CN102746986B - Tumor cell migration dynamics monitoring method based on microfluidic chip - Google Patents
Tumor cell migration dynamics monitoring method based on microfluidic chip Download PDFInfo
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- CN102746986B CN102746986B CN201210243148.9A CN201210243148A CN102746986B CN 102746986 B CN102746986 B CN 102746986B CN 201210243148 A CN201210243148 A CN 201210243148A CN 102746986 B CN102746986 B CN 102746986B
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- 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
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/02—Form or structure of the vessel
- C12M23/16—Microfluidic devices; Capillary tubes
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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
- C12M23/34—Internal compartments or partitions
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- 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
- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/10—Perfusion
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- 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
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/46—Means for regulation, monitoring, measurement or control, e.g. flow regulation of cellular or enzymatic activity or functionality, e.g. cell viability
Abstract
The invention relates to a tumor cell migration dynamics monitoring method based on a microfluidic chip. The method particularly aims at the process of tumor cells migrating and moving into three-dimensional substrates from two-dimensional planes, the microfluidic chip mainly consists of a cell inlet pool (1), a collagen inlet pool (2), a waste liquid pool (3), cell culture rooms (4) and cell migration rooms (5), wherein the cell inlet pool (1) is connected with the upper parts of the cell culture rooms (4), the waste liquid pool (3) is connected with the lower parts of the cell culture rooms (4), and one cell culture room is connected with three cell migration rooms. The tumor cell migration dynamics monitoring method based on the microfluidic chip has the characteristic that the real-time tracking on the cell movement can be realized, and meanwhile, the accurate positioning at the beginning of the cell movement can be realized.
Description
Technical field
The present invention relates to micro-fluidic chip technology to be applied to the technical field of the RESEARCH ON CELL-BIOLOGY of Real-Time Monitoring, be specifically related to a kind of tumor cell migration kinetics monitoring method based on micro-fluidic chip.
Background technology
Cytobiology is developed so far, and it is orifice plate and commercial transwell cell that main cultivation and research depend on, and concentrates single or the lower cellular form variation of many factors stimulation, process of growth, migration and the increment behavior etc. observed.And in the research of numerous cell behavior, cell migration is grown as organism and the basis of the important vital process such as morphogenesis, and receive much concern.Cell migration generally originates in the induction that cell stimulates its microenvironment, microenvironment stimulation activates a series of intracellular signal transduction path and genetic transcription by cell surface receptor, and and then multiple links such as the adhesion of change by cell polarity, cell and going adheres to, the rearrangement of cytoskeleton, finally complete the change of cellular form and position.For tumour cell, its transition process and metastases are closely related, metastases is an active process that multi-step continuity is very strong, can be divided into following step, local infiltration, infiltrate blood vessel, shift and survival, tumour cell exosmose and shift out blood vessel, settle down and breed at new position therein with blood circulation.Tumor cell migration relates to tumour cell and enters the process of three-dimensional micro-tissue around from two-dimentional blood vessel microenvironment, is also the process of metastases generating process rate determining step.Orifice plate or transwell cell are difficult to build in vitro two dimensional surface to the conversion of three-dimensional interface, so think simulation and reappear above-mentioned tumor cell migration process to be more difficult.
Micro-fluidic chip technology is as a science and technology developing rapidly, represent its unique advantage at biomedical sector, more, because it is close with physiological environment with cell size coupling, environment, manipulation more accurately can be provided on time and Spatial Dimension, being easy to realize the features such as various kinds of cell functional study by flexible design becomes the Important Platform of cell research of new generation.It can real-time tracing for experimental result, not only can obtain net result, also can obtain the temporary information that occurs in cell migration process, learns information for tumor cell migration process provides in routine analysis the likely important biomolecule of disappearance.And at present, utilize micro-fluidic chip to carry out the monitoring of tumor cell migration dynamic process, especially tumour cell researching and analysing also in the blank stage from two dimensional surface locomotory movement to three dimensional matrix process.
