Optical waveguide microfluidic detection system based on CMOS image sensor

Abstract

The application provides a kind of light waveguide microfluid detection system based on CMOS image sensing, comprising: microfluid chip, spectral collection device and analysis device;Microfluid chip includes: light waveguide and micro flow channel, light waveguide is used to guide light into micro flow channel along horizontal direction;Microfluid chip further includes: CMOS image sensing layer, lower cladding layer, waveguide layer, upper cladding layer and flow channel cover plate are sequentially arranged from bottom to top, waveguide layer is formed by silicon nitride material at 25-150 DEG C deposition temperature, waveguide layer is used to form light waveguide;Micro flow channel penetrates upper cladding layer, waveguide layer and lower cladding layer from top to bottom to expose CMOS image sensing layer;Micro flow channel width is 10-100 μm.It has beneficial effects: low-temperature deposition of silicon nitride light waveguide with adjustable optical performance on CMOS image sensing layer and high molecular polymer material, without damaging CMOS image sensing layer, reducing the preparation work such as adjusting the collection light path in the experiment, improving the experimental efficiency;Improve the portability of detection system, greatly increase the application scene of system.

Description

TECHNICAL FIELD

[0001] The application relates to a light waveguide microfluid detection system based on a CMOS image sensor, in particular to a light waveguide microfluid biological detection system based on a CMOS image sensor. BACKGROUND

[0002] In modern biochemical analysis processes, high-throughput detection equipment has been widely used. Most of these devices use biological chips based on microfluidic technology or microwell arrays, which are loaded in high-performance optical systems to analyze different sizes of biological samples such as nucleic acids, proteins, viruses, bacteria, cells and the like. The design of these optical systems is usually based on complex geometric optics, which has a large volume, high cost, requires optical collimation, and has a high maintenance cost.

[0003] In the era of precision medicine, miniaturized, high-performance, low-cost and mobile integrated analysis systems have attracted great attention. In particular, the concept of lab on chip has made great progress in the manipulation of biological samples based on microfluidic technology over the past few decades, but a real lab on chip system still lacks a high-throughput biological sample chip-level on-chip optical detection and analysis integrated system at the micro-nano scale.

[0004] A CMOS image sensor is an active pixel sensor using a CMOS semiconductor, in which each photosensor has a corresponding circuit near it to directly convert light energy into a voltage signal. Unlike the charge-coupled device (CCD), it does not involve signal charges. Under the same conditions, the CMOS image sensor has relatively fewer elements, lower power consumption, higher data throughput speed, shorter signal transmission distance, lower capacitance, inductance and parasitic delay, and faster data output using X-Y addressing. The data output rate of a CCD is generally not more than 70 million pixels per second, while a CMOS can reach 100 million pixels per second.

[0005] And depositing optical silicon nitride thin film and other materials on the polymer and CMOS image sensor, the flexible substrate formed by the polymer can separate the integrated optical device with SiN waveguide from the silicon or glass substrate, and the polymer has a certain ductility, which greatly increases the application range of the integrated optical device with SiN waveguide; the CMOS image sensor can directly form a spectrum or image, which can replace the laboratory microscope and other light signal collection devices and spectrum monitoring devices, reduce the preparation work such as adjusting the collection light path in the experiment, improve the experimental efficiency, and improve the portability of the detection system, greatly increasing the application scenarios of the system.

[0006] Depositing thin film on high molecular polymer and CMOS image sensor, in order to not destroy the molecular structure of the polymer and the CMOS image sensor, the deposition temperature needs to be controlled as low as possible, and the current mainstream SiN thin film growth temperature is about 400 degrees, which is still too high, and it is easy to soften and melt the high molecular polymer and damage the CMOS image sensor. SUMMARY

[0007] In order to solve the problems of large size and high cost of modern biochemical analysis instruments, and meet the new requirements of miniaturization, portability and integration of instruments in the era of precision medicine, the chip-level optical detection and analysis system is produced by integrated circuit mass production process, the functions of traditional optical system are realized by integrated optical or on-chip optical devices, a low-temperature light guide manufacturing process is adopted to form a light waveguide layer on a high molecular polymer material and a CMOS image sensor layer, so as to avoid softening, hardening and melting of the high molecular polymer material and damage to the CMOS image sensor, and the CMOS is used as a substitute to reduce the preparation work such as adjusting the light collection path in the experiment, improve the experimental efficiency, improve the portability of the detection system, greatly increase the application scenarios of the system, not only can the traditional desktop or even large optical system be reduced to chip size, but also can ensure the same or even better analysis performance, realize the high-throughput chip-level optical detection and analysis integrated system of biological samples under micro-nano scale, and greatly reduce the system cost.

