A microfluidic device for precisely separating micro-nano particles and its control method

Abstract

The present invention discloses a microfluidic device for precisely separating micro-nano particles and a control method thereof. The device includes a cover plate, a microfluidic chip, and a bottom plate. Magnets are respectively arranged between the microfluidic chip and the cover plate and between the microfluidic chip and the bottom plate. The cover plate is provided with an inlet hole and an outlet hole penetrating through both plate surfaces of the cover plate. On the plate surface of the cover plate close to the bottom plate, there is an upper chip groove for installing the upper half of the microfluidic chip, and an upper magnet groove for installing a magnet is provided at the bottom of the upper chip groove. An inertial flow channel is arranged in the microfluidic chip. One end of the inertial flow channel is provided with a liquid inlet hole communicated with the inlet hole, and the other end is provided with a liquid outlet hole communicated with the outlet hole. On the plate surface of the bottom plate close to the cover plate, there is a lower chip groove for installing the lower half of the microfluidic chip, and a lower magnet groove for installing a magnet is provided at the bottom of the lower chip groove. When the present invention controls micro-nano particles, high-throughput and precise separation are realized by utilizing the action of inertial force, secondary flow drag force, and magnetic force on the particles, and it has the advantages of high control precision and convenient operation.

Description

Technical Field

[0001] The present invention belongs to the technical field of microfluidics, and relates to a microfluidic device for precisely separating micro-nano particles and a control method thereof. Background Art

[0002] Portable point-of-care testing instruments have important application values in dealing with on-site diagnosis of acute diseases, early screening and prognosis evaluation of malignant diseases, and promoting the development of personalized medicine. They are important carriers for meeting the needs of people's livelihood and health, and have been highly valued by government departments of various countries in recent years. As a key technology of point-of-care testing instruments, microfluidic chips have the advantages of fast detection speed, high sensitivity, low cost, good integration, etc., which are very suitable for the technical requirements of point-of-care testing. At present, they have become a research hotspot in this field.

[0003] Precise manipulation of biological cells (such as capture, focusing, and separation, etc.) is an extremely important key step in the preprocessing link of point-of-care testing. Its efficiency and accuracy of sample processing directly determine the sensitivity and reliability of subsequent detection results. Therefore, scholars at home and abroad have conducted a large number of exploratory studies on cell manipulation methods based on microfluidic technology, and reported a series of manipulation technologies based on physical fields such as electricity, magnetism, sound, and light (i.e., active manipulation, such as dielectrophoresis, magnetophoresis, acoustic tweezers, optical tweezers, etc.), manipulation technologies based on the structure of microchannels themselves (i.e., passive manipulation, such as deterministic lateral displacement, micro-barrier filtration, inertial microfluidics, etc.), and manipulation technologies based on the combination of active and passive. Active manipulation has good real-time controllability, but the sample processing throughput is relatively low and the operation process is relatively complex; while passive manipulation has a higher processing throughput and does not require an external physical field, so it has better integration advantages in miniaturized devices.

[0004] Among them, inertial microfluidic technology uses the fluid inertia effect to induce cells to migrate under the action of inertial force in the microchannel to achieve precise manipulation, and has the advantages of simple microchannel structure, convenient operation, high manipulation accuracy, etc., and has received extensive attention from scholars at home and abroad. However, the fluid inertia effect has a strong dependence on the appearance size of cells, and it is difficult to precisely manipulate cells with high concentration and similar sizes (such as separating and capturing circulating tumor cells in blood), and the precise acquisition of such cells has great application and scientific value for the diagnosis, monitoring and treatment of some major diseases.

[0005] Therefore, breaking through traditional inertial microfluidic technology, improving the manipulation performance of micro-nano biological particles, and expanding the biomedical application scope of inertial microfluidics will provide a research basis for the early screening and prognosis treatment of major diseases, and provide technical support for the ultimate realization of the industrial application of inertial microfluidic chips. Summary of the Invention

[0006] The object of the present invention is to overcome the deficiencies in the prior art and provide a microfluidic device for precisely separating micro-nano particles and a control method thereof. The device is small in size, good in control precision, high in throughput, and can meet the precise control of micro-nano biological particles.

