Optofluidic analyte detection systems using multi-mode interference waveguides

Abstract

To provide systems and methods for optofluidic analyte detection and analysis using multi-mode interference (MMI) waveguides.SOLUTION: An MMI waveguide 102 intersects three different liquid-core waveguides 104, 106 and 108 at different distances L (in the direction of propagation of light along the MMI waveguide) from the beginning of the MMI waveguide (e.g., from an optical input port of the MMI waveguide). In some embodiments, the liquid-core waveguides are configured to receive one or more liquid solutions comprising one or more fluorescence-tagged analytes to be detected by a system, such as molecules, particles, biomarkers, nucleic acids, DNA, proteins, and the like.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] The present disclosure generally relates to optofluidic systems, and more particularly, to systems, methods, and techniques for using multimode interference (MMI) waveguides for spectral multiplexing and / or analyte detection within microfluidic channels.

Background Art

[0002] Optofluidics integrates photonics and microfluidic technology, resulting in very compact and highly sensitive biomedical sensors. Anti-resonant reflecting optical waveguide (ARROW) type optofluidic devices have been found to be a highly sensitive and reconfigurable platform for fluorescence spectroscopy.

[0003] Furthermore, spectrally dependent multi-spot excitation of analytes in capillaries and on-chip microchannels has been recently introduced and demonstrated to be a powerful method for performing multi-item simultaneous optical analysis of biomarkers and other targets. The principle is based on creating a wavelength-dependent spot pattern within the channel through which the target flows using an integrated optical element, such as a multimode interference (MMI) waveguide. To obtain the best performance and sensitivity, the spot pattern should be as clean as possible, with light hitting only the spot positions and little background in between. In addition, the signals created by multiple excitation wavelengths should be easily picked up by an appropriate signal processing algorithm. When one MMI waveguide is used, the background between spots can be non-zero, and the intensities of the different fluorescence signals at the collected wavelengths may vary so much as to cause color assignment problems.

[0004] In addition, optical multiplexing and demultiplexing - the spatial combination or separation of signals of different wavelengths - are important components for optoelectronic systems, such as optical communication or integrated biosensors. Established waveguide-based methods typically utilize arrayed waveguide gratings (AWGs), but these may not always be ideal, for example, when trying to avoid curved waveguides or when the wavelengths under consideration cover a relatively wide range. The latter applies, for example, to applications of fluorescence multiplex detection using commercially available dyes in the visible range.

[0005] Furthermore, when creating wavelength-dependent spot patterns using MMI waveguides, MMI waveguides made of solid materials may not be able to produce perfect spot patterns due to refractive index inhomogeneities, and the best patterns may deviate from the desired wavelengths due to variations in refractive index or slight changes in dimensions resulting from microfabrication processes such as standard CMOS or MEMS.

Summary of the Invention

Problems to be Solved by the Invention

[0006] As described above, if multiple target molecules can be identified with high sensitivity, the capabilities of optofluidic devices are improved. In recent years, therefore, MMI waveguides have been used for multiplex detection of multiple targets by creating spectrum-dependent excitation patterns within a single fluid channel. In addition, the signal-to-noise ratio and sensitivity of these biosensors have been further increased by the multi-spot excitation method. MMI multi-spot excitation can also be used for spatial multiplex detection by using different MMI waveguides in different channels. However, more enhanced and improved multiplexing techniques are still required. As disclosed herein, by combining spectral multiplexing and spatial multiplexing, the multiplexing power and capabilities of optofluidic devices may be further enhanced.

Means for Solving the Problems

[0007] According to some embodiments, the present disclosure describes a system and method for detecting optically active targets in a plurality of microfluidic channels by combining spatial and spectral multiplexing by using one MMI waveguide that intersects a fluid channel containing a target analyte.

[0008] As further described above, to obtain the best performance and sensitivity for creating a multi-spot pattern using an MMI waveguide, the spot pattern should be as clean as possible, with light hitting only the spot positions and little background in between. In addition, signals created by multiple excitation waveguides should be easily picked up by appropriate signal processing algorithms. When one MMI waveguide is used, the inter-spot background may be non-zero, and the intensities of the collected fluorescence signals at different wavelengths may vary enough to cause color assignment problems.

[0009] Therefore, the present disclosure describes a system, method, and technique for spectral multiplexing detection of optically active targets in a microfluidic channel by a two-stage photonic structure that creates spatially separated color-dependent excitation spot patterns. In some embodiments, the multi-stage approach features a first stage for spatially separating light at different wavelengths (multiplexing) and a second stage for using the multiplexed light to create wavelength-dependent spot patterns in different parts of a capillary or channel. As described below, the techniques disclosed herein may address the issue of distinguishing colors from each other using one MMI waveguide, regardless of the inter-spot background signal.

[0010] Furthermore, as described above, certain known methods using waveguides for optical multiplexing and / or demultiplexing, such as using an AWG, may not be ideal when, for example, it is desired to avoid curved waveguides, when the wavelengths under consideration are at relatively wide intervals, and / or when the intended application is fluorescence multiplexed simultaneous detection using commercially available dyes in the visible range (for example, visible range dyes may be widely spaced from each other).

[0011] Therefore, described herein are systems, methods, and techniques for spatial optical multiplexing and demultiplexing using MMI waveguides that may address the above-described drawbacks of known methods. In some embodiments, on-chip photonic multiplexing and / or demultiplexing may be achieved by using one or more MMI waveguides. The MMI waveguide may create a variable spatial pattern perpendicular to the optical propagation direction. As described herein, by using an MMI waveguide having inputs / outputs that are not centered laterally (e.g., in a direction perpendicular to the optical propagation direction), light of different wavelengths may be multiplexed / demultiplexed with each other at several distances along the propagation direction of the MMI waveguide, and at the same distance, light of one wavelength forms a self-image and light of other wavelengths forms a mirror image.

[0012] Furthermore, as described above, MMI waveguides fabricated from solid materials may create an imperfect spot pattern due to non-uniformity in the refractive index of the solid MMI waveguide material, which is the result of, for example, complementary metal oxide semiconductor microfabrication, microelectromechanical system microfabrication, etc.

[0013] Accordingly, the present disclosure describes systems, methods, and techniques for spectral multiplexed detection of optically active targets within a microfluidic channel by using a liquid-core MMI waveguide that is adjustable by the refractive index, pressure, temperature, flow rate, or any combination thereof. As described herein, an adjustable MMI waveguide of a liquid core (adjustable LC-MMI waveguide) may address one or more of the problems of the solid-core MMI waveguides described above. For example, the liquid-core MMI waveguide may have a more uniform core and / or to compensate for manufacturing defects, for example, by changing the liquid of the core (and thus changing the refractive index of the core of the MMI waveguide), by heating the liquid of the core, or by changing the dimensions of the liquid core of the LC-MMI waveguide (for example, when using a flexible material for the manufacture of the walls of the LC-MMI waveguide), it may be finely adjustable.

[0014] In some embodiments, an on-chip analyte detection system is provided, which includes a substrate, a first analyte channel disposed on the substrate and configured to receive a first liquid containing a first analyte to be detected by the system, a second analyte channel disposed on the substrate and configured to receive a second liquid containing a second analyte to be detected by the system, and a multimode interference (MMI) waveguide disposed on the substrate and intersecting the first analyte channel at a first position and the second analyte channel at a second position. The MMI waveguide is configured to receive incident light of a first wavelength and incident light of a second wavelength, generate a first spot pattern having a first number of spots of the light of the first wavelength incident on the first analyte channel, generate a second spot pattern having a second number of spots of the light of the first wavelength incident on the second analyte channel, generate a third spot pattern having a third number of spots of the light of the second wavelength incident on the first analyte channel, and generate a fourth spot pattern having a fourth number of spots of the light of the second wavelength incident on the second analyte channel. The system also includes a detector configured to detect a fluorescence burst from an analyte excited by one of the first spot pattern, the second spot pattern, the third spot pattern, and the fourth spot pattern, and one or more processors configured to receive a signal representing the detected fluorescence burst from the detector, identify which of the first channel and the second channel the signal corresponds to based on the number of detected bursts in the received signal, and identify which of the light of the first wavelength and the light of the second wavelength the signal corresponds to based on the number of detected bursts in the received signal.

[0015] In some embodiments, an on-chip analyte detection system is provided, which includes a substrate, an analyte channel disposed on the substrate and configured to receive an analyte including a liquid to be detected by the system, one or more first waveguides disposed on the substrate and intersecting the analyte channel, the one or more first waveguides being configured to receive incident light of a first wavelength at a first incident port and direct a first multi-spot pattern generated from the incident light of the first wavelength toward the analyte channel intersecting the first multi-spot pattern, one or more second waveguides disposed on the substrate and intersecting the analyte channel, the one or more second waveguides being configured to receive incident light of a second wavelength at a second incident port and direct a second multi-spot pattern generated from the incident light of the second wavelength toward the analyte channel intersecting the second multi-spot pattern, and a multiplexing multi-mode interference (MMI) waveguide disposed on the substrate, the multiplexing MMI waveguide including a third incident port disposed at a first end of the multiplexing MMI waveguide and configured to receive the incident light of the first wavelength and the incident light of the second wavelength, a first emission port disposed at a second end of the multiplexing MMI waveguide opposite the first end, the light of the first wavelength being directed toward a first incident port of a first group of one or more waveguides, and a second emission port disposed at the second end of the multiplexing MMI waveguide and configured to emit a mirror image of the light of the second wavelength, the light of the second wavelength being directed toward a second incident port of a second group of one or more waveguides.

[0016] In some embodiments, an on-chip analyte detection system is provided, which includes a substrate, an analyte channel disposed on the substrate and configured to receive an analyte including a liquid to be detected by the system, and a multiplexed multimode interference (MMI) waveguide disposed on the substrate. The multiplexed MMI waveguide includes a first input port disposed at a first end of the multiplexed MMI waveguide and configured to receive incident light of a first wavelength and incident light of a second wavelength, a first output port disposed at a second end of the multiplexed MMI waveguide opposite to the first end and configured to emit light of the first wavelength, and a second output port disposed at the second end of the multiplexed MMI waveguide and configured to emit light of the second wavelength. The multiplexed MMI waveguide is configured to direct the emitted light of the first wavelength and the emitted light of the second wavelength to be incident on the analyte channel, so as to excite one or more analytes in the channel.

[0017] In some embodiments, an on-chip analyte detection system is provided, which includes a substrate, an analyte channel disposed on the substrate and configured to receive an analyte including a liquid to be detected by the system, and a multiplexed multimode interference (MMI) waveguide disposed on the substrate. The multiplexed MMI waveguide includes a first input port disposed at a first end of the multiplexed MMI waveguide and configured to receive light of a first wavelength, a second input port disposed at the first end of the multiplexed MMI waveguide and configured to receive light of a second wavelength, and an output port disposed at a second end of the multiplexed MMI waveguide opposite to the first end and configured to emit light of the first wavelength and light of the second wavelength. The multiplexed MMI waveguide is configured to direct the emitted light of the first wavelength and the emitted light of the second wavelength to be incident on the analyte channel, so as to excite one or more analytes in the channel.

[0018] In some embodiments, an on-chip analyte detection system is provided, which includes a substrate, a first analyte channel disposed on the substrate and configured to receive a first analyte including a first solution to be detected by the system, and an adjustable liquid-core multimode interference (LC-MMI) waveguide disposed on the substrate and intersecting the first analyte channel. The LC-MMI waveguide includes a hollow channel configured to receive a first fluid, a sidewall in contact with the hollow channel, a first opening configured to allow the first fluid to enter and exit the hollow channel, and a first optical input port configured to receive incident light of a first wavelength. The LC-MMI waveguide is configured to direct a first multi-spot pattern generated from the incident light of the first wavelength toward the first analyte channel that intersects the pattern.

Brief Description of the Drawings

[0019]

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Mode for Carrying Out the Invention

[0020] Spectral, Spatial, and Spectral-Spatial Multiplexing Analyte Detection in Multiple Fluid Channels Using MMI Waveguides In some embodiments, the multi-target sensing platform may combine spatial multiplexing and spectral multiplexing of biological particles by using multiple (e.g., two or more) different excitation wavelengths along an MMI waveguide to create a channel-dependent and color-dependent multi-spot pattern in multiple (e.g., two, three, or more) separate intersecting fluid channels. The number of spots for each fluorescence signal may provide direct identification of multiple targets with high sensitivity.

[0021] Using a wide solid-core optical waveguide that functions as an MMI waveguide, a position-dependent multi-spot pattern for multiple, orthogonally intersecting liquid-core waveguides may be created. The MMI waveguide may support a number of wavelength modes with different propagation constants, such that they may interfere with each other as they propagate along the MMI structure. At a specific propagation distance where the relative phases of these modes are correctly matched, a well-defined spot pattern may be created. Since the multi-spot pattern created by the modes may vary with the distance in the propagation direction along the MMI waveguide, the multi-spot pattern for light of the same wavelength propagating through the MMI waveguide may be different in multiple, intersecting liquid-core channels / waveguides that intersect the MMI waveguide at different distances along the MMI waveguide.

[0022] In the embodiments of FIGS. 1A and 1B showing platform 100, three liquid-core waveguides 104, 106, and 108 along MMI waveguide 102 are shown to intersect MMI waveguide 102 at positions corresponding to well-defined integer spots for different excitation wavelengths.

[0023] Figure 1A shows a schematic diagram of an optofluidic platform 100, in which an MMI waveguide 102 intersects three different liquid core waveguides (104, 106, and 108) at different distances L from the beginning of the MMI waveguide (e.g., from the optical input port of the MMI waveguide) (in the direction of light propagation along the MMI waveguide). In some embodiments, the liquid core waveguides are configured to receive one or more solutions containing one or more fluorescent target analytes, such as molecules, particles, biomarkers, nucleic acids, DNA, proteins, etc., to be detected by the system.

[0024] In some embodiments, the liquid core waveguides may be configured such that the analyte solution can flow along the central hollow channel of the waveguide, whereby the analyte in the liquid flows through the spot pattern where it is incident on the waveguide by the MMI waveguide. In some embodiments, the flow through the analyte channel may be caused by a pressure applied to the fluid in the analyte channel (e.g., by one or more pumps) to cause the fluid to flow, whereby the analyte passes through the excitation spot. In some embodiments, the flow may be induced by electroosmosis. In some embodiments, the movement of the analyte particles in the analyte solution may be induced, for example, by electrophoresis, even without the flow of the analyte solution or in addition to the flow of the analyte solution.

[0025] When each analyte is excited by the spots of the spot pattern formed by the MMI waveguide, the fluorescent emission of the analyte may be guided to the detector by the liquid core waveguide, which may detect each fluorescent emission burst resulting from each signal.

[0026] As shown in Figure 1A, each of the liquid core waveguides may be fluidly connected to respective inlet wells 112a - c and one fluid outlet well 114. In some embodiments, one or more liquid core waveguides may have dedicated outlet wells that are not shared with other liquid core waveguides.

