CN112844501B - Multi-liquid-core hydrogel microcapsule chip based on double aqueous phases and application thereof - Google Patents
Multi-liquid-core hydrogel microcapsule chip based on double aqueous phases and application thereof Download PDFInfo
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Abstract
The invention provides a multi-liquid-core hydrogel microcapsule chip based on an aqueous two-phase system. The chip mainly comprises a core fluid inlet, a shell fluid inlet, a continuous phase inlet, a core fluid shunt port and a shell fluid shunt port, and the middle layer mainly comprises a continuous phase inlet, a continuous phase channel, a core fluid inlet, a shell fluid inlet, a core channel, a shell channel, a laminar flow channel, a main channel, a reaction channel and a fluid outlet. The invention can controllably prepare the multiliquid-core hydrogel microcapsule based on a two-aqueous-phase system. The stable and uniform double-water-phase microcapsule with controllable appearance is obtained by adjusting the core flow velocity, the shell flow velocity, the continuous phase flow velocity and the like. The chip can realize the preparation of various liquid core microcapsules according to the increase of the number of the core channels and the shell channels, wherein the microcapsules can contain more liquid cores such as a single liquid core, a double liquid core, a three liquid core, a four liquid core and the like. The system is expected to play a role in biological applications such as single cell pairing, cell zoning co-culture, controllable drug release and the like.
Description
Technical Field
The invention relates to the technical field of micro-fluidic, in particular to a multi-liquid-core hydrogel microcapsule chip based on double aqueous phases.
Background
Hydrogel microcapsules have attracted wide attention in the fields of biology, pharmacy, material chemistry and the like at present due to the advantages of good biocompatibility, permeability, high load capacity, adjustable responsiveness and the like. The core-shell hydrogel microcapsules are generally prepared from hydrogel materials such as polyethylene glycol, alginate, gelatin methacrylamide and the like by a hanging drop method, a coating method, a droplet microfluid method and the like. Since the microcapsule contains liquid core and hydrogel shell and has excellent biocompatibility and permeability, the microcapsule is widely used in the aspects of cell loading, drug delivery and release, molecular adsorption and the like. However, since the hydrogel microcapsule with a single liquid core is too single in structure, only single loading of a substance can be realized, and partitioned loading of multiple substances is difficult to meet, at present, a document reports that a hydrogel microcapsule containing multiple liquid cores can be prepared by adopting an emulsion polymerization mode, but the defects that the uniformity and stability of the microcapsule prepared by adopting the mode are poor, and the preparation process involves operations such as solvent volatilization or temperature polymerization and the like, and is very mild. Therefore, a simple, flexible and mild method for preparing the multi-liquid-core hydrogel microcapsule is urgently needed.
Microfluidic technology is a technology characterized by precise manipulation of fluids at the micrometer scale. The microfluidic droplet technology is an important branch of the technology, and has the advantages of uniform size, small volume, flexible use and the like, so the technology is widely applied to the fields of biological materials, tissue engineering, regenerative medicine and the like. The ability to achieve the preparation of multiliquid-core hydrogel microcapsules using microfluidic technology remains a challenge. In recent years, the aqueous two-phase system has attracted great attention of researchers. Aqueous two-phase systems, consisting of two different polymers in aqueous solution at concentrations above the critical value, produce spontaneous phase separation when the interaction energy of the system is higher than the gibbs free energy of mixing. The application of the microfluidic technology in the field is widened due to the good biocompatibility of the system. The invention provides a multi-liquid-core hydrogel microcapsule chip based on an aqueous two-phase system.
Disclosure of Invention
The invention aims to provide a multi-liquid-core hydrogel microcapsule chip based on double aqueous phases.
The chip for preparing the multi-liquid-core hydrogel microcapsule is formed by bonding three PDMS chips (an upper layer, a middle layer and a lower layer) which are formed by a conventional soft lithography method, wherein the upper layer adopts a flow dividing design, so that the limitation of simultaneous use of a plurality of pump devices is avoided.
