CN115950863A - Single-molecule fluorescence detection system - Google Patents
Single-molecule fluorescence detection system Download PDFInfo
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- CN115950863A CN115950863A CN202211547803.XA CN202211547803A CN115950863A CN 115950863 A CN115950863 A CN 115950863A CN 202211547803 A CN202211547803 A CN 202211547803A CN 115950863 A CN115950863 A CN 115950863A
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Abstract
The invention discloses a single-molecule fluorescence detection system, which comprises a fluorescence excitation unit, a liquid to be detected unit, a fluorescence collection unit and a signal processing unit, wherein the fluorescence excitation unit is used for exciting fluorescence; the fluorescence excitation unit comprises a laser, a conducting optical fiber and a first refractive index gradient lens, and a laser beam generated by the laser is conducted to the first refractive index gradient lens through the conducting optical fiber to obtain an excitation beam; the liquid to be detected unit comprises a micro pipeline, the micro pipeline allows single molecules to pass through, the liquid to be detected passes through the micro pipeline, the excitation light beam irradiates the micro pipeline, and the single-molecule fluorescent marker in the micro pipeline is excited to emit fluorescent photons; the fluorescence collection unit comprises a second refractive index gradient lens and a detection optical fiber, and the second refractive index gradient lens collects fluorescence photons in a dark field and transmits the fluorescence photons to the detection optical fiber; the detection optical fiber is connected with the signal processing unit, and the signal processing unit processes the fluorescence photons passing through the detection optical fiber to obtain the information of the fluorescence marker. The invention provides a micro single-molecule fluorescence detection system with low cost and high efficiency.
Description
Technical Field
The invention relates to the technical field of single-molecule fluorescence detection, in particular to a single-molecule fluorescence detection system.
Background
The fluorescence detection mainly utilizes the detection of special protein with a fluorescence label, can be used for diagnosing diseases such as respiratory tract diseases, autoimmunity and the like by detecting the concentration of the special protein, and is also the most common detection mode in-vitro diagnosis. With the continuous development of medicine and biology, the requirements for rapidness, accuracy and reliability are continuously improved, the conventional detection means (including the currently popular chemiluminescence method, ELISA, co-immunoprecipitation method and the like) cannot meet the current requirements, and the appearance of single-molecule fluorescence detection fills the requirements of people for the advantages of rapidness, high sensitivity, high reliability and the like, and is also called as the next-generation fluorescence detection technology. The single-molecule fluorescence detection can optimize the lowest detection limit to be more than 100 times or even 1000 times.
At present, two single-molecule fluorescence detection devices are available in the market, one of which is developed by quantrix corporation, and the single-molecule fluorescence detection devices utilize a semiconductor process to prepare a chip structure with a micropore array, limit analytes in each micropore, and utilize an imaging system to detect whether an analyte exists in each micropore, so that the content information of the analytes can be obtained. Another method developed by Singulex utilizes a confocal microscope to observe the focus range, excite the region by laser, and then collect the fluorescence intensity of the region to analyze the content of the analyte in the region, however, the confocal microscope has a complex structure, a large volume, a high price and is not easy to maintain.
In addition, the two single-molecule fluorescence detection devices are used for carrying out space segmentation on the analyte, the analyte is segmented into smaller units or individuals to be observed, the influence of high background noise is caused, long-time accumulated exposure is needed in each single step, and therefore the observable threshold value of a receiver is reached, and the final measurement time is far longer than that of a chemiluminescence method.
Therefore, the single-molecule fluorescence detection device is influenced by the problems of cost, measurement efficiency, instrument volume and the like, has low market share at present and is difficult to popularize.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a micro-type, low-cost and high-efficiency single-molecule fluorescence detection system.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a single-molecule fluorescence detection system comprises a fluorescence excitation unit, a liquid to be detected unit, a fluorescence collection unit and a signal processing unit;
the fluorescence excitation unit comprises a laser, a conducting optical fiber and a first refractive index gradient lens, wherein a laser beam generated by the laser is conducted to the first refractive index gradient lens through the conducting optical fiber, and is focused by the first refractive index gradient lens to obtain an excitation beam for exciting the liquid to be detected to generate fluorescence;
the liquid unit to be detected comprises a micro pipeline, the micro pipeline allows single molecules to pass through, the liquid to be detected passes through the micro pipeline, the excitation light beam irradiates the micro pipeline, and the single-molecule fluorescent marker in the micro pipeline is excited to emit fluorescent photons;
the fluorescence collection unit comprises a second refractive index gradient lens and a detection optical fiber, the second refractive index gradient lens is arranged on a light path which is not the excitation light beam, the second refractive index gradient lens collects the fluorescence photons in a dark field, and the fluorescence photons are focused by the second refractive index gradient lens and then are transmitted to the detection optical fiber;
the detection optical fiber is connected with the signal processing unit, and the signal processing unit processes the fluorescence photons passing through the detection optical fiber to obtain the information of the fluorescence marker.