[0027] As shown in the figure, the platform may include three separate liquid-core waveguides (104, 106, and 108) and an MMI waveguide 102 that intersects a Y coupler 109 to combine all signals of fluorescence emission from excited particles within the liquid-core waveguides. In some embodiments, any suitable combination of one or more waveguides, couplers, lenses, mirrors, MMI waveguides, or other optical elements may be used to transport fluorescence emission from excited particles within the liquid-core waveguide to a detector.

[0028] In some embodiments, the detector may be disposed coplanar with the liquid-core waveguide on the substrate of the platform 100, for example, when the platform 100 is a chip. In some embodiments, the detector may be configured to detect fluorescence emission of various different wavelengths.

[0029] In some embodiments, the MMI waveguide 102 may be fabricated from oxides such as SiO2, nitrides such as SiN, oxynitrides such as SiON, PDMS, plastic, and / or semiconductor. In some embodiments, the height of the MMI waveguide 102 may be greater than or equal to 0.01 μm, 0.05 μm, 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm. In some embodiments, the height of the MMI waveguide 102 may be less than or equal to 0.01 μm, 0.05 μm, 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm. In some embodiments, the height of the MMI waveguide 102 may be between 0.1 μm and 5 μm.

[0030] In some embodiments, the width of the MMI waveguide 102 may be greater than or equal to 1 μm, 5 μm, 10 μm, 25 μm, 50 μm, 100 μm, 250 μm, 500 μm, or 1000 μm. In some embodiments, the width of the MMI waveguide 102 may be less than or equal to 1 μm, 5 μm, 10 μm, 25 μm, 50 μm, 100 μm, 250 μm, 500 μm, or 1000 μm. In some embodiments, the width of the MMI waveguide 102 may be between 10 μm and 250 μm.

[0031] In some embodiments, the length of the MMI waveguide 102 may be greater than or equal to 0.1 mm, 0.25 m, 1 mm, 5 mm, 10 mm, 20 mm, 50 mm, or 100 mm. In some embodiments, the length of the MMI waveguide 102 may be less than or equal to 0.1 mm, 0.25 mm, 0.5 mm, 1 mm, 5 mm, 10 mm, 20 mm, 50 mm, or 100 mm. In some embodiments, the length of the MMI waveguide may be between 0.5 mm and 20 mm.

[0032] The MMI waveguide 102 is shown as rectangular in the example of the figure, but in some embodiments, it may have a square, circular, semi-circular, or any suitable cross-sectional shape.

[0033] In some embodiments, any one or more of the liquid core waveguides 104, 106, or 108 may be fabricated from oxides such as SiO2, nitrides such as SiN, oxynitrides such as SiON, PDMS, plastics, and / or semiconductors. In some embodiments, the solution inside any one or more of the liquid core waveguides 104, 106, or 108 may contain H2O, ethylene glycol, and / or ethyl cinnamate. In some embodiments, the solution inside any one or more of the liquid core waveguides 104, 106, or 108 may contain a zinc iodide solution, an ethylene glycol solution, a sodium iodide solution, or any other suitable liquid having a refractive index greater than that of the cladding, including, for example, the following: · Aqueous zinc iodide solution · Aqueous sodium iodide solution · Aqueous ZnCl2 solution · Ionic liquids, such as (cation / anion) 〇(1-Et-3-Me-Im-N) / (SO2F)2) 〇(1-Et-3-Me-Im-N / (CN)2) 〇(1-Et-3-Me-Im / TCB) 〇(1-Et-3-Me-Im / SCN) 〇(1-Et-3-Me-Im / SO3OH) 〇(1-Et-3-Me-Im / SO3CH3) 〇(Et-Py-N / (SO2F)2), and / or 〇(He-Py-N / (SO2F)2) · Other ionic liquids, such as 〇Choline dihydrogen phosphate, and / or · Melting point depression solvent · Ethylene glycol · Organic liquids, such as 〇Benzyl benzoate 〇2-Bromomethylbenzene 〇DMSO 〇1,1,2,2-Tetrabromoethane 〇1,1,2,2-Tetrachloroethane, and / or 〇Tetrachloroethylene, and / or · Aqueous solutions, such as 〇AgNO3 〇CdCl2 〇KBr+HgBr 〇Hg(NO3)2:H2O+HgBr2, and / or 〇Hg(NO3)2:H2O+HgI2

[0034] In some embodiments, the height of any one or more of the liquid core waveguides 104, 106, or 108 may be greater than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 25 μm, or 50 μm. In some embodiments, the height of any one or more of the liquid core waveguides 104, 106, or 108 may be less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 25 μm, or 50 μm. In some embodiments, the height of any one or more of the liquid core waveguides 104, 106, or 108 may be between 1 μm and 10 μm.

[0035] In some embodiments, the width of any one or more of the liquid core waveguides 104, 106, or 108 may be greater than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 20 μm, 50 μm, or 100 μm. In some embodiments, the width of any one or more of the liquid core waveguides 104, 106, or 108 may be less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 20 μm, 50 μm, or 100 μm. In some embodiments, the width of any one or more of the liquid core waveguides 104, 106, or 108 may be between 1 μm and 20 μm.

[0036] In some embodiments, the length of any one or more of the liquid core waveguides 104, 106, or 108 may be greater than or equal to 0.01 mm, 0.05 mm, 0.1 mm, 0.5 mm, 1 mm, 5 mm, 10 mm, 20 mm, 50 mm, or 100 mm. In some embodiments, the length of any one or more of the liquid core waveguides 104, 106, or 108 may be less than or equal to 0.01 mm, 0.05 mm, 0.1 mm, 0.5 mm, 1 mm, 5 mm, 10 mm, 20 mm, 50 mm, or 100 mm. In some embodiments, the length of any one or more of the liquid core waveguides 104, 106, or 108 may be between 0.1 mm and 20 mm.

[0037] The liquid core waveguides 104, 106, or 108 are shown as rectangles in the example of the figure, but in some embodiments, any one or more of them may have a square, round, semi-circular, or any suitable cross-sectional shape.

[0038] In some embodiments, the flow rate of the fluid through any one or more of the liquid core waveguides 104, 106, or 108 may be faster than or equal to 0.1 μm / second, 0.5 μm / second, 1 μm / second, 10 μm / second, 100 μm / second, 1 mm / second, 1 cm / second, 5 cm / second, 10 cm / second, 20 cm / second, or 50 cm / second. In some embodiments, the flow rate of the fluid through any one or more of the liquid core waveguides 104, 106, or 108 may be slower than or equal to 0.1 μm / second, 0.5 μm / second, 1 μm / second, 10 μm / second, 100 μm / second, 1 mm / second, 1 cm / second, 5 cm / second, 10 cm / second, 20 cm / second, or 50 cm / second. In some embodiments, the flow rate of the fluid through any one or more of the liquid core waveguides 104, 106, or 108 may be between 1 μm / second and 10 cm / second.

[0039] In some embodiments, one or more components of the platform 100 and / or the associated system may be disposed on the substrate 101, which may be the substrate of a chip in some embodiments. In some embodiments, the length and / or width of the substrate 101 may be greater than or equal to 0.5 mm, 1 mm, 2 mm, 5 mm, 1 cm, 2 cm, 5 cm, 10 cm, or 20 cm. In some embodiments, the length and / or width of the substrate 101 may be less than or equal to 0.5 mm, 1 mm, 2 mm, 5 mm, 1 cm, 2 cm, 5 cm, 10 cm, or 20 cm. In some embodiments, the length and / or width of the substrate 101 may be between 2 mm and 5 cm.

[0040] FIG. 1B shows an enlarged view of the platform 100 shown in FIG. 1A.

[0041] Figures 1C - 1F illustrate alternative embodiments of an optofluidic platform that direct one or more spot patterns to an analyte within one or more analyte channels using one or more MMI waveguides. In some embodiments, the optofluidic platforms and / or their subcomponents described hereinafter with respect to Figures 1C - 1F may share any one or more characteristics common to the optofluidic platform 100 and / or its subcomponents described above. As shown in the figures and described hereinafter, the platforms of Figures 1C - 1F may have a spatial arrangement different from the optical and fluidic components similar to those described above with respect to platform 100 and Figures 1A and 1B.

[0042] Figure 1C shows, on the left, a schematic diagram of an optofluidic platform 110 that includes a substrate 111, in which an MMI waveguide 112 intersects three different analyte channels (114, 116, and 118) at different distances L from the start of the MMI waveguide (e.g., from the optical input port of the MMI waveguide shown at the bottom of Figure 1C) (in the direction of light propagation along the MMI waveguide). Figure 1C further shows, on the right, an exemplary fluorescence output signal generated by an analyte within each of the three analyte channels of platform 110.

[0043] In some embodiments, platform 110 may also function as a liquid core waveguide for guiding fluorescence emission signals regarding analytes within each of three different analite channels 114, 116, and 118 of platform 110, and may be so called, but may be different from platform 100 in that each of them may intersect the same single spot pattern. That is, channels 104, 106, and 108 of platform 100 may intersect MMI waveguide 102 at different distances corresponding to different spot patterns (having different numbers of spots), while channels 114, 116, and 118 of platform 110 may all intersect one single spot pattern, whereby the same number of excitation spots may be incident on each of channels 114, 116, and 118. As shown in FIG. 1C, interference pattern 128 may form the same, or substantially the same, interference pattern 128 (e.g., spot pattern) on each of the three channels 114, 116, and 118, and spot length 126 of interference pattern 128 may be longer than the entire distance by which the three channels are spaced apart from each other. In some embodiments, spot length 126 may be greater than, or equal to, 1 μm, 5 μm, 10 μm, 25 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, or 500 μm. In some embodiments, spot length 126 may be less than, or equal to, 1 μm, 5 μm, 10 μm, 25 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, or 500 μm. In some embodiments, spot length 126 may be between 10 μm and 200 μm. In some embodiments, any two or more of channels 114, 116, and 118 may be spaced apart from each other by greater than, or equal to, 0.25 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 25 μm, 50 μm, 100 μm, 150 μm, 200 μm, or 250 μm.In some embodiments, any two or more of channels 114, 116, and 118 may be spaced from each other by less than or equal to 0.25 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 25 μm, 50 μm, 100 μm, 150 μm, 200 μm, or 250 μm. In some embodiments, any two or more of channels 114, 116, and 118 may be spaced from each other by between 1 μm and 150 μm.

[0044] Therefore, in some embodiments, each of the three channels may be disposed within the spot length of the single spot pattern of the interference pattern 128, and thus each channel within the same spot pattern may be excited by the same number of spots. (In some embodiments, a plurality of channels may be disposed within one spot pattern of the interference pattern, while a different plurality of channels may be disposed within another spot pattern of the same interference pattern at other positions along the same MMI waveguide.)

[0045] In some embodiments, multiplexing within platform 110 may be achieved by differentiating one annalite channel from another based on the velocity of the annalite moving within each respective channel. That is, different annalite channels of platform 100 may be differentiated from each other with respect to multiplexing by counting a different number of excitation spots (and resulting different number of fluorescence output bursts) from the annalite within each channel, although the annalite within each of the three channels within platform 110 may be excited by the same number of spots (from the same spot pattern) to produce the same figure of fluorescence output bursts. However, as shown in FIG. 1C, the annalite within each of the three channels within platform 110 may move at different respective velocities (v1, v2, and v3 as in the figure), and thus may produce fluorescence emission signals that are temporally differentiated from each other.

[0046] For example, as shown by the three signals 105a, 105b, and 105c on the right side of FIG. 1C, when moving through the same spot pattern, an analyte having a faster speed (e.g., v3 in channel 114) may generate a fluorescence output signal (e.g., signal 105a) that is more compressed than an analyte having a faster speed (e.g., v1 in channel 118 that generates signal 105c). Therefore, by analyzing the relative widths of the fluorescence bursts from each other and / or the relative intervals of the bursts, the system or user may be able to distinguish analytes moving at different speeds within different analyte channels.

[0047] In some embodiments, the movement of analytes moving at different speeds in different channels may be induced by different flow rates of the fluid within the channel and / or by electrophoretic movement subject to different electrophoretic forces or through fluids having different viscosities.

[0048] FIG. 1D shows a schematic diagram of an optofluidic platform 130 including a substrate 131, in which an MMI waveguide 132 intersects three different liquid core waveguides (134, 136, and 138) at different distances L from the beginning of the MMI waveguide (e.g., from the optical input port of the MMI waveguide shown at the bottom of FIG. 1D) (in the direction of light propagation along the MMI waveguide).

[0049] In some embodiments, platform 130 may share one or more characteristics common to platform 110 described above with respect to FIG. 1C, but also functions as a liquid core waveguide for guiding fluorescence emission signals regarding the analytes within each respective channel, and each of channels 134, 136, and 138, which may be so called, are coupled to each other and may flow towards a common downstream outlet region, and may be different from platform 110 in this regard. Further, as shown in the figure, platform 130 may include a Y coupler 139, which may have any one or more characteristics common to Y coupler 109 described above with respect to FIG. 1A. In some embodiments, Y coupler 139 may be configured to simultaneously collect fluorescence emission signals from two or more of channels 134, 136, and 138 within the plane of the channels. As shown in the figure, since all the analyte channels branch off at right angles on the left side of platform 130, Y coupler 139 can be efficiently coupled to the analyte channels that also function as liquid core waveguides to combine the fluorescence emission signals guided by the analyte channels and guide them to, for example, a single detector for detection.

[0050] FIG. 1E shows a schematic view of an optofluidic platform 150 including a substrate 151, in which an MMI waveguide 152 intersects three different liquid core waveguides (154, 156, and 158) at different distances L from the start of the MMI waveguide (e.g., from the optical input port of the MMI waveguide shown at the bottom of FIG. 1E) (in the direction of light propagation along the MMI waveguide).

[0051] Unlike the platforms 110 and 130 shown in FIGS. 1C and 1D, the analite channels 154, 156, and 158 within the platform 150 (also referred to as and functioning as liquid core waveguides) may each intersect the MMI waveguide 152 at positions corresponding to different spot patterns. As shown in FIG. 1E, the channels 154, 156, and 158 intersect the MMI waveguide 152 at positions corresponding to the spot patterns when the interference patterns have five spots (168a), four spots (168b), and three spots (168c), respectively. As shown in the figure, the fluorescence emission signals from the analite excited by the platform 150 may be guided to and thereby collected by the waveguides 159a, 159b, and 159c according to the channel emitting the emission signal. In some embodiments, the waveguides 159a, 159b, and 159c may be coupled to each other to form a Y-coupler and / or guide the fluorescence emission signal to one or more detectors. In some embodiments, the waveguides 159a, 159b, and 159c may not all be coupled and / or may guide the fluorescence emission signal to two or more different detectors.

