CN106442278B - Measuring device and measuring method for single particle beam scattering light intensity distribution - Google Patents
Measuring device and measuring method for single particle beam scattering light intensity distribution Download PDFInfo
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Abstract
The invention discloses a measuring device for single particle beam scattered light intensity distribution, which comprises a light source, a beam splitting light path, a light receiving and detecting assembly and a micro-fluidic chip assembly, wherein the light source comprises a main measuring light source, an auxiliary measuring light source and a system adjusting light source; the beam splitting optical path comprises a spectroscope and a PIN tube; the light receiving and detecting assembly comprises a 90-degree off-axis parabolic reflector, a telescope lens group, a diaphragm, an optical filter, an ICCD detector, a signal detecting and generating circuit, a composite optical filter, a PMT detector, an oscilloscope and a computer; the microfluidic chip assembly comprises a microfluidic chip, a light screen, a triaxial regulator and a microfluidic pump. In addition, the invention also discloses a measuring method of the scattered light intensity distribution of the single particle beam.
Description
Technical Field
The invention relates to the field of optics and measurement, in particular to a measuring device and a measuring method for single particle beam scattering light intensity distribution.
Background
Particle count and size measurement in liquids are important in clinical diagnostics, industry and environmental testing. Among them, flow cytometry is a multiparameter measurement method commonly used in the field of biological clinical rapid diagnosis and cell analysis. The sample suspension to be measured passes through the nozzle under the constraint of the sheath fluid to form single-cell liquid flow, and is irradiated by incident laser. The photomultiplier receives scattered light or fluorescent signals of sample particles, and the computer analyzes and processes the detection data. Flow cytometry can obtain more accurate results than particle swarm ensemble measurements. However, flow cytometry requires large sample volumes, complex instrumentation, and inconvenient use and maintenance.
Compared with the traditional counting and measuring method, the method for counting particles and measuring the particle size by using the microfluidic chip has the advantages of low sample consumption, capability of greatly shortening the measuring time, simplicity in operation, easiness in making portable equipment for field test and the like, and researchers have proposed a flow cytometry measuring device and method based on the microfluidic chip technology. In the measuring process, the fluid limits the sample particles to flow in the center of the microfluidic channel, so that the sample forms a single particle flow, and the problems of channel blockage, adhesion or absorption of the sample by the channel wall, sample overlapping and the like are avoided.
However, the existing flow cytometry measuring device based on the microfluidic chip is mostly limited to the sample flow only by the sheath liquid on a two-dimensional plane, so that the sample flow cannot be made into a cylindrical fluid, and the sample particles are easy to deviate from the central axis of the sample flow, which affects the measurement accuracy. In addition, since a photomultiplier is used as a light receiving device, the measurement angle of scattered light is limited, and measurement of the scattered light intensity distribution cannot be achieved.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a single particle beam scattering measurement device and a measurement method thereof based on a micro-fluidic chip, which can measure the scattering light intensity distribution of single particles in a single particle beam flowing through a micro-channel in real time, and has high measurement speed and high precision.
In order to achieve the above purpose, the invention provides a measuring device for single particle beam scattered light intensity distribution, which comprises a light source, a beam splitting optical path, a light receiving and detecting assembly and a micro-fluidic chip assembly, wherein the light source comprises a main measuring light source, an auxiliary measuring light source and a system adjusting light source; the beam splitting optical path comprises a spectroscope and a PIN tube; the light receiving and detecting assembly comprises a 90-degree off-axis parabolic reflector, a telescope lens group, a diaphragm, an optical filter, an ICCD detector, a signal detecting and generating circuit, a composite optical filter, a PMT detector, an oscilloscope and a computer; the microfluidic chip assembly comprises a microfluidic chip, a light screen, a triaxial regulator and a microfluidic pump; the three-axis three-dimensional optical system comprises a main measuring light source, a spectroscope, a 90-degree off-axis parabolic reflector, a three-axis adjusting tool, a micro-fluidic chip, a micro-fluidic pump, an oscilloscope, an ICCD detector, a micro-fluidic chip, a PIN tube, a system adjusting light source, a telescope lens group, a diaphragm, an optical filter and the ICCD detector, wherein the main measuring light source, the spectroscope, the 90-degree off-axis parabolic reflector and the three-axis adjusting tool are sequentially arranged on the same first straight line, the spectroscope divides laser emitted by the main measuring light source into a main light path and a reference light path, the main light path coincides with the first straight line, the reference light path is perpendicular to the main light path, the PIN tube is positioned on the reference light path, the system adjusting light source, the telescope lens group, the diaphragm, the optical filter and the ICCD detector are sequentially arranged on the same second straight line, the system adjusting light source and the 90-degree off-axis parabolic reflector are sequentially arranged on the three-axis adjusting tool and are positioned at the focal point of the 90-degree off-axis parabolic reflector, the micro-fluidic chip is arranged in the three-axis adjusting tool, the micro-fluidic pump is connected with the micro-fluidic chip, the auxiliary measuring light source is positioned on the left side of the micro-chip, the micro-axis, the composite light detector and the detector are sequentially arranged on the right PMT detector, and the detector.
