CN113214959B - Chip for separating and capturing Ewing sarcoma circulating tumor cells - Google Patents
Chip for separating and capturing Ewing sarcoma circulating tumor cells Download PDFInfo
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- CN113214959B CN113214959B CN202110365119.9A CN202110365119A CN113214959B CN 113214959 B CN113214959 B CN 113214959B CN 202110365119 A CN202110365119 A CN 202110365119A CN 113214959 B CN113214959 B CN 113214959B
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- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
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Abstract
The invention provides a chip for separating and capturing Ewing sarcoma circulating tumor cells, and provides a microfluidic chip for separating and capturing the Ewing sarcoma circulating tumor cells from peripheral blood, marking the captured cells by an immunofluorescence reagent, and then identifying the captured cells by a fluorescence microscope. The invention has the following beneficial effects: 1) the micro-fluidic multi-group micro-column array structure arranged according to the critical separation size can avoid the blockage problem of the filter membrane. 2) The surface antigen of the Ewing sarcoma CTC can be combined with CD99 antibody to generate specific antigen-antibody combination in the chip capture area, and the fish bone structure can generate vortex of fluid to increase the capture capacity of CTC by antibody. 3) And pretreatment operations such as red blood cell lysis and density gradient centrifugation which affect the cell activity are not needed for the blood sample, and the shearing force of the cells in the micro-column array and the fishbone groove is small, so that the cell activity can be well maintained.
Description
Technical Field
The invention relates to a micro-fluidic chip, in particular to a chip for separating and capturing circulating tumor cells of Ewing sarcoma.
Background
Ewing Sarcoma (ES) is a rare small round cell malignancy, belonging to the Ewing sarcoma family of tumors. It accounts for 6-8% of all primary bone tumors, and is the most common malignant primary bone tumor for children and teenagers. The tumors have high malignancy degree, easy relapse and poor prognosis. The sites of occurrence are often in the pelvis, chest wall and legs, but may occur in other parts of the body. The clinical manifestations are mainly local pain and swelling, and can also be accompanied by fever, hypodynamia and emaciation, the imaging examination shows that the tumor is damaged by osteolytic worm erosion, and the periosteum reaction is radial or onion skin. Tissue biopsy is an important basis for diagnosis, and imaging helps to determine the stage and prognosis of tumors. Approximately 20% -25% of patients have metastases at the time of confirmation, with the sites of metastasis being found in the lungs, bone marrow, and intracranial space. At present, the histological origin of ewing's sarcoma is not clear, but it is generally thought to originate from mesenchymal stem cells. The EWSR1-FLI1 fusion gene is present in 90% of patients with Ewing's sarcoma, which is characteristic of Ewing's sarcoma. Another feature is that the cell surface highly expresses the glycoprotein MIC2 (CD 99), so expression of MIC2 can be used to aid in the differential diagnosis of small round cell tumors.
Tissue biopsy has many limitations that it causes great pain to patients, it cannot be operated frequently, it can only detect a single organ, and it is easy to stimulate rapid growth of cancer cells. The liquid biopsy can greatly shorten the cancer confirmation time, track the treatment condition of a cancer patient at any time and really realize personalized accurate treatment. Circulating Tumor Cells (CTCs) are one of several novel molecular markers of tumors that have been studied for use in recent years. The tumor can be diagnosed, the prognosis can be judged and the curative effect can be monitored by detecting the quantity and the protein expression of CTC. For example, when CTCs show epithelial-mesenchymal transition (EMT), overexpression of epithelial cell adhesion molecules often suggests a poor prognosis for patients with tumors; by comparing the number of CTC in blood before and after operation or radiotherapy and chemotherapy, the method can judge whether the treatment is effective, and has important clinical research and application values.
Disclosure of Invention
The invention provides a microfluidic chip for separating and capturing circulating tumor cells of Ewing sarcoma from peripheral blood, marking the captured cells by an immunofluorescence reagent, and further identifying the captured cells by a fluorescence microscope.