Summary of the invention
The object of this invention is to provide a kind of tumor cell migration kinetics monitoring method based on micro-fluidic chip, the especially process from two dimensional surface locomotory movement to three dimensional matrix for tumour cell, the method has the feature to cell movement real-time tracing, can realize the accurate location at the beginning of cell movement simultaneously.
The invention provides a kind of micro-fluidic chip, this micro-fluidic chip is mainly by cell entrance pond (1), collagen entrance pond (2), waste liquid pool (3), cell culture chamber (4), cell migration chamber (5) composition; On cell culture chamber (4), connect cell entrance pond (1), connect waste liquid pool (3) under cell culture chamber (4), a cell culture chamber is laterally connected with three cell migration chambers.
Micro-fluidic chip provided by the invention, described micro-fluidic chip is formed by upper and lower two-layer irreversible sealing-in, and upper layer of material is the PDMS polymkeric substance that light-permeable is ventilative, and subsurface material is the clean glass that the vitriol oil boiled.
Micro-fluidic chip provided by the invention, described micro-fluidic chip upper and lower two-layer carries out respectively the ultraviolet sterilising treatment of irradiating of spending the night, and then Cement Composite Treated by Plasma 30-45s carries out sealing-in.
Micro-fluidic chip provided by the invention, described micro-fluidic chip is made up of highly different two portions; (1), (3), (4) be highly about (2) and (5) height three times; Wherein, (1), (3), (4) are highly 210 μ m, and (2) and (5) are highly 70 μ m.
The present invention also provides a kind of tumor cell migration kinetics monitoring method of the micro-fluidic chip based on described, and procedure is as follows:
(1) chip collagen perfusion
The collagen working fluid preparing is added to collagen entrance pond, every hole 0.4 μ L with pipettor; Add 1mLPBS damping fluid in culture dish, the culture dish of fixed chip is put into incubator and hatch 30min, impel collagen to become jelly shape gel from viscous liquid, after gelation process finishes, from cell entrance pond, collagen entrance pond respectively order add fresh cell culture fluid;
(2) inoculation of chip cell and cultivation
After cell dissociation, adjusting cell density is 1 × 10
6/ mL, gets 10 μ L cell suspensions and adds cell entrance pond, and siphon away 0.5 μ L cell culture fluid from waste liquid pool rapidly, impels cell under the effect of run by gravity, to enter fast, equably cell culture chamber; Have part cell to flow into waste liquid pool when observing under opticmicroscope, and cell in cell culture chamber is while being also uniformly distributed, immediately chip is erect, and moves in 37 DEG C of incubators and place.Vertical cube to be cell culture chamber upward, and cell migration chamber is down; Erect and place after 10min, take out and observe, if cell is close to the intersection of cell culture chamber and migration chamber, illustrate that cell inoculation is more successful; Chip is set level to move in 37 DEG C of incubators and continue to cultivate, change liquid once every 24h, and Taking Pictures recording tumour cell position;
(3) chip cell migration Real-Time Monitoring
Adopt viable cell workstation CO
2micro-Stage microscope incubator carries out cell long-period observation, opens instrument, opens air, dioxide bottle simultaneously, and regulated valve keeps gas to remain on scale value 0.8,0.04, and two kinds of air, under this ratio, can ensure the CO of Stage microscope incubator interior 5%
2concentration, regulates its temperature at 37 DEG C, and instrument stabilizer 30min left and right, puts into Stage microscope incubator by the culture dish of fixed chip, focuses and acquisition parameters, takes pictures one every 60min, and real time record cell movement position and form change;
After cell migration enters collagen, protein expression detects
Tumor cell inoculation, to chip, is cultivated after 3 days, carries out immunofluorescent staining, and concrete steps are as follows: paraformaldehyde is fixed, and damping fluid rinses; Pore-creating agent effect, damping fluid rinses; The effect of sealing serum, 4 DEG C of night incubation of primary antibodie, damping fluid rinses; Two anti-normal temperature are hatched, and damping fluid adds nucleus labeling dye after rinsing, and under fluorescent microscope, takes pictures, and record the expression that detects albumen in cell.
