CN110495855B - Cancer cell real-time detection, diagnosis and treatment method, device and system - Google Patents
Cancer cell real-time detection, diagnosis and treatment method, device and system Download PDFInfo
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- CN110495855B CN110495855B CN201910763099.3A CN201910763099A CN110495855B CN 110495855 B CN110495855 B CN 110495855B CN 201910763099 A CN201910763099 A CN 201910763099A CN 110495855 B CN110495855 B CN 110495855B
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Abstract
The invention discloses a method, a device and a system for real-time detection, diagnosis and treatment of cancer cells, wherein the system comprises a femtosecond laser operation device, an optical imaging device for real-time detection of cancer cells, a microfluidic channel and a computer; the femtosecond laser operation device is used for positioning the target cell in the microfluidic channel and acting on the target cell; the optical imaging device is used for imaging and detecting specific cells in human blood in real time; the microfluidic channel is used as a carrier for real-time detection and orientation of specific cells; the computer processes the analysis data in real time to judge whether the cells are specific cells and transmits the result to the femtosecond laser operation device. The invention detects cells in human blood in real time through the optical imaging device for detecting cancer cells in real time, judges whether the cells are target cells or not through an artificial intelligence algorithm according to the obtained data, and transmits the result to the femtosecond laser operation device, so that the target cells in the microfluidic channel can be quickly and accurately oriented.
Description
Technical Field
The invention relates to the field of optics, in particular to an optical imaging device for real-time detection of cancer cells, and a method and a system for real-time detection, diagnosis and treatment of cancer cells.
Background
Nowadays, the living standard and the living style of human beings are greatly changed, the incidence rate of various cancers is higher and higher, the health threat to human beings is extremely large, and the diseases become important diseases threatening the survival of human beings, and public data show that data published by the world health organization in 2 months in 2017 show that more than 1400 million new cancer cases are sent every year in the world, and the digital lecture is expected to increase to more than 2100 million by 2030. Every year 880 tens of thousands of people die from cancer, accounting for nearly one-sixth of the total deaths worldwide. Therefore, cancer diagnosis and treatment are also receiving increasing attention.
The current methods for cancer diagnosis are mainly biopsy, laboratory test, case slice test, nuclear magnetic resonance test, etc. Chinese patent publication No. CN 102781316 a, "cancer diagnosis and imaging", administering a therapeutically effective amount of a cell cycle inhibitor effective to terminate proliferation of eukaryotic cells at a cell cycle checkpoint between G1 and S phase, stopping administration of the cell cycle inhibitor for a period of time, administering a marker to the mammal and imaging the mammal. Although these methods are all available as a method for diagnosing cancer, the current examination means generally requires a long time for detection and requires a complicated procedure.
Meanwhile, cancer treatment often causes recurrence and metastasis of cancer, and cancer rechecking is an essential process. How to perform the review more quickly, accurately and simply is also a factor that must be considered for cancer treatment.
The main methods for treating cancer at present are surgical resection, radiotherapy, chemotherapy and pharmacotherapy, immunotherapy and the like. The traditional cancer treatment method has large wound, can kill cancer cells, inevitably kills normal cells of a human body, causes great harm to the health of the human body, and has the possibility of relapse. Therefore, a method of using laser treatment has been proposed by researchers. For example, chinese patent publication No. CN 103126866 a, "cancer metastasis treatment device", proposes to control and eliminate cancer metastasis by using laser, ultrasonic, microwave, or the like. Chinese patent publication No. CN 109718480 a, "an ion laser cancer treatment apparatus", proposes a method for treating cancer by using a laser ion beam. However, the current laser treatment methods are not accurate enough for positioning cancer cells.
Disclosure of Invention
The invention aims to solve the technical problem of providing an optical imaging device for cancer cell real-time detection, which can accurately judge the position of a cancer cell and transmit the result to a femtosecond laser operation device so as to kill the cancer cell rapidly and accurately in a directional manner, aiming at the defect of insufficient positioning precision of the cancer cell in the prior art.
