CN113671165B - Device and method for high-throughput precision detection of mechanical properties of living cells - Google Patents
Device and method for high-throughput precision detection of mechanical properties of living cells Download PDFInfo
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- CN113671165B CN113671165B CN202110965545.6A CN202110965545A CN113671165B CN 113671165 B CN113671165 B CN 113671165B CN 202110965545 A CN202110965545 A CN 202110965545A CN 113671165 B CN113671165 B CN 113671165B
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
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Abstract
The invention discloses a microfluidic device for high-flux precise detection of mechanical properties of living cells, wherein a microfluidic chip for detecting the mechanical properties of living cells is arranged above an optical microscope, parallel micro-channels are arranged in the microfluidic chip for extruding the cells, and a shunt channel is arranged to ensure that the extrusion pressure is basically unchanged; a method for high-throughput precision detection of mechanical properties of living cells comprises the following steps: s1: a method for measuring cell elastic modulus; s2: a microchannel differential pressure control method; the device and the method not only can rapidly detect the elastic modulus of a large number of living cells, but also are simple to operate and highly automated.
Description
Technical Field
The invention relates to the field of cell biology, in particular to a device and a method for high-throughput precision detection of mechanical properties of living cells.
Background
The elastic modulus of cells affects various aspects of cell proliferation, differentiation, migration, apoptosis, etc. An abnormality in the elastic modulus of cells may cause a change in cell functions, and even cause occurrence of diseases. For example, when humans are infected with plasmodium falciparum, the elastic modulus of erythrocytes in humans increases. The difficulty of passing hardened red blood cells through narrow capillaries can lead to poor blood flow and ultimately can lead to coma and even death of the person. In addition, in stem cell therapy, the safety and effectiveness thereof are limited by various factors such as pulmonary embolism caused by cell blockage of capillaries and insufficient activity and purity of cells before implantation, which are all closely related to the elastic modulus of cells. Thus, studying the elastic modulus of cells can be used to quantitatively reflect the health status of cells and is expected to be useful for rapid diagnosis and treatment of diseases.
Measurement studies of cell elastic modulus have been continued for half a century, and techniques such as optics, magnetism, and hydrodynamics have been applied to cell mechanical property studies. The most widely used conventional measurement technique is micropipette (Micropipette Aspiration). This technique utilizes the aspiration of spherical cells through glass capillaries to obtain the elastic modulus of the cells based on cell deformation data. Atomic force microscopy (Atomic Force Microscopy) is considered to be the most accurate technique for measuring single cell elastic modulus at present. The technique uses a precise cantilever free end to press against the cell, causing local deformation of the cell surface and obtaining the elastic modulus of the cell based on the deformation and the force required. However, atomic force microscope equipment is expensive, operation is complex, and measurement efficiency is very low. In addition, the conventional elastic modulus measurement technique of cells includes a magnetic distortion cell count method (Magnetic Twisting Cytometry), optical Tweezers (Optical Tweezers) and a Shear Flow technique (Shear Flow) [8], but these techniques have corresponding problems, such as the calibration of the extrusion force in the Optical Tweezers technique.
The conventional measurement techniques have some defects, such as low flux, expensive equipment and complicated operation. Because of the large individual differences in cells, a large number of cells should be measured as much as possible to obtain statistically significant reliable data. The microfluidic technology has the potential of high-throughput measurement of the elastic modulus of living cells because of the high-throughput treatment of cells. Related studies have been made to measure the elastic modulus of cells by microfluidic techniques. The flow induced deformation (Flow induced deformation) technique is to use shear flow in the microchannels to induce cell deformation and estimate its elastic modulus. Gossett et al use this technique to calculate cell deformability and achieve a flux of about 2000 cells per second. The real-time cell deformation technique developed by Otto et al also uses this technique to quantitatively calculate the elastic modulus of cells and achieve a flux of about 100 cells per second. Compression (Compression) techniques compress and deform cells in a microfluidic chip using deformable membranes to obtain elastic modulus data. Hohne et al used this technique to measure the mechanical properties of cells with Young's modulus in the range of 102-105 Pa. In addition, micropipette (Aspiration) technology is similar to micropipettes in conventional measurement methods, and the cells are deformed by compression in a microchannel to obtain elastic modulus data. The technique records the cell deformation process in a microfluidic device in combination with a microscopic imaging technique, thereby obtaining the elastic modulus of the cells. Guo et al developed a tapered constriction channel of micron order to deform cells through and thereby evaluate the deformability of the cells. Kim et al have the cells in a microfluidic chip passed through a plurality of parallel funnel-shaped constricting microchannels and deformed to obtain the elastic modulus of the cells.
