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WO2019227563A1 - Dispositif microfluidique représentant des paramètres multiples pour cellule unique - Google Patents

Dispositif microfluidique représentant des paramètres multiples pour cellule unique Download PDF

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Publication number
WO2019227563A1
WO2019227563A1 PCT/CN2018/093612 CN2018093612W WO2019227563A1 WO 2019227563 A1 WO2019227563 A1 WO 2019227563A1 CN 2018093612 W CN2018093612 W CN 2018093612W WO 2019227563 A1 WO2019227563 A1 WO 2019227563A1
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cell
cells
optical fiber
microfluidic device
suspension
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Chinese (zh)
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王文会
黄亮
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Tsinghua University
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Tsinghua University
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N3/00—Investigating strength properties of solid materials by application of mechanical stress
    • G01N3/08—Investigating strength properties of solid materials by application of mechanical stress by applying steady tensile or compressive forces
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis

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  • the invention relates to the technical field of microfluidic devices, in particular to a single-cell multi-parameter characterization microfluidic device.
  • Cell markers refer to the biochemical indicators of cells that can be objectively measured and evaluated. By measuring the cell markers, one can know the progress of the biological process in which the body is currently located. Examination of a specific cell marker has an important role in the identification of disease, early diagnosis and prevention, and monitoring during treatment. Therefore, measuring and characterizing cell markers has become an important focus of current research. Among them, the mechanical and electrical properties of cells are inherent properties of cells and can be used as cell markers. Simultaneous measurement of mechanical and electrical properties of cells is of great significance.
  • the mechanical properties of cells can be used as cell markers to reflect the cytoskeletal properties of cells.
  • the cytoskeleton not only provides mechanical strength, but also performs many important cellular functions. Among them, the morphological changes caused by the cytoskeleton are actually diagnostic for cancer. The changes in the skeleton content and structure of a cell can be reflected in the overall mechanical properties of the cell, so multi-parameter characterization of a single cell can allow researchers to explore single cells more thoroughly.
  • Cell electrical characteristics are mostly used in biology to describe cell survival, growth, and identify different cell types. Electrical parameters are closely related to the structure and chemical composition of cells, and their physiological functions can be explored by studying the electrical characteristics of cells. Quantitative analysis of cell electrical parameters can reflect the dielectric properties of cells and can be used as a marker for calibrating cell types. Among them, the electrical parameters of cells mainly include the conductivity and dielectric constant of cell membrane and cytoplasm. At present, the electrical characteristics of cells can be achieved through a variety of methods, including micro-impedance spectroscopy, impedance flow cytometry, and electrorotation methods. The electrorotation method is the only method to accurately extract cell membranes and internal electrical characteristics.
  • the cells Under the action of the rotating electric field, the cells will be polarized and rotated by the torque generated by the rotating electric field.
  • various electrical parameters of the cells can be measured, such as cell unit membrane capacitance and cytoplasmic conductivity.
  • the current electrorotation methods mostly use planar electrodes. Because the speed of rotation is related to the size of the electric field, the speed of rotation at different positions in the planar electrode is different, resulting in poor measurement accuracy and inability to accurately characterize the electrical parameters of cells.
  • cells will be affected by fluid forces and gravity to cause spatial instability. Since the dielectrophoretic force decays away from the electrode quickly, it is difficult to use dielectrophoretic force to fix the position of a single cell in space.
  • the disadvantages of the related technologies are as follows: (1) Instability of the spatial position when the cell rotates: Because the cell is easily affected by external forces such as fluid force and gravity, the center of mass is unstable before and during the rotation of the cell Easy to pan. Commonly used cell rotation methods are based on flat electrodes. Because the speed of electrical rotation is related to the electric field distribution, the speed of rotation at different positions in flat electrodes is different, which affects the accuracy of the measurement and cannot accurately characterize the electrical properties of the cells. parameter. (2) Limitations of measurement methods for cell mechanical properties: The commonly used single cell mechanical property measurement methods can only measure the local mechanical properties of cells and cannot truly reflect the overall mechanical characteristics of single cells. (3) Single cell characterization: Most technologies can only measure and characterize a single mechanical electrical characteristic of a single cell, and cannot perform multi-parameter characterization.
