CN109967150B - Inertial micro-fluidic chip for controlling micro-nano particles - Google Patents
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Abstract
The invention discloses an inertial microfluidic chip for controlling micro-nano particles, which comprises an upper substrate and a lower substrate; the upper substrate is provided with a liquid inlet hole, an upper half inlet liquid storage pool, an upper half inertia flow channel, an upper half outlet liquid storage pool and a liquid outlet hole, and the liquid inlet hole and the liquid outlet hole are communicated with the outside; a lower half inlet liquid storage tank, a lower half inertia flow channel and a lower half outlet liquid storage tank are arranged on the lower substrate; the upper half inlet liquid storage pool and the lower half inlet liquid storage pool are overlapped and assembled to form an inlet liquid storage pool, the upper half inertia flow channel and the lower half inertia flow channel are overlapped and assembled to form an inertia flow channel, and the upper half outlet liquid storage pool and the lower half outlet liquid storage pool are overlapped and assembled to form an outlet liquid storage pool; the liquid inlet hole is communicated with the inlet liquid storage pool, the inertia flow channel, the outlet liquid storage pool and the liquid outlet hole in sequence; the width of the flow channel of the inertia flow channel is larger than the height of the flow channel; the inertia runner spatial structure is a bent runner with a step-shaped cross section. The chip has small volume, good control precision, high flux and simple and convenient manufacture.
Description
Technical Field
The invention relates to an inertial microfluidic chip for controlling micro-nano particles, belongs to the field of microfluidics, and can be used for precise control application of micro-nano biological particles, such as precise capture, focusing and separation of micro-nano biological cells.
Background
The portable instant detection instrument has important application value in the aspects of dealing with on-site emergent acute disease diagnosis, malignant disease early screening and prognosis evaluation, promoting personalized medical development and the like, is an important carrier for the health requirements of people, and is highly valued by government departments of various countries in recent years. As a key technology of an instant detection instrument, the microfluidic chip has the advantages of high detection speed, high sensitivity, low cost, good integration and the like, is very suitable for the technical requirements of instant detection, and has become a research hotspot in the field at present.
The precise control (such as capture, focusing, separation and the like) of biological cells is an extremely important key step in the real-time detection pretreatment process, and the sensitivity and reliability of subsequent detection results are directly determined by the efficiency and the precision of sample processing. In view of this, the scholars at home and abroad have conducted a great deal of research and study on the cell manipulation method based on the microfluidic technology, and have reported a series of manipulation technologies based on physical fields such as electricity, magnetism, sound, light, etc. (i.e. active manipulation, such as dielectrophoresis, magnetophoresis, sound tweezers, light tweezers, etc.), manipulation technologies based on the self-structure of the microchannel (i.e. passive manipulation, such as deterministic lateral displacement, micro-barrier filtration, inertial microfluidic, etc.), and manipulation technologies based on active and passive mashup. The real-time controllability of active control is good, but the sample processing flux is low and the operation process is complex; the passive control has higher processing flux and does not need an external physical field, so the passive control has better integration advantage in a miniaturized device.
The inertial microfluidic technology utilizes the fluid inertia effect to induce cells to migrate in the flow channel under the action of inertia force so as to realize accurate control, has the advantages of simple flow channel structure, convenience in operation, high control precision and the like, and is widely concerned by domestic and foreign scholars. However, the fluid inertia effect has strong dependence on the apparent size of cells, and it is difficult to accurately control cells with high concentration and similar size (such as separating and capturing circulating tumor cells in blood), and the accurate acquisition of the cells has great application and scientific value for diagnosis, monitoring and treatment of some serious diseases.
