Interface self-assembly preparation method of soft rigid double-layer gel microspheres

Abstract

The invention relates to an interface self-assembly preparation method of soft rigid double-layer gel microspheres, which comprises the following steps: S1, under the condition of a weak acid solvent, carrying out grafting reaction on a main chain polymer and an activated branched chain material, and after the reaction is finished, carrying out post-treatment to obtain an amphiphilic grafted polymer; s2, dispersing and dissolving the amphiphilic graft polymer prepared in the step S1, a non-amphiphilic photo-crosslinking polymer and a photoinitiator in a solvent to obtain a hydrogel pre-polymerization liquid dispersion phase; and S3, mixing the hydrogel prepolymer dispersion phase prepared in S2 and an oily continuous phase stabilized by an emulsifier to prepare an emulsion, carrying out interface distribution for a preset time to prepare gel liquid drops, introducing the gel liquid drops into a receiving phase containing a cross-linking agent, and carrying out ultraviolet light curing to obtain the soft rigid double-layer gel microspheres of which the shell layers are cross-linked by the cross-linking agent and the core layers are cured by the ultraviolet light. The preparation method has the advantages of low manufacturing cost, controllable microsphere size and uniform physical and chemical properties.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of micro-nano materials, and in particular to an interfacial self-assembly preparation method of soft-rigid double-layer gel microspheres. BACKGROUND

[0002] A hydrogel is a three-dimensional polymer network made of natural or synthetic materials, which has high flexibility, water absorption and water retention, and also exhibits good biocompatibility and biodegradability. Gel microspheres are gel particles with a size of microns. The excellent colloidal stability and large specific surface area of gel microspheres make them widely used in the fields of cell culture, drug delivery, tissue engineering and the like. However, a single homogeneous gel microsphere is often difficult to meet the complex application requirements. For example, in the treatment of osteoarthritis, the microspheres need to have a flexible shell to better fit the damaged articular surface, and at the same time need a solid core to resist the extrusion at the joint.

[0003] A Chinese patent with publication number CN120399279A discloses a preparation method of dynamic silicone rubber microspheres, which is characterized by the following steps: injecting a polysiloxane solution containing dynamic bonds onto an ultrabiphobic coating to form a liquid column, spontaneously breaking to form polymer droplets under the driving force of interfacial tension, evaporating the solvent by heating to form polymer microspheres, and forming dynamic silicone rubber microspheres by crosslinking induced by ultraviolet light.

[0004] A Chinese patent with grant announcement number CN115873143B discloses a preparation method of core-shell double-layer structure microspheres, which is characterized by the following steps: first preparing collagen microspheres, then oxidizing hyaluronic acid with sodium periodate to prepare aldehyde-modified hyaluronic acid, preparing an aldehyde-modified hyaluronic acid aqueous solution, and performing fluidized bed spray coating on the collagen microspheres to obtain core-shell double-layer structure microspheres.

[0005] A Chinese patent with publication number CN115678855A discloses an application of exosome microspheres carrying bone differentiation promoting in bone repair, which uses GelMA and PEGDA mixed Exo as materials to produce PEGDA / GelMA / Exo microspheres through microfluidic chip technology.

[0006] In summary, the commonly used methods for preparing double-layer microspheres mainly include complex emulsion method, layer-by-layer self-assembly technology, coaxial electrostatic atomization method, etc. The complex emulsion method is to prepare a polymer solution into a W / O / W complex emulsion and then solidify, which is a relatively complex process and requires high control of parameters such as stirring speed and emulsifier concentration. The layer-by-layer self-assembly technology is based on the deposition of oppositely charged polyelectrolytes on the template particles through electrostatic interaction to form a precisely controlled multilayer film, but it is limited to the preparation of polyelectrolyte shell. The coaxial electrostatic atomization method is an advanced technology for preparing micro-nano particles using electric field force, which can realize the core-shell structure at one time, but the expensive equipment and precise requirements for fluid parameters limit its application. The microspheres with core-shell structure have excellent performance and high application value, but the existing preparation methods still have deficiencies and need to be improved. SUMMARY

[0007] The problem to be solved by the present application is to provide an interfacial self-assembly preparation method of soft rigid double-layer gel microspheres, which utilizes the difference in interfacial activity of amphiphilic grafting polymer and non-amphiphilic photo-crosslinking polymer, and controls the distribution and rigidity of the two polymers, so that the amphiphilic polymer spontaneously occupies the oil-water interface, and after solidification, a soft rigid double-layer gel microsphere is formed, which has the advantages of low manufacturing cost, adjustable microsphere size, and unified physical and chemical properties.

