A composite cell sorting chip
Patent Information
- Application Number
- CN202521772216.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Utility models(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-20
- Publication Date
- 2026-10-09
- Estimated Expiration
- 2035-08-20
AI Technical Summary
[0003]虽然抗体修饰微结构捕获法的特异性和灵敏度均很高，可以实现极高的捕获效率，但其具有局限性，一方面，具有高堵塞风险，当样本中细胞浓度高或存在细胞团块时，微结构区域易发生堵塞，导致流体阻力骤增及系统失效，另一方面，动态范围窄，适用于低浓度样本，高浓度下捕获效率衰减显著
[0021]该复合型细胞分选芯片在微流控芯片中有机结合免疫磁珠修饰技术和特异性抗体修饰的微结构，在微流控芯片的前半段，利用免疫磁珠修饰技术实现大部分靶标细胞的捕获，在微流控芯片的后半段，利用特异性抗体修饰的微柱结构，对剩余的靶标细胞进行捕获，从而实现靶标细胞的高效捕获，并避免流道堵塞。另外，该复合型细胞分选芯片采用永磁体和非晶合金共同构成的磁场源，利用永磁体构建初步的梯度磁场，并通过非晶合金对该磁场及其梯度进行强化，实现局域磁场增强。同时，在微流控芯片中增加鞘液，且采用鞘液和样本同步流动的芯片设计，鞘液和样本共用同一个出口，鞘液构建稳定流动边界，保障样本流动的稳定性，使低流量下流体脉动小，更平稳。
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Figure CN224832641U_ABST
Abstract
Description
Technical Field
[0001] This utility model relates to the field of cell sorting technology, and more specifically, to a composite cell sorting chip. Background Technology
[0002] Microfluidic technology, with its advantages of high throughput, single-cell precision, low sample consumption, and high integration, has become a core tool in biomedical research and clinical diagnosis in the field of cell sorting. Current mainstream microfluidic cell sorting technologies are mainly based on the principle of affinity enrichment, and their implementation methods mainly include: 1. Antibody-modified microstructure capture method: integrating microstructures with surface-modified specific antibodies (such as anti-EpCAM) within a chip, achieving specific capture of target cells (such as circulating tumor cells) through antigen-antibody binding; 2. Immunomagnetic bead sorting method: incubating target cells with immunomagnetic beads (such as Dynabeads) coated with antibodies, and then using an integrated magnetic field to achieve the separation of magnetically labeled cells.
[0003] While antibody-modified microstructure capture methods offer high specificity and sensitivity, achieving extremely high capture efficiency, they also have limitations. Firstly, they carry a high risk of clogging; when cell concentrations are high or cell clumps are present in the sample, the microstructure regions are prone to blockage, leading to a sharp increase in fluid resistance and system failure. Secondly, they have a narrow dynamic range, suitable only for low-concentration samples, with capture efficiency significantly decreasing at high concentrations. Furthermore, immunomagnetic bead sorting methods are limited by labeling efficiency; insufficient antibody specificity or uneven bead coating can result in missed target cells, and they also face bottlenecks in improving cell capture rates. Therefore, a composite cell sorting chip is urgently needed to overcome at least one of the aforementioned problems in existing technologies, achieving high target cell capture rates while avoiding blockage of the chip's internal flow channels. Utility Model Content
[0004] This application provides a composite cell sorting chip to solve at least one of the technical problems in the prior art.
[0005] According to an embodiment of this application, a composite cell sorting chip is provided, comprising:
[0006] A microfluidic chip, wherein a sheath fluid inlet and a sample inlet are provided at a first end along a first direction, and an outlet is provided at a second end along the first direction, wherein the sheath fluid inlet, the sample inlet and the outlet are respectively connected to the fluid channel of the microfluidic chip;
[0007] A micropillar array is disposed on the side of the fluid channel near the outlet;
[0008] A sealing surface that seals the fluid channel;
[0009] A magnetic field source is provided, wherein the sealing surface is disposed between the microfluidic chip and the magnetic field source, and the magnetic field source applies a magnetic force toward the sealing surface to the target cells labeled with magnetic beads in the fluid channel, thereby pulling the target cells toward the sealing surface by the magnetic force;
[0010] Wherein, the first direction is the fluid flow direction of the fluid channel.