[0008] The application provides a light waveguide microfluid detection system based on a CMOS image sensor, which comprises a microfluid chip, a spectrum collection device and an analysis device.

[0009] The spectrum collection device comprises a CMOS image sensor layer, the CMOS image sensor layer is used for collecting light signals in the microfluid channel, processing the light signals to generate analysis signals and transmitting the analysis signals to the analysis device, and the analysis device analyzes the analysis signals to form a spectrum or an image.

[0010] The microfluid chip further comprises a CMOS image sensor layer, a lower cladding layer, a waveguide layer, an upper cladding layer and a flow channel cover plate which are sequentially arranged from bottom to top, the waveguide layer is formed of silicon nitride material at a deposition temperature of 25-150 DEG C, and the waveguide layer is used for forming the light waveguide; the microfluid channel penetrates through the upper cladding layer, the waveguide layer and the lower cladding layer from top to bottom to expose the CMOS image sensor layer.

[0011] The flow channel cover plate covers the upper opening of the microfluid channel, and the flow channel cover plate comprises a liquid injection port used for injecting a solution containing biological molecules to be detected into the microfluid channel.

[0012] The lower cladding layer is a polymer material with a thickness of 15-30 μm, the upper cladding layer is a polymer material with a thickness of 15-30 μm, and the microchannel width is 10-100 μm.

[0013] Preferably, several of the optical waveguides are parallel to each other to guide light into the microchannel, and the width of the optical waveguides is 300-600 nm.

[0014] Preferably, the entire or most of the waveguide layer forms a sheet-like optical waveguide.

[0015] Preferably, the waveguide layer has a thickness of 150-1000 nm.

[0016] Preferably, it further includes an incident grating made of silicon nitride material to form a coupled optical waveguide with the optical waveguide, guiding light above the upper cladding into the optical waveguide until it is introduced into the microchannel; the incident grating protrudes from the waveguide layer and extends upward into the upper cladding.

[0017] Preferably, it includes a plurality of mutually parallel coupled optical waveguides.

[0018] Preferably, the waveguide layer has a thickness of 150nm-1000nm, and the coupling optical waveguide has a width of 300-600nm.

[0019] Preferably, the surface of the CMOS image sensing layer has a filter layer.

[0020] Preferably, the refractive index of the waveguide layer is 1.75-2.2.

[0021] Preferably, the polymeric material is SU-8 resin, polyimide, polydimethylsilane, polyethylene, or styrene.

[0022] This invention provides a microfluidic detection system based on CMOS image sensing and optical waveguides, which has the following advantages: it allows for the low-temperature deposition of optically tunable silicon nitride optical waveguides on the CMOS image sensing layer and polymer materials without damaging the CMOS image sensing layer, reducing the preparation work such as adjusting the collection optical path in experiments and improving experimental efficiency; it also improves the portability of the detection system and greatly expands the application scenarios of the system. Attached Figure Description

[0023] Appendix Figure 1 This is a side view of the optical waveguide microfluidic detection system based on CMOS image sensing according to the present invention;

[0024] Appendix Figure 2 This is a side view of the coupled optical waveguide microfluidic detection system based on CMOS image sensing according to the present invention;

[0025] Appendix Figure 3yes Figure 1 or Figure 2 A top view of a microfluidic chip;

[0026] Appendix Figure 4 yes Figure 1 or Figure 2 A top view of a microfluidic chip;

[0027] Appendix Figure 5 yes Figure 1 Side view of a single optical waveguide microfluidic;

[0028] Appendix Figure 6 yes Figure 2 Side view of a single coupled optical waveguide microfluidic. Detailed Implementation

[0029] The specific embodiments of the present invention will now be described in detail with reference to the accompanying drawings.

[0030] In the accompanying drawings, for ease of description, the dimensions of layers and regions are not actual proportions. When a layer (or film) is referred to as being "on" another layer or substrate, it may be directly on the other layer or substrate, or there may be intermediate layers. Similarly, when a layer is referred to as being "below" another layer, it may be directly below, and one or more intermediate layers may be present. Additionally, when a layer is referred to as being "between" two layers, it may be the only layer between the two layers, or one or more intermediate layers may be present. The same reference numerals always denote the same elements. Furthermore, when the term "connection" is used between two components, it includes physical connections, which, unless expressly specified in the specification, include, but are not limited to, electrical connections, contact connections, and wireless signal connections.