[0008] The above application object of the present application is realized by the following technical scheme:

[0009] An interfacial self-assembly preparation method of soft rigid double-layer gel microspheres, comprising the following steps,

[0010] S1, under weak acid solvent conditions, the main chain polymer and the activated branched material undergo grafting reaction, and after the reaction is completed, the two amphiphilic grafting polymers are obtained by post-treatment;

[0011] S2, the amphiphilic grafting polymer prepared in S1, the non-amphiphilic photo-crosslinking polymer, and the photo initiator are dispersed and dissolved in a solvent to obtain a hydrogel pre-polymer dispersion phase;

[0012] S3, the hydrogel pre-polymer dispersion phase prepared in S2 and the oil continuous phase stabilized by the emulsifier are mixed to prepare an emulsion, and after the gel droplets are prepared by interfacial distribution for a predetermined time, the receiving phase containing the crosslinking agent is introduced for ultraviolet curing to obtain the soft rigid double-layer gel microspheres with the shell layer crosslinked by the crosslinking agent and the core layer cured by ultraviolet light.

[0013] Further, in S1, the grafting rate of the branched material to the main chain polymer is 30-50%.

[0014] Further, in the S1, the main chain polymer is one or a combination of several of polylactic-co-glycolic acid, chitosan, alginate, hyaluronic acid, cellulose and its derivatives, starch, agarose, collagen, gelatin, silk fibroin, fibrin, polyethylene glycol and its derivatives, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol, poly(N-isopropylacrylamide), poly(2-hydroxyethyl methacrylate), clay (e.g. laponite), silica nanoparticles, carbon nanomaterials (e.g. graphene, carbon nanotube), hydroxyapatite.

[0015] Further, in the S1, the branched material is one or a combination of several of polyethylene glycol and its derivatives, polylactic-co-glycolic acid, polycaprolactone, poloxamer, poloxamine, 2-methacryloyloxyethyl phosphorylcholine, chitosan, hyaluronic acid, sodium alginate, albumin, glycine, arginine, serine, threonine, tyrosine, histidine, aspartic acid, lysine, glutamic acid, alanine, leucine, valine phosphatidylcholine, dodecanoic acid, octadecanoic acid, polydopamine.

[0016] Further, in the S2, the hydrogel pre-polymer dispersion phase is composed of 1.0-3.0 parts of amphiphilic graft polymer, 5.0-25.0 parts of non-amphiphilic photo-crosslinking polymer, 0.5-2.0 parts of photo-initiator, and 67.5-91.0 parts of water.

[0017] Further, in the S2, the non-amphiphilic photo-crosslinking polymer is one or a combination of several of polyethylene glycol diacrylate, polyurethane acrylate, epoxy acrylate, polyester acrylate, acrylated polyacrylate, epoxy resin.

[0018] Further, in the S2, the photo-initiator is one or a combination of several of Irgacure 2959, Irgacure 819, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), camphorquinone (CQ), Eosin Y.

[0019] Further, in the S3, the oily continuous phase is composed of 5-20 wt% emulsifier, and oily solvent.

[0020] Further, in the S3, the emulsifier is one or a combination of several of sodium dodecylbenzenesulfonate, sodium dodecyl sulfate, sodium stearate, phosphate ester salt, cetyltrimethylammonium bromide, fatty amine hydrochloride, dodecyl dimethyl betaine, sodium lauroyl sarcosinate, fatty alcohol polyoxyethylene ether, Tween, Span, sucrose ester, alkyl glycoside, rhamnolipid, phospholipid, fluorine surfactant, silicon surfactant, protein, gelatin, gum arabic, polyvinylpyrrolidone, polyethylene glycol.

