Supramolecular hydrogel microcapsules and methods of making the same

Abstract

The application discloses a supramolecular hydrogel microcapsule and a preparation method thereof. The preparation method utilizes a double-water phase system to realize directional self-assembly of a small molecule gel factor at a water-water interface in a catalytic regulation mode, and combines a self-assembly system of the small molecule gel factor with a water-in-oil-in-water multiple emulsification microfluidic system through a microfluidic chip to realize continuous preparation of the supramolecular hydrogel microcapsule. Meanwhile, the flow rate conditions capable of stably preparing W / W / O emulsion droplets are obtained by screening the flow rate ratio of each phase. The formed supramolecular hydrogel microcapsule has a typical cavity structure, and in the microstructure analysis and research, it is found that supramolecular gel fibers are generated directionally at the water-water interface inside the droplet. In addition, by controlling the flow rate of the continuous phase, the size of the supramolecular microcapsule can also be regulated.

Description

Technical Field

[0001] This invention belongs to the field of gel materials technology, specifically relating to a supramolecular hydrogel microcapsule and its preparation method. Background Technology

[0002] Compartmental structures are fundamental to maintaining cellular physiological functions. These structures not only allow various biochemical reactions to proceed undisturbed but also serve as carriers for the intercellular delivery of chemical substances. Inspired by this, the artificial synthesis of compartmentalized structures is not only beneficial for understanding the operational mechanisms of living systems but also facilitates the development of novel structured functional carriers for the encapsulation, delivery, and release of active ingredients (drugs, cells), thus possessing significant research value. It is noteworthy that cellular compartmentalized structures are often formed under the drive of supramolecular interactions, such as liquid-liquid phase separation and hydrophobic interactions. In recent years, the method of preparing compartmentalized structures through supramolecular self-assembly has attracted widespread attention from researchers.

[0003] Microcapsules are a common type of compartmentalized structure that encapsulates target substances within micrometer-sized chambers using film-forming materials. This protects these substances from damage caused by harsh external conditions such as light, oxygen, and mechanical forces, leading to their wide applications in pharmaceuticals, daily chemicals, and printing. Supramolecular microcapsules, on the other hand, are microcapsule structures obtained through molecular assembly. They are highly functional, tunable, and biocompatible. For example, in their work "One-Step Microfluidic Fabrication of Polyelectrolyte Microcapsules in Aqueous Conditions for Protein Release," Zhang et al. combined droplet microfluidics with polyelectrolyte materials, utilizing electrostatic complexation to prepare supramolecular microcapsules, which were then used as carriers for loading and controlled release of various biomolecules. In their work "Flexible Generation of Multi-Aqueous Core Hydrogel Capsules Using Microfluidic Aqueous Two-Phase System," Wang et al. utilized calcium ions to trigger the cross-linking of sodium alginate, thereby creating microcapsules with a sodium alginate supramolecular gel shell, which were successfully used for cell encapsulation.

[0004] Nevertheless, most of the supramolecular microcapsules constructed to date are based on macromolecular self-assembly, while supramolecular microcapsules prepared based on small molecule self-assembly processes have not been extensively studied. Summary of the Invention

[0005] To address the aforementioned shortcomings of existing technologies, this invention provides a supramolecular hydrogel microcapsule and its preparation method, which achieves spatially oriented assembly of small molecules through catalytic regulation, thereby realizing the preparation of supramolecular microcapsules based on small molecule self-assembly.

[0006] The technical solution adopted in this invention is as follows:

[0007] The first aspect of the present invention is to provide a method for preparing supramolecular hydrogel microcapsules. The method utilizes a two-phase system to achieve the directional self-assembly of small molecule gel factors at the water-water interface through catalytic regulation. The self-assembly system of small molecule gel factors is combined with a microfluidic chip to achieve a water-in-oil multiple emulsification microfluidic system, thereby realizing the preparation of supramolecular hydrogel microcapsules.

[0008] Furthermore, the small molecule gelling factor includes water-soluble precursor factors A and H, wherein the water-soluble precursor factor A is 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde, and the water-soluble precursor factor H is (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazine.

[0009] Furthermore, the preparation method of the supramolecular hydrogel microcapsules includes the following steps:

[0010] (1) Fabrication of the microfluidic chip: The microfluidic chip includes a dextran inlet, a polyethylene glycol inlet, an oil phase inlet, a cross-section, and a microcapsule outlet arranged sequentially from the inside to the outside. The dextran inlet, polyethylene glycol inlet, and oil phase inlet converge at the cross-section through a dextran dispersed phase channel, a polyethylene glycol dispersed phase channel, and a continuous phase channel, respectively. The cross-section and the microcapsule outlet are connected by an outflow channel, and a buffer channel is provided at the rear end of the outflow channel. The microfluidic chip is fabricated using conventional soft lithography.