[0052] In some embodiments, the platform 150 and its sub-components may share one or more characteristics common to the platform 100 and its corresponding sub-components described above with respect to FIGS. 1A and 1B. As described with respect to FIGS. 1A and 1B and further described below, multiplexing may also be achieved in the platform 150 by counting the different numbers of fluorescence bursts in the fluorescence emission signal and thereby inferring the number of excitation spots incident on the analite channel that emitted the emission signal, such that the system or user can distinguish emission signals from analite channels with different numbers of incident excitation spots.

[0053] FIG. 1F shows a schematic diagram of an optofluidic platform 180 including a substrate 181, in which three different liquid core waveguides (184, 186, and 188) intersect each of two MMI waveguides 182a and 182b at different distances L from the start of the MMI waveguide (e.g., from the optical input port of the MMI waveguide shown at the bottom of FIG. 1F) (in the direction of light propagation along the MMI waveguide).

[0054] In some embodiments, the platform 180 may share any one or more characteristics common with the platform 150 described above with respect to FIG. 1E, except that the platform 180 may have bilateral and / or symmetry. As shown in the figure, the platform 180 may include ananalyte channels (also referred to as and functioning as liquid core waveguides) 184, 186, and 188, which extend in two different (opposite) directions from a common channel source 199 at the center of the substrate 181. By extending in two different directions, the analyte channels may intersect one MMI waveguide 182a on one side and the other MMI waveguide 182b on the opposite side. As shown in the figure, spot patterns 198a(1), 198a(2), and 198a(3) may be incident on channels 184, 186, and 188, respectively, at positions where the respective channels intersect the MMI waveguide 182a. On the opposite side of the substrate 181, spot patterns 198b(1), 198b(2), and 198b(3) may be incident on channels 184, 186, and 188, respectively, at positions where the respective channels intersect the MMI waveguide 182b.

[0055] In some embodiments, the left spot pattern and the right spot pattern may have the same wavelength or different wavelengths, and may have the same or different numbers of spots per pattern. In some embodiments, the MMI waveguides 182a and 182b may have any one or more characteristics in common with each other, but they may differ from each other in size, width, height, the material from which they are fabricated, the angle at which they are disposed on the substrate 181, or any other suitable characteristic. The channels 184, 186, and 188 are shown as being symmetric in FIG. 1F, but in some embodiments, on one side of the substrate 181, they may have a different shape and spatial arrangement from the other side, whereby they may intersect, for example, with the MMI waveguides 182a and 182b at different respective distances L along each MMI waveguide. Due to the bilateral two MMIs and the asymmetric arrangement of the flat platform, in some embodiments, excitation light of different wavelengths can be used in different MMI waveguides, and thus multi-item data can be collected and analyzed.

[0056] As shown in FIG. 1F, the fluorescence emission signal from the analytes excited by the spot pattern of the platform 180 may be guided and collected by the waveguides 189a(1), 189a(2), and 189a(3) on the left side of the platform 181 and the waveguides 189b(1), 189b(2), and 189b(3) on the right side of the platform 181 according to the channel in which the emission signal is emitted. In some embodiments, one or more of the waveguides may be coupled to each other to form one or more Y-couplers, and / or the fluorescence emission signal may be guided to one or more detectors.

[0057] In some embodiments, any one or more components of the platforms 100, 110, 130, 150, 170, and / or 180 may be combined with any one or more components of each other, and / or with any one or more components of any other systems, platforms, or devices described herein.

[0058] Figure 2 shows photographs of the excitation patterns in three different channels at two wavelengths. The channels are filled with a fluorescent liquid for imaging in the photograph. The product of the number of spots N and the distance L and the wavelength λ for a particular MMI waveguide are shown as follows: [Equation] where w is the effective MMI waveguide width (in the example shown in FIG. 1A, the penetration depth of the mode into the 75 μm plus cladding), n c is the effective refractive index of the MMI waveguide (1.46 in the example of FIG. 1A), and λ is the excitation wavelength (762 nm in the example of FIG. 1(a)). Therefore, three spot patterns having 8, 6, and 4 clearly defined spots may be generated at MMI waveguide lengths L1 = 1426 μm, L2 = 1895 μm, and L3 = 2847 μm, respectively. For the same or a similar system, using Equation 1, at an excitation wavelength of λ = 520 nm, spot patterns having 10, 7, and 5 clearly defined spots may be generated at the same three MMI waveguide lengths (L1 = 1426 μm, L2 = 1895 μm, and L3 = 2847 μm), respectively.

[0059] By simultaneously propagating light of multiple wavelengths along the same MMI waveguide, both the spatial and spectral characteristics of the MMI waveguide can be combined to generate a large number of different spot patterns for multiplexing from a single MMI waveguide, and this number is greater than the number of different intersecting channels (e.g., the product of the number of different intersecting channels and the number of different wavelengths of light). That is, for the two different wavelengths λ1 = 762 nm and λ2 = 520 nm described above, using three intersecting channels, six different spot patterns (8, 6, 4, 10, 7, and 5 spots, respectively) may be generated, and each of the spot patterns may be distinguished from one or more of the other spot patterns by noting the difference in the number of spots or the time interval between signals from adjacent spots.

[0060] Figure 2 shows, in some embodiments, an excitation pattern that may be created when three intersecting fluid channels are filled with a solution containing a fluorescent liquid and imaged with an overhead CCD camera. As shown in Figure 2, the resulting excitation pattern may show clearly defined excitation spots for all three channels, with different spot patterns having 8, 6, 4, 7, and 5 spots respectively as described above.

Example

[0061] Example 1 For demonstration of a spatially multiplexed biosensing virus detection assay, the H2N2 inactivated virus type was labeled with a red (Dylight 633) fluorescent dye and the H1N1 inactivated virus type was labeled with a green (Dylight 550) fluorescent dye. These were mixed and pipetted into three inlet reservoirs covering the ends of three separate fluid channels that intersect the same MMI waveguide at three different distances L from the end of the MMI waveguide in the arrangement as shown in Figure 1A. Lasers tuned to 633 nm and 520 nm were used to simultaneously excite the labeled viruses at both wavelengths, and a vacuum was applied to the outlet reservoir to induce a flow of particles. As the viruses moved downstream in the liquid core waveguide, they passed through different numbers of excitation spots depending on the channel they were moving in. As they passed through the excitation spots, they were excited by different numbers of excitation spots (e.g., different spot patterns) according to the color they were tagged with. The fluorescence emission signal of the particles was captured by each of the liquid core waveguides the particles were moving in, then collected by a solid core focusing waveguide, and combined into one output waveguide using a 3×1 Y-junction (see, e.g., Figure 1A). Then, the signal passed through bandpass and notch optical filters to remove the excitation wavelengths and was finally detected by a single photon counting detector.

[0062] Figure 3A shows the resulting fluorescence signals having different numbers of peaks, with each peak emitted from H1N1 or H2N2 virus from one of three different channels. The analyte was excited by both wavelengths of λ = 520 nm and λ = 633 nm. By counting the number of peaks, six separate multiplexing routes were distinguished from each other, and both the channel and the virus type for each peak were identified. In the automatically obtained results, compared with manual inspection, 3% errors occurred during identification due to distorted signals caused by flow variations.

[0063] Figure 3B shows the individual virus signals generated from H2N2 and H1N1, showing six different peak groups (groups of 8 peaks, 6 peaks, and 4 peaks for H2N2 and groups of 10 peaks, 7 peaks, and 5 peaks for H1N1) from three separate channels. Further, the velocity and concentration of the sample were extracted using the time difference between peaks and the known spot interval Δx. The average velocity was found to be 0.87 cm / sec, and the concentration was estimated to be 6×10 5 particles / mL (by multiplying the number of peaks by the cross-sectional area and velocity), which is a clinically relevant concentration range.

[0064] Therefore, according to the above example, multiplexed detection of influenza virus (e.g., spatial and spectral) can be implemented on an optofluidic platform including a plurality of liquid-core waveguides intersecting a single MMI waveguide. The success of detecting influenza virus from each channel for two different strains may be achieved by one molecular detection sensitivity, and different strains and different channels may be distinguished from each other based on detecting the number of spots detected within the generated spot pattern or using signal processing techniques.

[0065] Example 2 FIG. 4A and 4B show another example of the detection of multiple viruses using three different analyte channels and two different optical wavelengths (520 nm and 633 nm) propagating through one MMI waveguide, similar to the example of FIGS. 3A and 3B. FIG. 4A shows the resulting fluorescence signals having different numbers of peaks, and FIG. 4B shows the individual virus signals, with six different peak groups from three separate channels (groups of eight peaks, six peaks, and four peaks for viruses excited by 633 nm light and groups of ten peaks, seven peaks, and five peaks for viruses excited by 520 nm light).

[0066] Cascaded MMI Waveguide for Dispersion Spectrum Multiplexing As described above, analyte-dependent multi-spot excitation in capillaries and chip-type microchannels has recently been introduced and has proven to be a powerful method for performing multi-item simultaneous optical analysis of biomarkers and other targets. The principle is based on creating a wavelength-dependent spot pattern in the channel through which the target flows using integrated optical elements, such as MMI waveguides.

[0067] To obtain the best performance and sensitivity, the spot pattern should be as distinct as possible, with light hitting only the spot positions and little background between them. In addition, the signals created by multiple excitation wavelengths should be easily picked up with an appropriate signal processing algorithm. When one MMI wavelength is used, the background between spots may be non-zero, and the intensity differences in the fluorescence signals collected at different wavelengths may be different enough to cause problems in color assignment.

[0068] Therefore, the present disclosure describes systems, methods, and techniques for spectrally multiplexing and detecting optically active targets within a microfluidic channel using a two-stage photonic structure that creates spatially separated color-dependent excitation spot patterns. As described below, the techniques disclosed herein may address the problem of distinguishing colors from each other using one MMI waveguide, regardless of the inter-spot background signal.

[0069] An inventive solution to the above problems is a multi-stage approach characterized by a first stage for spatial separation (multiplexing) of light of different wavelengths and a second stage for creating wavelength-dependent spot patterns in different parts of a capillary or channel using the multiplexed light. In some embodiments, an MMI waveguide may be used for the first (multiplexing) stage. In some embodiments, other spectral selection devices such as an arrayed waveguide grating (AWG) may be used alternatively or additionally.

[0070] The first stage may use an MMI section with an asymmetric (offset from the center) input. This configuration may be used to create a spatial switch and coupler (e.g., a 1×2 switch or coupler and / or a 2×2 switch or coupler). Here, relying on the spectral dependence of light propagation, multiplexing of light at different wavelengths may be realized. In the case of an MMI waveguide with an asymmetric input (e.g., shown in FIG. 5), there is a distance at which the input mode profile is reproduced (real image) for any wavelength, but there are other distances at which a mirror image is created. The conditions for these images are: Real image L = 3pL π , where p is an even number Mirror image L = 3qL π , where q is an odd number and,

Number

[0071] When properly designed, the length and width of the MMI waveguide may be selected such that two wavelengths incident through the same port are spatially split into a real image and a mirror image respectively, and thus the two wavelengths are spatially separated from each other and multiplexed by being emitted from two spatially separated outputs (as shown in FIG. 5, for example). The conditions for obtaining this effect are: pλ M =qλ S where λ M is the wavelength that generates the real image, and λ S is the wavelength that generates the mirror image.

[0072] After the spatial separation of the input colors in the first stage, a second stage may be used to create a wavelength-dependent spot pattern incident on the channel, which is, for example, a liquid core channel configured to include an analyte that will be excited by the light of the spot pattern incident on that channel. In some embodiments, the second stage may include a plurality of MMI waveguides, each of which is configured to receive one wavelength of the multiplexed light from the first stage. Each MMI waveguide of the second stage has the following formula:

Number

[0073] An example of an embodiment using MMI-based multi-stage multiplexing is shown by system 500 of FIG. 5. The first stage may include an MMI waveguide 502, which is designed to generate a real image of one color (yellow, represented by brighter dots in the example of the figure) and a mirror image of a second color (red, represented by darker dots in the example of the figure) that enter the first MMI waveguide through one, off-center input 504.

[0074] As shown in the figure, the MMI waveguide 502 may include a single, offset input 504, which may be an optical port configured to receive incident light of a plurality of wavelengths and couple this light into the waveguide. The input 504 may be disposed at a first end of the MMI waveguide 502 in the direction of propagation of light through the MMI waveguide, and may be offset by an offset distance in a direction perpendicular to the direction of propagation of light through the MMI waveguide from the center of the MMI waveguide 502. In some embodiments, the input 504 may be offset by an amount greater than or equal to 5%, 10%, 20%, 30%, 40%, or 45% of the width of the MMI waveguide in the offset direction. In some embodiments, the input 504 may be offset by an amount less than or equal to 10%, 20%, 30%, 40%, or 45% of the width of the MMI waveguide in the offset direction.

[0075] As shown in the figure, the MMI waveguide 502 may include offset outputs 506 and 508, which may be optical ports configured to emit light of one or more wavelengths from the MMI waveguide, for example, by coupling the light into a single-mode waveguide. In some embodiments, the output 506 may be aligned with the input 504 in the offset direction and may be configured to output a real image of the light entering from the input 504. In some embodiments, the output 508 may be offset from the center of the MMI waveguide 504 by the same offset distance as the input 504 in a direction opposite to the offset of the input 504, and may be configured to output a mirror image of the light entering from the input 504. In some embodiments, an offset distance other than the offset distance of the incident port 504 may be used for one or more of the outputs 506 and 508.

[0076] In some embodiments, a multiplexing / demultiplexing MMI waveguide, such as the MMI waveguide 502, may share any one or more characteristics common to the MMI waveguide 102 described above with respect to FIG. 1A, including the material composition and size.

[0077] Outputs 506 and 508 may then be guided to a second stage (e.g., by one or more waveguides or other suitable optical elements), which may include two separate MMI waveguides 510 and 512. In some embodiments, each of the different colors of the emitted light may be used as an input for one of the MMI waveguides of the second stage. One or more of the plurality of MMI waveguides of the second stage may each be configured to create a multi-spot pattern that will be incident on the analyzer channel 514. In some embodiments, the MMI waveguides for the second stage may be designed and optimized independently of each other, including having, for example, different sizes, compositions, output configurations, number of emission ports / couplings, or others. In some embodiments, the MMI waveguides for creating the spot pattern incident on the analyzer channel, such as MMI waveguides 510 and / or 512, may share any one or more characteristics common to the MMI waveguide 102 described above with respect to FIG. 1A, including the composition and size of the material. In some embodiments, analyzer channels, such as analyzer channel 514, may share any one or more characteristics common to the analyzer channels 104, 106, and / or 108 described above with respect to FIG. 1A, including the composition of the material, size, fluid content, flow rate, and control system, etc.

