CN115747382A - Quasi-two-dimensional cell trajectory magnetic regulation and control method and system - Google Patents
Quasi-two-dimensional cell trajectory magnetic regulation and control method and system Download PDFInfo
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Abstract
The invention discloses a quasi-two-dimensional cell track magnetic regulation and control method and a system. Introducing fluid to be sorted containing magnetic bead marked cells into a micro-channel of a quasi-two-dimensional cell track magnetic regulation chip from a sample inlet; soft magnetic strips parallel to the micro-channel are respectively arranged on the upper side and the lower side of the plane where the micro-channel is located in the chip, and the regulation and control boundary of the soft magnetic strips and the sample along the middle edge of the micro-channelAn included angle theta is formed between the non-magnetic fluids flowing from the inlet towards the direction of the residual liquid outlet, and the theta is more than 0 degree and less than or equal to 90 degrees; starting an external uniform magnetic field to magnetize the soft magnetic strips on two sides, and then magnetizing the soft magnetic strips according to
To the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel f Adjusting to enable the magnetic bead labeled cells to run along the regulation boundary at the regulation boundary and be parallel to the soft magnetic strip; where k =95403.3mT · s 2 /mm 2 ，0°＜θ≤90°，B 0 =21.6mT. The method realizes the accurate regulation and control of the wall-sticking prevention two-dimensional magnetic bead-cell track.
Description
Technical Field
The invention relates to a quasi-two-dimensional cell track magnetic regulation and control method and a system, and belongs to the technical field of microfluidics.
Background
Biomagnetic separation is commonly used in the biological fields of virus detection, cell manipulation, drug screening and the like, and has important application in clinical medicine, and medical products formed by industrial transformation of biomagnetic separation are also commonly used for health monitoring. The magnetophoretic antibody detection technology is generally that antibodies corresponding to surface antigens of certain viruses or cell proteins are firstly modified on the surfaces of magnetic beads, the magnetic beads-antibodies are specifically combined with biological macromolecules or even cell surface proteins, and finally the magnetic beads are controlled to move in a flow field by utilizing magnetic field regulation to drag biological molecules or cells to be transported, so that the biological microfluidic separation function is realized.
At present, the combination of the magnetophoresis technology and a micro-flow channel can generally select to place a magnet on one side of the micro-flow channel, and the magnetic bead track is changed through the attraction of the magnet, so that the sorting function is realized. However, the unilateral regulation and control micro-fluidic chip takes the adsorption effect as the leading factor, and has a serious magnetic bead adherence phenomenon, so that a flow channel is blocked, and the sorting precision and the flow are influenced; in order to avoid the adherence of magnetic beads as much as possible and ensure that the magnetic field can be effectively regulated, the magnetic regulation micro-fluidic chip is usually applied to low-flow-rate magnetic separation; because the dissipation speed of the magnetic field around the magnet is high, the magnetic flux density and the magnetic field gradient in the normal direction of the external magnetic field are quickly reduced, and the difference of magnetic field forces applied to magnetic beads originally positioned at different positions in the flow channel is large, so that uniform, stable and accurate regulation and control on magnetic particles in the flow channel cannot be realized; because the appearance and the size of the applied magnetic field of the existing magnet in the flow field are fixed, the magnetic field can be adjusted only by replacing the material composition of the magnet, so that the adjustment of the magnetic field is limited and the magnet forming process is complicated.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defect that the existing microfluidic chip cannot realize stable and accurate track regulation and control on magnetic beads in a flow channel, so that a quasi-two-dimensional cell track magnetic regulation and control method and a quasi-two-dimensional cell track magnetic regulation and control system are provided.
The technical scheme of the invention is as follows:
a quasi-two-dimensional cell track magnetic regulation method comprises the following steps:
introducing a fluid to be sorted containing magnetic bead marked cells into a micro-channel of a quasi-two-dimensional cell track magnetic regulation chip from a sample inlet; in the quasi-two-dimensional cell track magnetic regulation chip, soft magnetic strips parallel to a micro-channel are respectively arranged on the upper side and the lower side of the plane where the micro-channel is located, and an included angle theta is formed between the regulation boundary of the soft magnetic strips and a non-magnetic fluid flowing in the micro-channel along the direction from a sample inlet to a residual liquid outlet; wherein theta is more than 0 degree and less than or equal to 90 degrees;
starting an external uniform magnetic field to magnetize the soft magnetic strips on two sides
Magnetic flux density B to external uniform magnetic field and flow velocity v of fluid entering micro-channel f Adjusting to enable the magnetic bead labeled cells to run along the regulation boundary at the regulation boundary and be parallel to the soft magnetic strip; where k =95403.3mT · s 2 /mm 2 ，B 0 ＝21.6mT。
When the external uniform magnetic field is adjusted at a fixed flow rate, the method also comprises the step of adjusting the magnetic flux density within the range of B +/-15%; the adjustment is preferably performed within a range of B + -10% of the magnetic flux density.