  • the present invention aims to solve at least one of the technical problems in the related technology to a certain extent.
  • an object of the present invention is to provide a single-cell multi-parameter characterization microfluidic device, which can effectively improve the stability and accuracy of cell electrical rotation measurement, and realize accurate single-cell electrical parameter measurement.
  • the device uses a fiber stretcher to efficiently capture single cells, and provides a stable center of mass position for the cell's electrical rotation. It uses a fiber stretcher to test the mechanical properties of the single cells. It uses vertical electrodes to rotate the single cells, and Rotational spectrum enables characterization of the electrical properties of a single cell.
  • an embodiment of the present invention proposes a single-cell multi-parameter characterization microfluidic device, including: a microfluidic channel, the microfluidic channel being bonded in a reversible manner; a plurality of three-dimensional electrodes, the multiple Three-dimensional electrodes are embedded in the microfluidic channel for cell rotation; an optical fiber stretcher, the optical fiber stretcher includes a first optical fiber and a second optical fiber, to cause light momentum to change by irradiating light on the cell, Scattering forces and gradient forces are generated in the axial and normal directions of the cells, and the first and second optical fibers are arranged oppositely, so that the force balance is achieved in the axial and normal directions of the cells to form a light trap.
  • a microfluidic channel the microfluidic channel being bonded in a reversible manner
  • a plurality of three-dimensional electrodes the multiple Three-dimensional electrodes are embedded in the microfluidic channel for cell rotation
  • an optical fiber stretcher includes a first optical fiber and
  • the single-cell multi-parameter characterization microfluidic device of the embodiment of the present invention which captures and stretches a single cell through a fiber stretcher, can not only provide a stable spatial position for single-cell electrical rotation, but also can measure the tensile deformation of the cell
  • the mechanical characteristics of single cells so as to maintain the stability of the cell's spatial position, effectively improve the stability and accuracy of the cell's electrical rotation measurement, achieve accurate single-cell electrical parameter measurement, and provide a combined optical fiber stretching technology
  • dielectrophoresis technology a microfluidic device capable of multi-parameter characterization of a single cell, with two optical fibers to capture and stretch single cells and electrorotation of cells. These two operations further allow the mechanical properties and electrical parameters of single cells.
  • This device uses the principle of fiber stretching to efficiently and quickly capture and stretch single cells, and uses three-dimensional electrodes to accurately achieve stable rotation of single cells. By analyzing the deformation characteristics and rotation spectrum of single cells, the mechanical and electrical characteristics of single cells can be achieved. Characterization, based on the device's versatility in operation and analysis of single cells, can play an important role in the field of single cell research.
  • the single-cell multi-parameter characterization microfluidic device according to the above embodiments of the present invention may also have the following additional technical features:
  • the method further includes: an inlet and an outlet of the suspension, so as to introduce the cell suspension through the inlet of the suspension, and export the excess suspension through the outlet of the suspension.
  • the method further includes: a substrate for supporting.
  • the plurality of three-dimensional electrodes are first to fourth vertical electrodes, wherein the first to fourth vertical electrodes pass through the conductive conductive pattern.
  • the direction of the optical fiber is perpendicular to the direction of the flow channel.
  • FIG. 1 is a schematic structural diagram of a single-cell multi-parameter characterization microfluidic device according to an embodiment of the present invention
  • FIG. 2 is a structure top view of a single-cell multi-parameter characterization microfluidic device according to an embodiment of the present invention
  • FIG. 3 is a structural cross-sectional view of a single-cell multi-parameter characterization microfluidic device according to an embodiment of the present invention.
  • FIG. 4 is a schematic diagram of a single-cell multi-parameter characterization microfluidic device according to an embodiment of the present invention.