In summary, the background art has significant disadvantages compared to the present invention. Briefly summarized as follows:
1) Although the elastic modulus measurement of an atomic force microscope is high in accuracy, the flux is low, and a large amount of data with statistical significance is difficult to obtain. Real-time deformable cytometry (Real-time deformable cytometry) based on flow induced deformation, while high in throughput, has the disadvantages of limited induction force, inability to deform harder cells, and the need for a high-speed camera to capture cell deformation data.
2) The existing microfluidic device can process a plurality of single cells in parallel, but does not precisely measure and control the pressure difference at two ends of a cell deformation channel, and the situation that all shrinkage channels are blocked to cause severe change of the pressure difference possibly occurs, and the calculated value of the elastic modulus of the cells has huge errors.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a device and a method for high-flux precision detection of the mechanical properties of living cells, which not only can rapidly detect the elastic modulus of a large number of living cells, but also are simple to operate and high in precision.
The device for high-throughput precision detection of the mechanical property of living cells comprises a microfluidic chip and an optical microscope, wherein the microfluidic chip is arranged above the optical microscope, and parallel micro-channels are arranged in the microfluidic chip and used for extruding the cells;
the microfluidic chip comprises an inlet, an outlet, parallel micro-channels and a shunt channel, wherein the parallel micro-channels and the shunt channel are arranged in a middle extrusion area, a filtering section is arranged on the other side of the inlet, the shunt channel is arranged on the other side of the filtering section, the shunt channels are respectively arranged on two sides of the extrusion area, the micro-channels are arranged in the extrusion area, and the outlet is arranged on the other side of the shunt channel.
Preferably, parallel microchannels with a width of 4 microns are provided at the inlet of the distribution channel for preventing cells from entering the distribution channel, the parallel microchannels in the compression zone having a width smaller than the cell diameter for forcing cells to deform, and the pressure drop between the upstream and downstream of the microchannels in the compression zone is maintained at ΔP.
Preferably, a method for high-throughput precision detection of mechanical properties of living cells comprises the following steps:
s1: a microchannel differential pressure control method;
s2: a high-throughput and high-precision measurement method of cell elastic modulus.
Preferably, S1 comprises the sub-steps of:
s11: the chip is connected with an external differential pressure sensor and is used for determining an accurate pressure drop value of the extrusion area;
s12: injecting a cell-free liquid into the chip at a flow rate using a precision syringe pump or a pressure pump, the sensor detecting a pressure drop across the constriction channel of the extrusion zone, the pressure drop remaining substantially unchanged as the cells pass through the constriction channel;
s13: introducing a suspension containing the cells to be tested into the microfluidic chip using the same flow rate;
s14: most of the cells in the middle of the channel will flow along the flow line to the micro-channels of the extrusion zone, while individual cells near the wall will flow along the channel wall to the split channel inlet;
s15: because the micro-channels at the inlets of the extrusion area and the diversion channel are very narrow, the width of the main channel is 100 times that of the micro-channels, and the pressure drop of the channels is mainly concentrated at the micro-channels;
s16: when the cells reach the inlet of the diversion channel, the micro-channel width at the inlet is far smaller than the cell diameter, so that the cells are not easy to deform and cannot enter the diversion channel, and flow to the downstream extrusion area along the wall surface under the action of fluid;
s17: under the partial pressure effect of the micro-channel, the integral pressure change of the channel is very tiny and can be ignored in the process of extruding cells by the micro-channel in the extruding area, so that the high precision of elastic modulus detection is ensured;
preferably, S2 comprises the sub-steps of: :
s21: injecting the suspension containing the living cells to be tested into the main channel from the chip inlet by an external precise injection pump or a pressure pump at a certain flow rate;
s22: the cells then continue to flow under the influence of the fluid to the downstream extrusion zone, and when the cells flow to the microchannel of the extrusion zone, the cells are extruded and deformed into the microchannel due to the width of the constriction channel being smaller than the diameter of the cells;
s23: the cells continue downstream after passing through the microchannel and flow out of the chip from the outlet;
s24: 40 micro-channels are distributed in parallel in the channels, so that the cells can flow through the channels at high flux, and all the micro-channels can be observed through an optical microscope at the same time;
s25: recording and obtaining quantized cell deformation data by a microscopic imaging system according to the cell deformation condition in the microchannel;
s26: thanks to the shunt arrangement of the parallel micro-channels and the side shunt channels, high-precision and stable pressure drop can be obtained in the cell extrusion process, and high precision and high flux of cell mechanical property detection are ensured.