The embodiment of the invention has the following beneficial effects:
in the embodiment of the invention, the first refractive index gradual change lens and the second refractive index gradual change lens are arranged to replace a complex optical lens focusing structure consisting of a plurality of curved lenses in the prior art, so that the space size of light path transmission is effectively reduced, and the volume of the refractive index gradual change lens can be controlled in millimeter order, so that the volume and the structural complexity of the monomolecular fluorescence detection system are greatly reduced; the second refractive index gradient lens is arranged on the light path of the non-excitation light beam, and the dark field collects fluorescence photons, so that the light of the excitation light beam is prevented from being collected by the second refractive index gradient lens, larger background noise is formed, a weak monomolecular fluorescence signal is easily submerged, and the detection speed and the detection precision of the monomolecular fluorescence signal are improved; by arranging the second refractive index gradual change lens and the detection optical fiber, the front end of the second refractive index gradual change lens collects the generated fluorescence photons, the fluorescence photons are coupled to the detection optical fiber after being refracted and focused by the second refractive index gradual change lens, and the limitation of the optical fiber caliber of the detection optical fiber plays a role in diaphragm denoising, namely the function of a confocal pinhole in the conventional confocal microscope; the method has the advantages that only one analyte molecule exists in the sample volume detected each time by adopting the space limitation mode of the micro-channel, and then information such as concentration, content and the like of the fluorescence-labeled molecules to be detected in the liquid to be detected is obtained through statistics, so that the liquid to be detected is prevented from being subjected to space division, and the detection time is prevented from being prolonged.
In conclusion, on the premise of ensuring the advantages of ultra-sensitivity and high efficiency of the monomolecular fluorescence detection technology, the invention utilizes the refractive index gradient lens to effectively simplify a hypersensitive fluorescence detection system and obtain a miniature monomolecular fluorescence detection system. The micro system is of an all-solid-state structure, is stable, is easy to integrate with other functional modules, and has the manufacturing cost far lower than that of a large-scale micro system, so that the defects of complexity, high design difficulty, difficulty in maintenance and high cost of the conventional single-molecule fluorescence detection device are overcome.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art descriptions will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
Wherein:
FIG. 1 is a schematic structural diagram of a single-molecule fluorescence detection system according to an embodiment of the present invention.
FIG. 2 is a graph of refractive index N (r) at any point along the radial radius r of the first/second gradient index lens in accordance with one embodiment of the present invention.
FIG. 3 is a schematic diagram of light transmission of the first/second graded-index lenses according to an embodiment of the invention.
Fig. 4 is a schematic structural diagram of a liquid unit to be measured according to an embodiment of the invention.
Fig. 5 is a schematic structural diagram of a micro-pipe according to an embodiment of the invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Referring to fig. 1, the invention discloses a single molecule fluorescence detection system, comprising a fluorescence excitation unit 10, a liquid unit 20 to be detected, a fluorescence collection unit 30 and a signal processing unit 40.
The fluorescence excitation unit 10 includes a laser, a conducting fiber 11 and a first refractive index gradient lens 12, wherein a laser beam generated by the laser is conducted to the first refractive index gradient lens 12 through the conducting fiber 11, and is focused by the first refractive index gradient lens 12 to obtain an excitation beam for exciting the liquid to be detected to generate fluorescence.
The liquid unit 20 to be tested comprises a micro pipeline 21, the micro pipeline 21 allows single molecules to pass through, the liquid to be tested passes through the micro pipeline 21, the excitation light beam irradiates the micro pipeline 21, and the single-molecule fluorescent marker in the micro pipeline 21 is excited to emit fluorescent photons.