The technical scheme adopted by the invention for solving the technical problems is as follows:
an optical imaging device for real-time detection of cancer cells is provided, comprising:
a femtosecond laser generating femtosecond pulses;
the single-mode fiber is used for performing time domain stretching on the femtosecond pulse to complete the copying of a pulse spectrum to a time domain waveform;
the first collimator is used for enabling the pulse output by the single-mode fiber to enter the first diffraction grating from a certain angle in the form of space light through the beam splitter;
the beam splitter divides the pulse light output by the first collimator into two paths of signal light and reference light, the signal light enters the first diffraction grating, and the reference light enters the time delay assembly;
the time delay assembly is used for delaying the reference light;
the first diffraction grating disperses the pulses in space;
the focusing component is used for focusing the dispersed light into a microfluidic channel which is used as a carrier for real-time cell detection and orientation;
a collection assembly for collecting spatially-dispersed pulses transmitted through the microfluidic channel that encode cell surface information onto a spectrum of pulses to complete spatial encoding;
the second diffraction grating is used for reducing the spatial dispersion pulse into a single pulse;
the coupler is used for generating interference light by interfering the delayed reference light passing through the delay component and the single pulse passing through the second diffraction grating;
the photoelectric detector is used for converting the interference light into an analog electric signal;
and the analog-to-electric converter is used for converting the analog electric signal into a digital electric signal and transmitting the digital electric signal to a computer for processing.
According to the technical scheme, the focusing assembly comprises a first plano-convex lens, a second plano-convex lens and a first microscope objective lens which are sequentially arranged and have optical axes on the same straight line.
In connection with the above technical solution, the collecting assembly includes a second microscope objective, a third plano-convex lens, and a fourth plano-convex lens, which are sequentially disposed and have optical axes on a straight line.
In the above technical solution, a first mirror and a second collimator are further disposed between the second diffraction grating and the coupler.
According to the technical scheme, the time delay assembly comprises a plurality of reflecting mirrors.
According to the technical scheme, the time delay assembly comprises four reflectors which are arranged at a certain angle and change the propagation direction of light.
The invention also provides a cancer cell detection and positioning method, which comprises the following steps:
s1, acquiring the digital electric signal output by the optical imaging device for real-time detection of cancer cells to obtain cell intensity and phase data;
s2, processing the cell intensity and phase data to obtain cell information including cell surface appearance, size, refractive index, thickness and protein content;
and S3, judging whether the cell is a target cell according to the cell information, if so, positioning, and controlling the femtosecond laser operation device in real time to enable the laser to act on the target cell directionally.
The invention also provides a cancer cell real-time diagnosis and treatment system, which comprises:
the optical imaging device is used for detecting the cancer cells in real time;
the computer is used for acquiring the digital electric signal output by the optical imaging device and acquiring cell intensity and phase data; processing the cell intensity and phase data to obtain cell information including cell surface appearance, size, refractive index, thickness and protein content; judging whether the cell is a target cell according to the cell information, and if so, positioning;
a microfluidic channel for use as a carrier for real-time detection and orientation of cells;
a femtosecond laser surgical device for positioning and killing the target cells in the microfluidic channel under the control of the computer.
The invention has the following beneficial effects: the optical imaging device for real-time detection of cancer cells is used for real-time detection of cells in human blood in the microfluidic channel, and the construction of the optical device can enable reference light and signal light to generate beat frequency interference to obtain phase information of the cells, so that information such as refractive index and protein content of the cells can be deduced. And analyzing the received cell information by the computer, judging whether the cell is a cancer cell, and transmitting the positioning result to the femtosecond laser operation device so as to kill the cancer cell rapidly and accurately in an oriented manner.
Drawings
The invention will be further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is a first schematic structural diagram of an optical imaging apparatus for real-time detection of cancer cells according to an embodiment of the present invention;
FIG. 2 is a schematic structural diagram of a second optical imaging device for real-time detection of cancer cells according to an embodiment of the present invention;
FIG. 3 is a schematic diagram of a system for real-time cancer cell diagnosis and treatment according to an embodiment of the present invention;
fig. 4 is a flowchart of the operation of the real-time cancer cell diagnosing and treating system according to the embodiment of the present invention.