  • FIG. 5 is a block diagram of a single-cell multi-parameter characterization microfluidic device according to an embodiment of the present invention.
  • FIG. 6 is a diagram of a single light beam spreading on a cell according to the design principle of an optical fiber stretcher according to an embodiment of the present invention
  • FIG. 7 is an analysis diagram of different conditions of optical gradient force according to a design principle of an optical fiber stretcher according to an embodiment of the present invention.
  • FIG. 8 is a diagram illustrating an example in which a single cell is captured and stretched according to an embodiment of the present invention
  • FIG. 9 is a schematic diagram of a step stress tensile response curve of a cell according to an embodiment of the present invention.
  • FIG. 10 is a schematic diagram of electric rotation according to an embodiment of the present invention.
  • FIG. 11 is a schematic diagram of a clockwise rotation motion trace of a HELLA cell under an electric field according to an embodiment of the present invention.
  • FIG. 12 is a diagram of a cell single shell model and an equivalent uniform sphere model according to an embodiment of the present invention.
  • FIG. 13 is a schematic diagram of a rotation spectrum of a HeLa cell and a lymphocyte according to an embodiment of the present invention.
  • 10-Single cell multi-parameter characterization microfluidic device 100-microfluidic channel, 101-cell suspension inlet, 102-cell suspension outlet, 103-mainstream channel, 200-multi-dimensional electrodes, 201-204- First to fourth vertical electrodes, 300-fiber stretcher, 301-first fiber, 302-second fiber, and 400-substrate.
  • FIG. 1 is a schematic structural diagram of a single-cell multi-parameter characterization microfluidic device according to an embodiment of the present invention.
  • the single-cell multi-parameter characterization microfluidic device 10 includes a microfluidic channel 100, a plurality of three-dimensional electrodes 200, and a fiber stretcher 300.
  • the microchannel 100 is used for bonding the microchannel in a reversible manner.
  • the plurality of three-dimensional electrodes 200 are used for embedding the plurality of three-dimensional electrodes in the microchannel for cell rotation.
  • the optical fiber stretcher 300 includes a first optical fiber 301 and a second optical fiber 302 to cause a change in light momentum by irradiating light on a cell, so that a scattering force and a gradient force are generated in the axial and normal directions of the cell, and Because the first and second optical fibers are arranged oppositely, the force balance is achieved in the axial and normal directions of the cells to form a light trap to capture and stretch a single cell.
  • the device 10 of the embodiment of the present invention can capture and stretch a single cell by using an optical fiber stretcher, thereby effectively improving the stability and accuracy of the electrical rotation measurement of a cell while maintaining a stable spatial position of the cell, and achieving accurate single cell electrical power. Parameter measurement.
  • the embodiment of the present invention uses a fiber stretcher to efficiently capture single cells, provides a stable centroid position for the cell's electrical rotation, uses a fiber stretcher to test the mechanical properties of single cells, and uses vertical electrode pairs
  • the single cell is rotated, and the electrical characteristics of the single cell are characterized by the rotation spectrum, which can combine the advantages of optical fiber stretching to capture and stretch single cells efficiently and quickly, and use the principle of three-dimensional electrode dielectrophoresis technology to achieve single cell Simultaneous measurement of mechanical and electrical properties.
  • the electric rotating part is composed of a plurality of three-dimensional electrodes 200 embedded in the microchannel 100.
  • the optical fiber stretcher 300 is composed of two optical fibers perpendicular to the flow channel.
  • the first optical fiber 301 and the second optical fiber 302 can be single-mode optical fibers, and the type of the optical fiber can be selected according to the type of laser.
  • the space needs to be strictly aligned to ensure that the light emitted by the two fibers can be collimated, and the effect of single cell capture and stretching is guaranteed.
  • the entire flow channel of the embodiment of the present invention is bonded in a reversible manner.
  • the device After capturing a batch of cells, the device can be disassembled, and after necessary processing such as elution and disinfection, it is rebonded with a new substrate for capture testing Batch of cells.
