-33.

[0114] Referring now to FIGS. 34, 35 and 36, first referring to FIG. 34, the use of the GMR sensor platform in the GMR sensor platform is described.

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Sensor/detector architecture for fiber-coupled light transmission. Figure 34 shows a single-source system that uses a splitter and optical fiber transmission. A single light source is divided (using a beam splitter) into "M" channels and incident on the sensor array through optical fibers. The light from each fiber is shaped by an integrated or external lens/DOE, and then incident on the sensor element in free space. Alternatively, the divergent light leaving the optical fiber can be directly incident on the sensor element without using a beam-shaping element. As part of the system design, the fiber can be selected based on its numerical aperture or other characteristics. Polarization elements or polarization maintaining fibers can be used in the system to control one polarization state (multiple polarization states) incident on the sensor element. The incident wavelength can be tunable, thus allowing angular and spectral tuning in a single system.

[0115] The system can be constructed as a transmissive system, in which the light transmitted through the sensor array is detected with a detector matrix located on the side opposite to the incident light of the sensor array, as described. The system can also be constructed as a reflection system in which light is incident on the array at an angle, and the light beam reflected from the array is detected by a detector matrix arranged on the same side as the incident light of the array.

[0116] FIG. 35 depicts a single-channel schematic diagram of a label-free guided mode resonance sensor system for detecting chemical or biological analytes bound to antibodies. The antibody is represented by a "Y", and the analyte is represented by a ball in the cup-shaped part of the "Y". Antibodies should be selected based on one analyte or multiple analytes being detected. In some embodiments, bovine, camel or alpaca serum antibodies are used, and the present invention is not limited to these antibodies.

[0117] During operation, the divergent light beam from the fiber-coupled laser diode is incident on the sensor at a continuous angle range. When a binding event occurs on the sensor surface (through the binding of the analyte to the antibody), the change in the resonant peak can be tracked as a function of the angle of incidence. For the TE and TM polarization states of incident light, resonance occurs at different angles, which makes high-accuracy, cross-reference detection possible.

[0118] FIG. 36 shows a multi-channel array. It has a reflective architecture, which uses an optical fiber array for optical transmission. The fiber array can also be scanned across the sensor array (for either reflection or transmission).

[0119] For example, to screen an MXN sensor array, an M-fiber array can be scanned across the bottom of the N rows of sensor elements. Scanning can be performed in the following ways: (a) moving the optical fiber array + detector matrix across the sensor plate, or (b) moving the sensor plate across the optical fiber array + detector matrix.

[0120] FIG. 37 depicts a sensor/detector architecture using a scan line source. Although FIG. 37 describes a reflective sensor, it can also be constructed as a transmissive sensor by placing the detector element on the side of the array plate opposite to the incident light.

[0121] The light source may be a single-wavelength (or wavelength-selectable) source, which is shaped by a linear focusing element (for example, a cylindrical lens). The linear focusing light simultaneously irradiates the M-sensor elements in the MXN sensor array. The reflection response is measured on M rows of the detector matrix (for example, a row of CCD detector elements). The light line source and detector element assembly can be scanned across the bottom of the sensor board to effectively read the MXN sensor array. Note: The linear focusing element can also be used as a beam shaping element (for example, it can be divergent, convergent or any designed wavefront).

[0122] The following additional embodiments are also contemplated:

[0123] A GMR sensor assembly comprising a waveguide structure and a detector for TE and TM resonance, the waveguide structure being constructed to work at or near one or more leaky modes of incident light, the detector Includes a sensor array with at least NXM sensor elements.

[0124] The GMR sensor assembly defined above further includes a refractive lens to shape the illumination light.

[0125] The GMR sensor assembly defined above further includes an array of refractive lenses to shape the illumination light.

[0126] The GMR sensor assembly defined above further includes a diffractive lens to shape the illumination light.

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[0127] The GMR sensor assembly defined above further includes a device for determining the polarization state and waveform characteristics of the wavefront of the input light.

[0128] The GMR sensor assembly defined above further includes a device for providing input light having at least two different wavelengths.

[0129] The GMR sensor assembly defined above further includes a device for providing input light having at least a first polarization characteristic and a second polarization characteristic.

[0130] The GMR sensor assembly defined above further includes a device for detecting at least two resonance modes.

[0131] The GMR sensor assembly defined above further includes an integrated microfluidic flow channel adjacent to the waveguide structure.

[0132] The GMR sensor assembly defined above further includes a substrate, a light adjustment element, and a microvial integrated into a transparent medium.

[0133] The GMR sensor assembly defined above, wherein the array is arranged on an integrated medium selected from the group of semiconductors, semiconductor/dielectric mixtures, semiconductor/dielectric/metal mixtures, and dielectrics.

[0134] The GMR sensor assembly defined above, wherein the array sensor element is physically separated from the illumination source.

[0135] The GMR sensor assembly defined above, wherein the array sensor element is integrated with the illumination input light source.

[0136] The GMR sensor assembly defined above further includes a readout detector in the form of a compact biochip or microbench.

[0137] A guided mode resonance sensor, wherein the illumination source is a coupled optical fiber or waveguide.

[0138] A guided mode resonance sensor in which a waveguide or an optical fiber is selected to have a specific numerical aperture, polarization maintaining characteristics, or material specifications by design.

[0139] A guided mode resonance sensor, in which the illumination source is focused to a line with a line focusing element.

[0140] A guided mode resonance sensor, wherein the illumination source is focused to a line with a linear focusing element, and the linear focusing element includes a cylindrical lens.

[0141] A guided mode resonance sensor, wherein the illumination source and detector element are scanned across the sensor array.

[0142] A guided mode resonance sensor in which a single light source is divided into several channels by a spectroscope.

[0143] A guided mode resonance sensor with an optical fiber/waveguide array, which is used to transmit light to the sensor element array.

[0144] It is further understood from the above description that different modifications and changes can be used in the preferred embodiments of the present invention without departing from its true spirit. This description is for illustrative purposes only and should not be interpreted as a limitation. The scope of the present invention should be limited only by the language of the following claims.

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