The fluorescence collection unit 30 includes a second refractive index graded lens 31 and a detection optical fiber 32, the second refractive index graded lens 31 is disposed on the light path of the non-excitation light beam, the dark field collects fluorescence photons, and the fluorescence photons are focused by the second refractive index graded lens 31 and then transmitted to the detection optical fiber 32.
The detection fiber 32 is connected to the signal processing unit 40, and the signal processing unit 40 processes the fluorescence photons passing through the detection fiber 32 to obtain information of the fluorescence marker.
In the above embodiment, the first refractive index graded lens 12 and the second refractive index graded lens 31 are arranged to replace a complex optical lens focusing structure formed by a plurality of curved lenses in the prior art, so that the size of a light path transmission space is effectively reduced, and the volume of the refractive index graded lens can be controlled in millimeter order, so that the volume and the structural complexity of the single-molecule fluorescence detection system are greatly reduced; the second refractive index gradient lens 31 is arranged on the light path of the non-excitation light beam, fluorescence photons are collected in the dark field, the light of the excitation light beam is prevented from being collected by the second refractive index gradient lens 31, large background noise is formed, weak monomolecular fluorescence signals are easily submerged, and the detection speed and the detection precision of the monomolecular fluorescence signals are improved; by arranging the second refractive index gradual change lens 31 and the detection optical fiber 32, the front end of the second refractive index gradual change lens 31 collects the generated fluorescence photons, the fluorescence photons are coupled to the detection optical fiber 32 after being refracted and focused by the second refractive index gradual change lens 31, and the limitation of the optical fiber caliber of the detection optical fiber 32 plays a role in diaphragm denoising, namely the role is equivalent to a confocal pinhole in the conventional confocal microscope; the method has the advantages that only one analyte molecule exists in the sample volume detected each time by adopting the space limitation mode of the micro-channel, and then the information such as the concentration, the content and the like of the fluorescence-labeled molecules to be detected in the liquid to be detected is obtained through statistics, so that the space division of the liquid to be detected in the prior art is avoided, and the detection time is prevented from being prolonged.
In conclusion, on the premise of ensuring the advantages of ultra-sensitivity and high efficiency of the monomolecular fluorescence detection technology, the invention utilizes the refractive index gradient lens to effectively simplify a hypersensitive fluorescence detection system and obtain a miniature monomolecular fluorescence detection system. The micro system is of an all-solid-state structure, is stable, is easy to integrate with other functional modules, and has the manufacturing cost far lower than that of a large-scale micro system, so that the defects of complexity, high design difficulty, difficulty in maintenance and high cost of the conventional single-molecule fluorescence detection device are overcome.
In the above embodiment, each of the first graded-index lens 12 and the second graded-index lens 31 has a cylindrical structure having two planar end surfaces, the center of the cylindrical structure has a high refractive index, and the refractive index gradually decreases from the center of the cylindrical structure toward the outside in the radial direction.
Specifically, the formula of the refractive index N (r) in the radial direction of the first or second graded-index lens 31 is:
N(r)＝(0)(1-r 2 /2)
wherein N (0) is the refractive index of the center of the graded index lens, r is the radius of the graded index lens, a is the square of the refractive index distribution constant of the graded index lens, and the curve of the refractive index N (r) at any point on the radial radius r refers to fig. 2. The parameters of the first graded index lens 12 and the parameters of the second graded index lens 31 may be the same or different.
The principle of the self-focusing of the refractive index gradient lens is as follows: because the refractive index of the lens medium is changed, the light entering the lens is regularly bent, and the light can be converged to one point. The intensity of the change of the propagation direction of the light in the graded index lens can be adjusted by adjusting the change gradient of the radial refractive index of the graded index lens, so that the length of one period of change of the light in the graded index lens and the maximum diameter of the radial change of the light in the graded index lens are determined.
In one embodiment, the length of the first graded index lens 12 is an integral multiple of a quarter pitch, the length of the light rays performing a positive selective wave periodic variation in the graded index lens is a pitch, and the pitch P satisfies the following relation:
where Z is the length of the first graded index lens 12. The first graded-index lens 12 focuses the parallel light transmitted through the light-transmitting optical fiber 11 onto the central principal axis of the first graded-index lens 12 to exit, as shown in fig. 3.
In an embodiment, the length of the second graded-index lens 31 is also an integral multiple of a quarter pitch, P also satisfies the above relation, and the fluorescence photons enter the second graded-index lens 31 in parallel, are refracted by the second graded-index lens 31, and then exit from the central main axis of the second graded-index lens 31 to the detection fiber 32.