[0078] In some embodiments, one or more components of system 500 and / or related systems may be disposed on substrate 501, which in some embodiments may share any one or more characteristics common to substrate 101 described above with respect to FIG. 1A. In some embodiments, one or more components of system 500 may be combined with one or more components of any of the other systems, platforms, or devices described herein.

[0079] Figures 6A and 6B show system 600 and simulation output signals for the excitation of influenza virus particles flowing through the liquid core channel of a two-stage optical multiplexing separation and particle excitation system, labeled with different combinations of fluorescent dyes.

[0080] Figure 6A shows a two-stage system 600 for separating two different input wavelengths of 488 nm and 745 nm, each incident on a displaced input from the center, using the first-stage MMI waveguide. As shown in the figure, the 488 nm light is directed towards the second-stage MMI waveguide 610 shown on the upper side of the figure, and the 745 nm light is directed towards the second-stage MMI waveguide 612 shown on the lower side of the figure. Each of the second-stage MMI waveguides may be configured to separate incident light of a single wavelength (or predominantly a single wavelength) into a spot pattern, such as a spot pattern having nine spots or six spots as shown in the figure. In the example of Figure 6A, S-shaped waveguides 616a and 616b are used to guide light from the first-stage MMI waveguide 602 to each of the two second-stage MMI waveguides 610 and 612. In some embodiments, the S-shaped waveguides 616a and 616b may be single-mode waveguides.

[0081] FIG. 6B shows optical signals from various simulations created by exciting particles flowing through a liquid core channel and labeled with different combinations of trend dyes, for example, by excitation with a two-stage MMI waveguide as shown in FIG. 6A. As shown in the figure, the resulting time signal in FIG. 6B may include signals indicating H1N1 excited by a 9-spot pattern, H3N3 illuminated by a 6-spot pattern, and H2N2 illuminated by both a 9-spot pattern and a 6-spot pattern. As shown in the signal corresponding to H2N2, the signal corresponding to a single-color 9-spot pattern is temporally separated from the signal corresponding to a 6-spot pattern of another color, which is due to the fact that the MMI waveguides associated with each pattern are spatially separated from each other along the analyzer channel, so the particles may flow through each MMI waveguide sequentially at different times. This separation allows, in some embodiments, the mixed signals to be distinguished more clearly and easily.

[0082] In some embodiments, system 600 and its components may share any one or more characteristics common to system 500 and its corresponding components described with respect to FIG. 5. In some embodiments, any one or more components of system 600 may be combined with any one or more components of other systems, platforms, or devices described herein.

[0083] In some embodiments, the spot pattern may be created by alternative or additional devices and / or techniques in the second stage. For example, FIG. 7 shows an implementation of creating a desired number of spots at different intervals using a system 700 that includes a plurality of single-mode waveguides.

[0084] FIG. 7 shows an MMI-based multi-stage multiplexing system 700 according to some embodiments. In the system shown in FIG. 7, the emitted light from the first waveguide 702 is guided to a second stage that creates a multi-spot pattern that will be incident on the channels by using a plurality of single-mode waveguides whose number, length, and spacing can be designed and optimized independently, and may be used as an input therefor. In the example of the figure, the second stage includes single-mode waveguides 710 that are a group of three single-mode waveguides and single-mode waveguides 712 that are a group of six single-mode waveguides. As shown in the figure, the plurality of single-mode waveguides may be configured to receive light from the same input source (e.g., MMI waveguide 702) via one or more optical splitters 718a and 718b (e.g., y-splitters) or others. Therefore, in some embodiments, instead of relying on the MMI waveguide in the second stage to create a spot pattern from light of one wavelength, a simple single-mode waveguide (e.g., a splitter) may be used to create a spot pattern that is incident on an analyte channel (e.g., channel 714) for particle excitation. It should be noted that by using an MMI waveguide in the second stage, a spot pattern in which the spots are evenly spaced from each other may be created, but one or more single-mode waveguides may be easily configured to create a spot pattern in which the spots are irregularly spaced from each other because the spacing between the spots does not have to follow the spacing of any higher-order multi-spot mode.

[0085] In some embodiments, the system 700 and its components may share any one or more common characteristics with the system 500 and its corresponding components or the system 600 and its corresponding components described above with respect to FIGS. 5 and 6, respectively. In some embodiments, any one or more components of the system 600 may be combined with any one or more components of other systems, platforms, or devices described herein.

[0086] Wavelength Multiplexing and Demultiplexing Using MMI Waveguides As described above, optical multiplexing and demultiplexing may be important components of photonic systems such as optical communication systems or integrated biosensors. However, certain known methods using waveguides for optical multiplexing and / or demultiplexing, such as using an AWG, may not be ideal when, for example, it is desired to avoid curved waveguides, when the wavelengths under consideration are at relatively wide intervals, and / or when the intended application is fluorescence multiplexed assay using commercially available dyes in the visible range (e.g., visible range dyes may be widely spaced from each other).

[0087] Therefore, described herein are systems, methods, and techniques for spatially optically multiplexing and demultiplexing using MMI waveguides that may address the above-mentioned drawbacks of known methods.

[0088] In some embodiments, on-chip photonic multiplexing and / or demultiplexing may be achieved through the use of one or more MMI waveguides. The MMI waveguide may create a modal spatial pattern perpendicular to the optical propagation direction.

[0089] As described above, this effect may be used to create spatial switches and couplers (e.g., 1×2 switches or couplers and / or 2×2 switches or couplers). Here, depending on the spectral dependence of the optical propagation, optical demultiplexing at different wavelengths may be realized. In the case of an MMI waveguide with an asymmetric input (e.g., as shown in FIG. 8A), there is a distance at which the input mode profile is reproduced (real image) (for any wavelength), but there are other distances at which a mirror image is created. The conditions for these images are: Real image L = 3pL π , where p is an even number Mirror image L = 3qL π , where q is an odd number and,[[]]

Number

[0090] When properly designed, the length and width of the MMI waveguide may be selected such that two wavelengths incident through the same port are spatially split into a real image and a mirror image, respectively. Therefore, the two wavelengths are spatially separated from each other and multiplexed by being emitted from two spatially separated outputs (as shown in FIG. 8A for example). The conditions for obtaining this effect are: pλ M =qλ S where λM is the wavelength that generates the real image and λS is the wavelength that generates the mirror image.

[0091] In some embodiments, spectral multiplexing (as shown in FIG. 8B for example) may be performed by using the MMI waveguide in an operation opposite to the above-described demultiplexing. For example, when two lights of two different wavelengths are incident on two separated inputs of one MMI waveguide respectively, there may be a distance along the MMI waveguide in the propagation direction where the two light beams are combined into one multiplexed light beam, and it may be emitted from one (e.g., offset from the center) output of the MMI waveguide.

[0092] Examples of demultiplexing and multiplexing using the MMI waveguide are shown in FIGS. 8A - 8F and FIG. 9.

[0093] FIG. 8A shows a system 800 for demultiplexing using an MMI waveguide 802, and the MMI waveguide 802 is designed to generate a real image of one color (here, yellow light represented by a brighter dot) and a mirror image of a second color (here, red light represented by a darker dot) entering the MMI waveguide 802 from one, offset input 804. As shown in the figure, the generated mirror image and real image may be emitted from the MMI waveguide through spatially separated output ports 806 and 808 that are in a mirror relationship with each other.

[0094] In some embodiments, system 800, MMI waveguide 802, and any one or more of their components may share any one or more characteristics common to system 500, MMI waveguide 502, and their corresponding components described above with respect to FIG. 5, including material composition and size. In some embodiments, any one or more components of system 800 may be combined with any one or more components of any other system, platform, or device described herein.

[0095] FIG. 8B shows a system 810 for multiplexing by reversing the arrangement shown in FIG. 8A. In some embodiments, system 810 may be equivalent to system 800, except that it is reversed with respect to the direction of light propagation in the MMI waveguide. That is, MMI waveguide 812 is designed to generate a real image of one color (e.g., yellow) and a mirror image of a second color (e.g., red) entering the MMI waveguide from different, off - center inputs 814 and 816 that are in a mirror image relationship with each other. As shown in the figure, light of each wavelength may enter the MMI waveguide through spatially separated input ports that are in a mirror image relationship with each other, but the generated mirror image and real image may be aligned with one of the input ports (814) and exit the MMI waveguide through one output port 818 that is the mirror image of the other (816).

[0096] In some embodiments, system 810, MMI waveguide 812, and any one or more of their components may share any one or more characteristics common to system 800, MMI waveguide 802, and their corresponding components described above with respect to FIG. 8, or system 500, MMI waveguide 502, and their corresponding components described above with respect to FIG. 5, including material composition and size. In some embodiments, any one or more components of system 810 may be combined with any one or more components of any other system, platform, or device described herein.

[0097] In some embodiments, a demultiplexing MMI waveguide such as MMI waveguide 802 and a multiplexing MMI waveguide such as MMI waveguide 812 may be arranged in series with each other (in any suitable order) to separate light of different wavelengths and then recombine it, and / or to combine light of different wavelengths and then separate it again. In some embodiments, the demultiplexing and / or multiplexing MMI waveguides arranged in series with each other may be arranged on the same substrate and / or chip.

[0098] Figures 8C and 8D show systems that use a multiplexing or demultiplexing MMI waveguide to collect signals from an analite channel.

[0099] Figure 8C shows a system 830 that multiplexes two different emission signals received from a first excitation spot and a second excitation spot of one analite channel. As shown in the figure, the analite channel 839 may include an analite that generates emission signals (e.g., fluorescence emission light) at a first wavelength at the first excitation spot and at a second wavelength at a second excitation spot at a different position along the analite channel 839. Each of the excitation spots may be aligned with one of the plurality of inputs (one of inputs 834 and 836) that are offset from the center to collect the emission signal to the MMI waveguide 832. As the collected emission signals propagate from right to left in the MMI waveguide 832, the MMI waveguide 832 may multiplex the two emission signals to create a real image of the light from input 834 and a mirror image of the light from input 836, both of which may be emitted from the MMI waveguide 832 by one output 838.

[0100] In some embodiments, the system 830 may be designed such that excitation light for exciting particles at one or both of the excitation spots may enter the analite channel 839 from above, from a lateral analite channel 839, and / or along the analite channel 839. In some embodiments, the dimensions of the MMI waveguide 832 may be selected to correctly multiplex the emission signals according to the emission wavelengths of the particles in the analite channel 839.

[0101] In some embodiments, system 830 may share any one or more characteristics common to system 810 described above with respect to FIG. 8B, except that the light incident on the MMI waveguide is from the emission signal from the anallite channel. In some embodiments, system 830, MMI waveguide 832, and any one or more of them may share any one or more characteristics common to any one or more other MMI waveguides and related systems, including the multiplexing and / or demultiplexing MMI waveguides and related systems described elsewhere in this specification, which includes material composition and size. In some embodiments, any one or more components of system 830 may be combined with any one or more components of any other system, platform, or device described herein.

[0102] FIG. 8D shows a system 840 for demultiplexing two different emission signals received from one excitation spot of an anallite channel. As shown in the figure, anallite channel 849 may include an anallite that generates a plurality of emission signals (e.g., fluorescence emission light) of a first wavelength and a second wavelength at one excitation spot. One excitation spot may be aligned with one, off-center input 844 to collect the emission signals into MMI waveguide 842. As the collected emission signals propagate from right to left within MMI waveguide 842, MMI waveguide 842 demultiplexes the two emission signals, creating a real image of the light of one wavelength and a mirror image of the light of the other wavelength, directing the real image to output 846 and the mirror image to output 848.

[0103] In some embodiments, system 840 may be designed such that the excitation light for exciting particles at the excitation spot may be incident on anallite channel 849 from above, from the lateral anallite channel 849, and / or along anallite channel 849. In some embodiments, the dimensions of MMI waveguide 842 may be selected to correctly demultiplex the emission signals according to the emission wavelengths of the particles in anallite channel 849.

[0104] In some embodiments, system 840 may share any one or more characteristics common to system 800 described above with respect to FIG. 8A, except that the light incident on the MMI waveguide is from the emission signal from the anallite channel. In some embodiments, system 840, MMI waveguide 842, and any one or more of them may share any one or more characteristics common to any one or more other MMI waveguides and related systems, including the multiplexing and / or demultiplexing MMI waveguides and related systems described elsewhere in this specification, which includes material composition and size. In some embodiments, any one or more components of system 840 may be combined with any one or more components of any other systems, platforms, or devices described herein.

[0105] FIGS. 8E and 8F show a system that uses a multiplexing or demultiplexing MMI waveguide to deliver excitation light to one or more anallite channels.

[0106] FIG. 8E shows a system 850 that demultiplexes excitation light of two different wavelengths for delivery to two excitation spots of an anallite channel. As shown in the figure, MMI 852 may be configured to receive incident excitation light of two different wavelengths at input 854, demultiplex the light of the two wavelengths, and be configured to generate a real image of the light of the first wavelength at output 856 and a mirror image of the light of the second wavelength at output 858. Output 856 may direct the light of the first wavelength toward anallite channel 859 at a first position to generate a first excitation spot, while output 858 may direct the light of the second wavelength toward anallite channel 859 at a second position to generate a second excitation spot. In some embodiments, rather than being directed directly at the anallite channel, the light emitted from output 856 and / or 858 may pass through one or more intermediate waveguides, splitters, and / or MMI waveguides, for example, to create one or more multi-spot patterns from one output signal.

[0107] In some embodiments, the system 850 may be configured such that light emission (e.g., fluorescence emission signal) may be collected from the upper analyte channel 859, from the lateral analyte channel 859, and / or along the analyte channel 859. In some embodiments, the dimensions of the MMI waveguide 852 may be selected to correctly demultiplex the excitation signal according to the excitation wavelength of the particles in the analyte channel 859.

[0108] In some embodiments, the system 850 may share any one or more characteristics common to the system 800 described above with respect to FIG. 8A, except that the light emitted from the MMI waveguide may be directed towards the analyte channel. In some embodiments, the system 850, the MMI waveguide 852, and any one or more of them may share any one or more characteristics common to any one or more other MMI waveguides and related systems, including the multiplexing and / or demultiplexing MMI waveguides and related systems described elsewhere in this specification, which includes material composition and size. In some embodiments, any one or more components of the system 850 may be combined with any one or more components of any other systems, platforms, or devices described in this specification.

[0109] FIG. 8F shows a system 860 that demultiplexes excitation light of two different wavelengths for delivery to two excitation spots incident on separate analyte channels. As shown in the figure, the MMI 862 may be configured to receive incident excitation light of two different wavelengths at the input 854, and may also be configured to demultiplex the light of the two wavelengths to generate a real image of the light of the first wavelength at the output 866 and a mirror image of the light of the second wavelength at the output 868. The output 866 may direct the light of the first wavelength towards the analyte channel 869a at a first position to generate a first excitation spot, while the output 868 may direct the light of the second wavelength towards the analyte channel 869b at a second position to generate a second excitation spot.