Further, the microfluidic chip comprises a circular sheath liquid input runner, a linear sample liquid input runner and a linear main runner, wherein the linear sample liquid input runner and the linear main runner are positioned on the same third straight line, the circular sheath liquid input runner is symmetrical with respect to the third straight line, one end of the circular sheath liquid input runner is provided with a sheath liquid input hole, the other end of the circular sheath liquid input runner is communicated with the linear main runner, the sample liquid input runner is surrounded by the sheath liquid input runner and communicated with the main runner, the sample liquid input runner is provided with a sample liquid input hole, and the main runner is provided with an output hole.
Further, the diameters of the sample liquid input flow channel and the sheath liquid input flow channel are smaller than the diameter of the main flow channel.
Further, the middle part of the main flow channel is an observation area of the micro-fluidic chip, an observation surface of the micro-fluidic chip is a cylindrical surface, the cylindrical surface is positioned in the observation area, the axis of the cylindrical surface coincides with the axis of the main flow channel, and the bottom surface of the micro-fluidic chip is a plane.
Further, the main measuring light source and the auxiliary measuring light source are both lasers, and the system adjusting light source is a collimator.
In addition, the invention also provides a measuring method of the scattered light intensity distribution of the single particle beam, which comprises the following steps:
(1) The method comprises the steps that a system adjusting light source, a 90-degree off-axis parabolic reflector, a light screen and a three-axis adjusting tool are configured, wherein the 90-degree off-axis parabolic reflector and the three-axis adjusting tool are positioned on the same straight line, the system adjusting light source is parallel to the optical axis of the 90-degree off-axis parabolic reflector, and the light screen is arranged on the three-axis adjusting tool and positioned at the focus of the 90-degree off-axis parabolic reflector;
(2) Configuring a PMT detector and an oscilloscope, wherein the PMT detector is positioned on the right side of the triaxial regulator, connecting the PMT detector with the oscilloscope, and regulating the position and the direction of the PMT detector according to the reading of the oscilloscope so as to enable the PMT detector to be aligned with the focus of the 90-degree off-axis parabolic reflector;
(3) Removing the light screen, installing a micro-fluidic chip on the triaxial regulator, wherein the observation surface of the micro-fluidic chip faces the 90-degree off-axis parabolic reflector, the observation area of the micro-fluidic chip and the optical axis of the 90-degree off-axis parabolic reflector are at the same height, regulating the positions of the X axis, the Y axis and the Z axis of the micro-fluidic chip through the triaxial regulator, enabling the output signal of the PMT detector to reach the maximum value according to the reading of the oscilloscope, and after the regulation is completed, positioning the micro-fluidic chip at the focus of the 90-degree off-axis parabolic reflector;
(4) Removing the system adjusting light source and configuring a main measuring light source and a spectroscope, wherein the spectroscope is positioned between the main measuring light source and the 90-degree off-axis parabolic reflector, the spectroscope divides laser emitted by the main measuring light source into a main light path and a reference light path, the main measuring light source, the 90-degree off-axis parabolic reflector and the triaxial regulator are positioned on the same straight line, and the reference light path is vertical to the main light path;
(5) Adjusting the position and the direction of the main measuring light source according to the reading of the oscilloscope, so that the output signal of the PMT detector reaches the maximum value, and completing the alignment adjustment of the main measuring light source, the 90-degree off-axis parabolic reflector and the microfluidic chip;
(6) Configuring a PIN tube, wherein the PIN tube is positioned on the reference light path of the spectroscope, and meanwhile, the PIN tube is connected with the oscilloscope so as to monitor the light intensity fluctuation of main laser emitted by the main measuring light source in real time;
(7) Configuring an auxiliary measurement light source, wherein the auxiliary measurement light source is positioned at the left side of the triaxial adjuster, and the position and the direction of the auxiliary measurement light source are adjusted so that auxiliary laser emitted by the auxiliary measurement light source irradiates an observation area of the microfluidic chip, and the irradiation point is slightly higher than that of the main measurement light source, so that the PMT detector receives the auxiliary laser scattered by the microfluidic chip and emitted by the auxiliary measurement light source;
(8) A composite optical filter is arranged between the PMT detector and the triaxial adjuster, and the position of the composite optical filter and the height of the auxiliary measuring light source are adjusted, so that the PMT detector receives the main laser emitted by the main measuring light source and the auxiliary laser emitted by the auxiliary measuring light source scattered by the micro-flow hole chip at the same time;
(9) Configuring a microfluidic pump, connecting the microfluidic pump with the microfluidic chip, pumping sheath liquid into the microfluidic chip through a sheath liquid input hole of the microfluidic chip by the microfluidic pump, pumping sample liquid into the microfluidic chip through a sample liquid input hole of the microfluidic chip by the microfluidic pump, surrounding the sample liquid by the sheath liquid, and limiting the flow of the sample liquid, so that the sample liquid becomes a single particle beam;
(10) When the sample liquid flows through the observation area of the microfluidic chip, calculating the flow rate of the sample liquid according to the time difference of two adjacent peaks displayed on the oscilloscope and the distance of the light transmission hole of the composite optical filter;
(11) Configuring a signal detection and generation circuit and an ICCD detector, sequentially connecting the PMT detector, the signal detection and generation circuit and the ICCD detector, enabling a receiving surface of the ICCD detector to be perpendicular to an optical axis of the 90-degree off-axis parabolic reflector, enabling the PMT detector to send a light intensity signal to the signal detection and generation circuit, enabling the signal detection and generation circuit to send a detection trigger signal to the ICCD detector, and enabling the signal detection and generation circuit to receive the light intensity signal and send the detection trigger signal, wherein the time difference between the receiving surface and the receiving surface of the ICCD detector is determined by the flow velocity of the sample liquid;
(12) The method comprises the steps of configuring a telescope lens group, a diaphragm and an optical filter, wherein the telescope lens group, the diaphragm, the optical filter and the ICCD detector are sequentially positioned on the same straight line, the telescope lens group is parallel to the optical axis of the 90-degree off-axis parabolic reflector and faces the 90-degree off-axis parabolic reflector, the ICCD detector is connected with a computer, the ICCD detector acquires scattering patterns of sample particles in the sample liquid, and the scattering patterns of the sample particles are sent to the computer;
(13) Manually feeding a trigger signal to activate the ICCD detector, thereby obtaining a background pattern and transmitting the background pattern to the computer;
(14) And subtracting the intensity of the background pattern by the intensity of the scattering pattern of the sample particles by the computer to obtain the scattering light intensity distribution of the single particle beam.