Therefore, the traditional inertial microfluidic technology is broken through, the control performance of the micro-nano biological particles is improved, the biomedical application range of the inertial microfluidic is expanded, a research basis is provided for early screening and prognosis treatment of major diseases, and a technical support is provided for finally realizing industrial application of the inertial microfluidic chip.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects in the prior art, the invention provides the inertial microfluidic chip for controlling the micro-nano particles, which has the advantages of small volume, no need of sheath fluid, good control precision and high flux, and can meet the requirement of precise control application of the micro-nano biological particles.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention relates to an inertial microfluidic chip for controlling micro-nano particles, which comprises an upper substrate and a lower substrate; the upper substrate is provided with a liquid inlet hole, an upper half inlet liquid storage pool, an upper half inertia flow channel, an upper half outlet liquid storage pool and a liquid outlet hole, and the liquid inlet hole and the liquid outlet hole are communicated with the outside and used for leading in and out of micro-nano particle solution; a lower half inlet liquid storage tank, a lower half inertia flow channel and a lower half outlet liquid storage tank are arranged on the lower substrate; the upper half inlet liquid storage pool and the lower half inlet liquid storage pool are overlapped and assembled to form an inlet liquid storage pool, the upper half inertia flow channel and the lower half inertia flow channel are overlapped and assembled to form an inertia flow channel, and the upper half outlet liquid storage pool and the lower half outlet liquid storage pool are overlapped and assembled to form an outlet liquid storage pool; the liquid inlet hole is communicated with the inlet liquid storage pool, the inertia flow channel, the outlet liquid storage pool and the liquid outlet hole in sequence; the width of the flow channel of the inertia flow channel is larger than the height of the flow channel, and the inertia effect of the micro-nano particles in the inertia flow channel is enhanced; the spatial structure of the inertia flow channel is a bent flow channel with a step-shaped cross section, and the inertia flow channel is used for generating an asymmetric secondary flow field effect perpendicular to the main flow direction of the cross section in the inertia flow channel and enhancing the inertia migration regulation and control capability of micro-nano particles; the horizontal relative positions of the upper substrate and the lower substrate can be adjusted, so that the shape and the size of the cross section of the inertial flow channel are changed, and the shape, the direction, the size and the position of the asymmetric secondary flow field are adjusted and controlled.
The relationship between the size of the cross section of the inertial flow channel and the size of the micro-nano particles in the flow channel is as follows:
a/DH＜0.07，a/Dhnot less than 0.07, wherein a is the diameter of the micro-nano particles, and DHHeight of outer wall surface of cross section of inertial flow path, DhIs the height of the inner wall surface of the cross section of the inertia flow passage.
The step type includes an "L" shape or a "Z" shape.
The curved flow passage is of an Archimedes spiral line structure or a periodic sine wave structure.
The inertial microfluidic chip is used for realizing inertial separation of more than two micro-nano particles with different sizes, and the size difference of the two micro-nano particles is within 5 micrometers.
The inertia micro-fluidic chip is made of polydimethylsiloxane, thermoplastic polymer, glass or silica gel.
The beneficial effects produced by the invention are as follows:
the inertial microfluidic chip provided by the invention breaks through a general flow channel structure model of the traditional inertial microfluidic, designs a curved flow channel chip with a novel step-shaped cross section structure (such as an L-shaped section and a Z-shaped section), and generates an asymmetric secondary eddy current effect in the curved flow channel in a direction vertical to the main flow direction of the section; the sizes of the stepped cross section and the curved flow channel structure are changed, namely, the dragging force of the secondary flow borne by the micro-nano particles on any position in the cross section of the curved flow channel can be changed by changing the shape, direction, strength and position of the asymmetric secondary flow vortex.
The micro-nano particles are also under the action of the inertial lift force induced by the wall surface in the curved flow channel, so that the secondary flow dragging force borne by the micro-nano particles is coupled with the inertial lift force, the inertia regulation and control performance of the micro-nano particles can be further refined and improved by adjusting the resultant force of the secondary flow dragging force and the inertial lift force, the inertia control precision of the micro-nano particles can be remarkably improved, and the technical bottleneck problem of the precise separation and control aspect of the symmetric secondary flow effect of the traditional inertial microfluidic on particles with similar sizes is solved.
The chip disclosed by the invention is small in size, free of sheath liquid, good in control precision, high in flux, simple and convenient to manufacture, and has potential application value in the aspects of accurate control such as focusing, capturing and separating of micro-nano particles (such as biological cells).