A chip for separating and capturing ewing sarcoma circulating tumor cells, which is characterized in that the chip comprises a blood inlet, a first-stage enrichment area for removing most blood cells, a second-stage capture area positioned at the downstream of the first-stage enrichment area and communicated with the first-stage enrichment area and used for capturing ewing sarcoma CTCs, and a waste blood outlet; the first-stage enrichment area and the second-stage capture area are composed of a glass substrate and a polymer layer arranged above the glass substrate, three or more groups of enrichment micro-column array structures connected in series are arranged in the first-stage enrichment area, a CD99 antibody for specifically capturing Ewing sarcoma CTC is modified on the glass substrate of the second-stage capture area, and a V-shaped fishbone groove structure is arranged on the polymer layer of the second-stage capture area; and a fluid channel is formed between the V-shaped fishbone groove structure and the glass substrate.
Blood enters from a blood inlet of the cell enrichment area, is sorted by a first group of micro-column array structures in a first-stage enrichment area, small red blood cells, white blood cells, platelets and the like are not influenced by the critical dimension of the array, and enter a waste blood channel along the fluid direction to flow to a waste blood outlet; the large-size tumor cells and part of white blood cells are subjected to the effect of the shift of the critical dimension of the micro-column array, are gathered in the middle enrichment channel along the direction of the array shift, flow to the next group of micro-column array structures and are subjected to secondary enrichment; in the second group of micro-column array structures, the cells from the previous group of enrichment channels are continuously sorted according to the critical dimension, the small-sized cells continuously flow to a waste blood outlet, and the large-sized cells continuously gather in the middle channel of the second group of micro-column array structures and flow to the third group of micro-column array structures; preferably, through sorting and enrichment of the three groups of micro-column array structures, the critical dimension and the offset angle of each group of micro-column array can be the same or can be sequentially increased, and through sequential sorting of the multiple groups of micro-column arrays connected in series, waste blood cells are further eliminated, the sorting purity of tumor cells is improved, and the enrichment channel finally flows to the second-stage capture area. The in-situ capture of the Ewing sarcoma CTC is carried out in the secondary capture area, the CD99 antibody specifically binding the Ewing sarcoma CTC is modified on the glass substrate, so that the Ewing sarcoma CTC can be specifically captured, the polymer layer of the secondary capture area is provided with a V-shaped fishbone groove structure, and blood fluid flowing through the polymer layer can be swirled, so that the laminar flow of blood in a chip is broken, the contact opportunity and the binding force of the antibody and cells are increased, and the capture efficiency of the CTC is improved.
Preferably, the micro-column array structure is cylindrical or triangular.
Preferably, the microcolumn array structure of the first-stage enrichment region is provided with an enrichment channel for enriching tumor cells, the enrichment channel is positioned at the center of each group of microcolumn array structure, and the distribution of the microcolumn arrays is symmetrically arranged by taking the enrichment channel as a central axis.
Preferably, the tail end of the micro-column array structure is symmetrically provided with two first-stage waste blood outlets which are respectively and symmetrically arranged at two sides of the micro-column array structure; the end of the second-stage capture area is also provided with a second-stage waste blood outlet.
Preferably, the diameter or side length of the cylindrical or triangular micro-pillars in the micro-pillar array structure is 10-30 microns, the row spacing between two adjacent micro-pillars is 20-30 microns, the column spacing is 30-50 microns, the height is 30-40 microns, and the array offset angle is 1-30 degrees.
Preferably, each group of the V-shaped fishbone groove structure comprises 8 parallel micro-channels.
Furthermore, the width of the V-shaped fishbone groove is 30 micrometers, the height of the V-shaped fishbone groove is 20 micrometers, the distance between the two fishbone grooves is 50 micrometers, the depth of the channel is 40 micrometers, the included angle of the fishbone is 90 degrees, and the included angle of the fishbone and the edge of the chip is 45 degrees.
Furthermore, the V-shaped fishbone groove structures are arranged in a periodic staggered mode.
Preferably, a fluid channel is arranged between the V-shaped fishbone groove structure and the glass substrate.