[0011] (2) Preparation of aqueous two-phase solution: Take an appropriate amount of dextran and polyethylene glycol and dissolve them in a solvent. After complete dissolution, a dextran / polyethylene glycol aqueous two-phase emulsion is obtained. After centrifugation, a dextran phase solution and a polyethylene glycol phase solution are obtained.

[0012] (3) Preparation of precursor solution: Take an appropriate amount of water-soluble precursor factor A and catalyst and dissolve them in dextran phase solution, and adjust the pH to obtain dextran phase precursor solution; take an appropriate amount of water-soluble precursor factor H and dissolve it in polyethylene glycol phase solution to obtain polyethylene glycol phase precursor solution.

[0013] (4) Preparation of supramolecular hydrogel microcapsules:

[0014] The dextran-phase precursor solution, polyethylene glycol-phase precursor solution, and oil phase enter the microfluidic chip through the dextran inlet, polyethylene glycol inlet, and oil phase inlet, respectively. They then sequentially travel along the dextran dispersed phase channel, the polyethylene glycol dispersed phase channel, and the continuous phase channel to the intersection, forming W / W / O emulsion droplets. After the droplets have stabilized, the droplets at the microcapsule outlet are collected. The collected droplets are then allowed to stand to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0015] Further, in step (1), the channel height within the microfluidic chip is 80-120 μm, preferably 100 μm; the width of the polyethylene glycol dispersed phase channel, dextran dispersed phase channel, continuous phase channel, and effluent channel is 180-220 μm, preferably 200 μm; the width of the intersection is 60-100 μm, preferably 80 μm; and the width of the buffer channel is 480-520 μm, preferably 500 μm.

[0016] Further, in step (2), the solvent is ultrapure water or a 100mM, pH 7.4 MOPS buffer solution; the mass concentration of the dextran phase solution is 7.5-15wt%, and the mass concentration of the polyethylene glycol phase solution is 5-10wt%.

[0017] Further, in step (3), the concentration of the water-soluble precursor factor A is 60-180 mM, and the concentration of the water-soluble precursor factor H is 10-30 mM.

[0018] Further, in step (3), the catalyst is selected from one of aniline, indoline, (1H-benzis[d]imidazol-2-yl)methylamine, 1,4-phenylene diamine-15N2, 3,5-diaminobenzoic acid, m-aminobenzoic acid and p-aminobenzoic acid, preferably aniline; the concentration of the catalyst is 2.5-12 mM, preferably 10 mM; the pH is adjusted to 3-6, preferably pH 4.

[0019] Furthermore, in step (4), the oil phase is selected from isopropyl palmitate and isopropyl myristate.

[0020] Further, in step (4), the flow rate of the polyethylene glycol phase precursor solution is 0.05-0.30 μL / min, the flow rate of the dextran phase precursor solution is 0.70-0.95 μL / min, and the flow rate of the oil phase is 1-8 μL / min; preferably, the flow rate of the polyethylene glycol phase precursor solution is 0.25 μL / min, the flow rate of the dextran phase precursor solution is 0.75 μL / min, and the flow rate of the oil phase is 3-7 μL / min.

[0021] A second aspect of the present invention is to provide supramolecular hydrogel microcapsules prepared by the above-described preparation method.

[0022] The beneficial effects of this invention are as follows:

[0023] 1. This invention combines a multi-emulsified droplet microfluidic system with the directional self-assembly of a water-water interface based on an aqueous two-phase system (ATPS). It achieves spatial directional assembly of small molecules through catalytic regulation, thereby realizing the continuous preparation of supramolecular hydrogel microcapsules. At the same time, by screening the flow rate ratio of each phase, the flow rate conditions that can stably prepare W / W / O emulsion droplets were obtained.

[0024] 2. In this invention, by adjusting q aq (water phase flow velocity) and q oil (Oil phase flow rate) The designed microfluidic device can generate three flow modes: trickle flow, jet flow, and co-flow. In trickle flow mode, by adjusting q... PEG (PEG phase flow rate) and q Dex (Dex phase flow rate) yielded three types of droplets with different structures: concentric circle structure, eccentric circle structure, and sphere-within-a-sphere structure. Among them, the concentric circle structure has good concentricity between the inner and outer layers, and is therefore used for the preparation of supramolecular hydrogel microcapsules.

[0025] 3. Utilizing optimized flow rate combinations, the fabrication of small-molecule supramolecular hydrogel microcapsules was successfully achieved. The formed supramolecular hydrogel microcapsules exhibit a typical cavity structure. Microstructural analysis revealed that supramolecular gel fibers are directionally generated at the water-water interface within the droplets. Furthermore, the size of the supramolecular microcapsules can be controlled by adjusting the flow rate of the continuous phase. Attached Figure Description

[0026] Figure 1 This is a schematic diagram illustrating the principle of supramolecular hydrogel formation.

[0027] Figure 2 This is a physical image of the microfluidic chip of the present invention.

[0028] Figure 3 This is a schematic diagram of the microfluidic chip of the present invention.

[0029] Figure 4 This diagram illustrates the formation and continuous preparation of supramolecular microcapsules based on ATPS microfluidic technology according to the present invention.