  • a top view of the device 10 according to the embodiment of the present invention is shown in FIG. 2, and a cross-sectional view is shown in FIG. 3.
  • the device 10 of the embodiment of the present invention further includes: an inlet 101 and an outlet 102 of the suspension.
  • the inlet 101 and the outlet 102 of the suspension are introduced into the cell suspension through the inlet of the suspension, and the excess suspension is discharged through the outlet of the suspension.
  • the microchannel 100 includes a cell suspension inlet 101 and a cell suspension outlet 102, and further includes a main channel 103.
  • the height and width of the flow channel are matched and designed according to the cell size.
  • Cell suspension is introduced from the inlet, and excess cell suspension flows from the outlet.
  • the driving method of the cell suspension may be a micro-motion stage driving a syringe to push the suspension to flow, or a gravity adjustment method to push, which is not specifically limited herein.
  • the microchannel 100 is made of a mold through a photolithography process, and is formed by polymer PDMS PDMS inversion.
  • the cell suspension inlet 101 and outlet 102 can be connected to a microfluidic pump through a plastic hose, and the flow of the cell suspension in the microfluidic channel 100 is controlled by the microfluidic pump.
  • the microfluidic channel can be processed by photolithography technology, and can also be realized by using a capillary tube or the like, which is not specifically limited herein.
  • the plurality of three-dimensional electrodes 200 are first to fourth vertical electrodes, wherein the first to fourth vertical electrodes are extracted by bonding with a patterned conductive substrate.
  • the electrorotation part is composed of 4 vertical electrodes embedded in the microchannel.
  • the first to fourth vertical electrodes 201-204 are embedded in the microchannel 100, and the electrodes are embedded in the channel without affecting the shape of the microchannel.
  • the material of the electrode can be a conductive material such as a metal electrode, a conductive polymer, and the height and size of the electrode can be matched and designed according to the cell size.
  • Vertical electrodes can be extracted by bonding to a patterned conductive substrate.
  • the vertical electrode is a mixture of PDMS and conductive carbon powder, and is also formed by a photolithography process and an inverted mold.
  • the vertical electrode is connected to the signal generator after being bonded to the patterned conductive glass. It should be noted that the production of the vertical electrode can be achieved by methods such as electroplating and photolithography. Those skilled in the art can set it according to actual conditions, which is not specifically limited here.
  • the direction of the optical fiber is perpendicular to the direction of the flow channel.
  • the device 10 further includes: a substrate 400.
  • the substrate 400 is used for supporting.
  • the substrate can be made of transparent materials, such as glass and plexiglass.
  • the fiber in the device is a single-mode fiber, and the light emitted by the laser first passes through an optical isolator, then splits into two through a 50/50 optical coupler, and is then connected to the dual fiber.
  • the power of the emitted light is controlled to capture and stretch single cells, and the flow rate of the cell suspension is controlled by a microfluidic pump.
  • the electrode is connected to the signal generator through a wire, and the speed and direction of the cell are controlled by applying different electrical signal configurations to the electrode.
  • Cell feed The syringe is pushed by a microfluidic pump, and the cell suspension enters from the inlet of the microfluidic channel and flows through the capture test area.
  • the cells can be rotated by applying electrical signals with the same frequency and different phase differences to the electrodes.
  • the direction of rotation is related to the order of the phase difference of the electrodes.
  • the speed of rotation is related to the frequency and amplitude of the electrical signal.
  • the analysis of the rotation speed through the microscopic image can form the relationship between the rotation speed and the external electrical signal (that is, the rotation spectrum). Calculate the electrical properties of a single cell by rotating the model.
  • the design of the fiber stretcher is based on the fact that light irradiation on cells will cause changes in light momentum, so that scattering and gradient forces can be generated in the axial and normal directions of the cells. Achieving force balance to form a light trap allows single-cell capture. At the same time, the single cell can be stretched and deformed by changing the optical power.
  • the force of light on cells not only has a thrust force (scattering force) caused by the light radiation force, but also a pulling force (gradient force) on the cells.