[0007] To achieve the above object, the present invention is implemented by the following technical solutions:

[0008] A microfluidic device for precisely separating micro-nano particles, including a cover plate, a microfluidic chip for high-throughput separation of micro-nano particles, and a bottom plate. Magnets for precisely separating magnetic micro-nano particles and non-magnetic micro-nano particles are provided between the microfluidic chip and the cover plate and the bottom plate respectively;

[0009] An inlet hole and an outlet hole penetrating through both plate surfaces of the cover plate are provided on the cover plate. An upper chip groove for installing the upper half of the microfluidic chip is provided on the plate surface of the cover plate close to the bottom plate, and an upper magnet groove for installing the magnet is provided at the bottom of the upper chip groove;

[0010] An inertial flow channel is provided in the microfluidic chip. A liquid inlet hole communicated with the inlet hole is provided at one end of the inertial flow channel, and a liquid outlet hole communicated with the outlet hole is provided at the other end;

[0011] A lower chip groove for installing the lower half of the microfluidic chip is provided on the plate surface of the bottom plate close to the cover plate, and a lower magnet groove for installing the magnet is provided at the bottom of the lower chip groove.

[0012] Optionally, an inlet liquid storage cavity is provided between the inertial flow channel and the liquid inlet hole, and an outlet liquid storage cavity is provided between the inertial flow channel and the liquid outlet hole.

[0013] Optionally, the inertial flow channel is in an Archimedean spiral shape, and the cross-section of the inertial flow channel gradually decreases from the inlet liquid storage cavity to the outlet liquid storage cavity.

[0014] Optionally, the channel wall of the inertial flow channel is in an inwardly convex shape, and the width of the inertial flow channel is greater than the height of the inertial flow channel.

[0015] Optionally, the number of the liquid inlet holes is at least one; the number of the liquid outlet holes is at least two.

[0016] Optionally, the magnet is a permanent magnet and is in a ring shape.

[0017] Optionally, the magnetization direction of the magnet includes radial magnetization, axial magnetization or circumferential magnetization.

[0018] Optionally, the material of the magnet includes one or more of neodymium iron boron magnet, samarium cobalt magnet, alnico magnet, ferrite magnet.

[0019] Optionally, the material of the microfluidic chip includes polydimethylsiloxane, polyethylene terephthalate, polyvinyl chloride.

[0020] A method for controlling a microfluidic device for precisely separating micro- and nano-particles, comprising the following steps:

[0021] Inject the micro- and nano-particle solution into the inlet hole, and enter the inertial flow channel through the liquid inlet hole. Two counter-flowing asymmetric secondary flow vortices are generated in the inertial flow channel in a direction perpendicular to the main flow direction of the micro- and nano-particle solution. The flow field intensity of the asymmetric secondary flow vortices is weak in the middle and strong at both ends. The secondary flow drag force acting on the micro- and nano-particles changes with the cross-sectional position;

[0022] The micro- and nano-particles are subjected to the inertial lift force from the wall of the inertial flow channel in the inertial flow channel. Large-sized particles are focused on the inner wall of the inertial flow channel by the strong inertial lift force, and small-sized particles are focused on the outer wall of the inertial flow channel by the strong secondary flow drag force, realizing high-throughput separation of particles of different sizes; the micro- and nano-particles contain magnetic particles. During the inertial separation process, the magnetic particles are subjected to a strong magnetic force in the inertial flow channel and migrate to the outer wall close to the inertial flow channel, and move along the outer wall of the inertial flow channel at the outlet hole.

[0023] Compared with the prior art, the beneficial effects achieved by the present invention are:

[0024] The present invention provides a microfluidic device for precisely separating micro- and nano-particles and a method for controlling the same, which combines inertial microfluidics technology with magnetic field control technology; the inertial microfluidic chip is used for high-throughput inertial focusing separation of micro- and nano-particles, and the magnet is used for precise magnetic force control separation of magnetic micro- and nano-particles; the inertial effect of the inertial microfluidic chip can achieve separation of particles with large size differences, and the magnetic field generated by the magnet can separate magnetic particles from non-magnetic particles.