Further, the microfluidic chip comprises a circular sheath liquid input runner, a linear sample liquid input runner and a linear main runner, wherein the linear sample liquid input runner and the linear main runner are positioned on the same straight line, the circular sheath liquid input runner is symmetrical with respect to the straight line, one end of the circular sheath liquid input runner is provided with a sheath liquid input hole, the other end of the circular sheath liquid input runner is communicated with the linear main runner, the sample liquid input runner is surrounded by the sheath liquid input runner and communicated with the main runner, the sample liquid input runner is provided with a sample liquid input hole, and the main runner is provided with an output hole.
Further, the middle part of the main flow channel is an observation area of the micro-fluidic chip, an observation surface of the micro-fluidic chip is a cylindrical surface, the cylindrical surface is positioned in the observation area, the axis of the cylindrical surface coincides with the axis of the main flow channel, and the bottom surface of the micro-fluidic chip is a plane.
Further, the sheath liquid consists of silicone oil and paraffin oil, the refractive index of the sheath liquid is equal to that of the microfluidic chip, the sample liquid is formed by diluting a particle sample solution to be tested with deionized water, the dilution volume ratio is 1:1000-1:10000, and the sheath liquid and the sample liquid are not mutually soluble.
Further, the manufacturing method of the microfluidic chip comprises the following steps:
(a) Simulating the structure of a runner of the microfluidic chip to determine the size of the runner;
(b) A silicon single crystal wafer is used as a first substrate, a first negative photoresist is coated on the first substrate, and a plane template of an observation layer of the microfluidic chip is manufactured on the first negative photoresist and the first substrate through a two-time photoetching process;
(c) Manufacturing a semi-cylindrical template of the observation layer by using an acrylic material, performing reverse molding on the first polydimethylsiloxane by using a plane template and the semi-cylindrical template of the observation layer, and performing baking and curing and removing the plane template and the semi-cylindrical template of the observation layer to obtain the observation layer of the microfluidic chip;
(d) Coating a second negative photoresist on a second substrate by taking a silicon single crystal wafer as the second substrate, and manufacturing a template of the bottom layer of the microfluidic chip on the second negative photoresist and the second substrate through a two-time photoetching process;
(e) Reversing the mould of the second polydimethylsiloxane by using the template of the bottom layer, baking and solidifying the second polydimethylsiloxane, and removing the template of the bottom layer to obtain the bottom layer of the microfluidic chip;
(f) And carrying out ozone treatment and sealing on the bottom layer and the observation layer under the action of ultraviolet rays to obtain the complete microfluidic chip.
The invention has the beneficial effects that: the microfluidic chip of the invention focuses through three-dimensional fluid, so that the sample flow becomes cylindrical fluid, and the construction and accurate positioning of a single particle beam environment are realized; the observation surface of the micro-fluidic chip is cylindrical, and the influence of light refraction at the chip-air interface on the measurement result is reduced. In addition, the invention adopts the light receiving component composed of the 90-degree off-axis parabolic reflector, the telescope lens group, the diaphragm and the optical filter, thereby comprising a large-range scattered light measuring angle; the invention adopts the auxiliary measuring light source, the composite optical filter, the PMT detector and the oscilloscope, thereby realizing the real-time and accurate measurement of the scattered light intensity distribution of single particles flowing through the microfluidic chip.
Drawings
Fig. 1 is a schematic top view of a measuring device for a single particle beam scattered light intensity distribution according to the present invention in a measuring stage.
Fig. 2 is a schematic top view of the measuring device for the scattered light intensity distribution of the particle beam in the adjusting stage.
FIG. 3 is a schematic diagram of the connection of the composite filter, PMT detector and oscilloscope of the present invention during the measurement phase.
Fig. 4 is a schematic view of an angle structure of the microfluidic chip of the present invention.