Drawings
Fig. 1 is a schematic 3D structure of an inertial microfluidic chip;
FIG. 2 is a schematic diagram of a layered substrate 3D structure of an inertial microfluidic chip;
FIG. 3 is a schematic cross-sectional view of an "L" -shaped flow channel of an inertial microfluidic chip;
FIG. 4 is a schematic cross-sectional view of a Z-shaped flow channel of an inertial microfluidic chip;
FIG. 5 is a schematic diagram of a spiral flow channel structure of an inertial microfluidic chip;
FIG. 6 is a schematic diagram of a periodic sine wave flow channel structure of an inertial microfluidic chip;
FIG. 7 is a schematic diagram of a micro-nano biological particle separation experiment platform;
FIG. 8 is a schematic diagram of the random distribution of micro-nano biological particles at the inlet of a spiral flow channel with a Z-shaped cross section;
FIG. 9 is a simulation model diagram of an asymmetric secondary flow field in a spiral flow channel with a Z-shaped cross section;
FIG. 10 is a schematic diagram of inertial separation of micro-nano particles at the outlet of a spiral flow channel;
fig. 11 is a simulation model diagram of a dean flow field in a conventional rectangular cross-section spiral flow channel;
wherein, 1 is an upper substrate, 2 is a lower substrate, 3 is a liquid inlet hole, 4 is an inlet liquid storage tank, 5 is an inertia flow channel, 6 is an outlet liquid storage tank, 7 is a liquid outlet hole, 41 is an upper half inlet liquid storage tank, 42 is a lower half inlet liquid storage tank, 51 is an upper half inertia flow channel, 52 is a lower half inertia flow channel, 61 is an upper half outlet liquid storage tank, and 62 is a lower half outlet liquid storage tank.
Detailed Description
The preferred embodiments of the present invention will be described in conjunction with the accompanying drawings, and it will be understood that they are described herein for the purpose of illustration and explanation and not limitation.
As shown in fig. 1 and 2, the inertial microfluidic chip provided by the invention is composed of an upper substrate 1 and a lower substrate 2, and comprises a liquid inlet hole 3, an inlet liquid storage pool 4, an inertial flow channel 5, an outlet liquid storage pool 6 and a liquid outlet hole 7 which are sequentially communicated. The upper substrate 1 comprises an upper half inlet liquid storage tank 41, an upper half inertia flow channel 51, an upper half outlet liquid storage tank 61, a liquid inlet hole 3 and a liquid outlet hole 7, wherein the liquid inlet hole 3 and the liquid outlet hole 7 are communicated with the outside and used for leading in and leading out micro-nano particle solution; lower substrate 2 contains lower half inlet reservoir 42, lower half inertial flow channel 52 and lower half outlet reservoir 62. The number of the outlet liquid accumulation tanks 6 and the number of the liquid outlet holes 7 are two.
As shown in fig. 3 and 4, the upper half inertial flow passage 51 of the upper substrate 1 and the lower half inertial flow passage 52 of the lower substrate 2 are superposed and assembled together to form an "L" shaped cross section or a "Z" shaped cross section, and the horizontal relative positions of the two substrates are changed, so that the shape and size of the cross section can be effectively adjusted.
As shown in fig. 5 and 6, the inertia flow channel 5 of the inertia microfluidic chip is a curved flow channel, and the curved flow channel may be an archimedean spiral structure or a periodic sine wave structure. In order to generate a strong enough inertia effect for the micro-nano particles in the inertia flow channel 5, the inertia flow channel 5 needs to have a flow channel characteristic with a large aspect ratio, i.e. the flow channel width is larger than the flow channel height. In addition, the relationship between the cross section size of the inertia flow channel 5 and the size of the micro-nano particles in the flow channel needs to satisfy the following inequality:
a/DH＜0.07，a/Dhnot less than 0.07, wherein a is the diameter of the micro-nano particles, and DHHeight of outer wall surface of cross section of inertial flow path, DhIs the height of the inner wall surface of the cross section of the inertia flow passage.
In the embodiment, the inertial microfluidic chip is made of medical-grade PET plastic, has high strength and light transmittance and good biocompatibility, and is a preferred material for the low-cost microfluidic chip. The micro-fluidic chip is manufactured by adopting a micro-injection molding processing technology, and all microstructures on two layers of substrates of the chip can be formed at one time through precise injection molding. And after the substrates are manufactured, putting the two layers of substrates into a positioning tool, and assembling and aligning all the microstructures. And hot-pressing the two layers of substrates by adopting a hot melting process to ensure that the surfaces of the substrates are bonded together due to melting caused by temperature rise, thereby finishing the precise packaging of the chip. The micro-injection molding process can realize the mass production of the micro-fluidic chip.