[0025] The present invention can perform manipulation of micro- and nano-biological particles, improve the ability of the chip to manipulate micro- and nano-biological particles, and expand the application range of particle manipulation.

[0026] The device of the present invention has the advantages of small volume, high control precision, high throughput, and simple fabrication. Description of the Drawings

[0027] Figure 1 is an exploded view of a microfluidic device for precisely separating micro- and nano-particles of the present invention;

[0028] Figure 2 is a schematic structural view of the cover plate of a microfluidic device for precisely separating micro- and nano-particles of the present invention;

[0029] Figure 3 is a schematic structural view of the magnet of a microfluidic device for precisely separating micro- and nano-particles of the present invention;

[0030] Figure 4 It is a schematic structural diagram of a microfluidic chip of a microfluidic device for precisely separating micro-nano particles according to the present invention;

[0031] Figure 5 It is a schematic structural diagram of the bottom plate of a microfluidic device for precisely separating micro-nano particles according to the present invention;

[0032] Figure 6 It is a schematic diagram of the distribution of micro-nano biological particles at the end of the inertial flow path close to the liquid inlet hole of a microfluidic device for precisely separating micro-nano particles according to the present invention;

[0033] Figure 7 It is a schematic diagram of the distribution of micro-nano biological particles at the end of the inertial flow path close to the liquid outlet hole of a microfluidic device for precisely separating micro-nano particles according to the present invention;

[0034] Figure 8 It is a simulation result diagram of the magnetic flux magnitude of the magnet of a microfluidic device for precisely separating micro-nano particles according to the present invention;

[0035] Figure 9 It is the experimental result of 15 µm magnetic particles and 15 µm non-magnetic particles in a microfluidic chip without a magnetic field;

[0036] Figure 10 It is the experimental result of 15 µm magnetic particles and 15 µm non-magnetic particles in a microfluidic chip with a magnetic field.

[0037] Wherein: 1. Cover plate; 11. Inlet hole; 12. Outlet hole; 13. Upper magnet groove; 14. Upper chip groove; 2. Magnet; 3. Microfluidic chip; 31. Liquid inlet hole; 32. Inlet liquid storage cavity; 33. Inertial flow path; 34. Liquid outlet hole; 35. Outlet liquid storage cavity; 4. Bottom plate; 41. Lower chip groove; 42. Lower magnet groove. Embodiment

[0038] The present invention will be further described below with reference to the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and cannot be used to limit the protection scope of the present invention.

[0039] In the description of the present invention, it should be understood that the orientation or positional relationship indicated by the terms "center", "longitudinal", "transverse", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", etc. is based on the orientation or positional relationship shown in the drawings, and is only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and thus should not be construed as a limitation on the present invention. In addition, the terms "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first", "second", etc. may explicitly or implicitly include one or more of such features. In the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0040] In the description of the present invention, it should be noted that unless otherwise clearly specified and limited, the terms "mounted", "connected", and "coupled" should be understood in a broad sense. For example, it may be a fixed connection, a detachable connection, or an integral connection; it may be a mechanical connection or an electrical connection; it may be directly connected or indirectly connected through an intermediate medium, and it may be the communication inside two elements. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood through specific circumstances. Embodiment

[0041] As Figures 1 to 10 As shown, a microfluidic device for precisely separating micro-nano particles includes a cover plate 1, a microfluidic chip 3 for high-throughput separation of micro-nano particles with large size differences, and a bottom plate 4. A magnet 2 for precisely separating magnetic micro-nano particles from non-magnetic micro-nano particles is provided between the microfluidic chip 3 and the cover plate 1 and the bottom plate 4 respectively; the magnet 2 is a ring-shaped permanent magnet, and the magnetization direction of the magnet 2 includes radial magnetization, axial magnetization or circumferential magnetization. The material of the magnet 2 includes one or more of neodymium iron boron magnets, samarium cobalt magnets, alnico magnets, and ferrite magnets.

[0042] The cover plate 1 is provided with an inlet hole 11 and an outlet hole 12 penetrating through both plate surfaces of the cover plate 1. On the plate surface of the cover plate 1 close to the bottom plate 4, an upper chip groove 14 for installing the upper half of the microfluidic chip 3 is provided, and an upper magnet groove 13 for installing the magnet 2 is provided at the bottom of the upper chip groove 14.