  • Scattering force is caused by the impact of photons on the cell, and it is along the propagation direction of the beam.
  • Gradient force is caused by the unevenness of the intensity of the light field.
  • the magnitude of the scattering and gradient forces on the particles depends on the wavelength of the laser and the cell size. The calculation model of gradient force and scattering force of particles with different sizes in light field is different. Cell size relative to the laser wavelength conforms to the Mie scattering model.
  • the size of the cell is larger than the wavelength of the radiant light, and the magnitude and direction of the force depend on the shape of the cell.
  • any change in momentum will cause the cell to have the same size and opposite momentum.
  • the incident beam it can be broken down into multiple thin beams.
  • Figure 6 shows the propagation of one beam with power P1 incident on the cell.
  • the light beam will reflect and refract on the cell. Let the reflection and refraction coefficients be R and T.
  • ⁇ 1 is the angle of incidence and ⁇ 2 is the angle of refraction.
  • the scattering force Fscat and gradient force Fgrad received by the cell are:
  • n0 is the refractive index of the surrounding medium
  • P1 is the optical power of the incident beam
  • c is the speed of light in a vacuum
  • n1 is the refractive index of the cell.
  • Figure 7 is the distribution of the overall force on the cell.
  • the gradient force generated by the light on the cell will pull the cell to the position where the light intensity distribution is the largest (that is, the center position of the fiber).
  • the force will be uneven in the vertical direction, and the cells will be pulled back to the center position, as shown in Figure 7 (a).
  • the axial force generated on the cell will push the cell away from the fiber, because the two fibers are distributed relative to each other, which will form a force balance point between the two fibers.
  • a single cell can be captured in a light trap, as shown in Fig. 7 (b).
  • the magnitude of the axial force is related to the optical power.
  • particles such as cells have high elasticity.
  • the force on the cells will also increase, and the particles will be stretched along the propagation direction of the beam, as shown in Figure 7 ( c).
  • the captured cells are subjected to a tensile test. By analyzing the tensile deformation of the cells, mechanical properties of the cells, such as elastic modulus, can be extracted.
  • Figure 8 shows an example where a single cell is captured and stretched.
  • ⁇ r is the deformation of the cell along the optical axis
  • r is the initial cell diameter.
  • Figure 9 shows the step stress response curve of a cell.
  • Cell elongation is usually related to the cell's viscoelasticity.
  • viscoelastic behavior can usually be fitted by the following formula:
  • ⁇ 1 is the maximum stress exerted on the cell along the beam, and it can be calculated by formula (6):
  • n med is the refractive index of the medium (usually n med ⁇ 1.335)
  • n cell is the refractive index of the cell.
  • R is the reflection amount of light at the interface between the medium and the unit that is normally incident, and is calculated by formula (7):
  • I 0 is the laser intensity on the laser axis at the unit position, which can be calculated using the total power P and the radius of the laser beam at the cell ⁇ position:
  • fitting parameters a1, a2, and b1 can be determined.
  • Typical rheological parameters such as shear modulus G, steady state viscosity ⁇ or relaxation time ⁇ can be calculated by the following formula:
  • ⁇ is Poisson's ratio
  • Poisson's ratio of general cells is ⁇ 0.45-0.50.
  • the design of the single-cell rotating structure is based on dielectrophoresis technology and microfluidics technology.
  • dielectrophoresis is that particles are polarized in a non-uniform electric field to form an electric dipole, which is subject to the force generated by the external non-uniform electric field or Torque forces the dielectric particles to produce directional or rotational motion. If sinusoidal signals with different phase differences are applied to the four electrodes, a rotating electric field will be generated in the chamber, and a certain torque will be generated on the cell, which will cause a rotational motion, as shown in Figure 10 (a).
  • K CM is the Clausius-Mosotti coefficient
  • ⁇ m is the dielectric constant of the solution
  • ⁇ m is the conductivity of the solution.