[0011] In some embodiments of this application, each micropillar in the micropillar array is a cylindrical structure.
[0012] In some embodiments of this application, the height of each micropillar in the micropillar array is the same as the height of the fluid channel.
[0013] In some embodiments of this application, each micropillar in the micropillar array is modified with a specific antibody.
[0014] In some embodiments of this application, the magnetic field source includes a permanent magnet and a plurality of amorphous alloys. The permanent magnet is disposed away from the sealing surface, and the plurality of amorphous alloys are disposed close to the sealing surface. The plurality of amorphous alloys and the permanent magnet form an alternating stacked structure.
[0015] In some embodiments of this application, the fluid channel includes a central channel, two side transition sections, and an edge connecting section. The two ends of the central channel are integrally connected to one of the two side transition sections. The sample inlet and the outlet are respectively connected to the central channel via the two side transition sections. The sheath fluid inlet is connected to the central channel via the two edge connecting sections.
[0016] In some embodiments of this application, the micropillar array is disposed on the side of the central channel near the outlet, and in the first direction, a plurality of the amorphous alloys are located between the sheath fluid inlet and the micropillar array.
[0017] In some embodiments of this application, the central channel is rectangular in cross-section perpendicular to the second direction, and the two side transition sections are isosceles triangles in cross-section perpendicular to the second direction. The base of the two side transition sections is connected to the short side of the central channel, and the sample inlet and the outlet are respectively connected to the apex of the two side transition sections; wherein, the second direction is perpendicular to the first direction.
[0018] In some embodiments of this application, the two edge connecting segments are respectively connected to the two bottom corners of the two transition segments located on one side of the sample inlet.
[0019] In some embodiments of this application, the edge connecting segment includes a first straight segment, an arc segment, and a second straight segment. The two ends of the first straight segment are respectively connected to the midpoint of the arc segment and the sheath fluid inlet. The two ends of the arc segment are respectively connected to one end of the two second straight segments. The other ends of the two second straight segments are respectively connected to the two bottom corners of the two transition segments located on the side of the sample inlet.
[0020] The beneficial effects of the embodiments of this application are as follows:
[0021] This composite cell sorting chip organically combines immunomagnetic bead modification technology and specific antibody-modified microstructures within a microfluidic chip. In the first half of the microfluidic chip, immunomagnetic bead modification technology captures most target cells. In the second half, specific antibody-modified micropillar structures capture the remaining target cells, achieving highly efficient target cell capture and preventing channel blockage. Furthermore, this composite cell sorting chip employs a magnetic field source composed of permanent magnets and amorphous alloys. The permanent magnets construct an initial gradient magnetic field, which is then enhanced by the amorphous alloy, resulting in localized magnetic field strengthening. Simultaneously, a sheath fluid is added to the microfluidic chip, and a chip design allows for synchronous flow of the sheath fluid and sample. The sheath fluid and sample share a common outlet, and the sheath fluid creates a stable flow boundary, ensuring stable sample flow and minimizing fluid pulsation at low flow rates. Attached Figure Description
[0022] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this utility model. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0023] Figure 1 This is a schematic diagram of the overall structure of a composite cell sorting chip provided in an embodiment of this application;
[0024] Figure 2 A cross-sectional schematic diagram of the fluid channel in a composite cell sorting chip provided in an embodiment of this application;
[0025] Explanation of reference numerals in the attached figures: 1 is a microfluidic chip, 11 is a sheath fluid inlet, 12 is a sample inlet, 13 is an outlet, 14 is a fluid channel, 141 is a central channel, 142 is a transition section on both sides, 143 is an edge connection section, 1431 is the first straight segment, 1432 is an arc segment, 1433 is the second straight segment, 2 is a micropillar array, 21 is a micropillar, 3 is a sealing surface, 4 is a magnetic field source, 41 is a permanent magnet, and 42 is an amorphous alloy. Detailed Implementation
[0026] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this utility model, and not all embodiments. Based on the embodiments of this utility model, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the protection scope of this utility model.