The device and the method for high-flux precision detection of the mechanical properties of living cells have the following beneficial effects:
1. by arranging parallel extrusion channels and realizing constant pressure difference in the detection process, the cell elastic modulus detection flux is improved, a large amount of cell elastic modulus data can be rapidly provided, and the commercial application of the cell elastic modulus chip is possible.
2. Based on the arrangement of the flow channel, the stability of the pressure difference in the measurement process is strictly ensured, so that the accurate measurement of the elastic modulus of the cells is realized.
Drawings
FIG. 1 is a schematic diagram of a cell elastic modulus measuring apparatus.
FIG. 2 is a schematic view of a microfluidic chip channel and a partial enlarged view of a constriction channel.
FIG. 3 expanded view of cell compression zone and microchannel
Fig. 4 is a flow chart of elastic modulus measurement.
FIG. 5 (a) channel streamline profile;
FIG. 5 (b) shows a schematic of a flow diversion channel entrance blocking cell.
FIG. 6 (a) cell deformation map of the crush zone;
FIG. 6 (b) cell deformation map in single microchannel of extrusion zone;
FIG. 6 (c) shows the change in cell elongation with time and the result of fitting according to the cell model (solid line).
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and all the inventions which make use of the inventive concept are protected by the spirit and scope of the present invention as defined and defined in the appended claims to those skilled in the art.
As shown in fig. 1-3, the device consists essentially of a microfluidic chip and a microscopic imaging system, and uses parallel microchannels in the microfluidic chip to squeeze cells. The internal flow channels of the microfluidic chip are shown in fig. 3 and include an inlet, an outlet, parallel microchannels in the middle extrusion zone, and shunt channels on both sides. Wherein, the parallel micro-channels of the extrusion area can force the cells to deform due to the fact that the width is smaller than the diameter of the cells, and micro-channels are arranged at the inlets of the diversion channels and used for preventing the cells near the wall surfaces from entering the diversion channels. The pressure drop in the extrusion zone varies substantially negligible during extrusion of the cells under the split action of the parallel channels and the split channels.
The flow chart of the elastic modulus measurement chip is shown in fig. 4.
Before the elastic modulus measurement is performed, a cell-free liquid is injected into the chip at a certain flow rate using a precision injection pump, and an external differential pressure sensor is used to measure the accurate pressure drop value of the extrusion zone at different flow rates.
Subsequently, a suspension containing the cells to be tested is introduced into the microfluidic chip using a precision syringe pump or a pressure pump, and cell deformation at the microchannel is recorded using a microscopic imaging system.
As shown in fig. 5a, when the suspension containing living cells to be measured is flowed into the main channel from the inlet of the chip by the external precision syringe pump at a certain flow rate, most of the cells in the middle of the channel flow to the micro-channel of the extrusion zone along the flow line, and the individual cells flow to the inlet of the diversion channel along the wall of the channel due to the flow of the cells in the chip along the flow line.
When the cells reach the entrance of the shunt channel, the cells are not easily deformed and cannot enter the shunt channel because the 4 micron microchannel width at the entrance is much smaller than the cell diameter, as shown in FIG. 5 b.
The cells then continue to flow under the influence of the fluid to the downstream extrusion zone where they will deform and enter the microchannel as the cells flow to the microchannel because the width of the constriction channel is smaller than the diameter of the cells.
The cells continue downstream after passing through the microchannel and exit the chip from the outlet.
40 micro-channels are distributed in parallel in the channel, so that the high-flux flow of cells is ensured, and all the micro-channels can be observed simultaneously through a microscopic imaging system.
Cell deformation in the microchannel was recorded by an optical microscope and quantified cell deformation data was obtained.
Due to the split of the parallel microchannels and the side split channels, when the microchannels of the extrusion zone are blocked by the extruded cells, the blocking has very little effect on the flow resistance of the whole channel, so that the pressure drop of the microchannels of the extrusion zone is kept substantially unchanged during the extrusion of the cells.
The cell elastic modulus was calculated based on the microchannel differential pressure and cell deformation obtained by the above measurement. The radius of each micro-channel of the extrusion area is expressed by the radius of a circular tube with the same cross section
Where h and w represent channel height and width, respectively. Obtaining a test cell by a microscopic imaging systemElongation in the constriction channel. Then, using the cellular power law model deformation formula +.>
Calculate the modulus of elasticity, wherein>
To shrink the channel coefficient, R P Is the channel radius, delta P is the channel pressure difference, L is the cell elongation, alpha is the power law index, A J Is the shear modulus. When deformation time t=t 0 Cell elastic modulus a =1s G Can be->
And (5) calculating to obtain the product. Eventually, the elastic modulus of each cell passing through the constriction channel will be measured.