[0030] Figure 5 This invention relates to W / W / O type emulsion droplets prepared by microfluidic control.

[0031] Figure 6 This is an optical microscope image of the supramolecular microcapsules prepared in Example 2.

[0032] Figure 7 This is a CLSM image of the supramolecular microcapsules prepared in Example 2 (the samples were labeled with FITC-Dex (green), Rho-mPEG (yellow) and Cy5 (blue), respectively).

[0033] Figure 8 This is a fluorescence distribution map of the cross-section of the supramolecular microcapsules prepared in Example 2.

[0034] Figure 9 It's different q aq and q oil Flow patterns under combination.

[0035] Figure 10 These are schematic diagrams of different flow states.

[0036] Figure 11 It's different q Dex q PEG Droplet morphology in combination with qoil.

[0037] Figure 12 These are schematic diagrams of different droplet shapes.

[0038] Figure 13A ~C is a size distribution diagram of supramolecular microcapsules prepared at different oil phase flow rates.

[0039] Figure 3 In the middle: 1-dextran inlet; 2-polyethylene glycol inlet; 3-oil phase inlet; 4-cross; 5-microcapsule outlet; 6-dextran dispersed phase channel; 7-polyethylene glycol dispersed phase channel; 8-continuous phase channel; 9-outflow channel; 10-buffer zone channel. Detailed Implementation

[0040] The technical solution of the present invention will be clearly and thoroughly described below with reference to the accompanying drawings and specific embodiments. It should be understood that the following embodiments are only some embodiments of the present invention and are not intended to limit the scope of protection of the present invention.

[0041] Unless otherwise specified, the reagents used in the following examples are all commercially available products, and the instruments used are all conventional instruments in the art.

[0042] By using catalytic regulation to achieve spatially oriented assembly of small molecules, supramolecular microcapsules based on small molecule self-assembly were prepared.

[0043] The supramolecular hydrogel microcapsules prepared in this invention are composed of two water-soluble precursor factors, H and A, such as... Figure 1As shown, (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H) and 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) can react in situ in an aqueous phase to generate a gelling factor (HA3) linked by hydrazone bonds, which then self-assembles to form a supramolecular hydrogel. This invention combines a water-to-water interface-oriented self-assembly method for supramolecular hydrogels based on an aqueous two-phase system (ATPS) with microfluidic technology for water-in-oil (W / W / O) multiple emulsification, successfully achieving the controllable preparation of monodisperse supramolecular microcapsules.

[0044] Example 1: Fabrication of PDMS microfluidic chip

[0045] To achieve the preparation of the aforementioned supramolecular hydrogel microcapsules, this invention designs and prepares as follows: Figure 2 and Figure 3 The PDMS microfluidic chip shown includes, from the inside out, a dextran inlet 1, a polyethylene glycol inlet 2, an oil phase inlet 3, a cross-section 4, and a microcapsule outlet 5. The dextran inlet 1, polyethylene glycol inlet 2, and oil phase inlet 3 converge at the cross-section 4 via a dextran dispersed phase channel 6, a polyethylene glycol dispersed phase channel 7, and a continuous phase channel 8, respectively. The cross-section 4 and the microcapsule outlet 5 are connected by an outflow channel 9, and a buffer channel 10 is provided at the rear end of the outflow channel 9. The buffer channel 10 allows W / W / O droplets to quickly transform into a stable spherical-within-a-spherical structure after generation, preventing the formation of uneven capsule structures.

[0046] The channel height within the microfluidic chip is 80-120 μm, the width of the polyethylene glycol dispersed phase channel 6, the dextran dispersed phase channel 7, the continuous phase channel 8, and the outflow channel 9 is 180-220 μm, the width of the intersection 4 is 60-100 μm, and the width of the buffer channel 10 after droplet generation is 480-520 μm.

[0047] Preferably, the channel height within the microfluidic chip is 100 μm, the widths of the polyethylene glycol dispersed phase channel 6, the dextran dispersed phase channel 7, the continuous phase channel 8, and the outflow channel 9 are 200 μm, the width of the intersection 4 is 80 μm, and the width of the buffer channel 10 after droplet generation is 500 μm.

[0048] like Figure 2 As shown, multiple PDMS microfluidic chips can be connected in parallel, and one can be selected for use when preparing supramolecular hydrogel microcapsules.

[0049] During fabrication, a 3D printer was used to print the 3D file of the microfluidic chip designed above. The printed template was immersed in ethanol for ultrasonic cleaning, followed by post-curing under ultraviolet light to protect the resulting microstructure. To improve the release performance of PDMS, the template needed to undergo hydrophobic surface treatment before pattern transfer. During surface treatment, dust on the template surface was first purged with nitrogen, followed by spraying a high-efficiency PDMS release agent onto the surface, and then drying with nitrogen again.