As shown in fig. 7, the inertial microfluidic chip in this embodiment can be used for precise separation of micro-nano particles of different sizes. Taking the inertial flow channel 5 with an archimedes spiral line structure with an L-shaped cross section as an example, a precision injection pump is used to inject two micrometer particle solutions with different sizes into a micro-fluidic chip (an experimental platform in fig. 7) at a certain flow rate, and the micrometer particle solution enters the inertial flow channel 5 from an inlet liquid storage pool 4 through a liquid inlet hole 3. The microparticle solution is initially randomly distributed in the inlet channel (fig. 8) under the influence of turbulence of the microfluid in the inlet reservoir 4. Because the cross section of the inertial flow channel 5 is L-shaped, the microfluid generates two asymmetric secondary flow vortexes which flow oppositely in the direction perpendicular to the main flow direction of the micrometer particle solution, and the flow field strength of the asymmetric secondary flow vortexes is gradually enhanced from the inner wall surface of the flow channel to the outer wall surface of the flow channel (simulation result in fig. 9), so that the secondary flow dragging force F of the secondary flow vortexes acting on the micrometer particles is enabled to be generatedDAnd correspondingly changes along with the difference of the cross section positions, namely the dragging force of the secondary flow on the micron particles close to the outer wall surface of the flow channel is larger than the dragging force of the secondary flow on the micron particles at the inner wall surface of the flow channel. Because the micro-particles are also in the inertia flow channel 5Receives inertial lift force F from the wall surface of the flow passageLAnd the shape, direction, strength and position of the asymmetric secondary flow vortex can be adjusted by designing the L-shaped cross section of the spiral flow channel 5 and the optimized structure of the flow channel. Through accurately regulating and controlling the dragging force and the inertial lift force of the secondary flow, the micron particles with different sizes are subjected to different coupling forces of the dragging force and the inertial lift force of the secondary flow, namely, the small-size particles are mainly guided by the strong dragging force of the secondary flow and are trapped at a strong vortex position close to the outer wall surface of the flow channel, and the large-size particles are mainly guided by the strong inertial lift force and are focused on the inner wall surface of the flow channel, so that the accurate separation of the two kinds of particles with different sizes at the outlet of the flow channel is realized (figure 10).
In contrast, this example simulates the fluid movement in a conventional rectangular cross-section spiral flow channel, and the simulation model is shown in fig. 11. Because the section of the flow channel is rectangular, the microfluid generates two symmetrical and parallel secondary flow vortexes which are the dean flow effect in the direction vertical to the main flow direction. Because the flow field intensity of the dean flow in the vertical direction of the flow channel is equal, the secondary flow drag force generated when the dean flow acts on the micro-nano particles lacks flexibility, and the inertial focusing migration capability of the micro-nano particles cannot be further improved, so that the traditional rectangular-section spiral flow channel has poor control precision in the aspect of dealing with the separation application of biological cells with similar sizes. By adopting the spiral flow channel structure with the L-shaped cross section in the embodiment, a significant asymmetric secondary flow vortex effect can be generated in the inertial flow channel 5, and the spiral flow channel structure can be used for accurately separating biological cells with similar sizes, such as separating blood cells and circulating tumor cells (the size difference is about 5 μm) in blood, and is expected to provide technical support for early screening and prognosis diagnosis and treatment of malignant tumors.
In conclusion, the inertial microfluidic chip provided by the embodiment has accurate micro-nano particle inertia control performance, does not need sheath fluid supply, is small in size, simple and convenient to operate, and high in flux, can be used for control applications such as efficient capture, focusing and separation of micro-nano biological cells, and has wide application value in aspects such as integrated microfluidic chip laboratories and portable real-time detection instruments.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (5)
1. The utility model provides an inertia micro-fluidic chip for controlling micro-nano particle which characterized in that: comprises an upper substrate (1) and a lower substrate (2); the upper substrate (1) is provided with a liquid inlet hole (3), an upper half inlet liquid storage tank (41), an upper half inertia flow channel (51), an upper half outlet liquid storage tank (61) and a liquid outlet hole (7), and the liquid inlet hole (3) and the liquid outlet hole (7) are communicated with the outside and used for leading in and out of micro-nano particle solution; a lower half inlet liquid storage tank (42), a lower half inertia flow channel (52) and a lower half outlet liquid storage tank (62) are arranged on the lower substrate (2); the upper half inlet liquid storage pool (41) and the lower half inlet liquid storage pool (42) are assembled in an overlapping mode to form an inlet liquid storage pool (4), the upper half inertia flow channel (51) and the lower half inertia flow channel (52) are assembled in an overlapping mode to form an inertia flow channel (5), and the upper half outlet liquid storage pool (61) and the lower half outlet liquid storage pool (62) are assembled in an overlapping mode to form an outlet liquid storage pool (6); the liquid inlet hole (3) is sequentially communicated with an inlet liquid storage pool (4), an inertia flow channel (5), an outlet liquid storage pool (6) and a liquid outlet hole (7); the width of the inertial flow channel (5) is larger than the height of the flow channel, and the inertial flow channel is used for enhancing the inertial effect of the micro-nano particles in the inertial flow channel (5); the spatial structure of the inertia flow channel (5) is a bent flow channel with a step-shaped cross section, an upper half inertia flow channel (51) of the upper substrate (1) and a lower half inertia flow channel (52) of the lower substrate (2) are overlapped and assembled together to form an L-shaped cross section or a Z-shaped cross section, so that an asymmetric secondary flow field effect perpendicular to the main flow direction of the cross section is generated in the inertia flow channel (5), and the inertia migration regulation and control capability of micro-nano particles is enhanced; the horizontal relative positions of the upper substrate (1) and the lower substrate (2) can be adjusted, so that the shape and the size of the cross section of the inertial flow channel (5) are changed, and the shape, the direction, the size and the position of the asymmetric secondary flow field are adjusted and controlled.