Preferably, the surface of the glass substrate of the secondary capture structure is firstly treated by 3-mercaptopropyltrimethoxysilane and N-maleimidobutyryloxy succinimide ester; then the surface is doped with streptavidin; finally, the CD99 antibody was grafted.
The invention has the following beneficial effects: can simultaneously realize the separation and capture of the Ewing sarcoma CTC from the blood to be treated with high efficiency, high purity and high activity, and simultaneously realize the in-situ capture of target cells in the chip. The method comprises the following specific steps: 1) the micro-fluidic multi-group micro-column array structure arranged according to the critical sorting size can avoid the blocking problem of the filter membrane, large-size cells are enriched in the middle channel along the offset direction in each group of arrays, small-size cells flow to the waste blood outlet along the fluid direction, and the enrichment efficiency and purity are improved by the multi-group series structure. 2) The surface antigen of the Ewing sarcoma CTC can be combined with CD99 antibody to generate specific antigen-antibody combination in the chip capture area, and the fish bone structure can generate vortex of fluid to increase the capture capacity of CTC by antibody. 3) And pretreatment operations such as red blood cell lysis and density gradient centrifugation which affect the cell activity are not needed for the blood sample, and the shearing force of the cells in the micro-column array and the fishbone groove is small, so that the cell activity can be well maintained.
Drawings
FIG. 1 is a schematic diagram of a chip for isolating and capturing Ewing sarcoma cells according to the present invention;
FIG. 2 is a cross-sectional view of a second stage capture area of the present invention;
FIG. 3 is a schematic view of a V-shaped fish bone groove structure according to the present invention;
figure 4 is a graph of capture efficiency in the embodiment.
Detailed Description
Referring to fig. 1, a chip for isolating and capturing ewing sarcoma cells includes a primary enrichment region (1) and a secondary capture region (2) downstream of and in communication with the primary enrichment region (1); the first-stage enrichment region (1) comprises three or more groups of micro-column array structures (11) arranged according to the critical dimension of cells, three groups of micro-column array structures (11) are shown in figure 1, the micro-column array structures (11) comprise a cell enrichment region blood inlet arranged at the head end, an enrichment channel (31) positioned in the micro-column array structures and a waste blood channel (32) positioned at a waste blood outlet leading to the tail end of the micro-column array structures, and because each group of micro-column array structures (11) are communicated, the outlet (31) of the enrichment channel of the micro-column array structure (11) positioned in the previous group is directly connected to the inlet of the micro-column array structure (11) in the next group; as shown in fig. 2, a glass substrate (21) of the second-stage capture region (2) is modified with a CD99 antibody (23) for specifically capturing ewing sarcoma CTC, a polymer layer (22) is provided with a plurality of groups of V-shaped fishbone groove structures (24) arranged periodically, and a fluid channel with a height of 40 microns is formed between the V-shaped fishbone groove structures (24) and the glass substrate (21).
Blood enters from a blood inlet, is sorted by a first group of micro-column array structures (11) in a first-stage enrichment area (1), and small red blood cells, white blood cells, platelets and the like flow to a waste blood outlet through a waste blood channel along the fluid direction because the small red blood cells, the white blood cells, the platelets and the like are not influenced by the critical dimension of the array; the large-size tumor cells and part of white blood cells are blocked by the critical dimension of the micro-column array, collected in the middle enrichment channel along the direction of array deviation, flow to the next group of micro-column array structures (11) and are subjected to secondary enrichment; in the second group of micro-column array structures, the cells from the previous group of enrichment channels are continuously sorted according to the critical dimension, the small-sized cells continuously flow to a waste blood outlet, and the large-sized cells continuously gather in the middle channel of the second group of micro-column array structures and flow to the third group of micro-column array structures; as shown in figure 1, the sorting and enrichment of the three groups of the micro-column array structures (11) further improve the enrichment purity of the tumor cells, and the tumor cells flow to the second-stage capture area (2) after the enrichment is finished. The Ewing sarcoma CTC is captured in the second-stage capture area (2), the CD99 antibody (23) which is specifically bound with the Ewing sarcoma CTC is modified on the glass substrate, so that the specific capture on the Ewing sarcoma CTC can be performed, the V-shaped fishbone groove structure (24) on the polymer layer (22) can generate vortex of blood fluid flowing through the V-shaped fishbone groove structure, the laminar flow of blood in a chip is broken, the contact chance and the binding force of the Ewing sarcoma CTC and the CD99 antibody are increased, and the capture efficiency of the CTC is improved.