[0050] The PDMS substrate and curing agent are uniformly mixed at a ratio of 10:1 and slowly poured into an aluminum box containing a template. Vacuum defoaming is then performed for 30-35 minutes. The box is then placed in a leveled oven and cured at 55-60℃ for 6-7 hours. After the cured PDMS cools to room temperature, it is separated from the template. A 1.0mm biopsy needle is then used to drill holes at the fluid inlet and outlet. A separate flat PDMS sheet is taken, and surface dust is removed from both sheets using electrostatic tape. The cleaned PDMS is then treated in a plasma cleaner for 2-3 minutes. The two PDMS sheets are then bonded together, and finally, they are placed in an oven at 55-60℃ for 2-3 hours to complete encapsulation, yielding the PDMS microfluidic chip.

[0051] like Figure 4 and Figure 5 As shown, a dextran dispersion phase (Dex phase, inner aqueous phase) containing water-soluble precursor factor A, a polyethylene glycol dispersion phase (PEG phase, outer aqueous phase) containing water-soluble precursor factor H, and an oil phase enter the PDMS microfluidic chip from dextran inlet 1, polyethylene glycol inlet 2, and oil phase inlet 3, respectively. Then, they sequentially travel along polyethylene glycol dispersion phase channel 6, dextran dispersion phase channel 7, and continuous phase channel 8 to reach intersection 4. In the two-aqueous-phase system, water-soluble precursor factors H and A react in situ in the aqueous phase to generate gel factor (HA3) linked by hydrazone bonds, which then self-assembles to form a supramolecular hydrogel. The outer aqueous phase encapsulates the inner aqueous phase and is cut off under the shearing action of the external oil phase, forming a water-in-oil (W / W / O) emulsion droplet, thus realizing the controllable preparation of monodisperse supramolecular microcapsules.

[0052] In Examples 2-20 and Comparative Examples 1-2 below, supramolecular hydrogel microcapsules were prepared based on the PDMS microfluidic chip prepared in Example 1.

[0053] Example 2

[0054] (1) Preparation of aqueous two-phase solution

[0055] A certain amount of PEG and Dex were dissolved in MOPS buffer (100 mM, pH 7.4) to achieve final concentrations of 5 wt% and 7.5 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0056] (2) Preparation of precursor solution

[0057] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and aniline were dissolved in Dex solution, and the pH of the solution was adjusted to 4.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 180 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 10 mM of aniline. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 to prepare a PEG phase precursor solution with a concentration of 30 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H).

[0058] (3) Fluorescent labeling before observation with laser confocal microscope

[0059] In a 50 mL round-bottom flask, dextran (1.00 g, 2 μmol) and carbonate-bicarbonate buffer (pH 9.5, 20 mL) were added. FITC (22 mg, 56 mmol) was dissolved in dimethyl sulfoxide (2 mL) and added dropwise to the reaction mixture. The reaction mixture was then stirred in the dark for 24 h. After the reaction was complete, the reaction mixture was dialyzed against deionized water for 5 days in the dark (molecular weight cutoff 8000-14000). The dialyzed solution was lyophilized to obtain an orange, fluffy solid (0.91 g, 91%), i.e., FITC-Dex.

[0060] Prepare stock solutions of FITC-Dex, Rho-mPEG, and Cy5 at 1 mg / mL (solvent DMSO). Add 4 μL of FITC-Dex stock solution and 1 μL of Cy5 stock solution to 1 mL of Dex phase precursor solution, vortex to mix, and store protected from light. Add 2 μL of Rho-mPEG stock solution and 1 μL of Cy5 stock solution to 1 mL of PEG phase precursor solution, vortex to mix, and store protected from light.

[0061] (4) Preparation of supramolecular hydrogel microcapsules

[0062] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersion phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersion phase, and 1 mL of isopropyl palmitate (containing 7 wt%) to three separate 1 mL syringes. Using EM180 as the continuous phase, the syringe is connected to the dextran inlet 1, polyethylene glycol inlet 2 and oil phase inlet 3 of the PDMS microfluidic chip through a polytetrafluoroethylene tube (inner diameter / outer diameter of 0.6 mm / 1.0 mm), and the microcapsule outlet 5 is connected to a small glass bottle containing a certain amount of continuous phase.

[0063] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to start collecting the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly.

[0064] A small amount of supramolecular hydrogel microcapsules was gently pipetted into a confocal dish, and observed using a laser confocal microscope and an optical microscope. The optical microscope image, CLSM image, and fluorescence distribution map of the prepared supramolecular hydrogel microcapsules are shown below. Figure 6-8 As shown, the formed supramolecular hydrogel microcapsules have a typical cavity structure.

[0065] Example 3

[0066] (1) Preparation of aqueous two-phase solution

[0067] A certain amount of PEG and Dex were dissolved in ultrapure water to achieve final concentrations of 7 wt% and 10.5 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0068] (2) Preparation of precursor solution

[0069] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and aniline were dissolved in Dex solution, and the pH of the solution was adjusted to 4.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 180 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 10 mM of aniline. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 with hydrochloric acid to prepare a PEG phase precursor solution with a concentration of 30 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H).