Said flow velocity v f 0.012-0.035 mm/s, the magnetic flux density B is 25-80 mT; preferably, said flow velocity v f 0.015 to 0.025mm/s, and the magnetic flux density B is 32 to 55mT.
The regulation and control boundary is any one or combination of oblique lines, arc lines, straight lines and broken lines.
The included angle theta is 20-45 degrees.
The preparation process of the magnetic bead labeled cells comprises the following steps: and incubating the magnetic bead solution and the cell solution to be marked in a buffer solution environment to obtain the magnetic bead marked cells after the magnetic bead marking of the cells to be marked.
The concentration of the cell solution to be marked is 1-2.5 multiplied by 10 5 Per mL; and/or the ratio of the number of the magnetic beads to the number of the cells to be marked is as follows: 4 to 10; and/or, incubating for 30-40 min at 35-40 ℃; and/or the dosage ratio of the buffer solution to the cell solution to be marked is 5:1-8:1.
A quasi-two-dimensional cell track magnetic regulation and control system is used for the quasi-two-dimensional cell track magnetic regulation and control method, and comprises a quasi-two-dimensional cell track magnetic regulation and control chip, an external source uniform magnetic field and a fluid injection device;
the quasi-two-dimensional cell track magnetic regulation chip comprises: soft magnetic strips parallel to the micro-channel are respectively arranged on the upper side and the lower side of the plane where the micro-channel is located, and the soft magnetic strips on the upper side and the lower side are the same in size and shape and are aligned in position; the flow field of the micro-channel sequentially comprises a liquid inlet, a regulation area and a liquid outlet along the flow direction of the fluid; the liquid inlet comprises a sample inlet; the liquid outlet comprises a magnetic separation outlet and a residual liquid outlet; the flow direction of fluid between the sample inlet and the residual liquid outlet is the non-magnetofluid flow direction in the flow field, and an included angle is formed between the sample inlet and the magnetic separation outlet and the non-magnetofluid flow direction; the soft magnetic strip is arranged at the position of the regulation area, a regulation and control boundary extending from the adjacent sample inlet to the adjacent magnetic separation outlet is arranged on the soft magnetic strip, the included angle between the regulation and control boundary and the non-magnetic fluid flowing direction is theta, and theta is larger than 0 degree and is less than or equal to 90 degrees;
the fluid injection device is communicated with the sample inlet and is used for introducing a fluid to be sorted containing magnetic bead labeled cells into the micro-channel; the external uniform magnetic field is used for magnetizing the soft magnetic strips on the upper side and the lower side.
The linear distance d between the soft magnetic strips on the two sides is less than or equal to 500 mu m; wherein the linear distance between the soft magnetic strip and the surface of the micro-channel on the same side is 190-215 μm, and the height of the micro-channel is 50-70 μm; and/or the ratio of the height to the width of the micro flow channel is 1: (20-40); and/or the soft magnetic strip is an etched and formed amorphous metal strip with the thickness of 20-50 mu m; more preferably, the material of the amorphous metal strip is at least one of iron oxide, cobalt oxide and nickel oxide; and/or the micro-channel is formed by laminating and combining two templates, wherein one surface of one template is provided with a micro-channel pattern, and the micro-channel pattern is positioned between the two laminated templates and forms the micro-channel; preferably, the template is a soft template, and more preferably, the material of the soft template is PDMS (polydimethylsiloxane) or PMMA (polymethyl methacrylate).
The fluid injection device is a thrust injection pump; and/or the external source uniform magnetic field is a double-coil Helmholtz coil, the chip is positioned at the centers of the two coils, and each soft magnetic strip is positioned at the axis position of the Helmholtz coil corresponding to the soft magnetic strip.
The invention has the beneficial technical effects
1. The quasi-two-dimensional cell track magnetic regulation and control method is characterized in that under the condition that the included angle theta between the regulation and control boundary of the soft magnetic strip in the quasi-two-dimensional cell track magnetic regulation and control chip and the flow direction of the non-magnetic fluid in the flow field is fixed, the included angle theta is obtained according to the regulation and control boundary of the soft magnetic strip in the quasi-two-dimensional cell track magnetic regulation and control chip and the flow direction of the non-magnetic fluid in the flow field
Regulating the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid in the micro-channel f From the force of the magnetic bead particles in the control chip, a magnetic force (F) is generated at the control boundary Magnetic field ) With fluid drag force (F) Drag the ) The resultant force is approximately along the regulation and control boundary, so as to control the running track of the magnetic beads, and finally the magnetic beads drag the cells (V) Cells ) Moving along a set trajectory (the regulatory boundary of the soft magnetic strip), as shown in fig. 6; and the competitive capture of the magnetized soft magnetic strips on the upper side and the lower side of the micro-channel on the magnetic beads is utilized to weaken the adsorption and adherence of the soft magnetic strips on the magnetic beads, so that the magnetically labeled cells in the micro-channel rarely move along the height of the micro-channel but move along the flow field direction parallel to the soft magnetic strips, the adherence of the magnetic beads is avoided, and the high-flux magnetic separation function and the high-efficiency separation function can be realized. In conclusion, the regulation and control method of the invention leads the stress direction of the magnetic bead to approach to two dimensions through the space regulation of the magnetic field, and realizes an anti-adherence accurate regulation and control method of the quasi two-dimensional magnetic bead-cell track magnetismThe method provides a more optimal scheme for the new generation of flow detection based on magnetic sorting.