Wherein, 1-femtosecond laser operation device; 2-ultrafast optical imaging system; 3-a microfluidic channel; 4-a computer; 5-artery; 6-vein;
201-femtosecond laser; 202-single mode fiber; 203-a first collimator; 204-a beam splitter; 205-a first diffraction grating; 206-a first plano-convex lens; 207-second plano-convex lens; 208-a first microscope objective; 209-second microscope objective; 210-a third plano-convex lens; 211-fourth plano-convex lens; 212-a second diffraction grating; 213-a first mirror; 214-a second collimator; 215-a second mirror; 216-a third mirror; 217-fourth mirror; 218-a fifth mirror; 219-a third collimator; 220-a coupler; 221-a photodetector; 222-high speed oscilloscope.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
An optical imaging device for real-time detection of cancer cells according to an embodiment of the present invention is shown in fig. 1, and includes a femtosecond laser 201, a single-mode fiber 202, a first collimator 203, a beam splitter 204, a first diffraction grating 205, a focusing assembly B, a collecting assembly C, a second diffraction grating 212, a first mirror 213, a second collimator 214, a delay assembly a, a third collimator 219, a coupler 220, a photodetector 221, and a mode-to-electric converter 222 (e.g., a high-speed oscilloscope).
Wherein, the femtosecond laser 201 generates femtosecond pulses; the single-mode fiber 202 is used for performing time domain stretching on the femtosecond pulse to complete the copying of a pulse spectrum to a time domain waveform; a first collimator 203 for making a pulse output from the single-mode fiber incident on a first diffraction grating 205 through a beam splitter 204 in the form of spatial light from a certain angle; the beam splitter 204 splits the pulsed light output by the first collimator 203 into two paths, namely signal light and reference light, the signal light enters the first diffraction grating 205, and the reference light enters the delay assembly a; the time delay component A is used for delaying the reference light; the first diffraction grating 205, which disperses the pulses in space; the focusing component B is used for focusing the dispersed light into a microfluidic channel which is used as a carrier for real-time cell detection and orientation; a collection component C for collecting spatially-dispersed pulses that pass through the microfluidic channel and encode cell surface information onto the spectrum of the pulses to complete spatial encoding; a second diffraction grating 212 for reducing the spatially dispersed pulse to a single pulse; the coupler 220, the delayed reference light after passing through the delay component a and the single pulse after passing through the second diffraction grating 212 interfere at the coupler 220 to generate interference light; a photodetector 221 for converting the interference light into an analog electrical signal; and the analog-to-electrical converter 222 is used for converting the analog electrical signal into a digital electrical signal and transmitting the digital electrical signal to a computer for processing.
As shown in fig. 2, in a preferred embodiment of the present invention, the time delay assembly a specifically includes a second mirror 215, a third mirror 216, a fourth mirror 217, and a fifth mirror 218. The focusing assembly B specifically includes a first plano-convex lens 206, a second plano-convex lens 207, and a first microscope objective 208, which are placed in sequence with their optical axes in a straight line. The collecting assembly specifically comprises a second microscope objective 209, a third plano-convex lens 210 and a fourth plano-convex lens 211 which are sequentially arranged and have optical axes in a straight line.
The femtosecond laser 201 generates femtosecond pulses; the single-mode fiber 202 stretches the pulse in the time domain to complete the copying of the pulse spectrum to the time domain waveform; the first collimator 203 is used to inject a pulse from a certain angle to the first diffraction grating 205 in the form of spatial light; the beam splitter 204 divides the pulse into a signal path and a reference path; the first diffraction grating 205 disperses the pulses in space; the first plano-convex lens 206, the second plano-convex lens 207 and the first microscope objective 208 focus the dispersed pulse on the cell in the microfluidic channel 3, and encode the cell surface information onto the spectrum of the pulse to complete spatial encoding; the second micro objective 209, the third plano-convex lens 210 and the fourth plano-convex lens 211 collect spatially encoded dispersive pulses; the second diffraction grating 212 reduces the spatially dispersed pulse to a single pulse; the first mirror 213 changes the propagation direction of the light pulse; the second collimator 214 couples the recovered single pulse into the fiber; the second mirror 215 changes the propagation direction of the light pulse; the third mirror 216 and the fourth mirror 217 serve as delay lenses to change the propagation time of the pulse, so that the signal path pulse and the reference path pulse meet in time, interference can be formed, beat frequency interference is generated between the reference light and the signal light, phase information of the cell is obtained, and information such as refractive index and protein content of the cell can be deduced. The fifth mirror 218 changes the propagation direction of the light pulse; the third collimator 219 couples the optical pulse of the reference path into the optical fiber; the coupler 220 combines the pulses of the signal path and the reference path into one beam; the photodetector 221 converts the pulse signal into an analog electrical signal; the high speed oscilloscope 222 converts the analog electrical signal into a digital electrical signal and transmits the digital electrical signal to the computer 4 for processing.