[0070] (3) Preparation of supramolecular hydrogel microcapsules

[0071] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersion phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersion phase, and 1 mL of isopropyl palmitate (containing 7 wt%) to three separate 1 mL syringes. Using EM180 as the continuous phase, the syringe is connected to the dextran inlet 1, polyethylene glycol inlet 2 and oil phase inlet 3 of the PDMS microfluidic chip through a polytetrafluoroethylene tube (inner diameter / outer diameter of 0.6 mm / 1.0 mm), and the microcapsule outlet 5 is connected to a small glass bottle containing a certain amount of continuous phase.

[0072] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to collect the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0073] Example 4

[0074] (1) Preparation of aqueous two-phase solution

[0075] A certain amount of PEG and Dex were dissolved in MOPS buffer (100 mM, pH 7.4) to achieve final concentrations of 10 wt% and 15 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0076] (2) Preparation of precursor solution

[0077] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and aniline were dissolved in Dex solution, and the pH of the solution was adjusted to 4.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 180 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 10 mM of aniline. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 to prepare a PEG phase precursor solution with a concentration of 30 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H).

[0078] (3) Preparation of supramolecular hydrogel microcapsules

[0079] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersion phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersion phase, and 1 mL of isopropyl palmitate (containing 7 wt%) to three separate 1 mL syringes. Using EM180 as the continuous phase, the syringe is connected to the dextran inlet 1, polyethylene glycol inlet 2 and oil phase inlet 3 of the PDMS microfluidic chip through a polytetrafluoroethylene tube (inner diameter / outer diameter of 0.6 mm / 1.0 mm), and the microcapsule outlet 5 is connected to a small glass bottle containing a certain amount of continuous phase.

[0080] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to collect the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0081] Example 5

[0082] (1) Preparation of aqueous two-phase solution

[0083] A certain amount of PEG and Dex were dissolved in MOPS buffer (100 mM, pH 7.4) to achieve final concentrations of 5 wt% and 7.5 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0084] (2) Preparation of precursor solution

[0085] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and indoline were dissolved in Dex solution, and the pH of the solution was adjusted to 4.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 60 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 10 mM of indoline. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 to prepare a PEG phase precursor solution with a concentration of 10 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H).

[0086] (3) Preparation of supramolecular hydrogel microcapsules

[0087] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersion phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersion phase, and 1 mL of isopropyl palmitate (containing 7 wt%) to three separate 1 mL syringes. Using EM180 as the continuous phase, the syringe is connected to the dextran inlet 1, polyethylene glycol inlet 2 and oil phase inlet 3 of the PDMS microfluidic chip through a polytetrafluoroethylene tube (inner diameter / outer diameter of 0.6 mm / 1.0 mm), and the microcapsule outlet 5 is connected to a small glass bottle containing a certain amount of continuous phase.

[0088] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to collect the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0089] Example 6

[0090] (1) Preparation of aqueous two-phase solution

[0091] A certain amount of PEG and Dex were dissolved in MOPS buffer (100 mM, pH 7.4) to achieve final concentrations of 5 wt% and 7.5 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0092] (2) Preparation of precursor solution

[0093] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and (1H-benzo[d]imidazol-2-yl)methylamine were dissolved in Dex solution, and the pH of the solution was adjusted to 4.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 120 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 10 mM of (1H-benzo[d]imidazol-2-yl)methylamine. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxyhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 to prepare a PEG phase precursor solution with a concentration of 20 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxyhydrazide (H).

[0094] (3) Preparation of supramolecular hydrogel microcapsules

[0095] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersion phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersion phase, and 1 mL of isopropyl palmitate (containing 7 wt%) to three separate 1 mL syringes. Using EM180 as the continuous phase, the syringe is connected to the dextran inlet 1, polyethylene glycol inlet 2 and oil phase inlet 3 of the PDMS microfluidic chip through a polytetrafluoroethylene tube (inner diameter / outer diameter of 0.6 mm / 1.0 mm), and the microcapsule outlet 5 is connected to a small glass bottle containing a certain amount of continuous phase.

[0096] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to collect the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0097] Example 7

[0098] (1) Preparation of aqueous two-phase solution

[0099] A certain amount of PEG and Dex were dissolved in MOPS buffer (100 mM, pH 7.4) to achieve final concentrations of 5 wt% and 7.5 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0100] (2) Preparation of precursor solution

[0101] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 1,4-phenylene diamine-15N2 were dissolved in Dex solution, and the pH of the solution was adjusted to 4.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 180 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 2.5 mM of 1,4-phenylene diamine-15N2. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 to prepare a PEG phase precursor solution with a concentration of 30 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H).