2. The method also comprises the step of adjusting the magnetic flux density of the external uniform magnetic field within the range of B +/-15% at a fixed flow speed, and the magnetic beads can be guaranteed to move along the regulation and control boundary at the regulation and control boundary of the soft magnetic strip.
3. Preferred flow rate v f 0.012-0.035 mm/s, 25-80 mT magnetic flux density B; more preferably, the flow velocity v f 0.015 to 0.025mm/s and a magnetic flux density B of 32 to 55mT. Therefore, the magnetic bead-cell track can be regulated and controlled under the conditions of high-intensity magnetic field and high flow rate, and high-flux, high-efficiency and stable magnetic separation is realized.
4. The regulation and control boundary in the invention is any one or combination of several of oblique lines, arc lines, straight lines and broken lines, and the movement track of the magnetically marked cells is controlled by changing the boundary morphology of the soft magnetic strip, thereby realizing the patterned accurate control of the cell track.
5. The included angle theta in the invention is preferably 20-45 degrees, and the particle in the flow field can be conveniently and comprehensively regulated and controlled by the quasi-two-dimensional magnetic field in the angle range.
6. According to the quasi-two-dimensional cell track magnetic regulation and control system provided by the invention, soft magnetic strips on the upper side and the lower side of a chip regulate a magnetic field in a micro-channel under the magnetization effect of an external uniform strong magnetic field, the stress of magnetic beads in the micro-channel in the vertical direction is weakened through competitive capture of the two soft magnetic strips on the magnetic beads, the magnetic beads are prevented from attaching to the wall, and the stress of magnetic bead particles in the control channel is mainly in the horizontal direction; the magnetic field distribution at different positions in the micro-channel is not uniform, the magnetic force at the regulation and control boundary of the soft magnetic strip is strongest and points to the inner side of the soft magnetic strip, so that the magnetic bead-cell moves along the regulation and control boundary at the regulation and control boundary by regulating the magnetic flux density with uniform intensity of an external source and the flow velocity of fluid and regulating the stress of the magnetic bead. Therefore, the regulation and control system can realize the precise regulation and control of the magnetic bead-cell motion track on the quasi-two-dimensional plane.
7. The linear distance d between the soft magnetic strips on the two sides is less than or equal to 500 mu m; wherein, the linear distances d1 and d2 between the soft magnetic strip and the surface of the micro-channel on the same side are 190-215 μm, and the height d3 of the micro-channel is 50-70 μm. And adjusting the distances d1 and d2 between the soft magnetic strip and the surface of the micro channel according to the characteristics of the soft magnetic strip, and further adjusting the distance d, wherein the soft magnetic strip with high magnetic conductivity and thin thickness needs larger distances d1 and d2, and the soft magnetic strip with low magnetic conductivity and thick thickness needs smaller distances d1 and d2.d is less than or equal to 500 mu m, and d1 and d2 are 190-215 mu m, so that the magnetized soft magnetic strip can accurately regulate and control the magnetic beads in the micro-channel, and even the magnetic beads can be stably guided with high flux in a range of several millimeters in a flow field under the micrometer resolution. And the height of the micro-channel is 50-70 μm, magnetic beads can be concentrated in the high-efficiency regulation and control area, high flux of particles in the micro-channel is met, and the regulation and control efficiency is prevented from being influenced. To sum up, through the comprehensive setting of above-mentioned three distance for can realize the stable regulation of vertical direction in the magnetic regulation and control district that the soft magnetic strip in both sides formed, can realize the stable regulation of horizontal direction again, thereby can realize the accurate two-dimentional magnetic bead orbit regulation and control of preventing adherence of high flux, high velocity of flow, high stability.
The types of the common soft magnetic strips are MATS-2010S, ZC, 1J46, VAC17 and the like. The amorphous metal strip with the thickness of 20-50 mu m reduces the forming difficulty of the soft magnetic strip, ensures the rigidity of the soft magnetic strip and is not easy to deform; meanwhile, the magnetic flux density attenuation at the regulation and control boundary of the soft material strip is weakened, and the magnetic regulation and control effect at the regulation and control boundary of the soft material strip is ensured.
The two templates forming the micro-channel are both soft templates, so that the linear distance between the soft magnetic strip and the surface of the micro-channel on the same side can be regulated and controlled more easily, and the soft templates are tough, not easy to break and good in biocompatibility.