The upper layer of the chip mainly comprises a core fluid inlet, a shell fluid inlet, a continuous phase inlet, a core fluid shunt port and a shell fluid shunt port, the middle layer mainly comprises a continuous phase inlet, a continuous phase channel, a core fluid inlet, a shell fluid inlet, a core channel, a shell channel, a laminar flow channel, a main channel, a reaction channel and a fluid outlet, and the lower layer is a white board without a structure;
the shell fluid shunting port on the upper layer of the chip is communicated with the shell fluid inlet on the middle layer of the chip;
the branch fluid inlet of the shell fluid inlet is a shell fluid shunting port, and the branch fluid inlet of the core fluid inlet is a shell fluid shunting port.
The nuclear fluid enters the nuclear fluid inlet from the nuclear fluid inlet through the nuclear fluid diversion port respectively and flows into the laminar flow channel through the nuclear channel; the shell fluid flows into the laminar flow channel from the shell fluid inlet through the shell fluid shunting port, the shell fluid inlet of the middle layer of the chip and the shell channel respectively; the continuous flow flows into the main channel from the continuous phase inlet through the continuous phase inlet of the middle layer through the continuous phase channel; the core fluid, the shell fluid and the continuous fluid finally pass through the channel and the reaction channel, and the prepared multi-liquid-core hydrogel microcapsule flows out from the fluid outlet and is collected.
The width of the flow channel of the chip layer is 100-600 mu m, and the height is 100-500cm; the width of the main channel is 100-500 μm, the height is 50-500cm, the width of the core and shell channels is 20-200 μm, the height is 20-200 μm, the width of the continuous phase channel is 100-400 μm, and the height is 50-300cm.
The chip can realize the preparation of various liquid core microcapsules according to the increase of the number of the core channels and the shell channels, wherein the microcapsules can contain more liquid cores such as a single liquid core, a double liquid core, a three liquid core, a four liquid core and the like.
The number of the core channels is more than or equal to 1, and the number of the shell channels (8) is more than or equal to 1; realizing the multi-liquid-core hydrogel microcapsule.
The number of liquid cores of the microcapsule is more than or equal to 1.
The three PDMS layers are respectively sealed by plasma treatment for 25s, and channels are subjected to hydrophobic treatment by 1H, 2H-perfluorooctyltrichlorosilane; the concentration of the 1H,2H and 2H-perfluoro octyl trichlorosilane is 0.5-5%, and the treatment time is 20-60min.
The core of the multi-liquid-core hydrogel microcapsule is aqueous solution, and the shell is hydrogel.
The multi-liquid-core hydrogel microcapsule is prepared based on a double aqueous phase system, the selected material has biocompatibility and stability, the core is dextran (Dex), and the shell is polyethylene glycol (PEG); the molecular weight range of PEG is as follows: 8-20kDa, concentration range: 10 to 30 percent; dex molecular weight range: 70k-500kDa, concentration range: 10 to 40 percent;
in order to produce the multi-liquid-core hydrogel microcapsule, hydrogel prepolymer can be mixed into shell fluid, and the materials are sodium alginate (NaA) and ethylene diamine tetraacetic acid calcium disodium (Ca-EDTA), wherein the NaA is used in the viscosity range: 55-400 cps, concentration range: 0.1-2%, the concentration range used for Ca-EDTA is: 0.1-2%, adding acetic acid (HAc) into the shell fluid continuous phase, wherein the use concentration range is 0.05-0.25%, adding Span 80 into the continuous phase to enlarge the oil-water interface and facilitate the formation of stable liquid drops, wherein the concentration range of the Span 80 is 1-5%, and calcium chloride (CaCl) is used for a collecting pool 2 ) An aqueous solution with a concentration range of 0.5-4%;
the core fluid, the shell fluid and the continuous phase fluid are respectively introduced into the microfluidic chip from the core fluid inlet, the shell fluid inlet and the continuous phase fluid inlet, and the size of the multi-liquid-core hydrogel microcapsule, including the size of the liquid core and the whole size of the microcapsule, is adjusted by changing the core flow rate, the shell flow rate and the continuous phase flow rate; nuclear flow rate range: 0.01-2.0 μ L/min, shell flow rate range: 1-10 μ L/min, continuous phase flow rate range: 10-60 mu L/min. The invention is combined with the micro-fluidic technology, thereby realizing the flexibility of chip design; provides a new technical means for preparing the multi-liquid core hydrogel micro-gel with excellent biocompatibility. The vesicle process is simple, and the conditions are mild; the multi-liquid core hydrogel microcapsule with uniform size and controllable appearance can be obtained by adjusting the flow rate of the core fluid, the shell fluid, the continuous flow and the like, and the problems of poor uniformity and stability and extremely mild preparation conditions of the prepared microcapsule reported by the existing literature are avoided; in addition, the preparation of the multi-liquid-core hydrogel microcapsule also provides a technical means for cell zoning culture, drug co-loading and other biological applications.