The femtosecond laser 201 can be selected as a pulse laser with a center wavelength of 1064nm, a spectral width of 50nm, a pulse width of 100fs and a repetition frequency of 50 MHz; the single mode fiber 202 may be optionally a single mode fiber with a group velocity dispersion of 800 ps/nm; the first collimator 203 is selected as F220FC-1064 from Thorlabs; the divider 204 may be selected as BS041 of Thorlabs with a splitting ratio of 90: 10; the first diffraction grating 205 is optionally patterned with a groove density of 1200/mm; the first plano-convex lens 206 may be selected to have a focal length f of 50mm, and the second plano-convex lens 207 may be selected to have a focal length f of 100 mm; the first microscope objective 208 can be selected to have a numerical aperture of 0.65 and a magnification of 50 x; the second microscope objective 209 can be selected to have a numerical aperture of 0.65 and a magnification of 50 x; the third flat lens 210 may be selected to have a focal length f of 100 mm; the fourth plano-convex lens 211 may be selected to have a focal length f of 50 mm; the second diffraction grating 212 is optionally patterned with a groove density of 1200/mm; the first mirror 213 may be of the type BB2-E03 from Thorlabs; the second collimator 214 may be selected from F220FC-1064 from Thorlabs; the second, third, fourth and fifth mirrors 215, 216, 217, 218 may be of the type BB2-E03 from Thorlabs; the first collimator 219 may be selected from F220FC-1064 from Thorlabs; the coupler may be TW1064R5F1A of Thorlabs with a coupling ratio of 50: 50; photodetector 221 may be alternatively of the type Newport-1481-s from Newport corporation; the high-speed oscilloscope is selected from DSA91304A of Germany science and technology;
in a preferred embodiment of the present invention, the femtosecond laser 201 is connected to the single-mode fiber 202 and the first collimator 203 in sequence; the beam splitter 204 is at a distance d110mm in front of the first collimator; the first diffraction grating 205 is at a distance d210mm and angle theta1＝600Placed in front of the beam splitter 204; the first plano-convex lens 206 is at a distance d350mm in front of the first diffraction grating 205; the second plano-convex lens 207 is at a distance d4150mm in front of the first plano-convex lens 206; the first microscope objective 208 is at a distance d5100mm in front of the second plano-convex lens 207; the second microscope objective 209 is at a distance d620mm in front of the first microscope objective 208; the third plano-convex lens 210 is at a distance d7100mm in front of the second microscope objective 209; the fourth plano-convex lens 211 is at a distance d8150mm in front of the third plano-convex lens 210; the second diffraction grating 212 is at a distance d9Is 50mm in front of the fourth plano-convex lens 211; the first reflecting mirror 213 is spaced apart by a distance d1030mm and angle theta2＝150Placed in front of the second diffraction grating 212; the second collimator 214 is at a distance d1110mm and angle theta3＝150Is disposed in front of the first reflecting mirror 213; the second reflecting mirror 215 is at a distance d1250mm and angle theta4＝600To the left of the beam splitter 204; the third reflector 216 is at a distance d13500mm and angle theta5＝150Placed in front of the second mirror 215; fourth reflector217 at a distance d1450mm and angle theta6＝900Placed in front of the third mirror 216; the fifth mirror 218 is at a distance d15100mm in front of the fourth mirror 217; the third collimator 219 is at a distance d1520mm in front of the fifth mirror 218; the second collimator 214 and the third collimator 219 are connected to the coupler 220; the coupler 220 is connected to a photodetector 221 and a high-speed oscilloscope 222 in this order.