8. The system uses the Helmholtz coil as a magnetic field source, and the field intensity value is flexible and controllable, so that different requirements of chips with different included angles on the magnetic field intensity are met.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a schematic diagram of a quasi-two-dimensional cell trajectory magnetic regulation system of the present invention;
FIG. 2 is a schematic diagram of a quasi-two-dimensional cell trajectory magnetic control chip according to example 1 of the present invention;
FIG. 3 isbase:Sub>A schematic A-A diagram of FIG. 2;
FIG. 4 is a schematic diagram of the structure of the quasi-two-dimensional cell trajectory magnetic control chip of example 2;
FIG. 5 is a schematic diagram of the structure of a quasi-two-dimensional cell track magnetic control chip according to example 3;
FIG. 6 is a top view of the analysis of the magnetic force applied to the magnetically labeled cells in the micro flow channel at the control boundary of the soft magnetic strip in the quasi-two-dimensional cell track magnetic control chip according to the present invention;
FIG. 7 is a graph showing the results of sorting fluids in microchannels in examples 4 to 11 of the present invention; FIG. 7 (a) is a fluid microscopic view of the magnetic separation outlet with black particles representing magnetically labeled cells; FIG. 7 (b) is a fluid microscopic view of the raffinate outlet;
FIG. 8 is a diagram showing the distribution of a fluid in a microchannel in comparative example 1 of the present invention;
FIG. 9 is a graph showing the results of sorting fluids in the micro flow channel in comparative example 2 of the present invention;
FIG. 9 (a) is a fluid microscopic view of the raffinate outlet, with black particles representing magnetically labeled cells; FIG. 9 (b) is a fluid microscopic view of the magnetic separation outlet.
The method comprises the following steps of 1-glass sheet, 2-template, 3-soft magnetic strip, 4-micro channel, 5-packaging structure, 6-magnetic bead, 7-buffer liquid inlet, 8-sample inlet, 9-magnetic separation outlet, 10-residual liquid outlet, 11-regulation area, 12-regulation boundary, 13-quasi two-dimensional cell track magnetic regulation chip, 14-exogenous uniform magnetic field, 15-fluid injection device, 16-in-situ observation platform, 17-CCD, 18-microscope objective, 19-cell and 20-computer.
Detailed Description
Example 1
A quasi-two-dimensional cell track magnetic regulation system is shown in figure 1 and comprises a quasi-two-dimensional cell track magnetic regulation chip 13, an exogenous uniform magnetic field 14 and a fluid injection device 15. The fluid injection device 15 provides power for the fluid in the micro flow channel 4 of the quasi-two-dimensional cell track magnetic control chip 13, so that the fluid to be sorted containing the magnetic bead labeled cells in the injector flows into the micro flow channel 4. The fluid injection device 15 in this embodiment is a thrust syringe pump. The external uniform magnetic field 14 provides a local uniform magnetic field when being electrified so as to magnetize the soft magnetic strips 3 at the upper side and the lower side of the quasi-two-dimensional cell track magnetic regulation chip 13. In this embodiment, the external source uniform magnetic field 14 is a double-coil helmholtz coil, the quasi two-dimensional cell trajectory magnetic control chip 13 is located at the central position between the two coils, and the soft magnetic strip 3 is located at the axis position of the helmholtz coil.
As shown in fig. 2, in the quasi-two-dimensional cell track magnetic control chip 13, soft magnetic strips 3 parallel to the micro flow channel 4 are respectively disposed on the upper and lower sides of the plane where the micro flow channel 4 is located, and the soft magnetic strips 3 on the upper and lower sides have the same size and shape and are aligned in position. The micro flow channel 4 is formed by laminating and combining two templates 2, wherein a micro flow channel pattern is arranged on one side surface of the template 2 positioned on the lower side, and the micro flow channel pattern is positioned between the two templates 2 after laminating and combining and forms the micro flow channel. The micro flow channel 4 is located at the center position between the soft magnetic strips 3 on both sides. The linear distance d between the soft magnetic strips 3 on both sides was 450 μm, wherein the height d3 of the micro flow channel 4 was 70 μm, and the linear distances d1 and d2 between the soft magnetic strips 3 on both sides and the surface of the micro flow channel on the same side were 190 μm. The ratio of the height to the width of the micro flow channel 4 is 1:20. the two templates 2 are made of PDMS (polydimethylsiloxane).