Fig. 5 is a schematic view of another angle of the microfluidic chip according to the present invention.
Fig. 6 is a flowchart of a method for measuring a scattered light intensity distribution of a single particle beam according to the present invention.
Fig. 7 is a flowchart of a method of fabricating a microfluidic chip according to the present invention.
Detailed Description
For a better explanation of the present invention, the main content of the present invention is further elucidated below in conjunction with the specific examples, but the content of the present invention is not limited to the following examples only.
Referring to fig. 1 to 3, the measuring apparatus of the single particle beam scattered light intensity distribution of the present embodiment includes: comprises a light source, a beam splitting light path, a light receiving and detecting assembly and a micro-fluidic chip assembly.
Specifically, the light sources include a main measurement light source 10, an auxiliary measurement light source 11, and a system adjustment light source 12. The spectroscopic optical path includes a spectroscope 20 and a PIN tube 21. The light receiving and detecting assembly comprises a 90-degree off-axis parabolic reflector 30, a telescope lens group 31, a diaphragm 32, an optical filter 33, an ICCD detector 34, a signal detection and generation circuit 35, a composite optical filter 36, a PMT detector 37, an oscilloscope 38 and a computer 39. The microfluidic chip assembly includes a microfluidic chip 40, a screener 41, a tri-axial conditioner 42, and a microfluidic pump 43.
The main measurement light source 10, the spectroscope 20, the 90 ° off-axis parabolic mirror 30 and the triaxial adjuster 42 are sequentially arranged on the same first straight line, the spectroscope 20 divides laser emitted by the main measurement light source 10 into a main light path and a reference light path, the main light path coincides with the first straight line, the reference light path is perpendicular to the main light path, the PIN tube 21 is positioned on the reference light path, the system adjustment light source 12, the telescope mirror group 31, the diaphragm 32, the optical filter 33 and the ICCD detector 34 are sequentially arranged on the same second straight line, the system adjustment light source 12 is opposite to the paraboloid of the 90 ° off-axis parabolic mirror 30, the light screen (not shown) is arranged on the triaxial adjuster 42 and is positioned at the focal point of the 90 ° off-axis parabolic mirror 30, the microfluidic chip 40 is arranged in the triaxial adjuster 42, the microfluidic pump 43 is connected with the microfluidic chip 40, the auxiliary measurement light source 11 is positioned on the left side of the micro-fluidic chip 40, the optical filter 33 and the micro-channel 37 are sequentially connected with the micro-channel detector 37, the micro-channel detector 37 and the micro-channel detector 37, and the micro-channel detector 37 are sequentially arranged on the side of the micro-channel detector 37.
Further, the main measuring light source 10 and the auxiliary measuring light source 11 are both lasers, and the system adjusting light source 12 is a collimator. The wavelengths of the main measuring light source 10 and the auxiliary measuring light source 11 are different. The main measuring light source 10 is provided with a main measuring light source regulator 10a, the system adjusting light source 12 is provided with a system adjusting light source regulator 12a, the PIN tube 21 is provided with a PIN tube regulator 21a, the composite optical filter 36 is provided with a composite optical filter regulator 36a, and the PMT detector 37 is provided with a PMT detector regulator 37a.
In detail, referring to fig. 4-5, the microfluidic chip 40 includes an annular sheath fluid input channel 401, a linear sample fluid input channel 402 and a linear main channel 403, where the linear sample fluid input channel 402 and the linear main channel 403 are located on the same straight line, the annular sheath fluid input channel 401 is symmetrical with respect to the straight line, one end of the annular sheath fluid input channel 401 is provided with a sheath fluid input hole (not shown), the other end of the annular sheath fluid input channel 401 is communicated with the linear main channel 403, the sample fluid input channel 402 is surrounded by the sheath fluid input channel 401 and is communicated with the main channel 403, the sample fluid input channel 402 is provided with a sample fluid input hole (not shown), and the main channel 403 is provided with an output hole (not shown). In a preferred embodiment, the diameter of the sample fluid input channel 402 and the diameter of the sheath fluid input channel 401 are both smaller than the diameter of the primary channel 403. The sheath fluid consists of silicone oil and paraffin oil, the refractive index of the sheath fluid is equal to that of the microfluidic chip 40, the sample fluid is formed by diluting a particle sample solution to be tested with deionized water, the dilution volume ratio is 1:1000-1:10000, and the sheath fluid and the sample fluid are not mutually soluble.
Further, the middle part of the main channel 403 is an observation area C of the microfluidic chip 40, an observation surface of the microfluidic chip is a cylindrical surface, the cylindrical surface is located in the observation area C, an axis of the cylindrical surface coincides with an axis of the main channel 403, and a bottom surface of the microfluidic chip 40 is a plane.
