Optical waveguide microfluidic detection system

Abstract

The application provides an optical waveguide microfluid detection system, which comprises an optical waveguide, a microfluid channel, a spectrum collection device and an analysis device; the optical waveguide is used for guiding light into the microfluid channel in a horizontal direction; the microfluid chip further comprises a lower cladding layer, a waveguide layer, an upper cladding layer and a channel cover plate which are sequentially arranged from bottom to top; the waveguide layer is made of silicon nitride material and is used for forming the optical waveguide; the microfluid channel extends into the lower cladding layer through the upper cladding layer and the waveguide layer from top to bottom; the microfluid channel does not penetrate the lower cladding layer and has a width of 10-100 mu m. The application has the beneficial effects that: a silicon nitride film with adjustable optical performance is deposited on a flexible substrate, the application range and form of silicon nitride as an optical device material are expanded, a chip-level optical detection system is produced, a traditional benchtop or even large optical system is reduced to a chip size, equivalent or even better analysis performance is ensured, a high-throughput chip-level optical detection and analysis integrated system for biological samples under micro-nano scale is realized, and the system cost is greatly reduced.

Description

Technical Field

[0001] This invention relates to an optical waveguide microfluidic detection system, and more particularly to an optical waveguide microfluidic biological detection system. Background Technology

[0002] High-throughput detection devices are widely used in modern biochemical analysis workflows. These devices mostly employ biochips based on microfluidic technology or microporous arrays, mounted in high-performance optical systems, to analyze biological samples of varying sizes, such as nucleic acids, proteins, viruses, bacteria, and cells. The design of these optical systems is typically based on complex geometric optics, resulting in large size, high cost, the need for optical collimation, and high maintenance costs.

[0003] In the era of precision medicine, miniaturized, high-performance, low-cost, and portable integrated analytical systems have attracted much attention. In particular, the concept of lab-on-chip has made significant progress in manipulating biological samples based on microfluidic technology after decades of development. However, a true lab-on-chip system still lacks a chip-level integrated system for high-throughput biological sample processing at the micro- and nano-scale, enabling optical detection and analysis.

[0004] Meanwhile, depositing materials such as optical silicon nitride thin films on polymer films allows integrated optical devices with SiN waveguides to be separated from silicon or glass substrates, and the polymer has a certain degree of ductility, which greatly increases the application range of integrated optical devices with SiN and other materials as waveguides.

[0005] In order to avoid damaging the molecular structure of polymers, the deposition temperature needs to be controlled as low as possible when depositing thin films on polymers. However, the current mainstream SiN thin film growth temperature is around 400 degrees Celsius, which is still too high. Summary of the Invention

[0006] To address the challenges of bulky and costly modern biochemical analyzers and the evolving demands for miniaturization, portability, and integration in precision medicine, this invention utilizes integrated circuit mass production processes to manufacture a chip-scale optical detection and analysis system. This system integrates the functions of traditional optical systems with on-chip optics, miniaturizing traditional benchtop or even large optical systems to chip size while maintaining equal or superior analytical performance. This enables high-throughput chip-scale optical detection and analysis of biological samples at the micro- and nano-scale, significantly reducing system costs.

[0007] This invention provides an optical waveguide microfluidic detection system, comprising: a microfluidic chip, a spectral collection device, and an analysis device; the microfluidic chip includes: an optical waveguide and a microchannel, wherein the optical waveguide is used to guide light into the microchannel in a horizontal direction;

[0008] The spectral collection device includes a microscope and a measuring device. The microscope collects light signals within the microchannel and transmits the light signals to the measuring device. The measuring device processes the light signals, generates a signal to be analyzed, and transmits the signal to be analyzed to the analyzing device. The analyzing device analyzes the signal to be analyzed to form a spectrum. The device is characterized in that...