[0027] It should be noted that the terms "comprising" and "having," and any variations thereof, in the embodiments and accompanying drawings of this application are intended to cover non-exclusive inclusion. For example, it may include a series of structures, without being limited to the structures listed, but may optionally include structures not listed, or may optionally include other components inherent to these structures.
[0028] This application discloses a composite cell sorting chip. Detailed descriptions follow.
[0029] Figure 1 and Figure 2 A composite cell sorting chip according to an embodiment of this application is shown. Figure 1 and Figure 2 As shown, the composite cell sorting chip includes: a microfluidic chip 1, a micropillar array 2, a magnetic field source 4, and a sealing surface 3 disposed between the microfluidic chip 1 and the magnetic field source 4.
[0030] The microfluidic chip 1 in this embodiment adopts a chip design with synchronous flow of sheath fluid and sample. Specifically, the microfluidic chip 1 has a sheath fluid inlet 11 and a sample inlet 12 at its first end along the first direction, and an outlet 13 at its second end along the first direction. The sheath fluid inlet 11, sample inlet 12, and outlet 13 are all connected to the fluid channel 14 of the microfluidic chip 1. That is, the microfluidic chip 1 has two inlets, one of which is the sheath fluid inlet 11 and the other is the sample inlet 12, with the two inlets corresponding to the same outlet 13. When this composite cell sorting chip is applied, an external pump is connected to the outlet 13. When the external pump creates a negative pressure at the outlet end, guiding the fluid to flow in the fluid channel 14, the sheath fluid forms a stable flow protection layer on both sides of the sample. Thus, even if the sample parameters change, stable flow dynamics can be maintained, reducing fluid pulsation fluctuations. This solves the technical problems in the prior art, such as the inability to effectively cope with the sudden increase in fluid drag caused by fluid pulsation in the flow channel at low flow rates, and the extremely stringent deviation requirements due to sensitivity to the thickness parameters of the sealing surface.
[0031] In this embodiment, the micropillar array 2 is a group of regular columnar structures constructed within the microfluidic chip 1 using micro / nano fabrication technology. It is positioned on the side of the fluid channel 14 near the outlet 13, specifically a series of regularly arranged micropillars 21 near the outlet of the flow channel layer, for high-throughput sorting. Furthermore, the height of each micropillar 21 in the micropillar array 2 is the same as the height of the fluid channel 14, and the size of the micropillar 21 and the spacing between adjacent micropillars 21 are adjusted according to the cell size in the sample. In addition, each micropillar 21 in the micropillar array 2 is modified with a specific antibody to achieve the capture of target cells.
[0032] In this embodiment, the sealing surface 3 is a functional layer in the microfluidic chip 1 used to seal the fluid channel 14 and prevent leakage or contamination, thereby sealing the fluid channel 14.
[0033] In this embodiment, the magnetic field source 4 is a physical device that generates a magnetic field and provides the magnetic field energy required for sorting. It applies a magnetic force toward the sealing surface 3 to the target cells marked by magnetic beads in the fluid channel 14. The magnetic force pulls the target cells toward the sealing surface 3, and then the target cells are captured under the combined action of magnetic force, friction force, and fluid drag force.
[0034] In this embodiment, the second direction is perpendicular to the first direction. The first direction is the fluid flow direction of the fluid channel 14, and the second direction is the direction of the central axis of the sheath fluid inlet 11, the sample inlet 12, and the outlet 13. It should be noted and understood that the perpendicularity in this embodiment is not absolute and can be 90° ± 10°.
[0035] In some specific embodiments, the magnetic field source 4 includes a permanent magnet 41 and multiple amorphous alloys 42. The permanent magnet 41 is disposed away from the sealing surface 3, and the multiple amorphous alloys 42 are disposed close to the sealing surface 3. The multiple amorphous alloys 42 and the permanent magnet 41 form an alternating stacked structure. The amorphous alloys 42 are used in combination with the permanent magnet 41 as magnetic flux conduction / reinforcing materials to achieve local magnetic field enhancement. The permanent magnet 41 and the amorphous alloys 42 together constitute the magnetic field source 4, which applies a force towards the sealing surface 3 to the target cells labeled with magnetic beads. Under the combined action of magnetic force, friction force, and fluid drag force, the target cells are captured. Among them, the permanent magnet 41 is responsible for constructing the initial gradient magnetic field, and the amorphous alloys 42 utilize their high relative permeability to strengthen the gradient magnetic field, generating an induced magnetic field sufficient to attract and fix the target cells.