[0043] The microfluidic chip 3 is provided with an inertial flow channel 33. At one end of the inertial flow channel 33, there are two liquid inlet holes 31 communicating with the inlet hole 11, and at the other end, there are two liquid outlet holes 34 communicating with the outlet hole 12. An inlet liquid storage cavity 32 is provided between the inertial flow channel 33 and the liquid inlet hole 31, and an outlet liquid storage cavity 35 is provided between the inertial flow channel 33 and the liquid outlet hole 34. The lower channel wall of the inertial flow channel 33 is convex inward, and the cross-section of the inertial flow channel 33 gradually decreases from the inlet liquid storage cavity 32 to the outlet liquid storage cavity 35. The inertial flow channel 33 is in the shape of an Archimedean spiral, and the width of the inertial flow channel is 2 to 10 times the height of the inertial flow channel. The material of the microfluidic chip 3 is polydimethylsiloxane.

[0044] On the surface of the bottom plate 4 close to the cover plate 1, there is a lower chip groove 41 for installing the lower half of the microfluidic chip 3, and at the bottom of the lower chip groove 41, there is a lower magnet groove 42 for installing the magnet 2. Embodiment

[0045] As Figures 1 to 10 shown, based on the microfluidic device for precisely separating micro-nano particles described in Embodiment 1, this embodiment provides a control method for the microfluidic device for precisely separating micro-nano particles, including the following steps:

[0046] S1, Inject the micro-nano particle solution into the inlet hole 11, and enter the inertial flow channel 33 from the inlet liquid storage cavity 32 through the liquid inlet hole 31. Affected by the turbulent flow of the microfluid in the inlet liquid storage cavity 32, the micron particles move closely along the outer wall surface in the inertial flow channel 33 at the inlet. As Figure 6 , the inertial flow channel 33 generates two counter-flowing asymmetric secondary flow vortices in the direction perpendicular to the main flow direction of the micro-nano particle solution, and the flow field intensity of the asymmetric secondary flow vortices is weak in the middle and strong at both ends, so that the secondary flow drag force acting on the micro-nano particles changes with the cross-sectional position;

[0047] S2, Due to the inertial lift force acting on the micro-nano particles from the wall surface of the inertial flow channel 33, the large-sized particles are focused on the inner wall surface of the inertial flow channel by the strong inertial lift force, and the small-sized particles are focused on the outer wall surface of the inertial flow channel 33 by the strong secondary flow drag force, realizing the high-throughput separation of particles of different sizes; at the same time, the micro-nano particle solution contains magnetic particles. During the inertial separation process, the magnetic particles are affected by a strong magnetic force in the inertial flow channel 33. As the magnetic micron particles gradually move towards the outer circle of the inertial flow channel 33, the magnetic force gradually increases. As Figure 8 , the magnetic micron particles gradually migrate towards the outer wall surface of the inertial flow channel 33, and finally move closely along the outer wall surface of the inertial flow channel 33 at the liquid outlet hole 34. As Figure 7 , through the combined action of the inertial microfluidic chip and the magnet, the precise separation of three kinds of micron particles is realized.

[0048] To verify the effect of the combined action of inertia and magnetic field, two types of microparticles were used in this embodiment for experiments, namely 15-µm magnetic polystyrene microparticles and 15-µm non-magnetic polystyrene microparticles. As Figure 9 shown, in this experimental scenario, no magnetic field was added, and the microparticles were subjected to the coupled action of inertial lift and Dean drag in the inertial microchannel. Due to the relatively large particle size of the microparticles, the microparticles were mainly affected by the inertial lift force in the inertial microchannel and focused near the inner wall surface, and the separation of the two types of microparticles could not be achieved. When a magnetic field was added to the experimental scenario, the 15-µm magnetic polystyrene microparticles were affected by the magnetic field force and moved towards the outer wall surface of the microchannel, while the 15-µm non-magnetic polystyrene microparticles always focused on the inner wall surface of the microchannel, and finally, the precise separation of the two types of microparticles was achieved at the outlet of the microchannel.