[0009] The microfluidic chip further includes: a lower cladding layer, a waveguide layer, an upper cladding layer, and a flow channel cover plate arranged sequentially from bottom to top; the waveguide layer is made of silicon nitride material and is used to form the optical waveguide.

[0010] The microchannel extends from top to bottom through the upper cladding and the waveguide layer and into the lower cladding;

[0011] The flow channel cover plate covers the opening on the microchannel, and the microchannel cover plate includes an injection port for injecting a solution containing the biomolecule to be detected into the microchannel;

[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, the microchannel does not penetrate the lower cladding layer, and the width of the microchannel 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 150-1000 nm, and the coupling optical waveguide has a width of 300-600 nm.

[0019] Preferably, it further includes an optical fiber, which is optically connected to the optical waveguide.

[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 an optical waveguide microfluidic detection system that deposits optically tunable silicon nitride thin films on a flexible substrate, expanding the application range and forms of SiN optical device materials. It realizes the functions of traditional optical systems through integrated optics or on-chip optical devices, shrinking traditional benchtop or even large-scale optical systems to the chip size, ensuring equal or even better analytical performance, and realizing a high-throughput chip-level optical detection and analysis integrated system for biological samples at the micro-nano scale, significantly reducing system costs. Attached Figure Description

[0023] Appendix Figure 1 This is a side view of the optical waveguide microfluidic detection system of the present invention;

[0024] Appendix Figure 2 This is a side view of the coupled optical waveguide microfluidic detection system of the present invention;

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

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

[0027] Appendix Figure 5 yes Figure 1 Side view of the microfluidic waveguide in the optical waveguide;

[0028] Appendix Figure 6 yes Figure 2 Side view of a microfluidic coupled optical waveguide. 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 1-6 As shown, an 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 Figure 1 and 2 As shown, the spectral collection device includes a microscope 3 and a measuring device 4. The microscope 3 is used to collect light signals within the microchannel 2 and transmit the light signals to the measuring device 4. The measuring device 4 is used to process the light signals and generate a signal to be analyzed, which is then transmitted to the analyzing device 5. The analyzing device 5 analyzes the signal to be analyzed to form a spectrum. The characteristic of this device is that...

[0034] The microfluidic chip further includes: a lower cladding layer 141, a waveguide layer 13, an upper cladding layer 142, and a flow channel cover plate 15 arranged sequentially from bottom to top. The waveguide layer 13 is made of silicon nitride material and is used to form the optical waveguides 1311, 1312...131n.

[0035] The microchannel 2 extends from top to bottom through the upper cladding 142 and the waveguide layer 13 and into the lower cladding 141;

[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, and the upper cladding layer 142 is a polymer material with a thickness of 15-30 μm. The microchannel 2 does not penetrate the lower cladding layer, and the width of the microchannel 2 is 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, and significantly reduces system costs.

[0038] 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 130 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.

[0039] The following is an introduction Figure 1 and Figure 5 That is, the optical waveguide microfluidic chip that introduces the light source from the optical fiber 130 at the left end of the optical waveguide group 131:

[0040] like Figure 1 As shown, the optical waveguide group in the optical waveguide microfluidic chip may include only one optical waveguide.

[0041] like Figure 1 and Figure 3 As shown, a group of optical waveguides 131 on a microfluidic stream 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.

[0042] 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 labeled biomolecules, and greatly improve the detection rate of small biomolecules.

[0043] like Figure 1 As shown, the waveguide layer 13 has a thickness of 150-1000 nm, that is... Figure 1 , Figures 3-4 The thickness of the optical waveguides 1311, 1312...131n is 150-1000nm.

[0044] The optical fiber 130 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.

[0045] The following is an introduction Figure 2and Figure 6 That is, an optical waveguide microfluidic chip from which a light source is introduced above the optical waveguide assembly 131:

[0046] 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.