[0036] In other specific embodiments, the microfluidic chip 1 adopts a trapezoidal expansion-contraction channel. The fluid channel 14 includes a central channel 141, two side transition sections 142, and an edge connecting section 143. The two ends of the central channel 141 are integrally connected to one of the two side transition sections 142. The sample inlet 12 and the outlet 13 are respectively connected to the two side transition sections 142 and the central channel 141. The sheath fluid inlet 11 is connected to the central channel 141 through the two edge connecting sections 143, so as to achieve smooth flow rate switching through the two side transition sections 142 and synchronous flow of sheath fluid and sample through the edge connecting sections 143.
[0037] Additionally, the micropillar array 2 is located on the side of the central channel 141 near the outlet 13. In the first direction, multiple amorphous alloys 42 are located between the sheath fluid inlet 11 and the micropillar array 2. Simultaneously, the sealing surface 3 on the side of the microfluidic chip 1 where the micropillar array 2 is located also serves as the target cell capture interface. This is a specially functionalized surface area in the microfluidic chip 1 that specifically binds target cells (such as circulating tumor cells, pathogens, etc.) labeled with magnetic beads through physical or chemical action, thereby achieving enrichment or separation from complex samples (such as blood, saliva). The magnetic field source 4 pulls the target cells to the sealing surface 3 and uses friction to fix the target cells. This application organically combines immunomagnetic bead modification technology and specific antibody-modified microstructures in a microfluidic chip 1. In the first half of the microfluidic chip 1, immunomagnetic bead modification technology is used to capture most of the target cells. In the second half of the microfluidic chip 1, specific antibody-modified micropillar structures are used to capture the remaining target cells. Thus, this composite microfluidic chip 1 achieves efficient cell capture and avoids channel blockage. It solves the technical problems of existing antibody-modified microstructure capture methods, which are prone to channel blockage in samples with high concentrations or cell clumps, and immunomagnetic bead sorting methods, which have bottlenecks in improving the target cell capture rate of cell-sorting microfluidic chips.
[0038] Furthermore, the central channel 141 is rectangular in cross-section perpendicular to the second direction, and the two side transition sections 142 are isosceles triangles in cross-section perpendicular to the second direction. The base of the two side transition sections 142 is connected to the short side of the central channel 141. The sample inlet 12 and outlet 13 are respectively connected to the apex corners of the two side transition sections 142. The two edge connecting sections 143 are respectively connected to the two base corners of the two side transition sections 142 located on the side of the sample inlet 12. In addition, the edge connecting section 143 includes a first straight section 1431, an arc section 1432, and a second straight section 1433. The two ends of the first straight section 1431 are respectively connected to the midpoint of the arc section 1432 and the sheath fluid inlet 11. The two ends of the arc section 1432 are respectively connected to one end of the two second straight sections 1433. The other ends of the two second straight sections 1433 are respectively connected to the two base corners of the two side transition sections 142 located on the side of the sample inlet 12. This allows the sheath fluid to form a stable boundary layer inside the chip, ensuring steady-state flow of the sample and minimizing fluid pulsation.
[0039] In summary, this application discloses a composite cell sorting chip that organically combines immunomagnetic bead modification technology and specific antibody-modified microstructures within a microfluidic chip. In the first half of the microfluidic chip, immunomagnetic bead modification technology captures most of the target cells. In the second half, specific antibody-modified micropillar structures capture the remaining target cells, achieving efficient target cell capture and preventing channel blockage. Furthermore, this composite cell sorting chip employs a magnetic field source composed of permanent magnets and amorphous alloys. The permanent magnets construct an initial gradient magnetic field, which is then enhanced by the amorphous alloys to achieve localized magnetic field strengthening. Simultaneously, a sheath fluid is added to the microfluidic chip, and a chip design is adopted where the sheath fluid and sample flow synchronously. The sheath fluid and sample share a common outlet, and the sheath fluid constructs a stable flow boundary, ensuring the stability of sample flow and minimizing fluid pulsation at low flow rates, resulting in smoother flow.