In a specific embodiment, the signal processing unit 40 includes a single photon detector, a single photon calculator and a data processing module, the single photon detector is connected to the detection optical fiber 32, the single photon detector converts a single fluorescence photon passing through the detection optical fiber 32 into a TTL electrical signal and sends the TTL electrical signal to the single photon counter, the single photon calculator records the arrival time of the single fluorescence photon, the data processing module processes the TTL electrical signal and the arrival time of the single fluorescence photon into information of change of light intensity with time, and the information of the fluorescence marker passing through the micro-pipe 21 is calculated according to the information of the change of the light intensity with time. In the present invention, since the single molecule passes through the micro-pipe 21 separately in time, the TTL electrical signal is a TTL level pulse signal, which is displayed as the light intensity envelope of the pulse in time.
In one embodiment, calculating the fluorescent marker information through the micro-tube 21 based on the information on the change of the light intensity with time includes the following processes:
1) And calculating the number of light intensity envelopes obtained in unit time according to the information of the change of the light intensity along with the time, wherein the number of the light intensity envelopes represents the quantity of the fluorescent markers.
2) And calculating the concentration of the fluorescent marker in the liquid to be detected according to the light intensity envelope number obtained in unit time. The calculation formula of the concentration c of the fluorescent marker in the solution to be detected is as follows: c = N/Q, where N is the number of light intensity envelopes measured per unit time and Q is the flow rate. The flow rate Q may be calculated by measuring or observing the volume of a volume of liquid passing through the micro-pipe 21 by a flow meter.
Specifically, the single photon detector may use a photon counting PMT, a silicon photomultiplier, a single photon counting APD, a single photon counting MPPC, or the like. The single photon counter can be realized by a high-speed FPGA real-time data transmission program module or a time digital conversion card.
Referring to fig. 4, in a specific embodiment, the liquid-to-be-detected unit 20 includes a micro-pipe 21, a waste liquid pool, and a pump, the pump drives the liquid-to-be-detected to enter the micro-pipe 21 and flow into the waste liquid pool through the micro-pipe 21, and all the liquid-to-be-detected passes through the micro-pipe 21, so that the number of all the fluorescent markers in the liquid-to-be-detected can be obtained.
Referring to fig. 5, in one embodiment, the micro-channel 21 is a capillary, the diameter of the capillary can be determined according to the size of the fluorescent marker to be detected, and the capillary is easy to obtain and low in cost compared to a chip. Of course, the micro-pipe 21 can be micro-sized channels of other types and materials.
With continued reference to fig. 5, the liquid unit 20 to be measured includes a transparent substrate 22, a micro-pipe 21 is disposed in the transparent substrate 22, and the liquid pipe is connected to the micro-pipe 21 through an adapter 23.
Further, in one embodiment, the transparent substrate 22 is made of PDMS, but may be made of other transparent materials, such as silicon dioxide, quartz, etc.
In one embodiment, the diameter of the micro-pipe 21 is 1 μm to 50 μm, and the fluorescence detection can be performed within the diameter range of 5nm to 10 μm. In one embodiment, the micro-channel 21 is a square channel with a side length of 4 μm to 10 μm, so that PS fluorescent beads with a diameter of about 20nm can pass through the micro-channel 21 individually under the action of pressure.
In one embodiment, the end surface of the second graded-index lens 31 close to the detection fiber 32 is provided with a long-pass filter film for transmitting light longer than the cut-off wavelength to remove noise light of the incident excitation light and improve the signal-to-noise ratio.
In an embodiment, the fluorescence excitation unit 10 further includes a reflector 13, and an exit surface of the reflector 13 is provided with a band-pass filter film, the reflector 13 is disposed at an end of the first graded refractive index lens 12 away from the conducting optical fiber 11, the reflector 13 is configured to bend the excitation light beam exiting from the first graded refractive index lens 12 so that a light path direction of the excitation light beam is along a flowing direction of the liquid to be detected, the band-pass filter film is configured to filter stray light in the excitation light beam, and the stray light is mainly generated by a component through which the laser passes.
In one embodiment, the guiding fiber 11 is a single mode fiber, which transmits mainly a single wavelength of the excitation light beam.