[0049] In summary, a microfluidic device for precisely separating micro-nano particles proposed in this embodiment is small in volume, simple to operate, high in throughput and accuracy, and can be used for efficient capture, focusing, separation and other manipulation applications of micro-nano biological cells, and has broad application value in aspects such as integrated microfluidic chip laboratories and portable point-of-care testing instruments.

[0050] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the technical principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A microfluidic device for precisely separating micro-nano particles, characterized in that: It includes a cover plate, a microfluidic chip for high-throughput separation of micro-nano particles, and a bottom plate. Magnets for precise separation of magnetic micro-nano particles and non-magnetic micro-nano particles are provided between the microfluidic chip and the cover plate and between the microfluidic chip and the bottom plate respectively. An inlet hole and an outlet hole penetrating through both plate surfaces of the cover plate are provided on the cover plate. On the plate surface of the cover plate close to the bottom plate, an upper chip groove for installing the upper half of the microfluidic chip is provided, and an upper magnet groove for installing the magnet is provided at the bottom of the upper chip groove. An inertial flow channel is provided in the microfluidic chip. One end of the inertial flow channel is provided with a liquid inlet hole communicated with the inlet hole, and the other end is provided with a liquid outlet hole communicated with the outlet hole. On the plate surface of the bottom plate close to the cover plate, a lower chip groove for installing the lower half of the microfluidic chip is provided, and a lower magnet groove for installing the magnet is provided at the bottom of the lower chip groove. The magnet is a permanent magnet and is in a ring shape.

2. The microfluidic device for precisely separating micro-nano particles according to claim 1, characterized in that: An inlet liquid storage cavity is provided between the inertial flow channel and the liquid inlet hole, and an outlet liquid storage cavity is provided between the inertial flow channel and the liquid outlet hole.

3. The microfluidic device for precisely separating micro-nano particles according to claim 2, wherein: The inertial flow channel is in an Archimedean spiral shape, and the cross-section of the inertial flow channel gradually decreases from the inlet liquid storage cavity to the outlet liquid storage cavity.

4. The microfluidic device for precisely separating micro-nano particles according to claim 1, characterized in that: The wall of the inertial flow channel is in an inwardly convex shape, and the width of the inertial flow channel is greater than the height of the inertial flow channel.

5. The microfluidic device for precisely separating micro-nano particles according to claim 1, characterized in that: The number of the liquid inlet holes is at least one; the number of the liquid outlet holes is at least two.

6. The microfluidic device for precisely separating micro-nano particles according to claim 1, wherein: The magnetization direction of the magnet includes radial magnetization, axial magnetization or circumferential magnetization.

7. The microfluidic device for precisely separating micro-nano particles according to claim 1, characterized in that: The material of the magnet includes one or more of neodymium iron boron magnet, samarium cobalt magnet, alnico magnet, ferrite magnet.

8. The microfluidic device for precisely separating micro-nano particles according to claim 1, wherein: The material of the microfluidic chip includes polydimethylsiloxane, polyethylene terephthalate, polyvinyl chloride.

9. A method for controlling a microfluidic device for precisely separating micro-nano particles according to any one of claims 1 to 8, characterized in that, It includes the following steps: Inject the micro-nano particle solution into the inlet hole, and enter the inertial flow channel through the liquid inlet hole. The inertial flow channel generates two counter-flowing asymmetric secondary flow vortices in the direction perpendicular to the main flow direction of the micro-nano particle solution. The flow field intensity of the asymmetric secondary flow vortices is weak in the middle and strong at both ends. The secondary flow drag force acting on the micro-nano particles changes with the cross-sectional position. The micro-nano particles are subjected to the inertial lift force from the wall surface of the inertial flow channel in the inertial flow channel. Large-sized particles are focused on the inner wall surface of the inertial flow channel by the strong inertial lift force, and small-sized particles are focused on the outer wall surface of the inertial flow channel by the strong secondary flow drag force, realizing high-throughput separation of particles of different sizes. There are magnetic particles in the micro-nano particles. During the inertial separation process, the magnetic particles are subjected to a strong magnetic force in the inertial flow channel and migrate to the outer wall surface close to the inertial flow channel, and move along the outer wall surface of the inertial flow channel at the outlet hole.

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