[0110] In some embodiments, rather than being directed directly to one or more analite channels, the light emitted from outputs 866 and / or 868 may pass through one or more intermediate waveguides, splitters, and / or MMI waveguides, for example, to create one or more multi-spot patterns from one output signal.

[0111] In some embodiments, system 860 may be configured such that light emission (e.g., a fluorescence emission signal) may be collected from the upper analite channel 869a, from the lateral analite channels 869a and 869b, and / or along the analite channels 869a and 869b. As shown in the figure, system 860 may include light emission signal collection waveguides 867a and 867b, which may be disposed in the same plane as MMI 862 and / or analite channels 869a and 869b, and may also be configured to collect light emission signals generated from within analite channels 869a and 869b, respectively. In some embodiments, the dimensions of MMI waveguide 862 may be selected to correctly demultiplex the excitation signal according to the excitation wavelengths of the particles in analite channels 869a and 869b.

[0112] In some embodiments, system 860 may share any one or more characteristics common to system 800 described above with respect to FIG. 8A, except that the demultiplexed light emitted from the MMI waveguide may be directed to one or more analite channels. In some embodiments, system 860, MMI waveguide 862, and any one or more of them may share any one or more characteristics common to any one or more other MMI waveguides and related systems, including the multiplexing and / or demultiplexing MMI waveguides and related systems described elsewhere in this specification, which includes material composition and size. In some embodiments, any one or more components of system 860 may be combined with any one or more components of any other systems, platforms, or devices described in this specification.

[0113] Figure 9 shows a simulation demonstrating the principle of multiplex separation using MMI for two specific colors. The upper part of Figure 9 shows the representation of an MMI waveguide for blue light (488 nm) propagating from left to right. As shown in the figure, the blue light enters the MMI waveguide through an incident port offset from the center at the upper end on the left side, propagates, creates a real image on the right side of the MMI waveguide, and may exit here through an output port offset from the center at the upper end on the right side.

[0114] In contrast, the lower part of Figure 9 shows the representation of an MMI waveguide for red light (745 nm) propagating from left to right. As shown in the figure, the red light enters the MMI waveguide through an incident port offset from the center at the upper end on the left side, propagates, creates a mirror image on the right side of the MMI waveguide, and may exit here through an output port offset from the center at the lower end on the right side.

[0115] In some embodiments, one MMI waveguide may be used to propagate both the red light and the blue light in the figure, such that the light of both wavelengths enters the MMI waveguide through the same incident port (e.g., the upper end on the left side). The waveguide may be multiplex separated such that the blue light exits from one output port (e.g., the upper end on the right side) and the red light exits from another output port (e.g., the lower end on the right side), and both output ports are arranged at the same distance in the propagation direction from one incident port.

[0116] In some embodiments, for two specific wavelengths λ B and λ C the principle of multiplexing / multiplex separation may be shown as follows:

Number

[0117] In some embodiments, for multiplexing (including the demultiplexed light remultiplexing), the reverse arrangement of Figure 9 may be used. The red and blue lights enter one MMI waveguide from two different ports offset from the center on the right side of the MMI waveguide, propagate from right to left, and exit the MMI waveguide from one port offset from the center on the left side of the MMI waveguide.

[0118] Adjustable liquid-core MMI waveguide for spectral, spatial, and spectral-spatial multiplexing detection As described above, the MMI waveguide may be used for spectrally dependent multi-spot excitation of analytes in a capillary as a powerful tool for multi-item simultaneous optical analysis of biomarkers and other targets. However, an MMI waveguide fabricated from a solid material may create an imperfect spot pattern due to non-uniformities in the refractive index of the solid MMI waveguide material. Further, the best patterns may deviate from the desired wavelength due to variations in refractive index or slight changes in dimensions, both of which are the result of complementary metal oxide semiconductor microfabrication, microfabrication of microelectromechanical systems, or other processes.

[0119] In the present disclosure, systems, methods, and techniques for spectral multiplexing detection of optically active targets in a microfluidic channel are described by using a liquid-core MMI waveguide that is adjustable by core refractive index (e.g., by changing a liquid or temperature), pressure, or both. As described herein, the adjustable liquid-core MMI waveguide may address one or more of the aforementioned problems of solid MMI waveguides, which may be because, for example, the liquid-core MMI waveguide may have fewer manufacturing defects and / or may be finely tunable to compensate for manufacturing defects.

[0120] In some embodiments, implementing a liquid core instead of a solid core in the MMI waveguide may address one or more of the above problems. In some embodiments, the core liquid for the LC-MMI waveguide may be characterized by a more uniform refractive index than a solid core, and the spot pattern generated by the LC-MMI waveguide may be easily and effectively adjusted, for example, by exchanging the core liquid (and thus changing the core refractive index of the MMI waveguide), heating the core liquid, or changing the dimensions of the liquid core of the LC-MMI waveguide (e.g., when using a flexible material for manufacturing the walls of the LC-MMI waveguide).

[0121] Figure 10A shows an LC-MMI waveguide system 1000 for optofluidic multi-analyte simultaneous detection. Figure 10A shows a top view of an LC-MMI section 1002 that generates a tunable full spot pattern (having three spots in the example of the figure) that is incident on intersecting fluid channels 1008, which may contain one or more analytes that are to be excited by the spot pattern. As shown in the figure, the LC-MMI section 1002 may be a section of an LC-MMI waveguide that includes an inlet port 1004 and a fluid outlet port 1006, both of which are fluidly connected to a hollow channel defined in the center of the LC-MMI section 1002 so that the fluid / liquid inside the LC-MMI section 1002 is drained and can be exchanged with other liquids, such as other liquids having different optical properties, such as different refractive indices. By exchanging the liquid inside the LC-MMI section 1002 with other liquids having different refractive indices, the optical properties of the LC-MMI waveguide system 1000 may be correspondingly adjusted.

[0122] In some embodiments, the LC-MMI waveguide section 1002 may be fabricated from oxides such as SiO2, nitrides such as SiN, oxynitrides such as SiON, PDMS, plastics, and / or semiconductors. In some embodiments, the liquid or fluid inside the LC-MMI waveguide section 1002 may include any one or more of the fluids or liquids described above with respect to the liquid core waveguides 104, 106, or 108.

[0123] In some embodiments, the height of the LC-MMI waveguide section 1002 may be greater than or equal to 0.01 μm, 0.05 μm, 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 25 μm, or 50 μm. In some embodiments, the height of the LC-MMI waveguide section 1002 may be less than or equal to 0.01 μm, 0.05 μm, 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 25 μm, or 50 μm. In some embodiments, the height of the LC-MMI waveguide section 1002 may be between 0.1 μm and 10 μm.

[0124] In some embodiments, the width of the LC-MMI waveguide section 1002 may be greater than or equal to 1 μm, 5 μm, 10 μm, 50 μm, 100 μm, 250 μm, 500 μm, 1 mm, or 2 mm. In some embodiments, the width of the LC-MMI waveguide section 1002 may be less than or equal to 1 μm, 5 μm, 10 μm, 50 μm, 100 μm, 250 μm, 500 μm, 1 mm, or 2 mm. In some embodiments, the width of the LC-MMI waveguide section 1002 may be between 10 μm and 500 μm.

[0125] In some embodiments, the length of the LC-MMI waveguide section 1002 may be greater than or equal to 10 μm, 50 μm, 100 μm, 500 μm, 1 mm, 1 cm, 5 cm, 10 cm, or 20 cm. In some embodiments, the length of the LC-MMI waveguide section 1002 may be less than or equal to 10 μm, 50 μm, 100 μm, 500 μm, 1 mm, 1 cm, 5 cm, 10 cm, or 20 cm. In some embodiments, the length of the LC-MMI waveguide section 1002 may be between 100 μm and 5 cm.

[0126] It should be noted that the height, width, and length of the LC-MMI waveguide section 1002 described above may relate to the dimensions of the liquid core that defines the LC-MMI waveguide section 1002, rather than the outer surface of the LC-MMI waveguide section 1002.

[0127] In some embodiments, light may be delivered to the LC-MMI waveguide by a single-mode waveguide (e.g., a solid-core single-mode waveguide), such as single-mode waveguide 1010 shown in FIG. 10A. After coupling to multiple lateral modes in the broader MMI region 1002 of the LC-MMI system, the modes interfere and propagate a distance L, after which the following equation

Equation

[0128] The liquid for the MMI section may be supplied through an inlet (e.g., inlet 1004) and an outlet (e.g., outlet 1006) separate from the optical inlet. The MMI section 1002 may be separated from a second, intersecting fluid channel 1008, which may contain an analyte for optical analysis by a solid barrier 1012 through which the generated spot pattern may propagate. Then, particles flowing through the second channel may be exposed to the spot pattern created by Equation (2), and they may generate optical signals characterized by wavelengths, which may be used for spectral identification.

[0129] In some embodiments, any one or more components of system 1000 may be combined with any one or more components of any other system, platform, or device described herein.

[0130] Figure 10B shows a system 1020 including a plurality of LC-MMI waveguides 1022 and 1042 arranged in series with each other, whereby the spot pattern emitted from the LC-MMI waveguide 1022 of the first stage may be used as an input to the LC-MMI waveguide 1042 of the second stage, which may further propagate the light to create different spot patterns (having two spots in the example of the figure) resulting from different modes as an output from the second LC-MMI waveguide 1042. As shown in the figure, the output from each LC-MMI waveguide (1022 and 1042) may be incident on intersecting liquid core analyzer channels (1028 and 1048 respectively), which may be used to excite one or more analyzers within the channels. As shown in the figure, each LC-MMI segment of a multi-stage LC-MMI waveguide system such as system 1020 may have dedicated ports (here, ports 1024 / 1026 and ports 1044 / 1046) for the insertion and / or removal of liquid into / from the LC-MMI waveguide, whereby one or more liquids of the LC-MMI segment may be exchanged independently of the liquids within one or more other LC-MMI segments, and as a result, each of the LC-MMI segments may be adjusted independently. Further, in this way, spatial multiplexing is possible by creating a different number of spots at the same wavelength within subsequent analyzer channels.

[0131] As shown in the figure, in system 1020, light may initially enter LC-MMI waveguide 1022 through single-mode waveguide 1030. As shown in the figure, intersecting analyzer channels 1028 and 1048 may be separated from LC-MMI waveguides 1022 and / or 1042 by solid barriers 1032, 1052, and / or 1054. In some embodiments, LC-MMI waveguide 1042 and its related components may share any one or more characteristics common to LC-MMI waveguide 1022 and its corresponding related components. In the example of the figure, LC-MMI waveguide 1042 may be shorter than LC-MMI waveguide 1022. In the example of the figure, LC-MMI waveguide 1022 may be configured to generate a spot pattern having three spots incident on channel 1028, and then the LC-MMI waveguide may be configured to generate a spot pattern of the same wavelength having two spots incident on channel 1048.

[0132] In some embodiments, LC-MMI waveguide system 1020 and its components may share any one or more characteristics common to LC-MMI waveguide system 1000 and its corresponding components described above with respect to FIG. 10A, including material composition, size, fluid content, flow rate, and control system, etc. In some embodiments, any one or more components of system 1020 may be combined with any one or more components of other systems, platforms, or devices described herein.

[0133] In some embodiments, when the liquid core of the LC-MMI waveguide is surrounded by a solid rigid material, the only options for adjusting the spot pattern may be through λ and n as can be seen from Equation (2). However, in some embodiments, when the device is constructed of a flexible material, such as PDMS, w and L may also be adjustable. This concept is shown in FIGS. 11A - 11G according to some embodiments. c However, in some embodiments, when the device is constructed of a flexible material, such as PDMS, w and L may also be adjustable. This concept is shown in FIGS. 11A - 11G according to some embodiments.

[0134] FIG. 11A shows a solid-core and liquid-core waveguide based on PDMS. FIGS. 11B - 11F show exemplary implementations of a mechanically tunable LC-MMI waveguide on a PDMS chip fabricated by soft lithography techniques, and the results of spot pattern adjustment through deformation of the membrane wall using the flow rate and mechanical pressure of the central liquid. FIG. 11G shows how this principle may be applied to create a tunable spot pattern when interacting with the intersecting analyte channels as described above.

[0135] FIG. 11A is a diagram of a cross-sectional view of a PDMS-based solid-core and liquid-core waveguide according to some embodiments.

[0136] FIG. 11A shows a cross-sectional view of a liquid-core waveguide 1100 and a solid-core waveguide 1110. As shown in the figure, the liquid-core waveguide 1100 may include a lower layer 1102 and an upper layer 1104, which may be PDMS layers having a first refractive index. The liquid-core waveguide 1100 may include a liquid core 1106 between the layers 1102 and 1104, and the liquid core 1106 may include a hollow channel configured to be filled with a liquid having a second refractive index. In some embodiments, one or both of the layers 1102 and 1104 may be flexible, deformable, and / or movable, whereby the dimensions of the liquid core 1106 located between the layers 1102 and 1104 may change.

[0137] As shown in the figure, the solid core waveguide 1110 may include a lower layer 1112 and an upper layer 1114, which may be PDMS layers having a third refractive index. The solid core waveguide 1110 may include a solid core 1116 between the layers 1112 and 1114. The solid core 1116 may include a PDMS layer or other layers configured to transmit light, and this layer has a fourth refractive index. In some embodiments, one or both of the layers 1112 and 1114 may be flexible, deformable, and / or movable, whereby the position, dimension, angle, tension, or one or more other characteristics of the solid core 1116 disposed between the layers 1102 and 1104 may be changed. In some embodiments, lateral light guiding may be ensured by surrounding the solid core 1116 with an air passage, and as a result, the propagation loss is reduced.

[0138] FIG. 11B shows various views of an adjustable (e.g., mechanically adjustable) LC-MMI waveguide 1120. The LC-MMI waveguide 1120 is shown in a top view (1120(a)), a cross-sectional view in an unpressurized state (1120(b)), a cross-sectional view in a state compressed from the outside (1120(c)), and a cross-sectional view in a state compressed from the inside (1120(d)).

[0139] In some embodiments, the fiber-injected laser light may propagate through the excited solid core waveguide into the liquid core of the LC-MMI waveguide 1120. As shown in 1120(a) and 1120(b), the static (e.g., uncompressed) width of the liquid core may be w0. In some embodiments, the width of the liquid core waveguide decreases as shown in FIG. 1120(c) due to external air pressure, while the width of the waveguide may increase when the liquid flows as shown in 1120(d). In some embodiments, the width of the liquid core waveguide similar to that shown in 1120(c) decreases due to a negative pressure applied from the outside (e.g., vacuum force), while the width of the liquid core waveguide similar to that shown in 1120(d) may increase due to a positive pressure applied from the inside (e.g., fluid force).