[0031] This invention proposes an optical waveguide microfluidic detection system that incorporates a chip-level on-chip optical detection chip for high-throughput biological samples at the micro-nano scale into the detection and analysis system.

[0032] like Figures 1 to 4 As shown, a CMOS image sensing-based optical waveguide microfluidic detection system includes: a microfluidic chip (not shown), a spectral collection device (not shown), and an analysis device 5; the microfluidic chip includes: optical waveguides 1311, 1312...131n and microchannels 2, wherein the optical waveguides 1311, 1312...131n are used to guide light into the microchannels 2 in a horizontal direction;

[0033] like Figures 1 to 2 As shown, the spectral collection device includes a CMOS image sensing layer 18, which collects optical signals within the microchannel 2, processes the optical signals to generate a signal to be analyzed, and transmits the signal to be analyzed to the analysis device 5. The analysis device 5 analyzes the signal to be analyzed to form a spectrum or image; characterized in that...

[0034] The microfluidic chip further includes, in sequence from bottom to top, a CMOS image sensing layer 18, a lower cladding layer 141, a waveguide layer 13, an upper cladding layer 142, and a flow channel cover plate 15. The waveguide layer is a silicon nitride material formed at a deposition temperature of 25-150℃. The waveguide layer 13 is used to form the optical waveguides 1311, 1312…131n. The silicon nitride optical waveguides are formed on the CMOS image sensing layer and the polymer material using a low-temperature growth process, without damaging the CMOS image sensing layer. This reduces the preparation work such as adjusting the light collection path during experiments, improves experimental efficiency, enhances the portability of the detection system, and greatly expands the application scenarios of the system.

[0035] The microchannel 2 extends from top to bottom through the upper cladding 142, the waveguide layer 13, and the lower cladding 141 to expose the CMOS image sensing layer 18;

[0036] The flow channel cover plate 15 covers the opening on the microchannel 2. The microchannel cover plate 15 includes an injection port 151 for injecting a solution containing the biomolecule to be detected into the microchannel 2. It should be noted that it also includes an outlet (not shown) to form a circulation system corresponding one-to-one with the injection port 151. The outlet can be an opening on the flow channel cover plate 15. The outlet can also be an opening at both ends of the microchannel 2. The present invention does not limit this.

[0037] The lower cladding layer 141 is a polymer material with a thickness of 15-30 μm, the upper cladding layer 142 is a polymer material with a thickness of 15-30 μm, and the microchannel 2 has a width of 10-100 μm. This reduces the size of traditional benchtop or even large optical systems to the chip size, while ensuring the same or even better analytical performance. It realizes a high-throughput chip for biological sample detection at the micro-nano scale, significantly reducing system costs.

[0038] The surface of the CMOS image sensing layer 18 has a filter layer (not shown).

[0039] Depending on the direction of the light source introduced by the optical waveguide group 131, such as: Figure 1 The light source is introduced from the optical fiber (not shown) at the left end of the optical waveguide group 131, and Figure 2 The light source is introduced from above the optical waveguide group 131, and will be introduced separately.

[0040] The following is an introduction Figure 1 That is, the optical waveguide microfluidic chip that introduces the light source from the optical fiber (not shown) at the left end of the optical waveguide group 131:

[0041] like Figure 1 As shown, the optical waveguide in an optical waveguide microfluidic chip may include only one optical waveguide.

[0042] like Figure 1 and Figure 3 As shown, a microfluidic chip's optical waveguide group 131 includes several, such as n, parallel optical waveguides 1311, 1312...131n to guide light horizontally into the microchannel 2. In actual detection, for biomolecules containing different labels in the microchannel 2, optical waveguides 1311, 1312...131n can guide light with wavelengths λ1, λ2...λn horizontally into the microchannel 2, respectively. By using light of different wavelengths to excite labeled biomolecules 21 with different labels, these biomolecules can be recognized simultaneously. Unexcited biomolecules 20 not in the excitation light field introduced by optical waveguides 1311, 1312...131n will not be recognized. Unexcited biomolecules 20 are unlabeled normal biomolecules or labeled biomolecules located outside the light field and not excited; among them, such as... Figure 3 As shown, the width of the optical waveguides 1311, 1312...131n is 300-600nm.