[0021] Further, in the S3, the oily solvent is a combination of one or more of caprylic / capric triglyceride, ethylhexyl palmitate, isononyl isononanoate, isopropyl myristate, jojoba oil, apricot kernel oil, grape seed oil, olive oil, avocado oil, sesame oil, castor oil, wheat germ oil, liquid paraffin, vaseline, dimethicone, cyclopentasiloxane, phenyl-modified silicone oil, beeswax, candelilla wax / carnauba wax, microcrystalline wax / ozokerite, squalane, polyisobutylene

[0022] Further, in the S3, the receiving phase is composed of 0.1-30.0 wt% crosslinking agent, 0.1-1.0 wt% aspartic acid, and water.

[0023] Further, in the S3, the crosslinking agent is a combination of one or more of glutaraldehyde, genipin, N-hydroxysuccinimide, calcium ions, and tripolyphosphate.

[0024] Further, in the S3, the control interface distribution time is 1-60 min, the flow rate ratio of the hydrogel pre-polymer dispersion phase and the oily continuous phase is 1: (1-50), the crosslinking time is 3 min-2 h, and the ultraviolet light wavelength is 200-400 nm.

[0025] To sum up, the present application has the following beneficial technical effects:

[0026] 1. The present application selects two kinds of polymers with different interfacial activities to prepare a hydrogel pre-polymer, uses a microfluidic chip technology to prepare water-in-oil gel droplets, gives a certain time to make the amphiphilic polymers fully occupy the oil-water interface, uses a chemical crosslinking method to make the polymers crosslink at the interface, and uses an ultraviolet irradiation method to crosslink the non-amphiphilic photo-crosslinking polymers inside, so as to realize a soft-rigid double-layer structure, the equipment is simple, the production cost is low, the size of the prepared microspheres is controllable, and the physical and chemical properties are uniform.

[0027] 2. The present application realizes the controllable distribution of the polymers in the emulsion droplets by regulating the interfacial activity of the polymers, realizes the preparation of the microspheres with a core-shell structure by step-by-step solidification, exhibits different material characteristics on a single microsphere, has an excellent application prospect, the method is easy to operate, and the selection of the polymers is very extensive and has strong universality. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 is a flow chart of the method provided in Example 1 of the present application;

[0029] Figure 2 is an infrared spectrum of chitosan-arginine prepared in Example 2 of the present application;

[0030] Figure 3is a nuclear magnetic hydrogen spectrum of the chitosan-arginine prepared in Embodiment 2 of the present application;

[0031] Figure 4 is a comparison chart of the interfacial tension of chitosan-arginine prepared in Embodiment 2 of the present application and non-grafted chitosan and PEGDA;

[0032] Figure 5 is a chart showing the effect of the aspartic acid concentration added in Embodiment 4 of the present application on the stress-strain curve of chitosan-arginine;

[0033] Figure 6 is a chart showing the effect of the PEGDA concentration in Embodiment 4 of the present application on the stress-strain curve of the gel;

[0034] Figure 7 is a morphology chart of the microspheres prepared in Embodiment 4 of the present application under an optical microscope;

[0035] Figure 8 is a chart showing the fluorescence distribution of the microspheres prepared in Embodiment 4 of the present application under a fluorescence microscope. DETAILED DESCRIPTION

[0036] In order to make the technical means, creative features, purposes and effects realized by the present application more clear and easy to understand, the present application is further described below in combination with the drawings and specific embodiments.