As shown in FIG. 6a, there are several cells in the parallel microchannel that are deforming and elongating as the cells continue to flow into the pinch. Wherein the deformation image of each cell will be extracted and the change in cell elongation L with time measured as shown in fig. 6b and 6 c. Finally, according to the cell power law model deformation formula
Cell deformation data were used to fit and obtain the elastic modulus of the cells (as shown in solid lines in fig. 6 c).
Claims (1)
1. The device for high-throughput precision detection of the mechanical properties of living cells is characterized by comprising a microfluidic chip and an optical microscope, wherein the microfluidic chip is arranged above the optical microscope, and parallel micro-channels are arranged in the microfluidic chip and used for extruding the cells;
the microfluidic chip comprises an inlet, an outlet, parallel micro-channels and a shunt channel, wherein the parallel micro-channels are positioned in a middle extrusion area, a filtering section is arranged on the other side of the inlet, the shunt channel is arranged on the other side of the filtering section, the shunt channels are respectively arranged on two sides of the extrusion area, the micro-channels are arranged in the extrusion area, the parallel micro-channels are arranged at the inlet of the shunt channel, and the outlet is arranged on the other side of the shunt channel;
parallel micro-channels are arranged at the inlets of the shunt channels and used for preventing cells from entering the shunt channels, the width of the parallel micro-channels in the extrusion area is smaller than the diameter of the cells and used for forcing the cells to deform, and the pressure drop at the two ends of the micro-channels in the extrusion area is kept constant;
the method for high-throughput precision detection of the mechanical properties of living cells is set on the device and comprises the following steps:
s1: a microchannel differential pressure control method;
s2: a high-throughput and high-precision measurement method of cell elastic modulus;
the step S1 comprises the following substeps:
s11: the chip is connected with an external differential pressure sensor and is used for determining an accurate pressure drop value of the extrusion area;
s12: injecting a cell-free liquid into the chip at a flow rate using a precision syringe pump or a pressure pump, the sensor detecting a pressure drop across the constriction channel of the extrusion zone and no longer being measured in a subsequent step, the pressure drop remaining substantially unchanged as the cells pass through the constriction channel;
s13: introducing a suspension containing the cells to be tested into the microfluidic chip using the same flow rate;
s14: most of the cells in the middle of the channel will flow along the flow line to the micro-channels of the extrusion zone, while individual cells near the wall will flow along the channel wall to the split channel inlet;
s15: because the micro-channels at the inlets of the extrusion area and the diversion channel are very narrow, the width of the micro-channels is far smaller than that of the extrusion area and the diversion channel, and therefore the pressure drop of the chip is mainly concentrated at the micro-channels;
s16: when the cells reach the inlet of the diversion channel, the micro-channel width at the inlet is far smaller than the cell diameter, so that the cells are not easy to deform and cannot enter the diversion channel, and flow to the downstream extrusion area along the wall surface under the action of fluid;
s17: under the partial pressure action of the parallel micro-channels of the extrusion area and the shunt channel, the integral pressure change of the channel is very tiny and can be ignored in the process of extruding cells by the micro-channels of the extrusion area, so that the high precision of elastic modulus detection is ensured;
the step S2 comprises the following substeps:
s21: injecting the suspension containing the living cells to be tested into the main channel from the chip inlet by an external precise injection pump or a pressure pump at a certain flow rate;
s22: the cells then continue to flow under the influence of the fluid to the downstream extrusion zone, and when the cells flow to the microchannel of the extrusion zone, the cells are extruded and deformed into the microchannel due to the width of the constriction channel being smaller than the diameter of the cells;
s23: the cells continue downstream after passing through the microchannel and flow out of the chip from the outlet;
s24: 40 micro-channels are distributed in parallel in the channels, so that the cells can flow through the channels at high flux, and all the micro-channels can be observed through an optical microscope at the same time;
s25: recording and obtaining quantized cell deformation data by a microscopic imaging system according to the cell deformation condition in the microchannel;
s26: thanks to the split arrangement of the parallel micro-channels and the side split channels, the number of the micro-channels which are blocked is controlled by controlling the number of the cells which are simultaneously extruded in the cell extrusion process, so that high-precision and stable pressure drop is obtained, and high precision and high flux of cell mechanical property detection are ensured.
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