[0140] As shown in the figure, the LC-MMI waveguide 1120 may include a lower layer 1122 and an upper layer 1124, which may be PDMS layers having a first refractive index. The liquid core waveguide 1100 may include a liquid core 1106 between the layers 1122 and 1124. The liquid core 1126 may include a hollow channel configured to be filled with a liquid having a second refractive index and bounded by 1124 and 1122 at the top and bottom, respectively, and by sidewalls at the sides. In some embodiments, one or both of the layers 1122 and 1124 may be flexible, deformable, and / or movable, whereby the dimensions of the liquid core 1126 located between the layers 1122 and 1124 may change. In some embodiments, the sidewalls surrounding the hollow channel of the liquid core 1126 may be flexible, deformable, and / or movable, whereby the dimensions of the liquid core 1126 may change as shown in FIGS. 1120(b) - 1120(d).

[0141] As shown in the figure, the LC-MMI waveguide 1120 may include fluid inlet / outlet ports 1128, which are fluid ports configured to be fluidly connected to the hollow channel of the liquid core 1126 such that fluid / liquid can flow into and / or out of the hollow channel. In some embodiments, the ports 1128 may be used to drain and / or exchange the fluid in the liquid core 1126. In some embodiments, the ports 1128 may be used to allow the fluid in the liquid core 1126 to flow. In some embodiments, the ports 1128 may be used to apply pressure to the fluid in the liquid core 1126 such that the fluid applies an outward force to the top and / or sidewalls of the hollow channel, which may, in some embodiments, change the width of the liquid core 1126 as shown, for example, in FIG. 1120(d).

[0142] As shown in the figure, the LC-MMI waveguide 1120 may include pressure chambers 1130a and 1130b, which may be installed outside the sidewalls of the liquid core 1126, and may be configured to receive positive (e.g., see Fig. 1120(c)) or negative pressure to apply a force to the sidewalls of the liquid core 1126, and to change the liquid core 1126, for example, as shown in Fig. 1120(c). In some embodiments, the pressure chambers 1130a and / or 1130b may be pressurized with a suitable gas or fluid, such as air as shown in Fig. 1120(a).

[0143] As shown in the figure, light may initially enter the LC-MMI waveguide 1120 through the single-mode waveguide 1132.

[0144] In some embodiments, the LC-MMI waveguide 1120 and its related components may share any one or more common characteristics with the LC-MMI waveguide 1002 and its corresponding related components described above with respect to Fig. 10A, including material composition, size, fluid content, flow rate, and control system, etc.

[0145] In some embodiments, the sidewalls of the liquid core 1126 may be made of PDMS. In some embodiments, the thickness of the sidewalls of the liquid core 1126 may be greater than or equal to 0.1μm, 0.25μm, 0.5μm, 1μm, 5μm, 10μm, 20μm, 30μm, or 50μm. In some embodiments, the thickness of the sidewalls of the liquid core 1126 may be less than or equal to 0.1μm, 0.25μm, 0.5μm, 1μm, 5μm, 10μm, 20μm, 30μm, or 50μm. In some embodiments, the thickness of the sidewalls of the liquid core 1126 may be between 0.5μm and 20μm.

[0146] In some embodiments, one or more heights of the pressure chambers 1130a and 1130b may be greater than or equal to 0.1 μm, 0.5 μm, 1 μm, 5 μm, 10 μm, 20 μm, 30 μm, or 50 μm. In some embodiments, one or more heights of the pressure chambers 1130a and 1130b may be greater than or equal to 0.1 μm, 0.5 μm, 1 μm, 5 μm, 10 μm, 20 μm, 30 μm, or 50 μm. In some embodiments, one or more heights of the pressure chambers 1130a and 1130b may be between 1 μm and 20 μm.

[0147] In some embodiments, one or more of the pressure chambers 1130a and 1130b may be configured to be pressurized to a pressure greater than or equal to 0.1 psi, 0.5 psi, 1 psi, 5 psi, 10 psi, 25 psi, 50 psi, 100 psi, 150 psi, or 250 psi. In some embodiments, one or more of the pressure chambers 1130a and 1130b may be configured to be pressurized to a pressure less than or equal to 0.1 psi, 0.5 psi, 1 psi, 5 psi, 10 psi, 25 psi, 50 psi, 100 psi, 150 psi, or 250 psi. In some embodiments, one or more of the pressure chambers 1130a and 1130b may be configured to be pressurized to a pressure between 1 psi and 100 psi.

[0148] In some embodiments, the liquid core 1126 may be configured such that the fluid flows at a flow rate greater than or equal to 0.1 μm / second, 0.5 μm / second, 1 μm / second, 10 μm / second, 100 μm / second, 1 mm / second, 1 cm / second, 10 cm / second, 1 m / second, 2 m / second, or 5 m / second. In some embodiments, the liquid core 1126 may be configured such that the fluid flows at a flow rate less than or equal to 0.1 μm / second, 0.5 μm / second, 1 μm / second, 10 μm / second, 100 μm / second, 1 mm / second, 1 cm / second, 10 cm / second, 1 m / second, 2 m / second, or 5 m / second. In some embodiments, the liquid core 1126 may be configured such that the fluid flows at a flow rate between 1 μm / second and 1 m / second.

[0149] As shown in the figure, the width w0 of the liquid core 1126 may be changed by + / -Δw by pressurizing the chamber 1130a and / or 1130b and / or the flow of fluid in the core 1126, for example, w = w0+ / -Δw. In some embodiments, w may be greater than or equal to 0.1%, 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, 99%, 101%, 105%, 110%, 125%, 150%, 175%, 200%, 300%, or 500% of w0. In some embodiments, w may be less than or equal to 0.1%, 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, 99%, 101%, 105%, 110%, 125%, 150%, 175%, 200%, 300%, or 500% of w0.

[0150] In some embodiments, Δw may be greater than or equal to 0.01μm, 0.05μm, 0.1μm, 0.5μm, 1μm, 5μm, 10μm, 20μm, or 50μm. In some embodiments, Δw may be less than or equal to 0.01μm, 0.05μm, 0.1μm, 0.5μm, 1μm, 5μm, 10μm, 20μm, or 50μm. In some embodiments, Δw may be between 0.1μm and 10μm.

[0151] In some embodiments, the LC-MMI waveguide 1120 and / or any of the other LC-MMI waveguides discussed herein may be configured to be adjustable by heating and / or cooling. That is, in some embodiments, the LC-MMI waveguide may be configured such that the fluid in its core is heated or cooled to change the refractive index of the LC-MMI waveguide and thus change the propagation of light through the LC-MMI waveguide. In some embodiments, the LC-MMI waveguide may be disposed on a chip, substrate, or other system that includes one or more heating or cooling devices, such as a conduction heating device, a radiative heating device, a cooling device, and / or a thermoelectric heating and / or cooling device. In some embodiments, the LC-MMI waveguide 1120 may be configured such that the fluid within the waveguide is heated and / or cooled by an amount of temperature that is within a range that is less than or equal to the difference between the melting point and the boiling point of the fluid. In some embodiments, the fluid within the waveguide may be heated and / or cooled by an amount greater than or equal to 0.01 degrees Celsius, 0.1 degrees Celsius, 1 degree Celsius, 10 degrees Celsius, or 100 degrees Celsius. In some embodiments, the fluid within the waveguide may be heated and / or cooled by an amount less than or equal to 0.01 degrees Celsius, 0.1 degrees Celsius, 1 degree Celsius, 10 degrees Celsius, or 100 degrees Celsius.

[0152] In some embodiments, any one or more components of the LC-MMI waveguide 1120 may be combined with any one or more components of any of the other systems, platforms, or devices described herein.

[0153] FIG. 11C shows a multi-spot waveguide pattern by experiment (1140) and simulation (1150) for a liquid core waveguide with a width of 50 μm.

[0154] Figure 11D shows the relationship between the length and the number of spots for the fabricated seven LC-MMI waveguides. Each of the seven curves represents an LC-MMI waveguide with a different width, and the darker dots (lower curve) represent the narrower LC-MMI waveguides. The widths of the seven LC-MMI waveguides are 50μm, 75μm, 100μm, 125μm, 150μm, 175μm, and 200μm from the bottom curve to the top curve.

[0155] Figure 11E shows the relationship between the length and the refractive index of the LC-MMI waveguide for three different LC-MMI waveguides with static widths of 50μm (N = 2), 125μm (N = 12), and 200μm (N = 33), respectively. As shown in the figure, changing the refractive index of the liquid core may be used to dynamically adjust the LC-MMI waveguide to shift the length at which a certain number of spots appears.

[0156] Figure 11F shows the relationship between the width deformation (w / w0) and the number of spots N. The lower curve corresponds to an LC-MMI waveguide with w0 = 50, and the upper curve corresponds to an LC-MMI waveguide with w0 = 100μm. In some embodiments, the positive air pressure points may rise up to 20, 40, and 60 PSI to the left, and the liquid flow rate is 1 mL / min. As shown in the figure, changing the width of the variable LC-MMI waveguide may be utilized to dynamically adjust the LC-MMI waveguide.

[0157] In Figures 11D, 11E, and 11F, the dots represent data points, and the solid lines / curves represent the theoretical predictions using Equation (1).

[0158] FIG. 11G shows an implementation of an (mechanically, fluidically, and / or thermally) adjustable LC-MMI waveguide system 1160 for multi-item simultaneous particle detection using intersecting liquid core analyzer channels. System 1160 may share any one or more characteristics common to system 1000 described above with respect to FIG. 10A, except that system 1160 may be configured to be adjusted by using changes in external pressure or internal flow to vary the width of the liquid core of the LC-MMI waveguide according to one or more of the components, features, and characteristics described above with respect to FIG. 11B. As shown in the figure, system 1160, in some embodiments, includes an LC-MMI waveguide liquid core 1166, fluid inlet / outlet ports 1168, pressure chambers 1170a and 1170b, a single-mode excitation waveguide 1172, and a liquid core analyzer channel (and / or liquid core waveguide) 1174 separated from the LC-MMI waveguide liquid core 1166 by a solid barrier 1176.

[0159] In some embodiments, system 1160 and its components may share any one or more characteristics common to system 1000 and its corresponding components described above with respect to FIG. 10A. In some embodiments, system 1160 and its components may share any one or more characteristics common to a system including the LC-MMI waveguide 1120 and its corresponding components described above with respect to FIG. 11B. In some embodiments, system 1160 may be combined with any one or more components of other systems, platforms, or devices described herein.

[0160] FIG. 12 shows a computer according to some embodiments. The computer 1200 can be a component of a system that provides an integrated multi-layer CPS simulation, such as any of the system 100 and / or its sub-components described above with respect to FIG. 1. In some embodiments, the computer 1200 is configured to perform a method for providing, creating, and / or executing an integrated multi-layer CPS simulation, such as all or part of the methods 200 and / or 500 of FIGS. 2 and 5, respectively. In some embodiments, the computer 1200 is configured to control, monitor, or otherwise transmit and / or receive electrical signals to and / or from any one or more of the optofluidic analyte detection and / or MMI waveguide systems, devices, and / or platforms described herein. In some embodiments, the computer 1200 may be a microprocessing device configured to be installed on a substrate or chip included in or provided in relation to any one or more of the systems, devices, and / or platforms described herein.

[0161] The computer 1200 can be a host computer connected to a network. The computer 1200 can be a client computer or a server. As shown in FIG. 12, the computer 1200 can also be any suitable type of microprocessor-based device, such as a personal computer, a workstation, a server, or a handheld computing device such as a phone or a tablet. The computer can include, for example, one or more of a processor 1210, an input device 1220, an output device 1230, a storage 1240, and a communication device 1260.

[0162] The input device 1220 can be any suitable device that provides input, which can be, for example, a touch screen or monitor, a keyboard, a mouse, or a voice recognition device. The output device 1230 can be any suitable device that provides output, which can be, for example, a touch screen, a monitor, a printer, a disk drive, or a speaker.

[0163] The storage 1240 can be any suitable device that provides storage, which can be, for example, electrical, magnetic, or optical memory, etc., and this includes RAM, cache, hard drives, CD-ROM drives, tape drives, or removable storage disks. The communication device 1260 can include any suitable device that can transmit and receive signals over a network, which can be, for example, a network interface chip or card. The components of the computer can be connected in any suitable way, which can be, for example, via a physical bus or wirelessly. The storage 1240 can be a non-transitory computer-readable medium containing one or more programs, which, when executed by one or more processors such as the processor 1210, cause the one or more processors to perform all or part of the methods and / or techniques described herein, for example, but not limited to, the signal collection, system control, signal processing, data analysis, data transmission, and / or any specific method described herein, which includes those related to the optofluidic analyte detection and / or MMI waveguide system, apparatus, and / or platform described herein.

[0164] The software 1250 stored in the storage 1240 and executable by the processor 1210 can include, for example, programming that implements the functions of the present disclosure (for example, implemented in the systems, computers, servers, and / or devices described above). In some embodiments, the software 1250 can be implemented and executed in a combination of servers such as an application server and a database server.

[0165] Software 1250 can also be stored and / or transported in any computer-readable storage medium of the foregoing type, which can be fetched and executed by, or used with, an instruction execution system, apparatus, or device for fetching and executing instructions related to software from the instruction execution system, apparatus, or device. For the present disclosure, the computer-readable storage medium can be any medium such as storage 1240 that can include or store programming used by, or used with, an instruction execution system, apparatus, or device.

[0166] Software 1250 can also be propagated in any transport medium of the foregoing type, which can be fetched and executed by, or used with, an instruction execution system, apparatus, or device for fetching and executing instructions related to software from the instruction execution system, apparatus, or device. For the present disclosure, the transport medium can be any medium that can communicate, propagate, or transport programming used by, or used with, an instruction execution system, apparatus, or device. The transport-readable medium can include, but is not limited to, wired or wireless propagation media such as electronic, magnetic, optical, electromagnetic, or infrared.

[0167] Computer 1200 may be connected to a network, which can be any suitable type of communication system that is interconnected. The network can implement any suitable communication protocol and can be security protected by any suitable security protocol. The network can include any suitable arrangement of network links capable of transmitting and receiving network signals, such as a wireless network connection, a T1 or T3 line, a cable network, DSL, or a telephone line.

[0168] Computer 1200 can implement any operating system suitable for operating on a network. Software 1250 can be written in any suitable programming language such as C, C++, Java, or Python. In various embodiments, the application software embodying the functions of the present disclosure can be deployed in various configurations, such as in a client / server arrangement or through a web browser as, for example, a web-based application or web service.

[0169] The above description has been presented with respect to specific embodiments for purposes of illustration. However, the above exemplary discussion is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teachings. Embodiments have been chosen and described in order to best explain the principles of the technology and their practical applications, thereby enabling others skilled in the art to best utilize the technology and various embodiments with various modifications as are suited to the particular use contemplated.

[0170] The disclosure and examples have been described in sufficient detail with respect to the accompanying drawings, but it should be noted that various changes and improvements will be apparent to those skilled in the art. Such changes and improvements are understood to be included within the scope of the disclosure and examples as defined by the claims. Finally, the disclosures of all patents and publications mentioned in this application are hereby incorporated by reference into this application.