Drawings
FIG. 1 is a schematic diagram of a biliquid core hydrogel microencapsulation chip.
Wherein 1 is upper continuous phase inlet, 2 shell fluid inlet, 3 nuclear fluid inlet, 4 nuclear fluid shunt ports, 5 shell fluid shunt ports, 6 middle continuous phase inlet, 7 middle shell fluid inlet, 8 shell channel, 9 middle nuclear fluid inlet, 10 nuclear channel, 11 continuous phase channel, 12 laminar flow channel, 13 main channel, 14 reaction channel, 15 fluid outlet.
FIG. 2 is a schematic diagram of the preparation of a three-liquid core hydrogel microencapsulation chip.
Wherein 1 is upper continuous phase inlet, 2 shell fluid inlet, 3 nuclear fluid inlet, 4 nuclear fluid shunt ports, 5 shell fluid shunt ports, 6 middle continuous phase inlet, 7 middle shell fluid inlet, 8 shell channel, 9 middle nuclear fluid inlet, 10 nuclear channel, 11 continuous phase channel, 12 laminar flow channel, 13 main channel, 14 reaction channel, 15 fluid outlet.
FIG. 3 is a schematic diagram of the preparation of a four liquid core hydrogel microencapsulation chip.
Wherein 1 is upper continuous phase inlet, 2 shell fluid inlet, 3 nuclear fluid inlet, 4 nuclear fluid shunt ports, 5 shell fluid shunt ports, 6 middle continuous phase inlet, 7 middle shell fluid inlet, 8 shell channel, 9 middle nuclear fluid inlet, 10 nuclear channel, 11 continuous phase channel, 12 laminar flow channel, 13 main channel, 14 reaction channel, 15 fluid outlet.
FIG. 4 is a bright field photograph (Scale bar:100 μm) of the biliquid nuclear hydrogel microcapsules prepared in example 4.
FIG. 5 is a bright field photograph (Scale bar:200 μm) of the three-liquid core hydrogel microcapsules prepared in example 5.
Detailed Description
According to practical conditions, firstly, hydrogel microcapsule chips containing different liquid cores are designed, and then the PDMS chips are prepared by using a conventional soft lithography technology. The invention is further illustrated by the following examples in conjunction with the drawings.
Example 1
A double-liquid-core hydrogel microcapsule chip based on double aqueous phases.
The chip is formed by bonding three PDMS chips (an upper layer, a middle layer and a lower layer), the upper layer adopts a shunt design, and the limitation of simultaneous use of a plurality of pump devices is avoided by simplicity.