As shown in fig. 3, the flow field of the micro flow channel 4 sequentially includes a liquid inlet, a regulation region 11, and a liquid outlet along the flow direction of the fluid; the liquid inlet comprises a buffer liquid inlet 7 and a sample inlet 8; the liquid outlet comprises a magnetic separation outlet 9 and a residual liquid outlet 10. The regulation and control area 11 is a rectangular area, the buffer solution inlet 7 and the sample inlet 8 are arranged at intervals in the width direction of the micro-channel 4 at the inlet side of the regulation and control area 11, and the magnetic separation outlet 9 and the residual solution outlet 10 are arranged at intervals in the width direction of the micro-channel 4 at the outlet side of the regulation and control area 11. A connecting line between the sample inlet 8 and the residual liquid outlet 10 is a straight line, the flow direction of fluid between the sample inlet and the residual liquid outlet is the non-magnetic fluid flow direction in the flow field, and as shown by an arrow in fig. 3, the non-magnetic fluid flow direction is the straight line direction along the flow field of the micro channel 4, namely, the non-magnetic fluid flows from the sample inlet 8 to the residual liquid outlet 10 through the regulation area 11 along a straight line; the sample inlet 8 and the magnetic separation outlet 9 are arranged in a crossed manner, and an included angle is formed between the sample inlet 8 and the magnetic separation outlet 9 and in the direction of non-magnetic fluid flow. The soft magnetic strip 3 is arranged at the position of the regulation area 11, the soft magnetic strip 3 is provided with a regulation boundary 12 extending from the direction adjacent to the sample inlet 8 to the direction adjacent to the magnetic separation outlet 9, the regulation boundary 12 is in an oblique line shape, and the included angle theta between the regulation boundary 12 and the flow direction of the non-magnetic fluid in the flow field is 30 degrees. The size of the regulatory region 11 is 5mm × 5mm. The plurality of soft magnetic strip units form the whole soft magnetic strip 3, and the size of the whole soft magnetic strip 3 is slightly smaller than the regulating area 11. Any soft magnetic strip elements may be present or etched away as required to form a specific shape control boundary. The minimum dimension of each soft magnetic strip unit is 50 μm x 50 μm.
In order to perform real-time observation on the fluid in the micro flow channel 4, the regulation and control system is provided with an in-situ observation platform 16, wherein the in-situ observation platform 16 is a hollow structure and can be adapted to a microscope objective 18 and a CCD17 (charge coupled device, also called as an image controller). Wherein, the CCD17 is positioned at the top of the in-situ observation platform 16 and is connected with a computer 20; the microscope objective 18 is positioned at the bottom of the in-situ observation platform 16, and the bottom of the in-situ observation platform 16 is positioned above the quasi-two-dimensional cell track magnetic regulation chip 13.
The soft magnetic strip 3 is an amorphous metal strip with the thickness of 50 mu m, and the amorphous metal strip is bonded on the substrate and is etched and formed; the model of the soft magnetic strip is MATS-2010S, and the substrate is a glass plate with the thickness of 1 mm.
As shown in fig. 2, in order to improve the overall strength of the chip, the chip further includes a package structure 5, the package structure 5 is disposed on the upper side and the lower side of the plane where the micro flow channel 4 is located, the soft magnetic strip 3 on each side is located between the package structure 5 and the surface of the micro flow channel 4 on the same side, the package structure 5 is made of PDMS, and the total thickness from the top of the upper package structure 5 to the bottom of the lower package structure 5 is 3.5mm.
In order to ensure the rigidity of the core component of the magnetic control chip, the chip also comprises a support sheet, wherein the support sheet is a glass sheet 1 with the thickness of 1mm and is respectively arranged on the lower side packaging structure 5 and the upper side packaging structure 5. The thickness of the whole structure of the chip is 5.50mm. Therefore, the chip forms a multilayer structure of a glass sheet-PDMS packaging structure-soft magnetic strip-PDMS-micro flow channel-PDMS-soft magnetic strip-PDMS packaging structure-glass sheet.
Example 2
This embodiment is different from embodiment 1 in that the angle of the boundary 12 is regulated. As shown in fig. 4, in this embodiment, the angle θ between the control boundary 12 of the soft magnetic strip 3 and the flow direction of the non-magnetic fluid in the flow field is 45 °.
Example 3
This embodiment is different from embodiment 1 in that the angle of the boundary 12 is regulated. As shown in fig. 5, the angle θ between the control boundary 12 of the soft magnetic strip 3 and the flow direction of the non-magnetic fluid in the flow field is 60 °.
Example 4
A quasi-two-dimensional cell trajectory magnetic regulation method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation system described in embodiment 1, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 800. Mu.l of K562 cells at 37 ℃ for 30min at a cell concentration of 1.5X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory regulation
Leading the magnetically marked tumor cells obtained in the step (1) into a micro-channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13 through a sample inlet; starting Helmholtz coils to magnetize the soft magnetic strips 3 on both sides
For the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel 4 f The regulation is carried out so that the magnetic beads mark the tumor cells, which run along the regulatory boundary 12 at the regulatory boundary 12 and are parallel to the soft magnetic strip 3,and flows out along the magnetic separation outlet 9; wherein k =95403.3mT · s 2 /mm 2 ，θ＝30°，B 0 =21.6mT. The magnetic flux density of the magnetic field at the center of the Helmholtz coil is 30mT, and the fluid flow velocity v f The calculated value is 0.0188mm/s, the flow rate of the introduced fluid is 0.0170mm/s, and the error is-9.4%.