[0171] Various embodiments The following presents a listing of various non-limiting embodiments according to the disclosure of this specification. Any one or more of the following embodiments may be combined, in whole or in part, with any one or more of the other embodiments discussed herein.

[0172] Embodiment 1. In an on-chip analite detection system, a substrate, and A first analyte channel configured to receive a first liquid containing a first analyte that is installed on a substrate and will be detected by a system; A second analyte channel arranged on the substrate and configured to receive a second liquid containing a second analyte that will be detected by the system; A multimode interference (MMI) waveguide installed on the substrate and intersecting with the first analyte channel at a first position and the second analyte channel at a second position, Receiving incident light of a first wavelength and incident light of a second wavelength, Generating a first spot pattern having a first number of spots of light of the first wavelength incident on the first analyte channel, Generating a second spot pattern having a second number of spots of light of the first wavelength incident on the second analyte channel, Generating a third spot pattern having a third number of spots of light of the second wavelength incident on the first analyte channel, Generating a fourth spot pattern having a fourth number of spots of light of the second wavelength incident on the second analyte channel The configured MMI waveguide; A detector configured to detect a fluorescence burst from an analyte excited by one of the first spot pattern, the second spot pattern, the third spot pattern, and the fourth spot pattern; One or more processors, Receiving a signal from the detector representing the detected fluorescence burst, Identifying whether the signal corresponds to the first channel or the second channel based on the number of detected bursts in the received signal, Identifying whether the signal corresponds to light of the first wavelength or light of the second wavelength based on the number of detected bursts in the received signal One or more processors configured as such; Including.

[0173] Embodiment 2. In the on-chip analyte detection system of Embodiment 1, the processor is further configured to identify the analyte based on the number of detected bursts in the received signal.

[0174] Embodiment 3. In the on-chip analyte detection system according to any one of Embodiments 1 and 2, the first analyte channel and the second analyte channel are each configured to guide the light of the fluorescence burst toward the detector.

[0175] Embodiment 4. In the on-chip analyte detection system according to any one of Embodiments 1 to 3, the detector is installed on the chip and is configured to receive the light guided from the analyte channel in the same plane as the analyte channel.

[0176] Embodiment 5. In the on-chip analyte detection system according to any one of Embodiments 1 to 4, The first position is located at a first distance from the light incident port of the MMI waveguide, whereby the light of the first wavelength forms a first number of spots at the first position, and the light of the second wavelength forms a third number of spots at the first position. The second position is located at a second distance from the light incident port of the MMI waveguide, whereby the light of the first wavelength forms a second number of spots at the second position, and the light of the second wavelength forms a fourth number of spots at the fourth position.

[0177] Embodiment 6. In the on-chip analyte detection system according to any one of Embodiments 1 to 5, The height of the MMI waveguide is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, or 5 μm. The width of the MMI waveguide is less than or equal to 10 μm, 25 μm, 50 μm, 100 μm, or 250 μm.

[0178] Embodiment 7. In the on-chip analyte detection system according to any one of Embodiments 1 to 6, The height of the first analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm. The width of the first analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm.

[0179] Embodiment 8. In an on-chip analyte detection system according to any one of Embodiments 1 to 7, The width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm. The length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm.

[0180] Embodiment 9. In an on-chip analyte detection system, a substrate, an analyte channel installed on the substrate and configured to receive a liquid containing an analyte to be detected by the system, one or more first waveguides disposed on the substrate and intersecting the analyte channel, the one or more first waveguides configured to receive incident light of a first wavelength at a first incident port and direct a first multi-spot pattern generated from the incident light of the first wavelength to intersect the analyte channel, one or more second waveguides installed on the substrate and intersecting the analyte channel, the one or more second waveguides configured to receive incident light of a second wavelength at a second incident port and direct a second multi-spot pattern generated from the incident light of the second wavelength to intersect the analyte channel, a multiplexing multi-mode interference (MMI) waveguide installed on the substrate, a third incident port installed at a first end of the multiplexing MMI waveguide and configured to receive incident light of the first wavelength and incident light of the second wavelength, a first emission port installed at a second end of the multiplexing MMI waveguide opposite the first end, the first emission port configured such that light of the first wavelength is directed to the first incident ports of the first group of one or more waveguides, A second injection port installed at a second end of the multi-separation MMI waveguide and configured to emit an image of light of a second wavelength, wherein the light of the second wavelength is directed toward a second incident port of a second group of one or more waveguides. A multi-separation MMI waveguide including including.

[0181] Embodiment 10. In the on-chip analite detection system of Embodiment 9, the third incident port is offset from the center of the multi-separation MMI waveguide in a first direction perpendicular to the propagation direction of light in the multi-separation MMI waveguide.

[0182] Embodiment 11. In the on-chip analite detection system of Embodiment 10, The first injection port is offset from the center of the multi-separation MMI waveguide in the first direction and is configured to output a real image of light of the first wavelength. The second injection port is offset from the center of the multi-separation MMI waveguide in a second direction opposite to the first direction.

[0183] Embodiment 12. In the on-chip analite detection system according to any one of Embodiments 9 to 11, the first group of one or more waveguides includes a first analite excitation MMI waveguide configured to generate a first multi-spot pattern by multimode interference.

[0184] Embodiment 13. In the on-chip analite detection system according to any one of Embodiments 9 to 12, the second group of one or more waveguides includes a second analite excitation MMI waveguide configured to generate a second multi-spot pattern by multimode interference.

[0185] Embodiment 14. In the on-chip analite detection system according to any one of Embodiments 9 to 13, the first group of one or more waveguides includes one or more single-mode waveguides.

[0186] Embodiment 15. In the on-chip analyte detection system according to any one of Embodiments 9 to 14, the second group of one or more waveguides includes one or more single-mode waveguides.

[0187] Embodiment 16. The on-chip analyte detection system according to any one of Embodiments 9 to 15 further includes a detector configured to detect a fluorescence burst from an analyte excited by one or both of light of a first wavelength and light of a second wavelength.

[0188] Embodiment 17. In the on-chip analyte detection system according to any one of Embodiments 9 to 16, the height of the multiplexing MMI waveguide is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, or 5 μm, the width of the multiplexing MMI waveguide is less than or equal to 10 μm, 25 μm, 50 μm, 100 μm, or 250 μm.

[0189] Embodiment 18. In the on-chip analyte detection system according to any one of Embodiments 10 to 17, the offset distance by which the third incident port is offset from the center is greater than or equal to 10%, 25%, or 45% of the width of the multiplexing MMI waveguide.

[0190] Embodiment 19. In the on-chip analyte detection system according to any one of Embodiments 9 to 18, the height of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm, the width of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm.

[0191] Embodiment 20. In the on-chip analyte detection system according to any one of Embodiments 9 to 19, the width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm, the length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm.

[0192] Embodiment 21. In an on-chip analyte detection system, a substrate, an analyte channel installed on the substrate and configured to receive a liquid containing an analyte to be detected by the system, a multiplexing separation multimode interference (MMI) waveguide installed on the substrate, a first input port installed at the first end of the multiplexing separation MMI waveguide and configured to receive incident light of a first wavelength and incident light of a second wavelength, a first output port installed at the second end of the multiplexing separation MMI opposite the first end and configured to emit light of the first wavelength, a second output port installed at the second end of the multiplexing separation MMI waveguide and configured to emit light of the second wavelength, a multiplexing separation MMI waveguide including including the multiplexing separation MMI waveguide is configured to make the emitted light of the first wavelength and the emitted light of the second wavelength enter the analyte channel to excite one or more analytes in the channel.

[0193] Embodiment 22. In the on-chip analyte detection system of Embodiment 21, the first input port is offset from the center of the multiplexing separation MMI waveguide in a first direction perpendicular to the light propagation direction in the multiplexing separation MMI waveguide.

[0194] Embodiment 23. In the on-chip analyte detection system of Embodiment 22, the first output port is offset from the center of the multiplexing separation MMI waveguide in the first direction and is configured to output a real image of the light of the first wavelength, the second output port is offset from the center of the multiplexing separation MMI waveguide in a second direction opposite to the first direction and is configured to output a mirror image of the light of the second wavelength.

[0195] Embodiment 24. In the on-chip analyte detection system according to any one of Embodiments 21 to 23, it further includes a detector configured to detect a fluorescence burst from an analyte excited by one or both of the emitted light of the first wavelength and the emitted light of the second wavelength.

[0196] Embodiment 25. In the on-chip analyte detection system according to any one of Embodiments 21 to 24, it further includes a detector configured to detect a fluorescence burst from an analyte excited by one or both of the light of the first wavelength and the light of the second wavelength.

[0197] Embodiment 26. In the on-chip analyte detection system according to any one of Embodiments 21 to 25, the height of the multi-separation MMI waveguide is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, or 5 μm, the width of the multi-separation MMI waveguide is less than or equal to 10 μm, 25 μm, 50 μm, 100 μm, or 250 μm.

[0198] Embodiment 27. In the on-chip analyte detection system according to any one of Embodiments 22 to 26, the offset distance at which the first incident port is displaced from the center is greater than or equal to 10%, 25%, or 45% of the width of the multi-separation MMI waveguide.

[0199] Embodiment 28. In the on-chip analyte detection system according to any one of Embodiments 21 to 27, the height of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm, the width of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm.

[0200] Embodiment 29. In the on-chip analyte detection system according to any one of Embodiments 21 to 28, the width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm, The length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm.

[0201] Embodiment 30. In an on-chip analite detection system, a substrate, an analite channel installed on the substrate and configured to receive a liquid containing an analite to be detected by the system, a multiplexed multimode interference (MMI) waveguide installed on the substrate, a first input port installed at a first end of the multiplexed MMI waveguide and configured to receive light of a first wavelength, a second input port installed at the first end of the multiplexed MMI waveguide and configured to receive light of a second wavelength, an output port installed at a second end of the multiplexed MMI waveguide opposite to the first end and configured to emit light of the first wavelength and light of the second wavelength, a multiplexing / demultiplexing MMI waveguide including the above, including, the multiplexed MMI waveguide is configured to make the emitted light of the first wavelength and the emitted light of the second wavelength enter the analite channel to excite one or more analites in the channel.

[0202] Embodiment 31. In the on-chip analite detection system of Embodiment 30, the first input port is offset from the center of the multiplexed MMI waveguide in a first direction perpendicular to the light propagation direction of the multiplexed MMI waveguide, the second input port is offset from the center of the multiplexed MMI waveguide in a second direction opposite to the first direction.

[0203] Embodiment 32. In the on-chip analite detection system of Embodiment 30, the output port is offset from the center of the multiplexed MMI waveguide in the first direction and is configured to output a real image of the light of the first wavelength and a mirror image of the light of the second wavelength.

[0204] Embodiment 33. In the on-chip analyte detection system of Embodiment 30, it further includes a detector configured to detect fluorescence bursts from an analyte excited by one or both of the emitted light of the first wavelength and the emitted light of the second wavelength.

[0205] Embodiment 34. In the on-chip analyte detection system of Embodiment 30, The height of the multiplexed MMI waveguide is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, or 5 μm, The width of the multiplexed MMI waveguide is less than or equal to 10 μm, 25 μm, 50 μm, 100 μm, or 250 μm.

[0206] Embodiment 35. In the on-chip analyte detection system of Embodiment 31, the offset distance at which the first incident port is offset from the center is greater than or equal to 10%, 25%, or 45% of the width of the multiplexed MMI waveguide.

[0207] Embodiment 36. In the on-chip analyte detection system of Embodiment 30, The height of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or less than 1 μm, The width of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm.

[0208] Embodiment 37. In the on-chip analyte detection system of Embodiment 30, The width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm, The length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm.

[0209] Embodiment 38. In the on-chip analyte detection system, a substrate, a first analyte channel installed on the substrate and configured to receive a first solution containing a first analyte to be detected by the system, An adjustable liquid-core multimode interference (LC-MMI) waveguide disposed on a substrate and intersecting a first analite channel, A first liquid-core portion, A hollow channel configured to receive a first fluid, Sidewalls defining the boundary of the hollow channel, A first opening configured such that the first fluid can flow into or out of the hollow channel, The first liquid-core portion including, A first optical input port configured to receive incident light of a first wavelength, The LC-MMI waveguide including, Including, The LC-MMI waveguide is configured to direct a first multi-spot pattern generated from incident light of a first wavelength to a first analite channel that intersects it.

[0210] Embodiment 39. In the on-chip analite detection system of Embodiment 38, the first liquid-core portion is configured such that the first fluid can flow out of the hollow channel and the first fluid can be exchanged with a second fluid, and the second fluid has a refractive index different from that of the first fluid.

[0211] Embodiment 40. In the on-chip analite detection system according to any one of Embodiments 38 and 39, further including a temperature control device disposed on the substrate and configured to change the temperature of the first fluid to adjust the temperature of the LC-MMI waveguide by 0.01 degrees Celsius, 0.1 degrees Celsius, 1 degree Celsius, 10 degrees Celsius, or more than 100 degrees Celsius.

[0212] Embodiment 41. In the on-chip analite detection system according to any one of Embodiments 38 to 40, The system further includes a second analite channel disposed on the substrate and configured to receive a second solution containing a second analite to be detected by the system, The LC-MMI waveguide is configured to direct a second multi-spot pattern generated from incident light of a first wavelength toward a second analite channel that intersects the second multi-spot pattern, and further includes a second liquid core portion configured to be adjustable independently of the first liquid core portion.

[0213] Embodiment 42. In the on-chip analite detection system according to any one of Embodiments 38 to 41, it further includes a detector configured to detect a fluorescence burst from an analite excited by a first multi-spot pattern.

[0214] Embodiment 43. In the on-chip analite detection system according to any one of Embodiments 38 to 42, The height of the hollow channel is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, or 10 μm, The width of the hollow channel is less than or equal to 10 μm, 50 μm, 100 μm, 250 μm, or 500 μm.

[0215] Embodiment 44. In the on-chip analite detection system according to any one of Embodiments 38 to 43, The height of the first analite channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm, The width of the first analite channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm.

[0216] Embodiment 45. In the on-chip analite detection system according to any one of Embodiments 38 to 44, The width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm, The length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm.

[0217] Embodiment 46. In any one of the on-chip analyte detection systems of Embodiments 38 to 45, it further includes a pressurized channel separated from the hollow channel by one or more side walls, and by pressurizing the pressurized channel, one or more of the side walls are deformed to adjust the width of the first liquid core portion.

[0218] Embodiment 47. In any one of the on-chip analyte detection systems of Embodiments 38 to 46, the system is configured to pressurize the first fluid in the liquid core portion to deform one or more of the side walls to adjust the width of the first liquid core portion.