[0037] Embodiment 1: Reference Figure 1 The present application discloses a method for preparing a soft-rigid double-layer gel microsphere by interfacial self-assembly, comprising the following steps,

[0038] S1: grafting reaction between a main-chain polymer and an activated branched material under weakly acidic solvent conditions, and obtaining an amphiphilic graft polymer after post-treatment after the reaction ends;

[0039] S2: dispersing and dissolving the amphiphilic graft polymer prepared in S1, a non-amphiphilic photocrosslinking polymer, and a photoinitiator in a solvent to obtain a hydrogel pre-polymer dispersion phase;

[0040] S3: mixing the hydrogel pre-polymer dispersion phase prepared in S2 and an oil continuous phase stabilized by an emulsifier to prepare an emulsion, and after gel droplets are prepared by interfacial distribution for a predetermined time, passing into a receiving phase containing a crosslinking agent for ultraviolet light curing to obtain a soft-rigid double-layer gel microsphere with a shell layer crosslinked by the crosslinking agent and a core layer cured by ultraviolet light.

[0041] In S1, the grafting rate of the branched material to the main-chain polymer is 30-50%;

[0042] The main chain polymer is one or a combination of several of polylactic acid-glycolic acid copolymer, chitosan, alginate, hyaluronic acid, cellulose and its derivatives, starch, agarose, collagen, gelatin, silk fibroin, fibrin, polyethylene glycol and its derivatives, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol, poly(N-isopropylacrylamide), poly(2-hydroxyethyl methacrylate), clay (such as laponite), silicon dioxide nanoparticles, carbon nanomaterials (such as graphene, carbon nanotubes), hydroxyapatite;

[0043] The branched material is one or a combination of several of polyethylene glycol and its derivatives, polylactic acid-glycolic acid copolymer, polycaprolactone, poloxamer, poloxamine, 2-methacryloyloxyethyl phosphorylcholine, chitosan, hyaluronic acid, sodium alginate, albumin, glycine, arginine, serine, threonine, tyrosine, histidine, aspartic acid, lysine, glutamic acid, alanine, leucine, valine phosphatidylcholine, dodecanoic acid, octadecanoic acid, polydopamine.

[0044] In S2, the hydrogel pre-polymer dispersion phase is composed of 1.0-3.0 parts of amphiphilic graft polymer, 5.0-25.0 parts of non-amphiphilic photo-crosslinking polymer, 0.5-2.0 parts of photo initiator, and 67.5-91.0 parts of water;

[0045] The non-amphiphilic photo-crosslinking polymer is one or a combination of several of polyethylene glycol diacrylate, polyurethane acrylate, epoxy acrylate, polyester acrylate, acrylated polyacrylate, epoxy resin.

[0046] The photo initiator is one or a combination of several of Irgacure 2959, Irgacure 819, lithium phenyl-2,4,6-trimethylbenzoyl phosphinate (LAP), camphorquinone (CQ), Eosin Y.

[0047] In S3, the continuous phase is composed of 5-20 wt% emulsifier and oily solvent;

[0048] The emulsifier is one or a combination of several of sodium dodecylbenzenesulfonate, sodium dodecyl sulfate, sodium stearate, phosphate ester salt, cetyltrimethylammonium bromide, fatty amine hydrochloride, dodecyl dimethyl betaine, sodium lauroyl sarcosinate, fatty alcohol polyoxyethylene ether, Tween, Span, sucrose ester, alkyl glycoside, rhamnolipid, phospholipid, fluorine surfactant, silicon surfactant, protein, gelatin, gum arabic, polyvinylpyrrolidone, polyethylene glycol;

[0049] The oily solvent is a combination of one or more of caprylic / capric triglyceride, ethylhexyl palmitate, isononyl isononanoate, isopropyl myristate, jojoba oil, apricot kernel oil, grape seed oil, olive oil, avocado oil, sesame oil, castor oil, wheat germ oil, liquid paraffin, vaseline, dimethicone, cyclopentasiloxane, phenyl-modified silicone oil, beeswax, candelilla wax / carnauba wax, microcrystalline wax / ozokerite, squalane, polyisobutylene;

[0050] The receiving phase is composed of 0.1-30.0 wt% crosslinking agent, 0.1-1.0 wt% aspartic acid, and water;

[0051] The crosslinking agent is a combination of one or more of glutaraldehyde, genipin, N-hydroxysuccinimide, calcium ions, and tripolyphosphate;

[0052] The method for preparing the emulsion by mixing includes, but is not limited to, any one or a combination of several of microfluidization, mechanical stirring, simple homogenizer, phase inversion, emulsion inversion, and self-emulsification;

[0053] The control interface distribution time is 1-60 min, the flow rate ratio of the hydrogel pre-polymer dispersion phase and the oily continuous phase is 1: (1-50), the crosslinking time is 3 min-2 h, and the ultraviolet light wavelength is 200-400 nm.