The device mainly comprises an upper-layer continuous phase inlet 1, a shell fluid inlet 2, a nuclear fluid inlet 3, a nuclear fluid shunting port 4 and a shell fluid shunting port 5; the device comprises an intermediate layer continuous phase inlet 6, an intermediate layer shell fluid inlet 7, a shell channel 8, an intermediate layer core fluid inlet 9, a core channel 10, a continuous phase channel 11, a laminar flow channel 12, a main channel 13, a reaction channel 14 and a fluid outlet 15;
nuclear fluid enters a nuclear fluid inlet 9 from a nuclear fluid inlet 3 through a nuclear fluid diversion port 4 respectively and flows into a laminar flow channel 12 through a nuclear channel 10; the shell fluid flows from the shell fluid inlet 2 through the shell fluid diversion ports 5, respectively, through the shell channel 8 into the laminar flow channel 12; a continuous flow flows from the continuous phase inlet 1 through the intermediate layer continuous phase inlet 6 through the continuous phase channel 11 into the main channel 13; the core fluid, the shell fluid and the continuous fluid finally pass through the channel 13 and the reaction channel 14, and the prepared multi-liquid core hydrogel microcapsule flows out from the fluid outlet 15 and is collected.
The chip layer flow channel has a width of 400 μm and a height of 360cm; the width of the main channel is 400 μm, the height is 360cm, the width of the core and shell channels is 50 μm, the height is 300 μm, and the width of the continuous phase channel is 320 μm, and the height is 360cm. As shown in fig. 1.
Example 2
A three-liquid-core hydrogel microcapsule chip based on double aqueous phases.
The chip is formed by bonding three PDMS chips (an upper layer, a middle layer and a lower layer), wherein the upper layer adopts a flow distribution design, and the limitation of simultaneous use of a plurality of pump devices is avoided by simplifying and avoiding the complicated process.
The device mainly comprises an upper-layer continuous phase inlet 1, a shell fluid inlet 2, a nuclear fluid inlet 3, a nuclear fluid shunting port 4 and a shell fluid shunting port 5; the device comprises a middle layer continuous phase inlet 6, a middle layer shell fluid inlet 7, a shell channel 8, a middle layer nuclear fluid inlet 9, a nuclear channel 10, a continuous phase channel 11, a laminar flow channel 12, a main channel 13, a reaction channel 14 and a fluid outlet 15;
nuclear fluid enters the nuclear fluid inlet 9 from the nuclear fluid inlet 3 through the nuclear fluid diversion ports 4 respectively and flows into the laminar flow channel 12 through the nuclear channel 10; the shell fluid flows from the shell fluid inlet 2 through the shell fluid diversion ports 5, respectively, through the shell channel 8 into the laminar flow channel 12; a continuous flow flows from the continuous phase inlet 1 through the intermediate layer continuous phase inlet 6 through the continuous phase channel 11 into the main channel 13; the core fluid, the shell fluid and the continuous fluid finally pass through the channel 13 and the reaction channel 14, and the prepared multi-liquid core hydrogel microcapsule flows out from the fluid outlet 15 and is collected.
The width of the chip layer flow channel is 300 mu m, and the height is 300cm; the main channel width is 300 μm and height is 300cm, the core and shell channel width is 70 μm and height is 100 μm, and the continuous phase channel width is 300 μm and height is 300cm, as shown in FIG. 2.
Example 3
A four-liquid-core hydrogel microcapsule chip based on double aqueous phases.
The chip is formed by bonding three PDMS chips (an upper layer, a middle layer and a lower layer), the upper layer adopts a shunt design, and the limitation of simultaneous use of a plurality of pump devices is avoided by simplicity.