[0102] (3) Preparation of supramolecular hydrogel microcapsules

[0103] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersion phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersion phase, and 1 mL of isopropyl palmitate (containing 7 wt%) to three separate 1 mL syringes. Using EM180 as the continuous phase, the syringe is connected to the dextran inlet 1, polyethylene glycol inlet 2 and oil phase inlet 3 of the PDMS microfluidic chip through a polytetrafluoroethylene tube (inner diameter / outer diameter of 0.6 mm / 1.0 mm), and the microcapsule outlet 5 is connected to a small glass bottle containing a certain amount of continuous phase.

[0104] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to collect the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0105] Example 8

[0106] (1) Preparation of aqueous two-phase solution

[0107] A certain amount of PEG and Dex were dissolved in MOPS buffer (100 mM, pH 7.4) to achieve final concentrations of 5 wt% and 7.5 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0108] (2) Preparation of precursor solution

[0109] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 3,5-diaminobenzoic acid were dissolved in Dex solution, and the pH of the solution was adjusted to 4.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 180 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 12 mM of 3,5-diaminobenzoic acid. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 to prepare a PEG phase precursor solution with a concentration of 30 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide (H).

[0110] (3) Preparation of supramolecular hydrogel microcapsules

[0111] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersion phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersion phase, and 1 mL of isopropyl palmitate (containing 7 wt%) to three separate 1 mL syringes. Using EM180 as the continuous phase, the syringe is connected to the dextran inlet 1, polyethylene glycol inlet 2 and oil phase inlet 3 of the PDMS microfluidic chip through a polytetrafluoroethylene tube (inner diameter / outer diameter of 0.6 mm / 1.0 mm), and the microcapsule outlet 5 is connected to a small glass bottle containing a certain amount of continuous phase.

[0112] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to collect the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0113] Example 9

[0114] (1) Preparation of aqueous two-phase solution

[0115] A certain amount of PEG and Dex were dissolved in MOPS buffer (100 mM, pH 7.4) to achieve final concentrations of 5 wt% and 7.5 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0116] (2) Preparation of precursor solution

[0117] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and m-aminobenzoic acid were dissolved in Dex solution, and the pH of the solution was adjusted to 3.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 180 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 10 mM of m-aminobenzoic acid. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxyhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 to prepare a PEG phase precursor solution with a concentration of 30 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxyhydrazide (H).

[0118] (3) Preparation of supramolecular hydrogel microcapsules

[0119] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersion phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersion phase, and 1 mL of isopropyl palmitate (containing 7 wt%) to three separate 1 mL syringes. Using EM180 as the continuous phase, the syringe is connected to the dextran inlet 1, polyethylene glycol inlet 2 and oil phase inlet 3 of the PDMS microfluidic chip through a polytetrafluoroethylene tube (inner diameter / outer diameter of 0.6 mm / 1.0 mm), and the microcapsule outlet 5 is connected to a small glass bottle containing a certain amount of continuous phase.

[0120] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to collect the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0121] Example 10

[0122] (1) Preparation of aqueous two-phase solution

[0123] A certain amount of PEG and Dex were dissolved in MOPS buffer (100 mM, pH 7.4) to achieve final concentrations of 5 wt% and 7.5 wt%, respectively. The mixture was stirred vigorously until the solids were completely dissolved, yielding a PEG / Dex aqueous two-phase emulsion. The solution was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 10 min to separate the solution into two phases. The two layers were slowly aspirated with a dropper to obtain the PEG phase and the Dex phase, respectively. The two phases were collected in separate centrifuge tubes and stored at room temperature for later use.

[0124] (2) Preparation of precursor solution

[0125] A certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and p-aminobenzoic acid were dissolved in Dex solution, and the pH of the solution was adjusted to 6.0 with hydrochloric acid to prepare a Dex phase precursor solution with a concentration of 180 mM of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 10 mM of p-aminobenzoic acid. Separately, a certain amount of (Cis,Cis)-cyclohexane-1,3,5-tricarboxyhydrazide (H) was dissolved in PEG solution, heated and sonicated until completely dissolved, and the pH of the solution was adjusted to 7.4 to prepare a PEG phase precursor solution with a concentration of 30 mM of (Cis,Cis)-cyclohexane-1,3,5-tricarboxyhydrazide (H).

[0126] (3) Preparation of supramolecular hydrogel microcapsules

[0127] Add 500 μL of Dex phase precursor solution (Dex phase) as the inner dispersed phase, 500 μL of PEG phase precursor solution (PEG phase) as the outer dispersed phase, and 1 mL of isopropyl myristate as the continuous phase to three independent 1 mL syringes. Connect the syringes to the dextran inlet 1, polyethylene glycol inlet 2, and oil phase inlet 3 of the PDMS microfluidic chip through polytetrafluoroethylene tubes (inner / outer diameter 0.6 mm / 1.0 mm), respectively. Connect the microcapsule outlet 5 to a small glass bottle containing a certain amount of continuous phase.