[0047] like Figure 2 and Figure 3 As shown, an optical waveguide assembly 131 on a microfluidic 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. By using light of different wavelengths to excite the labeled biomolecules 21, these biomolecules can be recognized simultaneously. Unexcited biomolecules 20, which are not in the excitation light field introduced by the coupled optical waveguides, will not be recognized. Unexcited biomolecules 20 are 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 150-1000 nm.

[0048] In this invention, the polymer material is SU-8 resin, polyimide, polydimethylsilane, polyethylene, or styrene.

[0049] In this invention, the flow channel cover 15 is made of PDMS, quartz, or the aforementioned polymer materials.

[0050] In this invention, the silicon nitride waveguide layer 13 is a silicon nitride thin film layer 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. This enables the integration of silicon nitride optical waveguides on flexible substrates such as polymer materials, which can be attached to other detection devices or materials, greatly expanding the application range. 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.

[0051] 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:

[0052] 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.

[0053] 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;

[0054] 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 130 guides the light of n different wavelengths corresponding to the above n labels into the optical waveguide group 131, the optical waveguides 1311, 1312...131n, and then guides them horizontally into the microchannel 2. 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 microscope 3 is used to collect the fluorescence (light signal) of specific wavelengths and transmit it to the measuring device 4. The measuring device 4 processes the collected fluorescence (light signal) of specific wavelengths and generates the signal to be analyzed and transmits the signal to be analyzed to the analyzing device 5. The analyzing 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.

[0055] 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.

[0056] 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. An optical waveguide microfluidic detection system, comprising: The microfluidic chip, the light spectrum collection device and the analysis device are characterized in that the microfluidic chip comprises: an optical waveguide and a microfluidic channel, the optical waveguide is used to guide light into the microfluidic channel in a horizontal direction; The light spectrum collection device comprises a microscope and a measuring device, the microscope is used to collect a light signal in the microfluidic channel and transmit the light signal to the measuring device, the measuring device is used to process the light signal and 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 light spectrum; The microfluidic chip further comprises: a lower cladding layer, a waveguide layer, an upper cladding layer and a channel cover plate arranged in sequence from bottom to top, the waveguide layer is a silicon nitride material, and the waveguide layer is used to form the optical waveguide; The microfluidic channel extends through the upper cladding layer and the waveguide layer into the lower cladding layer from top to bottom; The channel cover plate covers an opening of the microfluidic channel, and the channel cover plate comprises a liquid injection port used to inject a solution containing biological molecules to be detected into the microfluidic channel; The lower cladding layer is a high polymer polymerization material with a thickness of 15-30 µm, the upper cladding layer is a high polymer polymerization material with a thickness of 15-30 µm, the microfluidic channel does not penetrate the lower cladding layer, and the width of the microfluidic channel is 10-100 µm; A plurality of optical waveguides are parallel to each other to guide light into the microfluidic channel, and the width of the optical waveguide is 300-600 nm; An incident grating of a silicon nitride material is further included to form a coupling optical waveguide with the optical waveguide, guide light above the upper cladding layer into the optical waveguide and then into the microfluidic channel; and the incident grating protrudes upward from the waveguide layer into the upper cladding layer.

2. The system of claim 1, wherein, The entire or most of the waveguide layer forms a sheet-shaped optical waveguide.

3. The system of claim 2, wherein, The thickness of the waveguide layer is 150-1000 nm.

4. The system of claim 2, wherein, A plurality of coupling optical waveguides are parallel to each other.

5. The system of claim 1, wherein, The thickness of the waveguide layer is 150-1000 nm, and the width of the coupling optical waveguide is 300-600 nm.

6. The system of claim 1, wherein, An optical fiber is further included, and the optical fiber is optically connected with the optical waveguide.

7. The system of claim 1, wherein, The refractive index of the waveguide layer is 1.75-2.

2.

8. The system of claim 1, wherein, The high polymer polymerization material is SU-8 resin, polyimide, polydimethylsilane, polyethylene or phenylpropylcyclobutene.

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