Referring to fig. 6 to 7, the method for measuring the scattered light intensity distribution of the single particle beam of the present embodiment includes:
step S1: configuring a system adjustment light source 12, a 90 off-axis parabolic reflector 30, a light screen (not shown) and a tri-axial adjustment fixture 42, the 90 off-axis parabolic reflector 30 and the tri-axial adjustment fixture 42 being on a common line, the system adjustment light source 12 being parallel to the optical axis of the 90 off-axis parabolic reflector 30, the light screen being mounted on the tri-axial adjustment fixture 42 and being located at the focal point of the 90 off-axis parabolic reflector 30;
step S2: configuring a PMT detector 37 and an oscilloscope 38, wherein the PMT detector 37 is positioned on the right side of the triaxial adjuster 42, connecting the PMT detector 37 with the oscilloscope 38, and adjusting the position and direction of the PMT detector 37 according to the reading of the oscilloscope 38 so that the PMT detector 37 is aligned with the focus of the 90-degree off-axis parabolic mirror 30;
step S3: removing the light screen, mounting a micro-fluidic chip 40 on the three-axis regulator 42, wherein an observation surface of the micro-fluidic chip 40 faces the 90-degree off-axis parabolic reflector 30, an observation area C of the micro-fluidic chip 40 and an optical axis of the 90-degree off-axis parabolic reflector 30 are at the same height, positions of an X axis, a Y axis and a Z axis of the micro-fluidic chip 40 are regulated by the three-axis regulator 42, and an output signal of the PMT detector 37 reaches a maximum value according to the reading of the oscilloscope 38, and after the regulation is completed, the micro-fluidic chip 40 is positioned at a focus of the 90-degree off-axis parabolic reflector 30;
step S4: removing the system adjustment light source 12 and configuring a main measurement light source 10 and a spectroscope 20, wherein the spectroscope 20 is positioned between the main measurement light source 10 and the 90-degree off-axis parabolic reflector 30, the spectroscope 20 divides laser emitted by the main measurement light source 10 into a main light path and a reference light path, the main measurement light source 10, the 90-degree off-axis parabolic reflector 30 and the triaxial regulator 42 are positioned on the same straight line, and the reference light path is perpendicular to the main light path;
step S5: adjusting the position and direction of the main measuring light source 10 according to the reading of the oscilloscope 38 to ensure that the output signal of the PMT detector 37 reaches the maximum value, and completing the alignment adjustment of the main measuring light source 10 and the 90-degree off-axis parabolic reflector 30 and the microfluidic chip 40;
step S6: a PIN tube 21 is configured, the PIN tube 21 is positioned on the reference light path of the spectroscope 20, and meanwhile, the PIN tube 21 is connected with the oscilloscope 38 so as to monitor the light intensity fluctuation of the main laser emitted by the main measuring light source 10 in real time;
step S7: configuring an auxiliary measuring light source 11, wherein the auxiliary measuring light source 11 is positioned at the left side of the triaxial adjuster 42, and adjusts the position and the direction of the auxiliary measuring light source 11 so that auxiliary laser emitted by the auxiliary measuring light source 11 irradiates on an observation area C of the micro-fluidic chip 40, and the irradiation point is slightly higher than the irradiation point of the main measuring light source 10, so that the PMT detector 37 receives the auxiliary laser emitted by the auxiliary measuring light source 11 scattered by the micro-fluidic chip 40;
step S8: a composite optical filter 36 is arranged between the PMT detector 37 and the triaxial adjuster 42, and the position of the composite optical filter 36 and the height of the auxiliary measuring light source 11 are adjusted so that the PMT detector 37 receives the main laser light emitted by the main measuring light source 10 and the auxiliary laser light emitted by the auxiliary measuring light source 11 scattered by the micro-flow hole chip 40 at the same time;
step S9: a microfluidic pump 43 is configured, the microfluidic pump 43 is connected with the microfluidic chip 40, sheath fluid is pumped into the microfluidic chip 40 through the sheath fluid input hole of the microfluidic chip 40 by the microfluidic pump 43, sample fluid is pumped into the microfluidic chip 40 through the sample fluid input hole of the microfluidic chip 40 by the microfluidic pump 43, the sheath fluid surrounds the sample fluid and restricts the flow of the sample fluid, and therefore the sample fluid becomes a single particle beam;
step S10: when the sample liquid flows through the observation area of the microfluidic chip 40, calculating the flow rate of the sample liquid according to the time difference between two adjacent peaks displayed on the oscilloscope 38 and the distance between the light passing holes of the composite optical filter 36;
step S11: a signal detection and generation circuit 35 and an ICCD detector 34 are configured, the PMT detector 37, the signal detection and generation circuit 35 and the ICCD detector 34 are sequentially connected, a receiving surface of the ICCD detector 34 is perpendicular to an optical axis of the 90-degree off-axis parabolic reflector 30, the PMT detector 37 sends a light intensity signal to the signal detection and generation circuit 35, the signal detection and generation circuit 35 sends a detection trigger signal to the ICCD detector 34 so as to start the ICCD detector 34, and the time difference between receiving the light intensity signal and sending the detection trigger signal by the signal detection and generation circuit 35 is determined by the flow rate of the sample liquid;
step S12: a telescope lens group 31, a diaphragm 32 and an optical filter 33 are configured, the telescope lens group 31, the diaphragm 32, the optical filter 33 and the ICCD detector 34 are sequentially positioned on the same straight line, the telescope lens group 31 is parallel to the optical axis of the 90-degree off-axis parabolic reflector 30 and faces the 90-degree off-axis parabolic reflector 30, the ICCD detector 34 is connected with a computer 39, the ICCD detector 34 acquires scattering patterns of sample particles in the sample liquid, and the scattering patterns of the sample particles are sent to the computer 39;
step S13: manually feeding a trigger signal to activate the ICCD detector 34 to obtain a background pattern and send the background pattern to the computer 39;
step S14: the computer 39 subtracts the intensity of the background pattern from the intensity of the scattering pattern of the sample particles to obtain the scattering light intensity distribution of the single particle beam.