[0128] First, the dextran dispersed phase channel 6, the polyethylene glycol dispersed phase channel 7, and the continuous phase channel were vented separately. After venting, the flow rates of the PEG phase were adjusted to 0.25 μL / min, the Dex phase to 0.75 μL / min, and the oil phase to 3 μL / min. After the droplets stabilized, the receiving bottle was switched to collect the droplets. The collected droplets were then allowed to stand for 4 hours to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

[0129] Example 11, different q aq and q oil Flow patterns under combination

[0130] The preparation method in this embodiment is basically the same as that in Example 2, except that the flow rate (q) of the PEG phase in step (4) is adjusted. PEG ), the flow velocity of the Dex phase (q) Dex ) and the flow rate of the oil phase (q) oil The study investigated its impact on flow patterns.

[0131] First, keep q PEG q Dex The same, and the sum of the two, that is, the water phase velocity q. aqThe continuous phase flow rate q varies between 0.1 and 10 μL / min. oil The flow rate varied between 1 and 8 μL / min. Different q aq and q oil Flow patterns under combination, such as Figure 9 and Figure 10 As shown, Figure 9 Different regions represent flow patterns under different combinations of flow velocities.

[0132] Depend on Figure 9 and Figure 10 The results show that by adjusting q PEG q Dex and q oil Three flow modes can be generated within the microfluidic chip: dripping, jetting, and co-flowing. Adjusting q... aq At a flow rate of 0.1-5 μL / min, a trickle can be formed.

[0133] Examples 12-20, q Dex and q PEG Effect of ratio on droplet morphology

[0134] Examples 12-20 are prepared using methods basically the same as those in Example 2, except that the flow rate ratio between the two aqueous phases is adjusted within the flow rate range of the trickle flow mode to study its effect on the morphology of the generated droplets. Specifically, q Dex With q PEG The sum was fixed at 1 μL / min, and q was adjusted. Dex q PEG The ratio of continuous phase flow velocity q oil The flow rate varied between 1 and 8 μL / min. Different q Dex q PEG The droplet morphology when combined with qoil is as follows Figure 11 and Figure 12 As shown, Figure 11 Different regions represent droplet morphology under different flow rate combinations. Figure 13A ~C is a size distribution diagram of supramolecular microcapsules prepared at different oil phase flow rates (D1 in the figure is the diameter of the internal phase, and D2 is the diameter of the microcapsule).

[0135] Table 1

[0136]

[0137]

[0138] Depend on Figure 11 and Figure 12 The results show that in the trickle flow model, the continuous phase velocity q oilWhen the flow rate varies between 1 and 8 μL / min, three main droplet morphologies emerge at different aqueous phase flow ratios: concentric circles, eccentric circles, and spheres within spheres. When the Dex phase is the dominant component of the droplet, the droplet exhibits a concentric circle structure. As the proportion of the PEG phase increases, the volume of the Dex phase within the droplet decreases and it shifts to one side of the droplet. Further increasing the proportion of the PEG phase causes the Dex phase to gradually transform into a droplet that can move freely within the PEG phase due to surface tension, forming a sphere within sphere structure. Among these, the concentric circle structure exhibits good concentricity between the inner and outer layers, making this flow rate range the preferred location for preparing supramolecular microcapsules.

[0139] Depend on Figure 13A The results from -C show that the size of supramolecular hydrogel microcapsules can be controlled by adjusting the flow rate of the continuous phase.

[0140] Comparative Example 1

[0141] This embodiment is basically the same as Example 2, except that in step (2) of preparing the precursor solution, a certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) is dissolved in Dex solution, and hydrochloric acid is added to adjust the pH of the solution to 4.0, thus preparing a Dex phase precursor solution with a 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) concentration of 180 mM. The final product is close to a gel sphere and cannot form supramolecular hydrogel microcapsules.

[0142] Comparative Example 2

[0143] This embodiment is basically the same as Example 2, except that in the preparation of the precursor solution in step (2), a certain amount of 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and aniline are dissolved in Dex solution to prepare a Dex phase precursor solution with a concentration of 180 mM for 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde (A) and 10 mM for aniline. The final product is close to a gel sphere and cannot form supramolecular hydrogel microcapsules.

[0144] As can be seen from the comparison between Example 2 and Comparative Examples 1-2, the addition of catalyst and acid can accelerate the formation of hydrazone bonds and speed up the self-assembly process. However, the addition of catalyst or acid alone cannot form supramolecular hydrogel microcapsules.

[0145] The technical solution of the present invention has been described in detail above through specific embodiments. However, it is worth noting that, under the inventive concept of this application, various equivalent changes, modifications or substitutions are obvious to those skilled in the art and should be covered within the protection scope of this application.

Claims

1. A method for preparing supramolecular hydrogel microcapsules, characterized in that, The preparation method utilizes a two-phase system to achieve the directional self-assembly of small molecule gel factors at the water-water interface through catalytic regulation. The self-assembly system of the small molecule gel factors is combined with a microfluidic chip to achieve a water-in-oil multiple emulsification microfluidic system, thereby preparing supramolecular hydrogel microcapsules. The small molecule gel factors include water-soluble precursor factors A and H. The water-soluble precursor factor A is 3,4-bis(2-(2-methoxyethoxy)ethoxy)benzaldehyde, and the water-soluble precursor factor H is (Cis,Cis)-cyclohexane-1,3,5-tricarboxylhydrazide.