The device mainly comprises an upper-layer continuous phase inlet 1, a shell fluid inlet 2, a nuclear fluid inlet 3, a nuclear fluid shunting port 4 and a shell fluid shunting port 5; the device comprises an intermediate layer continuous phase inlet 6, an intermediate layer shell fluid inlet 7, a shell channel 8, an intermediate layer core fluid inlet 9, a core channel 10, a continuous phase channel 11, a laminar flow channel 12, a main channel 13, a reaction channel 14 and a fluid outlet 15;
nuclear fluid enters the nuclear fluid inlet 9 from the nuclear fluid inlet 3 through the nuclear fluid diversion ports 4 respectively and flows into the laminar flow channel 12 through the nuclear channel 10; the shell fluid flows from the shell fluid inlet 2 through the shell fluid diversion ports 5, respectively, through the shell channel 8 into the laminar flow channel 12; a continuous flow flows from the continuous phase inlet 1 through the intermediate layer continuous phase inlet 6 through the continuous phase channel 11 into the main channel 13; the core fluid, the shell fluid and the continuous fluid finally pass through the channel 13 and the reaction channel 14, and the prepared multi-liquid core hydrogel microcapsule flows out from the fluid outlet 15 and is collected.
The width of the chip layer flow channel is 400 mu m, and the height is 400cm; the main channel width is 300 μm and height is 400cm, the core and shell channel width is 70 μm and height is 200 μm, and the continuous phase channel width is 400 μm and height is 300cm, as shown in FIG. 3.
Example 4
An application of a double-liquid-core hydrogel microcapsule chip based on double aqueous phases.
The double liquid core hydrogel microcapsule chip based on the double liquid phase in example 1 is used to prepare the double liquid core hydrogel microcapsule, the core fluid component is Dex, the shell fluid is a mixture of PEG, sodium alginate (NaA) and disodium calcium ethylenediaminetetraacetate (Ca-EDTA), and the continuous phase is a mixture of mineral oil, acetic acid (HAc) and Span 80.
The molecular weight of the PEG is as follows: 20kDa, concentration: 17 percent; dex molecular weight: 50kDa, concentration: 15 percent; concentration of NaA: 1%, viscosity 55cps, concentration of Ca-EDTA: 1%, the concentration of HAc is 0.15%, and the concentration of Span 80 is 2%.
Respectively introducing core, shell and continuous phase fluid into the microfluidic chip from the core, shell and continuous phase fluid inlets, wherein the core flow rate is as follows: 0.6. Mu.L/min, shell flow rate: 4 μ L/min, continuous phase flow rate: 30 μ L/min. The brightfield pattern of the biliaryhydrogel microcapsules prepared based on the above conditions is shown in fig. 4.
Example 5
An application of a three-liquid-core hydrogel microcapsule chip based on two aqueous phases.
The double-liquid-core hydrogel microcapsule is prepared by using the double-liquid-phase three-liquid-core hydrogel microcapsule chip in example 2, wherein the core fluid component is Dex, the shell fluid is a mixture of PEG, sodium alginate (NaA) and disodium calcium ethylene diamine tetraacetate (Ca-EDTA), and the continuous phase is a mixture of mineral oil, acetic acid (HAc) and Span 80.
The molecular weight of the PEG is as follows: 20kDa, concentration: 17 percent; dex molecular weight: 50kDa, concentration: 15 percent; concentration of NaA: 1%, viscosity 55cps, concentration of Ca-EDTA: 1%, HAc concentration 0.10%, span 80 concentration 2%.
Respectively introducing core, shell and continuous phase fluid into the microfluidic chip from the core, shell and continuous phase fluid inlets, wherein the core flow rate is as follows: 0.3. Mu.L/min, shell flow rate: 9 μ L/min, continuous phase flow rate: 20 μ L/min. The bright field pattern of the three liquid core hydrogel microcapsule prepared based on the above conditions is shown in fig. 5.