[0040] It will be understood by those skilled in the art that the accompanying drawings are merely schematic diagrams of one embodiment, and the components shown in the drawings are not necessarily essential for implementing this invention. It should also be noted that similar reference numerals and letters in the following drawings denote similar items; therefore, once an item is defined in one drawing, it does not need to be further defined and explained in subsequent drawings.
[0041] In the description of the embodiments of this application, unless otherwise expressly specified and limited, the terms "installation," "connection," and "linking" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art can understand the specific meaning of the above terms in this utility model based on the specific circumstances. Furthermore, in the description of the embodiments of this application, it should be noted that the terms "center," "upper," "lower," "left," "right," "vertical," "horizontal," "inner," and "outer," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this utility model and simplifying the description, and do not indicate or imply that the device or component referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this utility model.
[0042] Finally, it should be noted that the above-described embodiments are merely specific implementations of this utility model, used to illustrate the technical solution of this utility model, and not to limit it. The protection scope of this utility model is not limited thereto. Although this utility model has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that any person skilled in the art can still modify or easily conceive of changes to the technical solutions described in the foregoing embodiments, or make equivalent substitutions for some of the technical features, within the technical scope disclosed in this utility model. These modifications, changes, or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of this utility model, and should all be covered within the protection scope of this utility model. Therefore, the protection scope of this utility model should be determined by the protection scope described in the claims.
Claims
1. A composite cell sorting chip, characterized in that, include: A microfluidic chip, wherein a sheath fluid inlet and a sample inlet are provided at a first end along a first direction, and an outlet is provided at a second end along the first direction, wherein the sheath fluid inlet, the sample inlet and the outlet are respectively connected to the fluid channel of the microfluidic chip; A micropillar array is disposed on the side of the fluid channel near the outlet; A sealing surface that seals the fluid channel; A magnetic field source is provided, wherein the sealing surface is disposed between the microfluidic chip and the magnetic field source, and the magnetic field source applies a magnetic force toward the sealing surface to the target cells labeled with magnetic beads in the fluid channel, thereby pulling the target cells toward the sealing surface by the magnetic force; The magnetic field source includes a permanent magnet and a plurality of amorphous alloys. The permanent magnet is disposed away from the sealing surface, and the plurality of amorphous alloys are disposed close to the sealing surface. The plurality of amorphous alloys and the permanent magnet form an alternating stacked structure. The fluid channel includes a central channel, two side transition sections, and an edge connecting section. The two ends of the central channel are integrally connected to one of the two side transition sections. The sample inlet and the outlet are respectively connected to the central channel through the two side transition sections. The sheath fluid inlet is connected to the central channel through the two edge connecting sections. The micropillar array is disposed on the side of the central channel near the outlet, and in the first direction, a plurality of the amorphous alloys are located between the sheath fluid inlet and the micropillar array; The central channel is rectangular in cross-section perpendicular to the second direction, and the two side transition sections are isosceles triangles in cross-section perpendicular to the second direction. The base of the two side transition sections is connected to the short side of the central channel. The sample inlet and the outlet are respectively connected to the apex of the two side transition sections. The second direction is perpendicular to the first direction. Wherein, the first direction is the fluid flow direction of the fluid channel.
2. The composite cell sorting chip according to claim 1, characterized in that, Each micropillar in the micropillar array is a cylindrical structure.
3. The composite cell sorting chip according to claim 1, characterized in that, The height of each micropillar in the micropillar array is the same as the height of the fluid channel.
4. The composite cell sorting chip according to claim 1, characterized in that, Each micropillar in the micropillar array is modified with a specific antibody.
5. The composite cell sorting chip according to claim 1, characterized in that, The two edge connecting segments are respectively connected to the two bottom corners of the two transition segments located on one side of the sample inlet.
6. The composite cell sorting chip according to claim 5, characterized in that, The edge connecting segment includes a first straight segment, an arc segment, and a second straight segment. The two ends of the first straight segment are respectively connected to the midpoint of the arc segment and the sheath fluid inlet. The two ends of the arc segment are respectively connected to one end of the two second straight segments. The other ends of the two second straight segments are respectively connected to the two bottom corners of the two transition segments located on one side of the sample inlet.