In one embodiment, the detection fiber 32 is a multimode fiber, and the excitation beam excites the fluorescent marker to generate fluorescent photons having multiple wavelengths, and the multimode fiber can collect the fluorescent photons within a certain wavelength range. The fiber diameter of the detection fiber 32 can be determined according to the size of the confocal field.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the claims. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent should be subject to the appended claims.
Claims (10)
1. A single-molecule fluorescence detection system is characterized by comprising a fluorescence excitation unit, a liquid to be detected unit, a fluorescence collection unit and a signal processing unit;
the fluorescence excitation unit comprises a laser, a conducting optical fiber and a first refractive index gradient lens, wherein a laser beam generated by the laser is conducted to the first refractive index gradient lens through the conducting optical fiber, and is focused by the first refractive index gradient lens to obtain an excitation beam for exciting the liquid to be detected to generate fluorescence;
the liquid unit to be detected comprises a micro pipeline, the micro pipeline allows single molecules to pass through, the liquid to be detected passes through the micro pipeline, the excitation light beam irradiates the micro pipeline, and the single-molecule fluorescent marker in the micro pipeline is excited to emit fluorescent photons;
the fluorescence collection unit comprises a second refractive index gradient lens and a detection optical fiber, the second refractive index gradient lens is arranged on a light path which is not the excitation light beam, the fluorescence photons are collected in a dark field, and the fluorescence photons are focused by the second refractive index gradient lens and then are transmitted to the detection optical fiber;
the detection optical fiber is connected with the signal processing unit, and the signal processing unit processes the fluorescence photons passing through the detection optical fiber to obtain the information of the fluorescence marker.
2. The single-molecule fluorescence detection system according to claim 1, wherein the signal processing unit comprises a single-photon detector, a single-photon calculator and a data processing module, the single-photon detector is connected with the detection optical fiber, the single-photon detector converts the single fluorescence photon passing through the detection optical fiber into a TTL electrical signal and sends the TTL electrical signal to the single-photon counter, the single-photon calculator records the time of arrival of the single fluorescence photon, the data processing module processes the TTL electrical signal and the time of arrival of the single fluorescence photon into information of the change of the light intensity with time, and the information of the fluorescence marker passing through the micro-tube is calculated according to the information of the change of the light intensity with time.
3. The single-molecule fluorescence detection system of claim 1, wherein the single-photon detector is a photon-counting PMT, a silicon photomultiplier, a single-photon-counting APD, or a single-photon-counting MPPC;
the single photon counter is a high-speed FPGA real-time data transmission program module or a time digital conversion card.
4. The single molecule fluorescence detection system of claim 1, wherein the micro-tube is a capillary tube.
5. The single-molecule fluorescence detection system according to claim 1 or 4, wherein the liquid-to-be-detected unit further comprises a pump and a waste liquid pool, and the pump drives the liquid-to-be-detected into the micro-pipeline and flows into the waste liquid pool through the micro-pipeline.
6. The single-molecule fluorescence detection system of claim 1, wherein the liquid unit to be detected comprises a transparent substrate, and the micro-pipeline is disposed in the transparent substrate.
7. The system of claim 1, wherein the end surface of the second graded-index lens close to the detection fiber is provided with a long-pass filter film.
8. The system according to claim 7, wherein the fluorescence excitation unit further comprises a reflector, and a band-pass filter is disposed on an exit surface of the reflector, the reflector is disposed on an end of the first lens with graded refractive index away from the transmission fiber, the reflector is configured to bend the excitation light beam exiting from the first lens with graded refractive index, and the band-pass filter is configured to filter stray light in the excitation light beam.
9. The single molecule fluorescence detection system of claim 1, wherein the conducting fiber is a single mode fiber.
10. The single molecule fluorescence detection system of claim 1, wherein the detection fiber is a multimode fiber.
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| CN116297377A (en) * | 2023-05-22 | 2023-06-23 | 深圳高性能医疗器械国家研究院有限公司 | Single-molecule fluorescence detection chip, preparation method thereof and single-molecule fluorescence detector |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116297377A (en) * | 2023-05-22 | 2023-06-23 | 深圳高性能医疗器械国家研究院有限公司 | Single-molecule fluorescence detection chip, preparation method thereof and single-molecule fluorescence detector |
| CN116297377B (en) * | 2023-05-22 | 2023-07-28 | 深圳高性能医疗器械国家研究院有限公司 | Single-molecule fluorescence detection chip, preparation method thereof and single-molecule fluorescence detector |
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