Example 5
A quasi-two-dimensional cell trajectory magnetic regulation method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation system described in embodiment 1, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory regulation
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; starting Helmholtz coils to magnetize the soft magnetic strips 3 on both sides
To the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel 4 f Adjusting to enable the magnetic bead marked tumor cells to run along the regulation boundary 12 at the regulation boundary 12 and be parallel to the soft magnetic strip 3, and flow out along the magnetic separation outlet 9; where k =95403.3mT · s 2 /mm 2 ，θ＝30°，B 0 The magnetic flux density of the magnetic field at the center of the Helmholtz coil is 40mT, the calculated fluid flow rate is 0.0278mm/s, the introduced fluid flow rate is 0.0260mm/s, and the error is-6.4%.
Example 6
A quasi-two-dimensional cell trajectory magnetic regulation method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation system described in embodiment 1, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking concentration of 410 8 Mu.l/ml EpCAM-labeled magnetic beads, in the presence of 50mol/L of 1000. Mu.l PBS buffer, at a concentration of 2X 10 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory regulation
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; starting Helmholtz coils to magnetize the soft magnetic strips 3 on both sides
To the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel 4 f Adjusting to enable the magnetic bead marked tumor cells to run along the regulation boundary 12 at the regulation boundary 12 and be parallel to the soft magnetic strip 3, and flow out along the magnetic separation outlet 9; wherein k =95403.3mT · s 2 /mm 2 ，θ＝30°，B 0 The magnetic flux density of a magnetic field at the center of the Helmholtz coil is 70mT, the flow velocity of the fluid is calculated to be 0.0450mm/s, the flow velocity of the introduced fluid is 0.0470mm/s, and the error is +4.3%.
Example 7
A quasi-two-dimensional cell trajectory magnetic regulation method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation system described in embodiment 1, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory regulation
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-flow channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; starting Helmholtz coils to magnetize the soft magnetic strips 3 on both sides
To the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel 4 f Adjusting to enable the magnetic bead marked tumor cells to run along the regulation boundary 12 at the regulation boundary 12 and be parallel to the soft magnetic strip 3, and flow out along the magnetic separation outlet 9; where k =95403.3mT · s 2 /mm 2 ，θ＝30°，B 0 The magnetic flux density of the magnetic field at the center of the Helmholtz coil is 80mT, the calculated fluid flow rate is 0.0495mm/s, the flow rate of the introduced fluid is 0.0480mm/s, and the error is-3.0%.
Example 8
A quasi-two-dimensional cell trajectory magnetic regulation and control method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation and control system described in embodiment 2, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory control
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; the Helmholtz coils are started to magnetize the soft magnetic strips 3 on the two sides
For the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel 4 f Adjusting to enable the magnetic bead marked tumor cells to run along the regulation and control boundary 12 at the regulation and control boundary 12 and to be parallel to the soft magnetic strip 3, and to flow out along the magnetic separation outlet 9; where k =95403.3mT · s 2 /mm 2 ，θ＝45°，B 0 The magnetic flux density of a magnetic field at the center of the Helmholtz coil is 25mT, the calculated fluid flow rate is 0.0084mm/s, the introduced fluid flow rate is 0.0080mm/s, and the error is-5.2%.
Example 9
A quasi-two-dimensional cell trajectory magnetic regulation and control method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation and control system described in embodiment 2, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory regulation
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; starting Helmholtz coils to magnetize the soft magnetic strips 3 on both sides
For the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel 4 f Adjusting to enable the magnetic bead marked tumor cells to run along the regulation and control boundary 12 at the regulation and control boundary 12 and to be parallel to the soft magnetic strip 3, and to flow out along the magnetic separation outlet 9; where k =95403.3mT · s 2 /mm 2 ，θ＝45°，B 0 The magnetic flux density of the magnetic field at the center of the Helmholtz coil is 70mT, the calculated fluid flow rate is 0.0319mm/s, the flow rate of the introduced fluid is 0.0320mm/s, and the error is +0.5%.
Example 10
A quasi-two-dimensional cell trajectory magnetic regulation and control method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation and control system described in embodiment 3, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory regulation
Introducing the magnetically marked tumor cells obtained in the step (1) into a quasi-two-dimensional cell track for magnetic regulationIn the micro flow channel 4 of the chip 13; starting Helmholtz coils to magnetize the soft magnetic strips 3 on both sides
For the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel 4 f Adjusting to enable the magnetic bead marked tumor cells to run along the regulation boundary 12 at the regulation boundary 12 and be parallel to the soft magnetic strip 3, and flow out along the magnetic separation outlet 9; wherein k =95403.3mT · s 2 /mm 2 ，θ＝60°，B 0 The magnetic flux density of the magnetic field at the center of the Helmholtz coil is 40mT, the calculated fluid flow rate is 0.0160mm/s, the introduced fluid flow rate is 0.0150mm/s, and the error is-6.5%.