Specifically, referring to fig. 7, the method for manufacturing the microfluidic chip 40 includes the following steps:
(a) Simulating the structure of the flow channel of the microfluidic chip 40 to determine the size of the flow channel;
(b) A silicon single crystal wafer is used as a first substrate 50, a first negative photoresist 51 is coated on the first substrate 51, and a plane template of an observation layer 53 of the microfluidic chip 40 is manufactured on the first negative photoresist 51 and the first substrate 50 through a two-time photoetching process;
(c) Manufacturing a semi-cylindrical template of the observation layer 53 by using acrylic materials, performing reverse molding on the first polydimethylsiloxane 52 by using a plane template and the semi-cylindrical template of the observation layer 53, and performing baking and curing and removing the plane template and the semi-cylindrical template of the observation layer 53 to obtain the observation layer 53 of the microfluidic chip 40;
(d) A silicon single crystal wafer is used as a second substrate 60, a second negative photoresist 61 is coated on the second substrate 60, and a template of a bottom layer 63 of the microfluidic chip 40 is manufactured on the second negative photoresist 61 and the second substrate 60 through a two-time photoetching process;
(e) The second polydimethylsiloxane 62 is subjected to reverse molding by using the template of the bottom layer 63, baking and curing are carried out, and the template of the bottom layer 63 is removed, so that the bottom layer 63 of the microfluidic chip 40 is obtained;
(f) The observation layer 53 and the bottom layer 63 are subjected to ozone treatment and sealing under the action of ultraviolet rays, so that the complete microfluidic chip 40 is obtained.
Other parts not described in detail are prior art. Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (10)
1. The utility model provides a measuring device of single particle beam scattering light intensity distribution, it includes light source, beam split light path, light receiving and detection subassembly and micro-fluidic chip subassembly, its characterized in that:
the light source comprises a main measuring light source (10), an auxiliary measuring light source (11) and a system adjusting light source (12);
the beam splitting optical path comprises a beam splitter (20) and a PIN tube (21);
the light receiving and detecting assembly comprises a 90-degree off-axis parabolic reflector (30), a telescope lens group (31), a diaphragm (32), an optical filter (33), an ICCD detector (34), a signal detecting and generating circuit (35), a composite optical filter (36), a PMT detector (37), an oscilloscope (38) and a computer (39);
the microfluidic chip assembly comprises a microfluidic chip (40), a light screen, a triaxial regulator (42) and a microfluidic pump (43);
the main measuring light source (10), the spectroscope (20), the 90-degree off-axis parabolic reflector (30) and the three-axis regulator (42) are sequentially arranged on the same first straight line, the spectroscope (20) divides laser emitted by the main measuring light source (10) into a main light path and a reference light path, the main light path coincides with the first straight line, the reference light path is perpendicular to the main light path, the PIN tube (21) is positioned on the reference light path, the system adjusting light source (12), the telescope mirror group (31), the diaphragm (32), the optical filter (30) and the ICCD detector (34) are sequentially arranged on the same second straight line, the system adjusting light source (12) is opposite to the parabolic reflector (30) with 90-degree off-axis parabolic reflector, the light screen is arranged on the three-axis regulator (42) and is positioned at the focus of the 90-degree off-axis parabolic reflector (30), the microchip (40) is arranged in the three-axis regulator (42), the micro-pump (43) is connected with the micro-channel detector (38), the micro-channel detector (40) is sequentially arranged on the side of the micro-channel detector (40), and the micro-channel detector (37) is sequentially arranged on the side of the micro-channel (37) The PMT detector (37), the signal detection and generation circuit (35), the ICCD detector (34) and the computer (39) are sequentially connected;
the irradiation point of the auxiliary measuring light source (11) irradiated onto the observation area (C) of the micro-fluidic chip (40) is slightly higher than the irradiation point of the main measuring light source (10) irradiated onto the observation area (C) of the micro-fluidic chip (40), so that the PMT detector (37) receives the main laser light scattered by the micro-fluidic chip (40) and emitted by the main measuring light source (10) and the auxiliary laser light emitted by the auxiliary measuring light source (11) at the same time.
2. The measuring device for the scattered light intensity distribution of the single particle beam according to claim 1, wherein the microfluidic chip (40) comprises a circular sheath liquid input runner (401), a linear sample liquid input runner (402) and a linear main runner (403), the linear sample liquid input runner (402) and the linear main runner (403) are located on the same third straight line, the circular sheath liquid input runner (401) is symmetrical with respect to the third straight line, a sheath liquid input hole is formed in one end of the circular sheath liquid input runner (401), the other end of the circular sheath liquid input runner (401) is communicated with the linear main runner (403), the sample liquid input runner (402) is surrounded by the sheath liquid input runner (401) and is communicated with the main runner (403), a sample liquid input hole is formed in the sample liquid input runner (402), and an output hole is formed in the main runner (403).