2. The method for preparing supramolecular hydrogel microcapsules according to claim 1, characterized in that, Includes the following steps: (1) Fabrication of the microfluidic chip: The microfluidic chip includes a dextran inlet, a polyethylene glycol inlet, an oil phase inlet, a cross-section, and a microcapsule outlet arranged sequentially from the inside to the outside. The dextran inlet, polyethylene glycol inlet, and oil phase inlet converge at the cross-section through a dextran dispersed phase channel, a polyethylene glycol dispersed phase channel, and a continuous phase channel, respectively. The cross-section and the microcapsule outlet are connected by an outflow channel, and a buffer channel is provided at the rear end of the outflow channel. The microfluidic chip is fabricated using conventional soft lithography. (2) Preparation of aqueous two-phase solution: Take an appropriate amount of dextran and polyethylene glycol and dissolve them in a solvent. After complete dissolution, a dextran / polyethylene glycol aqueous two-phase emulsion is obtained. After centrifugation, a dextran phase solution and a polyethylene glycol phase solution are obtained. (3) Preparation of precursor solution: Take an appropriate amount of water-soluble precursor factor A and catalyst and dissolve them in dextran phase solution, and adjust the pH to obtain dextran phase precursor solution; take an appropriate amount of water-soluble precursor factor H and dissolve it in polyethylene glycol phase solution to obtain polyethylene glycol phase precursor solution; (4) Preparation of supramolecular hydrogel microcapsules: The dextran-phase precursor solution, polyethylene glycol-phase precursor solution, and oil phase enter the microfluidic chip through the dextran inlet, polyethylene glycol inlet, and oil phase inlet, respectively. They then sequentially travel along the dextran dispersed phase channel, the polyethylene glycol dispersed phase channel, and the continuous phase channel to the intersection, forming W / W / O emulsion droplets. After the droplets have stabilized, the droplets at the microcapsule outlet are collected. The collected droplets are then allowed to stand to allow complete self-assembly, thus obtaining supramolecular hydrogel microcapsules.

3. The method for preparing supramolecular hydrogel microcapsules according to claim 2, characterized in that, In step (1), the channel height in the microfluidic chip is 80-120 μm; the width of the polyethylene glycol dispersed phase channel, dextran dispersed phase channel, continuous phase channel and outflow channel is 180-220 μm; the width of the intersection is 60-100 μm; and the width of the buffer channel is 480-520 μm.

4. The method for preparing supramolecular hydrogel microcapsules according to claim 2, characterized in that, In step (2), the solvent is ultrapure water or a 100 mM, pH 7.4 MOPS buffer solution; the mass concentration of the dextran phase solution is 7.5-15 wt%, and the mass concentration of the polyethylene glycol phase solution is 5-10 wt%.

5. The method for preparing supramolecular hydrogel microcapsules according to claim 2, characterized in that, In step (3), the concentration of the water-soluble precursor factor A is 60-180 mM, and the concentration of the water-soluble precursor factor H is 10-30 mM.

6. The method for preparing supramolecular hydrogel microcapsules according to claim 2, characterized in that, In step (3), the catalyst is selected from one of aniline, indoline, (1H-benzis[d]imidazol-2-yl)methylamine, 1,4-phenylenediamine-15N2, 3,5-diaminobenzoic acid, m-aminobenzoic acid and p-aminobenzoic acid; the concentration of the catalyst is 2.5-12 mM; and the pH is adjusted to 3-6.

7. The method for preparing supramolecular hydrogel microcapsules according to claim 2, characterized in that, In step (3), the catalyst is aniline; the concentration of the catalyst is 10 mM; and the pH is adjusted to 4.

8. The method for preparing supramolecular hydrogel microcapsules according to claim 2, characterized in that, In step (4), the oil phase is selected from isopropyl palmitate and isopropyl myristate.

9. The method for preparing supramolecular hydrogel microcapsules according to claim 2, characterized in that, The flow rate of the polyethylene glycol phase precursor solution is 0.05-0.30 μL / min, the flow rate of the dextran phase precursor solution is 0.70-0.95 μL / min, and the flow rate of the oil phase is 1-8 μL / min.

10. The method for preparing supramolecular hydrogel microcapsules according to claim 2, characterized in that, The flow rate of the polyethylene glycol phase precursor solution is 0.25 μL / min, the flow rate of the dextran phase precursor solution is 0.75 μL / min, and the flow rate of the oil phase is 3-7 μL / min.

11. A supramolecular hydrogel microcapsule, characterized in that, The supramolecular hydrogel microcapsules are prepared by the method for preparing supramolecular hydrogel microcapsules according to any one of claims 1-10.

Images