Claims (5)
1. A multiliquid core hydrogel microcapsule chip based on double aqueous phases is characterized in that: the chip is manufactured by a conventional soft lithography method, and is a three-layer PDMS chip formed by bonding an upper chip layer, a middle chip layer and a lower chip layer, wherein the upper chip layer adopts a shunting design;
the upper layer of the chip mainly comprises a core fluid inlet (3), a shell fluid inlet (2), a continuous phase inlet (1), a core fluid shunting port (4) and a shell fluid shunting port (5); the chip middle layer mainly comprises a continuous phase inlet (6), a continuous phase channel (11), a core fluid inlet (9), a shell fluid inlet (7), a core channel (10), a shell channel (8), a laminar flow channel (12), a main channel (13), a reaction channel (14) and a fluid outlet (15); the lower layer of the chip is a white board without a structure;
the nuclear fluid shunting port (4) on the upper layer of the chip is communicated with the nuclear fluid inlet (9) on the middle layer of the chip; the nuclear fluid inlet of the chip middle layer is communicated with the nuclear channel;
the shell fluid shunting port (5) on the upper layer of the chip is communicated with the shell fluid inlet (7) on the middle layer of the chip; a shell fluid inlet of the chip intermediate layer is communicated with the shell channel;
the continuous phase inlet (1) of the upper layer of the chip is communicated with the continuous phase inlet (6) of the middle layer of the chip; a branch fluid inlet of a shell fluid inlet (2) on the upper layer of the chip is a shell fluid shunting port (5), and a branch fluid inlet of a core fluid inlet (3) on the upper layer of the chip is a core fluid shunting port (4); the shell fluid shunting port, the shell fluid inlet of the chip middle layer and the shell channel are correspondingly equal in number; the number of the nuclear fluid shunt ports, the number of the nuclear fluid inlets in the chip middle layer and the number of the nuclear channels are correspondingly equal; the number of the core channels (10) is 2, 3 or 4, and the number of the shell channels (8) is 3, 4 or 5 correspondingly; realizing the multi-liquid-core hydrogel microcapsule.
2. The aqueous two-phase based multi-liquid-core hydrogel microencapsulation chip of claim 1, wherein: nuclear fluid enters a nuclear fluid inlet (9) of the chip middle layer from a nuclear fluid inlet (3) of the chip upper layer through a nuclear fluid diversion port (4) and flows into a laminar flow channel (12) through a nuclear channel (10); the shell fluid flows into the laminar flow channel (12) from the shell fluid inlet (2) on the upper layer of the chip through the shell fluid shunting port (5), passes through the shell fluid inlet (7) on the middle layer of the chip and flows into the shell channel (8); a continuous flow flows into a main channel (13) from a continuous phase inlet (1) on the upper layer of the chip through a continuous phase inlet (6) on the middle layer and through a continuous phase channel (11); the core fluid, the shell fluid and the continuous fluid finally pass through the main channel (13) and the reaction channel (14), and the prepared multi-liquid-core hydrogel microcapsule flows out from the fluid outlet (15) and is collected.
3. The aqueous two-phase based multi-liquid-core hydrogel microencapsulation chip of claim 1, wherein: the laminar flow channel (12) has a width of 100-600 μm and a height of 100-500cm; the width of the main channel (13) is 100-500 mu m, and the height is 50-500cm; the width of the core channel (10) and the shell channel (8) is 20-200 μm, and the height is 20-200 μm; the width of the continuous phase channel (11) is 100-400 μm, and the height is 50-300cm.
4. The aqueous two-phase based multi-liquid-core hydrogel microencapsulation chip of claim 1, wherein: the number of liquid cores of the microcapsule is more than or equal to 1.
5. The aqueous two-phase based multi-liquid-core hydrogel microencapsulation chip of claim 1, wherein: the core of the formed multi-liquid-core hydrogel microcapsule is aqueous solution, and the shell is hydrogel.
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| CN103386333A (en) * | 2013-08-07 | 2013-11-13 | 苏州扬清芯片科技有限公司 | Micro-fluidic liquid drop production chip |
| CN103386336A (en) * | 2013-08-07 | 2013-11-13 | 苏州扬清芯片科技有限公司 | Microfluidic chip for producing droplets with concentration gradients |
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| CN109647547A (en) * | 2017-10-12 | 2019-04-19 | 中国科学院大连化学物理研究所 | A kind of preparation method of the controllable aqueous two-phase drop based on microflow control technique |
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