Tumor cell migration kinetics monitoring method based on micro-fluidic chip technology provided by the invention, described collagen is I type mouse tail collagen, under normal temperature, it is the liquid that is thick, work as pH=7, temperature reaches in the situation of 37 DEG C, hatches 30min, can present the gel of jelly shape.
Tumor cell migration kinetics monitoring method based on micro-fluidic chip technology provided by the invention, can adopt biologically conventional cell detection means to detect to the cell in collagen locomotory movement, comprise cell mark dyeing, immunofluorescent staining, PCR detection, protein detection etc. anyway.
Brief description of the drawings
Fig. 1 micro-fluidic chip one-piece construction of the present invention schematic diagram; Wherein, the chip height of black region is 65 μ m, and the chip height of gray area is 200 μ m;
Fig. 2 micro-fluidic chip collagen adds the clear interface of two dimensional surface and the three dimensional matrix of rear formation;
Cell while erectting 10min after the inoculation of Fig. 3 chip cell attaches situation;
The collagen of Fig. 4 different concns is hatched the situation of condensing after 30min in 37 DEG C of incubators;
The graph of a relation of Fig. 5 HepG-2 cell migration area and incubation time in different concns collagen;
Fig. 6 HepG-2 cell migration enters the collagen front and back metamorphosis of 2.5mg/mL concentration, and (a) two dimensional surface is cultivated; (b) in the collagen of three-dimensional 2.5mg/mL concentration;
Fig. 7 HepG-2 cell migration enters the statistical study of collagen front and back cell proportion;
Fig. 8 SMMC-7721 cell adds the Real Time Monitoring that 24h starts after chip;
The relation of Fig. 9 SMMC-7721 cell migration area and incubation time;
Figure 10 adds SMMC-7721 cell migration behavior changing conditions after Relaxin D;
Figure 11 adds the relation of SMMC-7721 cell migration area and incubation time after Relaxin D;
F-actin expression in Figure 12 SMMC-7721 cell, (a) light field is to photograph and picture, with fluorescence picture is corresponding below; (b) two dimensional surface is cultivated; (c) in the collagen of three-dimensional 2.5mg/mL concentration.Arrow logo place shows the clear expression of F-actin.
Embodiment
The following examples will be further described the present invention, but not thereby limiting the invention.
Embodiment 1
The cell migration motion conditions of HepG-2 cell in the collagen of different concns
The collagen working fluid of three kinds of different concns of preparation, concentration is respectively 1mg/mL, 2.5mg/mL, 5mg/mL, the collodion silk of different concns collagen distributes as shown in Figure 4.Utilize the micro-fluidic chip of laboratory designed and produced, configuration as shown in Figure 1.Collagen perfusion is hatched after 30min to chip, can see the clear interface (Fig. 2) of collagen and two dimensional surface.Add 10 μ L1 × 10 from cell entrance pond
6/ mL HepG-2 cell suspension, erects chip 10min, makes cell be attached to collagen one side, as shown in Figure 3.Taking Pictures recording cell starting position, changes liquid once every 24h, and Taking Pictures recording signaling situation.Statistics HepG-2 cell migration enters the area in collagen, can find the rising along with collagen concentration, and the area that HepG-2 cell is invaded collagen reduces gradually, and its result as shown in Figure 5.The form of HepG-2 cell occurs obviously to change in 2.5mg/mL collagen simultaneously, and cell gradually becomes elongated interstitial sample form by paving stone sample, and result as shown in Figure 6.The data statistic analysis of cell proportion as shown in Figure 7.