3. The measurement device of a single particle beam scattered light intensity distribution according to claim 2, wherein the diameter of both the sample liquid input flow channel (402) and the sheath liquid input flow channel (401) is smaller than the diameter of the main flow channel (403).
4. The measuring device for single particle beam scattering light intensity distribution according to claim 2, wherein the middle part of the main flow channel (403) is an observation area (C) of the microfluidic chip (40), the observation surface of the microfluidic chip (40) is a cylindrical surface, the cylindrical surface is located in the observation area (C) and the axis of the cylindrical surface coincides with the axis of the main flow channel (403), and the bottom surface of the microfluidic chip (40) is a plane.
5. The measuring device of single particle beam scattered light intensity distribution according to claim 1, wherein the main measuring light source (10) and the auxiliary measuring light source (11) are both lasers, and the system adjusting light source (12) is a collimator.
6. A method for measuring a single-particle beam scattered light intensity distribution by using the single-particle beam scattered light intensity distribution measuring apparatus according to any one of claims 1 to 5, comprising the steps of:
(1) Configuring a system adjustment light source (12), a 90-degree off-axis parabolic reflector (30), a light screen and a three-axis adjusting tool (42), wherein the 90-degree off-axis parabolic reflector (30) and the three-axis adjusting tool (42) are positioned on the same straight line, the system adjustment light source (12) is parallel to the optical axis of the 90-degree off-axis parabolic reflector (30), and the light screen is arranged on the three-axis adjusting tool (42) and positioned at the focus of the 90-degree off-axis parabolic reflector (30);
(2) Configuring a PMT detector (37) and an oscilloscope (38), wherein the PMT detector (37) is positioned on the right side of the triaxial adjuster (42), connecting the PMT detector (37) with the oscilloscope (38), and adjusting the position and the direction of the PMT detector (37) according to the reading of the oscilloscope (38) so that the PMT detector (37) is aligned with the focus of the 90-DEG off-axis parabolic reflector (30);
(3) Removing the light screen, mounting a micro-fluidic chip (40) on the three-axis adjusting tool (42), wherein an observation surface of the micro-fluidic chip (40) faces the 90-degree off-axis parabolic reflector (30), an observation area of the micro-fluidic chip (40) and an optical axis of the 90-degree off-axis parabolic reflector (30) are at the same height, positions of an X axis, a Y axis and a Z axis of the micro-fluidic chip (40) are adjusted through the three-axis adjusting tool (42), an output signal of the PMT detector (37) reaches a maximum value according to the reading of the oscilloscope (38), and the micro-fluidic chip (40) is positioned at a focus of the 90-degree off-axis parabolic reflector (30) after adjustment is completed;
(4) Removing the system adjusting light source (12) and configuring a main measuring light source (10) and a spectroscope (20), wherein the spectroscope (20) is positioned between the main measuring light source (10) and the 90-degree off-axis parabolic reflector (30), the spectroscope (20) divides laser emitted by the main measuring light source (10) into a main light path and a reference light path, and the main light path, the main measuring light source (10), the 90-degree off-axis parabolic reflector (30) and the triaxial regulator (42) are positioned on the same straight line, and the reference light path is perpendicular to the main light path;
(5) Adjusting the position and direction of the main measuring light source (10) according to the reading of the oscilloscope (38) to ensure that the output signal of the PMT detector (37) reaches the maximum value, and completing the alignment adjustment of the main measuring light source (10) and the 90-degree off-axis parabolic reflector (30) and the microfluidic chip (40);
(6) A PIN tube (21) is configured, the PIN tube (21) is positioned on the reference light path of the spectroscope (20), and meanwhile, the PIN tube (21) is connected with the oscilloscope (38) so as to monitor the light intensity fluctuation of main laser emitted by the main measuring light source (10) in real time;
(7) Configuring an auxiliary measuring light source (11), wherein the auxiliary measuring light source (11) is positioned at the left side of the triaxial adjuster (42), and the position and the direction of the auxiliary measuring light source (11) are adjusted so that auxiliary laser emitted by the auxiliary measuring light source irradiates on an observation area (C) of the micro-fluidic chip (40), and the irradiation point is slightly higher than that of the main measuring light source (10), so that the PMT detector (37) receives the auxiliary laser scattered by the micro-fluidic chip (40) and emitted by the auxiliary measuring light source (11);
(8) A composite optical filter (36) is arranged between the PMT detector (37) and the triaxial adjuster (42), and the position of the composite optical filter (36) and the height of the auxiliary measuring light source (11) are adjusted so that the PMT detector (37) receives the main laser light emitted by the main measuring light source (10) and the auxiliary laser light emitted by the auxiliary measuring light source (11) scattered by the micro-fluidic chip (40) at the same time;
(9) A microfluidic pump (43) is configured, the microfluidic pump (43) is connected with the microfluidic chip (40), sheath liquid is pumped into the microfluidic chip (40) through the sheath liquid input hole of the microfluidic chip (40) by the microfluidic pump (43), sample liquid is pumped into the microfluidic chip (40) through the sample liquid input hole of the microfluidic chip (40) by the microfluidic pump (43), the sheath liquid surrounds the sample liquid, and the flow of the sample liquid is limited, so that the sample liquid is a single particle beam;