2. The inertial microfluidic chip for manipulating micro-nano particles of claim 1, wherein: the relationship between the cross section size of the inertia flow channel (5) and the size of the micro-nano particles in the flow channel is as follows:
a/DH is less than 0.07, a/Dh is more than or equal to 0.07, wherein a is the diameter of the micro-nano particles, DH is the height of the outer wall surface of the cross section of the inertia flow channel, and Dh is the height of the inner wall surface of the cross section of the inertia flow channel.
3. The inertial microfluidic chip for manipulating micro-nano particles of claim 1, wherein: the curved flow passage is of an Archimedes spiral line structure or a periodic sine wave structure.
4. The inertial microfluidic chip for manipulating micro-nano particles of claim 1, wherein: the inertial microfluidic chip can be used for realizing inertial separation of more than two micro-nano particles with different sizes, and the size difference of the two micro-nano particles is within 5 micrometers.
5. The inertial microfluidic chip for manipulating micro-nano particles of claim 1, wherein: the inertia micro-fluidic chip is made of polydimethylsiloxane, thermoplastic polymer, glass or silica gel.
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| CN110465339B (en) * | 2019-09-03 | 2021-02-09 | 浙江大学 | Method for positioning particles in fluid-solid two-phase transportation |
| CN110975775A (en) * | 2019-10-29 | 2020-04-10 | 肇庆市华师大光电产业研究院 | High-flux three-dimensional microfluid mixing device based on dean flow effect and mixing method thereof |
| CN110975948A (en) * | 2019-11-06 | 2020-04-10 | 佛山市铬维科技有限公司 | Micro-fluidic cell counter |
| CN111744565B (en) * | 2020-05-26 | 2022-03-08 | 东南大学 | Microfluidic device and system for multi-channel parallel detection of cell deformability |
| CN111774108B (en) * | 2020-06-19 | 2021-11-12 | 东南大学 | Wall surface separation type spiral micro-fluidic chip |
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| CN112547145B (en) * | 2020-11-19 | 2022-04-12 | 东南大学 | Rare cell rapid screening micro-fluidic device |
| WO2022138525A1 (en) * | 2020-12-21 | 2022-06-30 | 株式会社Ihi | Solid-liquid separation device and solid-liquid separation system |
| CN114798014A (en) * | 2021-01-29 | 2022-07-29 | 广州万孚生物技术股份有限公司 | Biological particle sorting flow channel and micro-fluidic chip |
| CN112509724B (en) * | 2021-02-03 | 2021-04-27 | 之江实验室 | Method and device for supporting optical trap particles |
| CN114534809B (en) * | 2022-02-25 | 2023-12-01 | 河海大学常州校区 | Microfluidic particle control device with adjustable cross section shape and particle control method |
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| CN107058060B (en) * | 2017-04-10 | 2019-06-21 | 东南大学 | A kind of tumour cell high throughput sorting enrichment micro-fluidic chip |
| CN107164213A (en) * | 2017-04-21 | 2017-09-15 | 华中科技大学 | One kind is based on the cellifugal chip of principle of inertia point |
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