The embodiment of the invention provides a target cell real-time detection and positioning treatment system, as shown in fig. 3, comprising a femtosecond laser operation device 1, an optical imaging device 2 for cancer cell real-time detection, a microfluidic channel 3 and a computer 4.
The femtosecond laser operation device 1 is used for directionally killing cancer cells of a human body; the optical imaging device 2 for real-time detection of cancer cells is used for real-time imaging and detection of specific cells in human blood, such as cancer cells; the microfluidic channel 3 is used as a carrier for real-time detection and orientation of target cells; the computer 4 is used as a data processing center, processes and analyzes data in real time to judge whether the cells are target cells or not and transmits the result to the femtosecond laser operation device. The optical imaging device 2 for real-time detection of cancer cells is connected with a computer 4, the femtosecond laser surgery device 1 is connected with the computer 4, an artery 5 is connected with the microfluidic channel 3, and a vein 6 is connected with the microfluidic channel 3. The microfluidic channel 3 is used as a carrier for cell real-time detection, and the flow rate of the cells is controlled so that the cells are separated at equal intervals in the channel and flow at a constant speed, thereby being convenient for accurately positioning the cells.
The whole blood cell detection is to detect and treat all cells in the body, and when the whole blood cell detection and treatment are carried out on a patient, an arterial blood vessel of the patient is connected to the inlet of the microfluidic channel; the partial blood cell detection is cell detection and treatment of specific tissue in vivo, and according to the average size of normal cells in the tissue, the filter screen is designed, so that the cells with the cell volume smaller than that of the filter screen are directly connected to the venous blood vessel and returned to the patient after being directly filtered, and the cells with the cell volume larger than that of the filter screen are connected to the inlet of the microfluidic channel after being filtered;
as shown in fig. 4, the working process of the cancer cell real-time diagnosis and treatment system of the present invention is as follows:
step 1: when the whole blood cell detection and treatment are carried out on a patient, the arterial blood vessel of the patient is connected to the inlet of the microfluidic channel, and the blood cells of the patient can stably flow in the microfluidic channel at a constant speed by controlling the flow rate of the cells and designing the appropriate microfluidic channel;
step 2: when partial blood cells of a specific tissue of a patient are detected and treated, the filter screen is designed according to the average size of normal cells in the tissue, cells with the cell volume smaller than that of the filter screen are directly filtered and then directly connected to a venous blood vessel to return to the body of the patient, cells with the cell volume larger than that of the filter screen are connected to an inlet of a microfluidic channel after being filtered, and the blood cells of the patient can stably flow in the microfluidic channel at a constant speed by controlling the flow rate of the cells and designing the appropriate microfluidic channel;
and step 3: connecting the venous blood vessel of the patient to the outlet of the microfluidic channel so that the detected and treated blood cells are returned to the human body;
and 4, step 4: the ultrafast optical imaging system is used for rapidly detecting cells in the microfluidic channel in real time, obtaining cell intensity and phase data and transmitting the cell intensity and phase data to the computer;
and 5: the computer processes the received cell strength and phase data and processes the data to obtain information of the surface appearance, size, refractive index, thickness, protein content and the like of the cell;
step 6: before treatment, the computer extracts a large amount of cell characteristics of known cell states by means of an artificial intelligence algorithm, trains to obtain an operation model, and during treatment, the computer judges the cell states by obtaining information of the surface appearance, size, refractive index, thickness, protein content and the like of cells through the model obtained by training before treatment;
and 7: before treatment, the femtosecond laser power and action time of the femtosecond laser operation device are adjusted, so that specific cells can be killed accurately, and other cells cannot be killed due to overlarge laser action range caused by overlarge power or overlong action time;
and 8: the computer judges whether the detected cell is the target cell, if the detected cell is the target cell, the femtosecond laser operation device is controlled in real time, so that the laser acts on the target cell in a directional manner, and the target cell in the microfluidic channel is killed.