[0043] Such as 1 and Figure 4 As shown, the entire or most of the waveguide layer 13 forms a sheet-like optical waveguide 1311. The excitation light field introduced by the sheet-like optical waveguide 1311 can reduce the background light signal in the detected biomolecules and greatly improve the detection rate of small biomolecules.

[0044] like Figure 1 As shown, the waveguide layer 13 has a thickness of 150-1000 nm, that is... Figure 1 , Figures 3 to 4 The thickness of the optical waveguides 1311, 1312...131n is 150-1000nm.

[0045] The optical fiber (not shown) is optically connected to the optical waveguide group 131, and then optically connected to the optical waveguides 1311, 1312...131n in the optical waveguide group 131.

[0046] The following is an introduction Figure 2 That is, an optical waveguide microfluidic chip from which a light source is introduced above the optical waveguide assembly 131:

[0047] like Figure 2 As shown, it also includes an incident grating (not shown) made of silicon nitride material to form a coupled optical waveguide with the optical waveguides 1311, 1312...131n, guiding light above the upper cladding 142 into the coupled optical waveguide until it is guided into the microchannel 2 in the horizontal direction. The upper cladding 142 and the channel cover plate 15 are light-transmitting layers. The incident grating protrudes from the waveguide layer 13 and extends upward into the upper cladding 142.

[0048] like Figure 2 and Figure 3As shown, an optical waveguide assembly 131 on a microfluidic chip includes several, such as n, parallel coupled optical waveguides to guide light horizontally into the microchannel 2. In actual detection, for biomolecules containing different labels in the microchannel 2, the coupled optical waveguides can guide light with wavelengths λ1, λ2…λn into the microchannel 2 horizontally, respectively. Different wavelengths of light excite the labeled biomolecules 21, allowing simultaneous recognition of these biomolecules. Unexcited biomolecules 20, not in the excitation light field introduced by the coupled optical waveguides, will not be recognized. Unexcited biomolecules 20 are either unlabeled normal biomolecules or labeled biomolecules located outside the light field and not excited. For example, ... Figure 3 As shown, the width of the coupled optical waveguide is 300-600 nm, wherein, as... Figure 2 As shown, the waveguide layer 13 has a thickness of 150nm-1000nm.

[0049] In this invention, the polymer material is SU-8 resin, polyimide, polydimethylsilane, polyethylene, or styrene.

[0050] In this invention, the flow channel cover 15 is made of PDMS, quartz, or the aforementioned polymer materials.

[0051] In this invention, the silicon nitride waveguide layer 13 is a silicon nitride thin film with a thickness of 150nm-1000nm formed at a low deposition temperature of 25-150℃, avoiding softening, hardening, or melting of the lower cladding layer 141 of the polymer material. The silicon nitride optical waveguide is formed on the CMOS image sensing layer 18 and the lower cladding layer 141 of the polymer material using a low-temperature growth process, without damaging the CMOS image sensing layer. This reduces the preparation work such as adjusting the light collection path during experiments, improving experimental efficiency; it also improves the portability of the detection system and greatly expands the system's application scenarios. The refractive index of the silicon nitride thin film is 1.75-2.2. It should be noted that the silicon nitride thin film can be a film with a uniform refractive index or a film with a non-uniform refractive index, such as a silicon nitride thin film with a refractive index layered structure.

[0052] Circulating tumor cells (CTCs) are a collective term for various types of tumor cells that detach from tumor tissue and enter the human bloodstream. By detecting trace amounts of CTCs in peripheral blood and monitoring trends in their type and quantity, tumor dynamics can be monitored in real time, treatment efficacy can be assessed, and real-time personalized treatment can be achieved. The following describes an embodiment of using the optical waveguide microfluidic detection system of this invention to detect and analyze circulating tumor cells. The main steps are as follows:

[0053] Step 1: Use immunomagnetic bead technology (such as immunomagnetic bead positive sorting) or microfluidic technology to sort and enrich various types of tumor cells that may exist in the collected patient blood samples to obtain a solution containing circulating tumor cells. Alternatively, patient blood samples can be used directly.