  • Fig. 10 (b) shows the electric field changes (top view) in an electrode chamber surrounded by four electrodes at different times in a cycle. The electric field will change clockwise.
  • the device design uses vertical three-dimensional electrodes, so the cells will not rotate at different speeds due to different heights in the flow channel.
  • the rotation spectrum of cells measured under the effect of stereo electrodes will be more accurate.
  • Figure 11 shows an example of a device in which a single cell rotates clockwise under the action of an electric field.
  • the speed and direction of cell rotation are related to the electrical properties of the cell, the electrical properties of the solution, and the configuration of the electrical signals.
  • cells are mainly composed of cell membrane and cytoplasm, and their electrical properties are also a more complicated model. Assuming that the internal structure of cytoplasm is uniform, cells can be equivalent to a single-shell model, as shown in Figure 12.
  • the equivalent complex dielectric constant of the cell is:
  • R and d are the radius of the cell and the cell membrane, respectively; with The complex dielectric constants of the cytoplasm and the cell membrane, ⁇ cyto and ⁇ cyto are the dielectric constant and conductivity of the cytoplasm, ⁇ mem and ⁇ mem are the dielectric constant and conductivity of the cell membrane, and ⁇ is the angular frequency of the electrical signal.
  • C mem is the unit membrane capacitance of the cell membrane
  • G mem is the unit membrane conductivity
  • ⁇ is the angular velocity of rotation
  • R is the radius of the cell
  • ⁇ is the viscosity of the solution.
  • the cells rotate at a constant speed, and the corresponding angular velocity can be expressed as:
  • the parameter optimization method is used to minimize the residual error, that is:
  • the embodiment of the present invention combines the optical fiber stretching technology and the dielectrophoresis technology, and a microfluidic device and system capable of performing multi-parameter characterization of a single cell. These two operations further allow the simultaneous measurement of the mechanical properties and electrical parameters of single cells, and the fast and efficient capture and stretching of single cells using the principle of fiber stretching, and the accurate rotation of single cells using three-dimensional electrodes. Deformation features and rotating spectral lines can characterize the mechanical and electrical properties of single cells.
  • the multifunctionality of the embodiments of the present invention on operation and analysis of single cells can play an important role in the field of single cell research.
  • a single-cell multi-parameter characterization microfluidic device is proposed, and the problem of spatial position stability of a single-cell sample is effectively solved by using the fiber stretching technology, thereby improving the stability and accuracy of the electric rotation operation, and using The electrode is electrically rotated, which effectively improves the stability of rotation and the accuracy of the measurement of electrical parameters. Stretch, rotate.
  • first and second are used for descriptive purposes only and cannot be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as “first” and “second” may explicitly or implicitly include at least one of the features. In the description of the present invention, the meaning of "a plurality” is at least two, for example, two, three, etc., unless it is specifically and specifically defined otherwise.

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Abstract

L'invention concerne un dispositif microfluidique représentant des paramètres multiples pour une cellule unique, comprenant un canal microfluidique (100) réalisant une liaison de manière réversible; une pluralité d'électrodes tridimensionnelles (200) intégrées dans le canal microfluidique (100) et servant à la rotation de cellule; et un tendeur de fibre (300) comprenant une première fibre optique (301) et une seconde fibre optique (302) et servant à provoquer un changement d'impulsion lumineuse sur une cellule par rayonnement lumineux, de sorte qu'une force de diffusion et une force de gradient soient produites dans la direction axiale et dans la direction normale de la cellule, et un équilibre de forces d'action est réalisé dans la direction axiale et dans la direction normale de la cellule au moyen de la première fibre optique (301) et de la seconde fibre optique (302), qui sont agencées de façon opposée pour former un piège à lumière, de façon à capturer et à étirer la cellule unique. Une mesure précise de paramètres électriques de la cellule unique est réalisée.
PCT/CN2018/093612 2018-05-29 2018-06-29 Dispositif microfluidique représentant des paramètres multiples pour cellule unique Ceased WO2019227563A1 (fr)

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