Embodiment 2
SMMC-7721 is locomotory movement Real-Time Monitoring in 2.5mg/mL collagen
Utilize the micro-fluidic chip of laboratory designed and produced, configuration as shown in Figure 1.After the collagen perfusion of 2.5mg/mL is condensed to chip, adopt cell inoculation and the training method identical with example 1.Cell is inoculated into after chip 24h, and the culture dish of fixed chip is put into Stage microscope incubator.Focus and acquisition parameters, take pictures one every 60min, take pictures real time record cell movement position and form of microscope changes, and takes altogether 19h, and shooting results as shown in Figure 8.
Embodiment 3
Add after Relaxin D, SMMC-7721 is locomotory movement analysis in 2.5mg/mL collagen.
Utilize the micro-fluidic chip of laboratory designed and produced, configuration as shown in Figure 1.After the collagen perfusion of 2.5mg/mL is condensed to chip, adopt cell inoculation and the training method identical with example 1.SMMC-7721 cell migration to the relation of the area in collagen and incubation time as shown in Figure 9.When cell is inoculated into after chip 24h, in nutrient solution, add 1 μ g/mL Relaxin D irritation cell, record metamorphosis and the migratory behaviour of cell at Relaxin D effect 24h, as shown in figure 10, the relation of SMMC-7721 cell migration area and incubation time as shown in Figure 11 for result.
Embodiment 4
SMMC-7721 cell migration enters the detection of expression of F-actin after collagen
SMMC-7721 cell is inoculated on chip, cultivates after 3 days, carries out immunofluorescent staining, and monitoring albumen is Actin muscle F-actin.Method is as follows: 4% paraformaldehyde carries out cell to be fixed, and PBS damping fluid rinses three times, each 10min; 0.1%triton X-100 pore-creating agent effect 10min, PBS damping fluid rinses three times, each 10min; Goat sealing serum effect 1h, primary antibodie (the anti-human F-actin of rabbit) 1:100 dilution, 4 DEG C of night incubation, PBS damping fluid rinses three times, each 10min; Two anti-(goat anti-rabbit igg of FITC mark) 1:100 dilutions, normal temperature is hatched 1h, and PBS damping fluid rinses three times, each 10min; After flushing, add the DAPI working fluid of 1:2000 dilution, under fluorescent microscope, take pictures, record the expression of F-actin in cell, result as shown in figure 12.SMMC-7721 migration is accompanied by the rising that F-actin expresses after entering collagen, illustrates that its motor capacity is improved to a certain extent.
Claims (4)
1. a micro-fluidic chip, is characterized in that: this micro-fluidic chip is mainly by cell entrance pond (1), collagen entrance pond (2), waste liquid pool (3), cell culture chamber (4), cell migration chamber (5) composition; On cell culture chamber (4), connect cell entrance pond (1), connect waste liquid pool (3) under cell culture chamber (4), a cell culture chamber is laterally connected with three cell migration chambers;
Collagen entrance pond is connected one to one with cell migration chamber.
2. according to micro-fluidic chip claimed in claim 1, it is characterized in that: described micro-fluidic chip is formed by upper and lower two-layer irreversible sealing-in, and upper layer of material is the PDMS polymkeric substance that light-permeable is ventilative, and subsurface material is the clean glass that the vitriol oil boiled.
3. according to micro-fluidic chip claimed in claim 2, it is characterized in that: described micro-fluidic chip upper and lower two-layer carries out respectively the ultraviolet sterilising treatment of irradiating of spending the night, and then Cement Composite Treated by Plasma 30-45s carries out sealing-in.
4. according to micro-fluidic chip claimed in claim 1, it is characterized in that: described micro-fluidic chip is made up of highly different two portions, cell entrance pond (1), waste liquid pool (3), cell culture chamber (4) are highly 210 μ m, and collagen entrance pond (2) and cell migration chamber (5) are highly 70 μ m.
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