To sum up, the optical imaging device for real-time detection of cancer cells detects cells in human blood in a microfluidic channel in real time, the obtained cell intensity and phase data are obtained, information such as surface appearance, size, refractive index, thickness and protein content of the cells is obtained by a computer, the computer trains a large number of cells with known cell states through an artificial intelligence algorithm before treatment to obtain an operation model, analyzes the received cell information, judges whether the detected cells are specific cells or not, and transmits the result to a femtosecond laser operation device, so that the specific cells are killed quickly and accurately in an oriented manner. Before real-time detection and diagnosis, the time required for the whole process of detecting cells by an optical imaging system and analyzing the state of the cells by a computer is obtained in advance, and the path traveled by the detected cells is judged by the flow rate of the cells, so that the cells are killed at a specific position.
It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (7)
1. An optical imaging apparatus for real-time detection of cancer cells, comprising:
a femtosecond laser generating femtosecond pulses;
the single-mode fiber is used for performing time domain stretching on the femtosecond pulse to complete the copying of a pulse spectrum to a time domain waveform;
the first collimator is used for enabling the pulse output by the single-mode fiber to enter the first diffraction grating from a certain angle in the form of space light through the beam splitter;
the beam splitter divides the pulse light output by the first collimator into two paths of signal light and reference light, the signal light enters the first diffraction grating, and the reference light enters the time delay assembly;
the time delay assembly is used for delaying the reference light;
the first diffraction grating disperses the pulses in space;
the focusing component is used for focusing the dispersed light into a microfluidic channel which is used as a carrier for real-time cell detection and orientation;
a collection assembly for collecting spatially-dispersed pulses transmitted through the microfluidic channel that encode cell surface information onto a spectrum of pulses to complete spatial encoding;
the second diffraction grating is used for reducing the spatial dispersion pulse into a single pulse;
the coupler is used for generating interference light by interfering the delayed reference light passing through the delay component and the single pulse passing through the second diffraction grating;
the photoelectric detector is used for converting the interference light into an analog electric signal;
and the analog-to-electric converter is used for converting the analog electric signal into a digital electric signal and transmitting the digital electric signal to a computer for processing.
2. The optical imaging device for real-time cancer cell detection according to claim 1, wherein the focusing assembly comprises a first plano-convex lens, a second plano-convex lens and a first microscope objective lens, which are sequentially arranged with the optical axes in a straight line.
3. The optical imaging device for real-time cancer cell detection according to claim 1, wherein the collecting assembly comprises a second microscope objective, a third plano-convex lens and a fourth plano-convex lens, which are sequentially arranged with the optical axes in a straight line.
4. The optical imaging device for real-time detection of cancer cells according to any of claims 1-3, wherein a first mirror and a second collimator are further disposed between the second diffraction grating and the coupler.
5. The optical imaging device for real-time detection of cancer cells according to any of claims 1-3, wherein the time delay assembly comprises a plurality of mirrors.
6. The optical imaging device for real-time detection of cancer cells as claimed in claim 5, wherein the time delay assembly comprises four mirrors disposed at an angle to change the propagation direction of light.
7. A system for real-time diagnosis and treatment of cancer cells, comprising:
an optical imaging device for real-time detection of cancer cells according to claim 1;
the computer is used for acquiring the digital electric signal output by the optical imaging device and acquiring cell intensity and phase data; processing the cell intensity and phase data to obtain cell information including cell surface appearance, size, refractive index, thickness and protein content; judging whether the cell is a target cell according to the cell information, and if so, positioning;
a microfluidic channel for use as a carrier for real-time detection and orientation of cells;
a femtosecond laser surgical device for positioning and killing the target cells in the microfluidic channel under the control of the computer.
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| CN107233076B (en) * | 2017-05-24 | 2018-02-23 | 西北核技术研究所 | A kind of insertion type is in the real-time tumor imaging system of body |
| CN109100304B (en) * | 2018-08-10 | 2020-12-01 | 武汉大学 | Single-pixel high-speed super-resolution imaging device and method based on time domain stretching |
| CN109884657B (en) * | 2019-02-25 | 2021-07-13 | 北京化工大学 | High-speed high-flux particle velocity measurement system based on optical time stretching |
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