Example 11
A quasi-two-dimensional cell trajectory magnetic regulation and control method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation and control system described in embodiment 3, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads, in the presence of 50mol/L of 1000. Mu.l PBS buffer, at a concentration of 2X 10 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory regulation
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; starting Helmholtz coils to magnetize the soft magnetic strips 3 on both sides
For the magnetic flux density B of the external uniform magnetic field and the flow velocity v of the fluid entering the micro-channel 4 f Adjusting to enable the magnetic bead marked tumor cells to run along the regulation boundary 12 at the regulation boundary 12 and be parallel to the soft magnetic strip 3, and flow out along the magnetic separation outlet 9; where k =95403.3mT · s 2 /mm 2 ，θ＝60°，B 0 Magnetic flux density of magnetic field at Helmholtz coil center position is 70mT, flow =21.6mTThe calculated volume flow rate was 0.0260mm/s, the inlet flow rate was 0.0240mm/s, and the error was-7.7%.
Comparative example 1
A quasi-two-dimensional cell trajectory magnetic regulation method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation system described in embodiment 1, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 800. Mu.l of K562 cells at 37 ℃ for 30min at a cell concentration of 1.5X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory control
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; the Helmholtz coil is started to magnetize the soft magnetic strips 3 on the two sides, the magnetic flux density of the external uniform magnetic field and the flow velocity of fluid entering the micro-channel 4 are adjusted, the magnetic flux density of the magnetic field at the center of the Helmholtz coil is 30mT, and the flow velocity of the fluid is 0.0320mm/s.
Comparative example 2
A quasi-two-dimensional cell trajectory magnetic regulation method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation system described in embodiment 1, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory regulation
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-flow channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; the Helmholtz coil is started to magnetize the soft magnetic strips 3 on the two sides, the magnetic flux density of the external uniform magnetic field and the flow rate of fluid entering the micro-channel 4 are adjusted, the magnetic flux density of the magnetic field at the center of the Helmholtz coil is 40mT, and the flow rate of the fluid is 0.0150mm/s.
Comparative example 3
A quasi-two-dimensional cell trajectory magnetic regulation and control method, which adopts the quasi-two-dimensional cell trajectory magnetic regulation and control system described in embodiment 2, and comprises the following steps:
(1) Magnetic marking of tumor cells
Taking the mixture with the concentration of 4 multiplied by 10 8 Mu.l/ml EpCAM-labeled magnetic beads in a concentration of 2X 10 in 50 mol/L1000. Mu.l PBS buffer 5 The K562 cells at 800. Mu.l/ml were incubated at 37 ℃ for 30min at a cell concentration of 2X 10 5 /mL。
(2) Tumor cell quasi-two-dimensional trajectory control
Introducing the magnetically marked tumor cells obtained in the step (1) into a micro-channel 4 of a quasi-two-dimensional cell track magnetic regulation chip 13; the Helmholtz coil is started to magnetize the soft magnetic strips 3 on the two sides, the magnetic flux density of the external uniform magnetic field and the flow rate of the fluid entering the micro-channel 4 are adjusted, the magnetic flux density B of the magnetic field at the center of the Helmholtz coil is 70mT, and the actual flow rate of the fluid is 0.0140mm/s.
Analysis of results
In examples 4-11, the K562 cells do not move in the micro flow channel along the non-magnetic fluid flow direction from the sample inlet 8 to the residual liquid outlet 10 all the time, but move along the regulatory boundary 12 at the regulatory boundary 12 of the soft magnetic strip 3, and the movement locus is parallel to the soft magnetic strip 3, and finally the magnetic beads 6-cells 19 flow out from the magnetic separation outlet 9, as shown in fig. 6 and fig. 7 (a) of fig. 7; while no magnetic particles or magnetically labeled cells were detected at the raffinate outlet 10, as shown in FIG. 7 (b).
No cells or magnetic beads were discharged from the magnetic separation outlet 9 and the raffinate outlet 10 in comparative example 1 and comparative example 3. Since the magnetic field level regulation force is much greater than the fluid drag force, the magnetic particles cannot be desorbed from the magnetic regulation region, and therefore, after stopping flowing, the K562 cells and the magnetic beads are both retained in high concentration in the microchannel under the microscope, as shown in fig. 8.
Comparative example 2 no cells or magnetic beads flowed out of the magnetic separation outlet 9 but from the raffinate outlet 10. Since both the K562 cells and the magnetic beads in the micro flow channel are not sufficiently regulated, the track regulation of the cells cannot be realized, and the cells still move along the running track of the flow field, the magnetically labeled cells are detected at the residual liquid outlet 10, as shown in fig. 9 (a) of fig. 9; however, no magnetic particles or magnetic labeled cells could be detected at the magnetic separation outlet 9, as shown in FIG. 9 (b).