The micro-column array structure (11) is a cylindrical structure.
The blood enrichment channel (31) is positioned at the center of the micro-column array structure, and the micro-column array is symmetrically arranged by taking the enrichment channel as a central axis.
Two first-stage waste blood outlets (32) are symmetrically arranged at the tail end of the micro-column array structure. The end of the second-stage capture area is also provided with a second-stage waste blood outlet.
The microcolumns in the microcolumn array structure of the first-stage capture area are cylindrical or triangular, the diameter or side length of each microcolumn is 10-30 micrometers, the row spacing between two adjacent microcolumns is 20-30 micrometers, the column spacing is 30-50 micrometers, the height of each microcolumn is 30-40 micrometers, the offset angle of the microcolumn array to the middle enrichment channel is 1-30 degrees, and the above parameters of the enrichment areas formed by three groups of series structures can be the same or can be increased gradually by 1-10 percent. The plan view of the V-shaped fishbone groove structures (24) is shown in figure 3, and each group of V-shaped fishbone groove structures comprises 8 parallel micro-channels.
The width of the V-shaped fishbone groove is 30 micrometers at W1, the height H1 is 20 micrometers, the distance G1 between the two fishbone grooves is 50 micrometers, the depth of a fluid channel formed between the V-shaped fishbone groove structure (24) and the glass substrate (21) is 40 micrometers, the included angle gamma of the fishbone is 90 degrees, and the included angle alpha of the fishbone and the edge of the chip is 45 degrees.
The V-shaped fishbone groove structures (24) are arranged in a periodic staggered mode, the periodic arrangement is shown in figure 1, every 8 fishbones form a group, and micro-channels between the V-shaped fishbone groove structures and the glass substrate can enable fluid to generate vortex, so that the capture efficiency of CTC and antibodies is improved.
A fluid channel is arranged between the V-shaped fishbone groove structure (24) and the glass substrate (21), and the depth is 40 microns.
The polymer layer may be made of Polydimethylsiloxane (PDMS), polymethyl methacrylate, polycarbonate, polyethylene, polypropylene, polyvinyl chloride, polystyrene, polyurethane, or the like.
In operation, peripheral blood is introduced into the chip from a blood inlet at a flow rate of 6ml/h, and is enriched in a first-stage enrichment region, waste blood flows out from a waste blood outlet, large-size enriched liquid cells enter a second-stage capture region, in the capture region, Ewing sarcoma CTC in the blood is subjected to specific antigen-antibody combination on the cell surface with CD99 antibody modified on the chip surface, and is captured in situ in the chip, and the rest blood cells are flushed out of the chip along with continuously introduced fluid. After cell capture, the following steps were performed:
1) introducing PBS solution for washing;
2) fixing by introducing 4% paraformaldehyde solution and washing by PBS;
3) 0.2% Triton X-100 solution was passed through and washed with PBS;
4) blocking with 4% BSA solution for 60min and washing with PBS;
5) adding specific antibody of Ewing sarcoma CTC;
6) washing with PBS after overnight protection from light;
7) the chip is observed under a fluorescence microscope to judge whether the expression condition of capturing the Ewing sarcoma CTC and the antibody exists.
Capture efficiency validation
In total, 5 groups of 3 experiments were performed, each experiment simulating about 5mL of blood (i.e., non-target cells are mainly white blood cells and red blood cells in blood), the ewing sarcoma cell line RD-ES as target cells was directly added to the blood at a concentration of about 100 cells per mL, and the 5 groups of experiments had fluxes of 6mL/h, 9mL/h, 12mL/h, 15mL/h and 18mL/h, respectively, and the capture efficiency was analyzed by chip sorting, observing and counting the amount of cells captured in the cell capture zone, and after averaging 3 results from each group, the capture efficiency was as shown in fig. 4.