[0054] Step 2: Add antibody groups that specifically bind to various tumor cell surface antigens, or aptamer groups that bind to various tumor cell surfaces, to the above-mentioned solution or blood sample containing circulating tumor cells. The antibody groups and aptamer groups are modified with labels, wherein the labels modified on the antibodies or aptamers that bind to specific tumor cells are unique, thereby obtaining a solution or blood sample containing labeled circulating tumor cells; there are n types of labels, and the labels can be fluorescent molecular target probes;

[0055] Step 3: As Figure 1 As shown, the solution or blood sample obtained in the second step is added into the microchannel 2 through the injection port 151. The optical fiber guides the light of different wavelengths corresponding to the above n labels into the optical waveguide group 131, the optical waveguides 1311, 1312...131n, and then guides them into the microchannel 2 in the horizontal direction. The above-mentioned labeled biomolecules 21 containing different labels are fluorescently labeled circulating tumor cells that are excited by the light of different wavelengths to emit fluorescence of specific wavelengths. The CMOS image sensing layer 18 is used to collect the fluorescence (light signal) of specific wavelengths, process the collected fluorescence (light signal) of specific wavelengths, generate the signal to be analyzed, and transmit the signal to be analyzed to the analysis device 5. The analysis device 5 analyzes the spectrum of fluorescence of specific wavelengths formed by the signal to be analyzed. By reading the spectrum, the type of circulating tumor cells in the solution or blood sample can be determined. Multiple circulating tumor cells can be detected at the same time, realizing a high-throughput chip for detecting multiple tumor cells at the micro-nano scale, thereby real-time monitoring of tumor dynamics, evaluation of treatment effects, and realization of real-time individualized treatment.

[0056] The optical waveguide microfluidic chip provided by this invention has the following advantages: it reduces the size of traditional benchtop or even large optical systems to the chip size, while ensuring the same or even better analytical performance, realizing a high-throughput chip for biological sample detection at the micro-nano scale, and significantly reducing system costs.

[0057] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

[0058] This invention provides a method for manufacturing an optical waveguide multi-microchannel chip, forming an integrated matrix structure of optical waveguide and multi-microchannel, which can rapidly construct a chip-level on-chip optical detection and analysis integrated system for high-throughput biological samples at the micro-nano scale.

[0059] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A waveguide microfluidic detection system based on CMOS image sensing, comprising: Microfluidic chip, spectral collection device, and analysis device; characterized in that the microfluidic chip comprises: an optical waveguide and a microchannel, wherein the optical waveguide is used to guide light into the microchannel in a horizontal direction; The spectral collection device includes a CMOS image sensing layer, which is used to collect optical signals in the microchannel, process the optical signals to generate a signal to be analyzed and transmit the signal to be analyzed to the analysis device, and the analysis device analyzes the signal to be analyzed to form a spectrum or image. The microfluidic chip further includes: a CMOS image sensing layer, a lower cladding layer, a waveguide layer, an upper cladding layer, and a channel cover plate arranged sequentially from bottom to top; the waveguide layer is a silicon nitride material formed at a deposition temperature of 25-150°C, and the waveguide layer is used to form the optical waveguide; the microchannel penetrates the upper cladding layer, the waveguide layer, and the lower cladding layer from top to bottom to expose the CMOS image sensing layer; The flow channel cover plate covers the opening on the microchannel, and the flow channel cover plate includes an injection port for injecting a solution containing the biomolecule to be detected into the microchannel; The lower cladding layer is a polymer material with a thickness of 15~30µm, the upper cladding layer is a polymer material with a thickness of 15~30µm, and the microchannel width is 10-100µm; Several optical waveguides are parallel to each other to guide light into the microchannel, and the width of the optical waveguides is 300-600nm; It also includes an incident grating made of silicon nitride material to form a coupled optical waveguide with the optical waveguide, guiding light above the upper cladding into the optical waveguide until it is guided into the microchannel; the incident grating protrudes from the waveguide layer and extends upward into the upper cladding.

2. The system according to claim 1, characterized in that, The entire or most of the waveguide layer forms a sheet-like optical waveguide.

3. The system according to claim 2, characterized in that, The waveguide layer has a thickness of 150-1000 nm.

4. The system according to claim 2, characterized in that, It includes several mutually parallel coupled optical waveguides.

5. The system according to claim 1, characterized in that, The waveguide layer has a thickness of 150nm-1000nm, and the coupling optical waveguide has a width of 300-600nm.

6. The system according to claim 1, characterized in that, The CMOS image sensing layer has a filter layer on its surface.

7. The system according to claim 1, characterized in that, The refractive index of the waveguide layer is 1.75-2.

2.

8. The system according to claim 1, characterized in that, The polymer material is SU-8 resin, polyimide, polydimethylsilane, polyethylene, or phenylcyclobutene.

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