(10) When the sample liquid flows through the observation area of the micro-fluidic chip (40), calculating the flow rate of the sample liquid according to the time difference of two adjacent peaks displayed on the oscilloscope (38) and the distance of the light transmission hole of the composite optical filter (36);
(11) A signal detection and generation circuit (35) and an ICCD detector (34) are configured, the PMT detector (37), the signal detection and generation circuit (35) and the ICCD detector (34) are sequentially connected, a receiving surface of the ICCD detector (34) is perpendicular to an optical axis of the 90-degree off-axis parabolic mirror (30), the PMT detector (37) sends a light intensity signal to the signal detection and generation circuit (35), the signal detection and generation circuit (35) sends a detection trigger signal to the ICCD detector (34) for starting the ICCD detector (34), and the time difference between receiving the light intensity signal and sending the detection trigger signal by the signal detection and generation circuit (35) is determined by the flow rate of the sample liquid;
(12) The method comprises the steps of configuring a telescope lens group (31), a diaphragm (32) and an optical filter (33), wherein the telescope lens group (31), the diaphragm (32), the optical filter (33) and an ICCD detector (34) are sequentially positioned on the same straight line, the telescope lens group (31) is parallel to an optical axis of a 90-degree off-axis parabolic mirror (30) and faces the 90-degree off-axis parabolic mirror (30), the ICCD detector (34) is connected with a computer (39), and the ICCD detector (34) acquires scattering patterns of sample particles in a sample liquid and sends the scattering patterns of the sample particles to the computer (39);
(13) -manually feeding a trigger signal to activate the ICCD detector (34) to obtain a background pattern and send the background pattern to the computer (39);
(14) The computer (39) subtracts the intensity of the background pattern from the intensity of the scattering pattern of the sample particles to obtain a scattered light intensity distribution of the single particle beam.
7. The method for measuring the scattered light intensity distribution of a single particle beam according to claim 6, wherein the microfluidic chip (40) comprises a circular sheath liquid input runner (401), a linear sample liquid input runner (402) and a linear main runner (403), the linear sample liquid input runner (402) and the linear main runner (403) are positioned on the same straight line, the circular sheath liquid input runner (401) is symmetrical with respect to the straight line, a sheath liquid input hole is formed at one end of the circular sheath liquid input runner (401), the other end of the circular sheath liquid input runner (401) is communicated with the linear main runner (403), the sample liquid input runner (402) is surrounded by the sheath liquid input runner (401) and is communicated with the main runner (403), a sample liquid input hole is formed in the sample liquid input runner (402), and an output hole is formed in the main runner (403).
8. The method for measuring the scattered light intensity distribution of the single particle beam according to claim 7, wherein the middle part of the main flow channel (403) is an observation area (C) of the microfluidic chip (40), the observation surface of the microfluidic chip (40) is a cylindrical surface, the cylindrical surface is located in the observation area (C) and the axis of the cylindrical surface coincides with the axis of the main flow channel (403), and the bottom surface of the microfluidic chip (40) is a plane.
9. The method for measuring the scattered light intensity distribution of the single particle beam according to claim 6, wherein the sheath fluid consists of silicone oil and paraffin oil, the refractive index of the sheath fluid is equal to that of the microfluidic chip (40), the sample fluid is formed by diluting a sample solution of particles to be measured with deionized water, the dilution volume ratio is 1:1000-1:10000, and the sheath fluid and the sample fluid are not mutually dissolved.
10. The method for measuring the scattered light intensity distribution of a single particle beam according to claim 6, wherein the method for manufacturing the microfluidic chip comprises the steps of:
(a) Simulating the structure of a flow channel of the microfluidic chip (40) to determine the size of the flow channel;
(b) A silicon single crystal wafer is used as a first substrate (50), a first negative photoresist (51) is coated on the first substrate (50), and a plane template of an observation layer (53) of the microfluidic chip (40) is manufactured on the first negative photoresist (51) and the first substrate (50) through a two-time photoetching process;
(c) Manufacturing a semi-cylindrical template of the observation layer (53) by acrylic materials, performing reverse molding on the first polydimethylsiloxane (52) by using a plane template and the semi-cylindrical template of the observation layer (53), and performing baking and curing and removing the plane template and the semi-cylindrical template of the observation layer (53) to obtain the observation layer (53) of the microfluidic chip (40);
(d) A silicon single crystal wafer is used as a second substrate (60), a second negative photoresist (61) is coated on the second substrate (60), and a template of a bottom layer (63) of the microfluidic chip (40) is manufactured on the second negative photoresist (61) and the second substrate (60) through a two-time photoetching process;
(e) Reversing the second polydimethylsiloxane (62) with a template of the bottom layer (63), baking and curing the second polydimethylsiloxane (62) and removing the template of the bottom layer (63) to obtain the bottom layer (63) of the microfluidic chip (40);
(f) And (3) carrying out ozone treatment and sealing on the observation layer (53) and the bottom layer (63) under the action of ultraviolet rays to obtain the complete microfluidic chip (40).
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