In conclusion, the regulation and control method can realize the accurate regulation and control of high-flux accurate two-dimensional wall-sticking-preventing magnetic beads-cell track magnetism.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. A quasi-two-dimensional cell track magnetic regulation method is characterized by comprising the following steps:
introducing a fluid to be sorted containing magnetic bead marked cells into a micro-channel of a quasi-two-dimensional cell track magnetic regulation chip from a sample inlet; in the quasi-two-dimensional cell track magnetic regulation chip, soft magnetic strips parallel to a micro-channel are respectively arranged on the upper side and the lower side of the plane where the micro-channel is located, and an included angle theta is formed between the regulation boundary of the soft magnetic strips and a non-magnetic fluid flowing in the micro-channel along the direction from a sample inlet to a residual liquid outlet; wherein theta is more than 0 degree and less than or equal to 90 degrees;
starting an external uniform magnetic field to magnetize the soft magnetic strips on two sides
Magnetic flux density B to external uniform magnetic field and flow velocity v of fluid entering micro-channel f Adjusting to enable the magnetic bead labeled cells to run along the regulation boundary at the regulation boundary and be parallel to the soft magnetic strip; wherein k =95403.3mT · s 2 /mm 2 ，B 0 ＝21.6mT。
2. The control method according to claim 1, further comprising the step of adjusting the magnetic flux density within a range of B ± 15% when the external uniform magnetic field is adjusted at a fixed flow rate; the adjustment is preferably performed within a range of B + -10% of the magnetic flux density.
3. The method of claim 1 or 2, wherein the flow rate v is f 0.012-0.035 mm/s, the magnetic flux density B is 25-80 mT; preferably, said flow velocity v f 0.015 to 0.025mm/s, and the magnetic flux density B is 32 to 55mT.
4. The regulation and control method according to any one of claims 1 to 3, wherein the regulation and control boundary is any one of or a combination of oblique lines, arc lines, straight lines and broken lines.
5. A regulation and control method according to any one of claims 1 to 4, characterized in that the angle θ is from 20 ° to 45 °.
6. The method for controlling according to any one of claims 1 to 5, wherein the cells labeled with magnetic beads are prepared by: and incubating the magnetic bead solution and the cell solution to be marked in a buffer solution environment to obtain the magnetic bead marked cells after the magnetic bead marking of the cells to be marked.
7. The method according to claim 6, wherein the concentration of the solution of the cells to be labeled is 1 to 2.5X 10 5 Per mL;
and/or the ratio of the number of the magnetic beads to the number of the cells to be marked is as follows: 4 to 10;
and/or, incubating for 30-40 min at 35-40 ℃;
and/or the dosage ratio of the buffer solution to the cell solution to be marked is 5:1-8:1.
8. A quasi-two-dimensional cell track magnetic regulation system is characterized in that the quasi-two-dimensional cell track magnetic regulation system is used for the quasi-two-dimensional cell track magnetic regulation method according to any one of claims 1 to 7, and comprises a quasi-two-dimensional cell track magnetic regulation chip, an external uniform magnetic field and a fluid injection device;
the quasi-two-dimensional cell track magnetic regulation chip comprises: soft magnetic strips parallel to the micro-channel are respectively arranged on the upper side and the lower side of the plane where the micro-channel is located, and the soft magnetic strips on the upper side and the lower side are the same in size and shape and are aligned in position; the flow field of the micro flow channel sequentially comprises a liquid inlet, a regulation and control area and a liquid outlet along the flow direction of fluid; the liquid inlet comprises a sample inlet; the liquid outlet comprises a magnetic separation outlet and a residual liquid outlet; the flow direction of fluid between the sample inlet and the residual liquid outlet is the non-magnetofluid flow direction in the flow field, and an included angle is formed between the sample inlet and the magnetic separation outlet and the non-magnetofluid flow direction; the soft magnetic strip is arranged at the position of the regulation area, a regulation and control boundary extending from the adjacent sample inlet to the adjacent magnetic separation outlet is arranged on the soft magnetic strip, the included angle between the regulation and control boundary and the non-magnetic fluid flowing direction is theta, and theta is larger than 0 degree and is less than or equal to 90 degrees;
the fluid injection device is communicated with the sample inlet and is used for introducing a fluid to be sorted containing magnetic bead labeled cells into the micro-channel;
the external uniform magnetic field is used for magnetizing the soft magnetic strips on the upper side and the lower side.
9. The control system according to claim 8, wherein the linear distance d between the soft magnetic strips on both sides is less than or equal to 500 μm; wherein the linear distance between the soft magnetic strip and the surface of the micro-channel on the same side is 190-215 μm, and the height of the micro-channel is 50-70 μm;
and/or the ratio of the height to the width of the micro flow channel is 1: (20-40);
and/or the soft magnetic strip is an etched and formed amorphous metal strip with the thickness of 20-50 mu m; more preferably, the material of the amorphous metal strip is at least one of iron oxide, cobalt oxide and nickel oxide;
and/or the micro-channel is formed by laminating and combining two templates, wherein one surface of one template is provided with a micro-channel pattern, and the micro-channel pattern is positioned between the two laminated templates and forms the micro-channel; preferably, the template is a soft template, and more preferably, the material of the soft template is PDMS or PMMA.
10. The regulation system of claim 8, wherein the fluid injection device is a thrust syringe pump; and/or the external source uniform magnetic field is a double-coil Helmholtz coil, the chip is positioned at the centers of the two coils, and each soft magnetic strip is positioned at the axis position of the Helmholtz coil.
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