Claims (5)
1. A chip for separating and capturing ewing sarcoma circulating tumor cells, which is characterized in that the chip comprises a blood inlet, a first-stage enrichment area for removing most blood cells, a second-stage capture area positioned at the downstream of the first-stage enrichment area and communicated with the first-stage enrichment area and used for capturing ewing sarcoma CTCs, and a waste blood outlet; the waste blood outlet comprises a first-stage waste blood outlet arranged at the tail end of the first-stage enrichment area micro-column array structure and a second-stage waste blood outlet arranged at the tail end of the second-stage capture area, and the two first-stage waste blood outlets are symmetrically arranged on two sides of the micro-column array structure respectively; the first-stage enrichment area and the second-stage capture area are composed of a glass substrate and a polymer layer arranged above the glass substrate, three or more groups of enrichment micro-column array structures connected in series are arranged in the first-stage enrichment area, the critical dimension and the offset angle of each enrichment micro-column array structure are sequentially increased in an increasing mode, a CD99 antibody for specifically capturing Ewing sarcoma CTC is modified on the glass substrate of the second-stage capture area, and a V-shaped fishbone groove structure is arranged on the polymer layer of the second-stage capture area; a fluid channel is formed between the V-shaped fishbone groove structure and the glass substrate;
the microcolumn array structure of the first-stage enrichment region is internally provided with an enrichment channel for enriching tumor cells, the enrichment channel is positioned at the center of each group of microcolumn array structure, and the distribution of the microcolumn arrays is symmetrically arranged by taking the enrichment channel as a central axis; the outlet of the enrichment channel of the microcolumn array structure positioned in the previous group is directly connected to the inlet of the microcolumn array structure of the next group, the microcolumns in the microcolumn array structure of the first-stage enrichment region are cylindrical or triangular, the diameter or the side length of each microcolumn is 10-30 micrometers, the row spacing between two adjacent microcolumns is 20-30 micrometers, the column spacing is 30-50 micrometers, the height of each microcolumn is 30-40 micrometers, and the offset angle of the microcolumn array to the middle enrichment channel is 1-30 degrees;
v font fish bone recess width be 30 microns, highly be 20 microns, the interval in two fish bone grooves is 50 microns, the degree of depth of passageway is 40 microns, the contained angle between the fish bone is 90 degrees, the contained angle of fish bone and chip is 45 degrees.
2. The chip of claim 1, wherein the polymer layer is polydimethylsiloxane, polymethylmethacrylate, polycarbonate, polyethylene, polypropylene, polyvinyl chloride, polystyrene and/or polyurethane.
3. The chip of claim 1, wherein the V-shaped fish bone groove structures are periodically staggered, and each groove structure comprises 8 or more parallel microchannels.
4. The chip of claim 1, wherein the surface of the glass substrate is treated with 3-mercaptopropyltrimethoxysilane and N-maleimidobutyryloxysuccinimide ester; then the surface is doped with streptavidin; finally grafting the CD99 antibody.
5. The chip of claim 1, wherein the CTCs captured by the antibody are identified by observation under a fluorescence microscope after being subjected to immobilization, permeabilization, blocking, and antibody staining.
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| CN113649094B (en) * | 2021-08-23 | 2023-03-31 | 启东中科光电遥感中心 | Integrated multilayer microfluidic chip for capturing circulating tumor cells |
| CN114317201B (en) * | 2021-12-15 | 2023-10-20 | 深圳先进技术研究院 | Microfluidic chip for capturing circulating tumor cells and manufacturing method thereof |
| CN115228521A (en) * | 2022-07-01 | 2022-10-25 | 清华大学 | Biological particle separation device and microfluidic chip |
| CN116024067A (en) * | 2022-12-19 | 2023-04-28 | 深圳职业技术学院 | Circulating fetal cell separation device and preparation method thereof |
| CN115957838B (en) * | 2023-01-13 | 2023-09-26 | 睿思生命(广东)科技有限公司 | Microfluidic chip |
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