[0219] Embodiment 48. In the on-chip analyte detection system of Embodiment 47, adjusting the width of the first liquid core portion includes adjusting the width to be greater than or equal to 0.1 μm, 0.5 μm, 1 μm, 5 μm, or 10 μm.

[0220] Embodiment 49. In any one of the on-chip analyte detection systems of Embodiments 47 and 48, adjusting the width of the first liquid core portion includes increasing the width to be greater than or equal to 125%, 150%, 200%, or 500% of the static width of the portion.

[0221] Embodiment 50. In any one of the on-chip analyte detection systems of Embodiments 38 to 49, adjusting the width of the first liquid core portion includes decreasing the width to be less than or equal to 1%, 10%, 25%, 50%, or 75% of the static width of the portion.

Claims

1. In the on-chip analyte detection system, A substrate; a first analyte channel disposed on the substrate and configured to receive a first liquid containing a first analyte to be detected by the system; a second analyte channel disposed on the substrate and configured to receive a second fluid containing a second analyte to be detected by the system; a multi-mode interference (MMI) waveguide disposed on the substrate and intersecting the first analyte channel at a first location and the second analyte channel at a second location, receiving incident light at a first wavelength and incident light at a second wavelength; generating a first spot pattern having a first number of spots of light at the first wavelength incident on the first analyte channel; generating a second spot pattern having a second number of spots of light at the first wavelength incident on the second analyte channel; generating a third spot pattern having a third number of spots of light at the second wavelength incident on the first analyte channel; generating a fourth spot pattern having a fourth number of spots of light at the second wavelength incident on the second analyte channel. An MMI waveguide configured as described above; a detector configured to detect a fluorescence burst from an analyte excited by one of the first spot pattern, the second spot pattern, the third spot pattern, and the fourth spot pattern; One or more processors, receiving a signal from the detector representative of the detected fluorescent burst; determining whether the signal corresponds to the first channel or the second channel based on a number of detected bursts in the received signal; Identifying whether the signal corresponds to light of the first wavelength or light of the second wavelength based on the number of the detected bursts in the received signal. one or more processors configured to An on-chip analyte detection system comprising:

2. The on-chip analyte detection system of claim 1 , wherein the processor is further configured to identify an identity of the analyte based on the number of the detected bursts in the received signal.

3. The on-chip analyte detection system of claim 1 or 2, wherein the first analyte channel and the second analyte channel are each a waveguide configured to guide light of a fluorescent burst towards the detector.

4. The on-chip analyte detection system of claim 1 , wherein the detector is mounted on the chip and configured to receive light guided from the analyte channel in the same plane as the analyte channel.

5. the first location is located a first distance from a light input port of the MMI waveguide, whereby the light of the first wavelength forms the first number of spots at the first location and the light of the second wavelength forms the third number of spots at the first location; the second location is located a second distance from the light input port of the MMI waveguide, whereby the light of the first wavelength forms the second number of spots at the second location and the light of the second wavelength forms the fourth number of spots at the fourth location. The on-chip analyte detection system according to any one of claims 1 to 4.

6. the height of the MMI waveguide is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, or 5 μm; The width of the MMI waveguide is less than or equal to 10 μm, 25 μm, 50 μm, 100 μm, or 250 μm; The on-chip analyte detection system according to any one of claims 1 to 5.

7. the height of the first analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm; the width of the first analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm; The on-chip analyte detection system according to any one of claims 1 to 6.

8. the width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; the length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; An on-chip analyte detection system according to any one of claims 1 to 7.

9. In the on-chip analyte detection system, A substrate; an analyte channel disposed on the substrate and configured to receive a liquid containing an analyte to be detected by the system; one or more first waveguides disposed on the substrate and intersecting the analyte channels, the one or more first waveguides configured to receive incident light at a first input port at a first wavelength and direct a first multi-spot pattern generated from the incident light at the first wavelength into the intersecting analyte channels; one or more second waveguides disposed on the substrate and intersecting the analyte channels, the one or more second waveguides configured to receive incident light at a second wavelength at a second input port and direct a second multi-spot pattern generated from the incident light at the second wavelength into the intersecting analyte channels; a demultiplexed multimode interference (MMI) waveguide disposed on the substrate, a third input port disposed at a first end of the demultiplexed MMI waveguide and configured to receive incident light at the first wavelength and incident light at the second wavelength; a first exit port located at a second end of the demultiplexed MMI waveguide opposite the first end such that light of the first wavelength is directed to the first entry ports of a first group of one or more waveguides; a second exit port disposed at the second end of the demultiplexed MMI waveguide and configured to exit a mirror image of the second wavelength of light, the second exit port being directed to the second entrance port of a second group of one or more waveguides; a demultiplexed MMI waveguide including: An on-chip analyte detection system comprising:

10. 10. The on-chip analyte detection system of claim 9, wherein the third input port is offset from a center of the demultiplexed MMI waveguide in a first direction perpendicular to a propagation direction of light in the demultiplexed MMI waveguide.

11. the first exit port is offset from the center of the demultiplexing MMI waveguide in the first direction and configured to output a real image of light at the first wavelength; the second exit port is offset from the center of the demultiplexed MMI waveguide in a second direction opposite to the first direction. The on-chip analyte detection system of claim 10.

12. 12. The on-chip analyte detection system of claim 9, wherein the first group of one or more waveguides includes a first analyte excitation MMI waveguide configured to generate the first multi-spot pattern by multimode interference.

13. 13. The on-chip analyte detection system of claim 9, wherein the second group of one or more waveguides includes a second analyte excitation MMI waveguide configured to generate the second multi-spot pattern by multimode interference.

14. The on-chip analyte detection system of any one of claims 9 to 13, wherein the first group of one or more waveguides comprises one or more single mode waveguides.

15. The on-chip analyte detection system of any one of claims 9 to 14, wherein the second group of one or more waveguides comprises one or more single mode waveguides.

16. 16. The on-chip analyte detection system of claim 9, further comprising a detector configured to detect a fluorescence burst from an analyte excited by one or both of the light at the first wavelength and the light at the second wavelength.

17. the height of said demultiplexed MMI waveguide is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, or 5 μm; The width of the demultiplexed MMI waveguide is less than or equal to 10 μm, 25 μm, 50 μm, 100 μm, or 250 μm; An on-chip analyte detection system according to any one of claims 9 to 16.

18. 18. The on-chip analyte detection system of claim 10, wherein the offset distance of the third input port from the center is greater than or equal to 10%, 25%, or 45% of the width of the multiplexed MMI waveguide.

19. the height of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm; The width of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm; An on-chip analyte detection system according to any one of claims 9 to 18.

20. the width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; the length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; An on-chip analyte detection system according to any one of claims 9 to 19.

21. In the on-chip analyte detection system, A substrate; an analyte channel disposed on the substrate and configured to receive a liquid containing an analyte to be detected by the system; a demultiplexed multimode interference (MMI) waveguide disposed on the substrate, a first input port disposed at a first end of the demultiplexed MMI waveguide and configured to receive input light of a first wavelength and input light of a second wavelength; a first launch port disposed at a second end of the demultiplexing MMI waveguide opposite the first end of the demultiplexing MMI waveguide and configured to launch light of the first wavelength; a second launch port disposed at the second end of the demultiplexed MMI waveguide and configured to launch light at the second wavelength; a demultiplexed MMI waveguide including: Including, The on-chip analyte detection system, wherein the demultiplexing MMI waveguide is configured to direct output light of the first wavelength and output light of the second wavelength into the analyte channel to excite one or more analytes in the channel.

22. 22. The on-chip analyte detection system of claim 21, wherein the first input port is offset from a center of the demultiplexed MMI waveguide in a first direction perpendicular to a direction of propagation of light in the demultiplexed MMI waveguide.

23. the first exit port is offset from the center of the demultiplexing MMI waveguide in the first direction and configured to output a real image of light at the first wavelength; the second exit port is offset from the center of the demultiplexed MMI waveguide in a second direction opposite to the first direction and is configured to output a mirror image of the light at the second wavelength.

23. The on-chip analyte detection system of claim 22.

24. 24. The on-chip analyte detection system of claim 21, further comprising a detector configured to detect a fluorescence burst from an analyte excited by one or both of the emitted light at the first wavelength and the emitted light at the second wavelength.

25. 25. The on-chip analyte detection system of claim 21, further comprising a detector configured to detect a fluorescence burst from an analyte excited by one or both of the light at the first wavelength and the light at the second wavelength.

26. the height of said demultiplexed MMI waveguide is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, or 5 μm; The width of the demultiplexed MMI waveguide is less than or equal to 10 μm, 25 μm, 50 μm, 100 μm, or 250 μm; An on-chip analyte detection system according to any one of claims 21 to 25.

27. 27. The on-chip analyte detection system of claim 22, wherein the offset distance of the first entrance port from the center is greater than or equal to 10%, 25%, or 45% of the width of the multiplexed MMI waveguide.

28. the height of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm; The width of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm; An on-chip analyte detection system according to any one of claims 21 to 27.

29. the width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; the length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; An on-chip analyte detection system according to any one of claims 21 to 28.

30. In the on-chip analyte detection system, A substrate; an analyte channel disposed on the substrate and configured to receive a liquid containing an analyte to be detected by the system; a multiplexed multimode interference (MMI) waveguide disposed on the substrate, a first input port disposed at a first end of the multiplexed MMI waveguide and configured to receive light of a first wavelength; a second input port disposed at a first end of the multiplexed MMI waveguide and configured to receive light at a second wavelength; an injection port disposed at a second end of the multiplexed MMI waveguide opposite the first end of the multiplexed MMI waveguide and configured to inject light of the first wavelength and light of the second wavelength; a demultiplexed MMI waveguide including: Including, An on-chip analyte detection system, wherein the multiplexed MMI waveguide is configured to direct output light at the first wavelength and output light at the second wavelength into the analyte channel to excite one or more analytes in the channel.

31. the first input port is offset from a center of the multiplexed MMI waveguide in a first direction perpendicular to a direction of light propagation in the multiplexed MMI waveguide; the second input port is offset from the center of the multiplexed MMI waveguide in a second direction opposite to the first direction.

31. The on-chip analyte detection system of claim 30.

32. the exit port is offset from the center of the multiplexed MMI waveguide in the first direction and configured to output a real image of light at the first wavelength and a mirror image of light at the second wavelength.

31. The on-chip analyte detection system of claim 30.

33. 31. The on-chip analyte detection system of claim 30, further comprising a detector configured to detect a fluorescence burst from an analyte excited by one or both of the emitted light at the first wavelength and the emitted light at the second wavelength.

34. the height of said multiplexed MMI waveguide is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, or 5 μm; The width of the multiplexed MMI waveguide is less than or equal to 10 μm, 25 μm, 50 μm, 100 μm, or 250 μm; 31. The on-chip analyte detection system of claim 30.

35. 32. The on-chip analyte detection system of claim 31, wherein an offset distance of the first entrance port from the center is greater than or equal to 10%, 25%, or 45% of the width of the multiplexed MMI waveguide.

36. the height of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm; The width of the analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm; 31. The on-chip analyte detection system of claim 30.

37. the width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; the length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; 31. The on-chip analyte detection system of claim 30.

38. In the on-chip analyte detection system, A substrate; a first analyte channel disposed on the substrate and configured to receive a first solution containing a first analyte to be detected by the system; a tunable liquid-core multimode interference (LC-MMI) waveguide disposed on the substrate and intersecting the first analyte channel, A first liquid core portion, a hollow channel configured to receive a first fluid; a sidewall defining the hollow channel; and a first opening configured to allow the first fluid to flow into or out of the hollow channel; a first liquid core portion comprising: a first light input port configured to receive input light at a first wavelength; an LC-MMI waveguide comprising: Including, The on-chip analyte detection system, wherein the LC-MMI waveguide is configured to direct a first multi-spot pattern generated from the incident light at the first wavelength into the first intersecting analyte channel.

39. 39. The on-chip analyte detection system of claim 38, wherein the first liquid core portion is configured to allow the first fluid to flow out of the hollow channel and exchange the first fluid with a second fluid, the second fluid having a different refractive index than the first fluid.

40. 40. The on-chip analyte detection system of any one of claims 38 and 39, further comprising a temperature control device disposed on the substrate and configured to change the temperature of the first fluid to temperature adjust the LC-MMI waveguide by greater than or equal to 0.01 degrees Celsius, 0.1 degrees Celsius, 1 degree Celsius, 10 degrees Celsius, or 100 degrees Celsius.

41. The system further includes a second analyte channel disposed on the substrate and configured to receive a second solution containing a second analyte to be detected by the system; the LC-MMI waveguide is configured to direct a second multi-spot pattern generated from the incident light at the first wavelength into the intersecting second analyte channel, and further comprises a second liquid-core portion configured to be adjustable independently of the first liquid-core portion. An on-chip analyte detection system according to any one of claims 38 to 40.

42. 42. The on-chip analyte detection system of any one of claims 38 to 41, further comprising a detector configured to detect a fluorescence burst from an analyte excited by the first multi-spot pattern.

43. the height of the hollow channel is less than or equal to 0.1 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, or 10 μm; The width of the hollow channel is less than or equal to 10 μm, 50 μm, 100 μm, 250 μm, or 500 μm; An on-chip analyte detection system according to any one of claims 38 to 42.

44. the height of the first analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, or 10 μm; the width of the first analyte channel is less than or equal to 1 μm, 2 μm, 5 μm, 10 μm, or 20 μm; An on-chip analyte detection system according to any one of claims 38 to 43.

45. the width of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; the length of the substrate is less than or equal to 2 mm, 5 mm, 1 cm, 2 cm, or 5 cm; An on-chip analyte detection system according to any one of claims 38 to 44.

46. 46. ​​The on-chip analyte detection system of any one of claims 38 to 45, further comprising a pressure channel separated from the hollow channel by one or more of the side walls, wherein pressurizing the pressure channel causes the one or more of the side walls to deform and adjust the width of the first liquid core portion.

47. 47. The on-chip analyte detection system of claim 38, wherein the system is configured to pressurize the first fluid in the liquid core portion to deform one or more of the side walls and adjust a width of the first liquid core portion.

48. 48. The on-chip analyte detection system of claim 47, wherein adjusting the width of the first liquid core portion comprises adjusting the width by greater than or equal to 0.1 μm, 0.5 μm, 1 μm, 5 μm, or 10 μm.

49. 49. The on-chip analyte detection system of claim 47 or 48, wherein adjusting the width of the first liquid core portion comprises increasing the width to greater than or equal to 125% of the static width of the portion, 150% of the static width of the portion, 200% of the static width of the portion, or 500% of the static width of the portion.

50. 50. The on-chip analyte detection system of claim 38, wherein adjusting the width of the first liquid core portion comprises reducing the width to be less than or equal to 1% of the static width of the portion, 10% of the static width of the portion, 25% of the static width of the portion, 50% of the static width of the portion, or 75% of the static width of the portion.

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