[0054] Embodiment 2: The method for preparing a soft-rigid double-layer gel microsphere by interfacial self-assembly according to the present application is different from Embodiment 1 in that the specific implementation of S1 is as follows:

[0055] S11: 2.64 g of L-arginine is weighed into a 100 mL beaker, 20 mL of a morpholine ethanesulfonic acid buffer (0.1 mol / L) is added, the L-arginine is stirred to fully dissolve, and then 1.75 g of N-hydroxysuccinimide (NHS) is slowly added to activate the carboxyl group. After fully stirring and dissolving, 4.35 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) dissolved in 10 mL of a morpholine ethanesulfonic acid buffer solution is slowly added to the mixed solution of L-arginine and N-hydroxysuccinimide (NHS), 10% hydrochloric acid (HCl) is used to adjust the pH value of the reaction solution to 6.0, and stirring is continued for 2 h to obtain activated branched materials;

[0056] S12: 0.5 g of chitosan powder (50% degree of deacetylation, molecular weight 50000) is weighed into a 100 mL beaker, 25 mL of an aqueous solution containing 1% acetic acid is added, and magnetic stirring is performed until complete dissolution to obtain a main chain polymer;

[0057] S13 The activated branched material was added to the main-chain polymer and stirred until homogeneous. The pH of the reaction solution was adjusted to 6.0 with 10 mg / mL sodium hydroxide aqueous solution. The reaction was stirred at room temperature for 24 h. After the reaction was completed, the reaction product was placed in a dialysis bag (M). w In a solution containing CO=8000-14000Da, dialysis with deionized water was performed for 7 days, with the water changed twice a day. After dialysis, the solution was freeze-dried to obtain arginine-chitosan, which is an amphiphilic graft polymer.

[0058] Example 3: This is a method for preparing soft-rigid bilayer gel microspheres through interfacial self-assembly, as disclosed in this invention. The difference from Example 2 is that S2 is specifically implemented as follows:

[0059] 0.2g of arginine-chitosan (amphiphilic graft polymer) prepared in Example 2, 1.5g of polyethylene glycol diacrylate (PEGDA-1000, non-amphiphilic photocrosslinking polymer), 0.05g of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone (I2959, photoinitiator), 0.05g of glacial acetic acid (pH adjuster), and 8.2g of purified water (solvent) were mixed evenly and then sonicated for 20min to completely disperse and dissolve the mixture. The mixture was then filtered through a needle filter with a pore size of 0.22μm and placed in a brown reagent bottle for later use, thus obtaining the hydrogel prepolymer dispersion phase.

[0060] Example 4: This is a method for preparing soft-rigid bilayer gel microspheres through interfacial self-assembly, as disclosed in this invention. The difference from Example 3 is that the specific implementation of step S3 is as follows:

[0061] The oily solvent for the S31 oily continuous phase is liquid paraffin. To stabilize the generated droplets and prevent droplet coalescence, 5 wt% of Span 80 is added as a surfactant. After thorough mixing, an oily continuous phase stabilized by an emulsifier is obtained.

[0062] S32 uses 10wt% tripolyphosphate as the crosslinking agent for chitosan, 0.2wt% aspartic acid to improve the mechanical strength of chitosan after crosslinking, and purified water as the solvent. After preparation, it is stored in a reagent bottle for later use to obtain the receiving phase.

[0063] The S33 uses a flow-focusing microfluidic chip to simultaneously introduce an oily continuous phase and a hydrogel prepolymer dispersion phase into the microfluidic chip at flow rates of 1 μL / min and 20 μL / min, respectively. At the interface between the two phases, the continuous phase acts as a symmetrical shear force to generate gel droplets. The generated gel droplets are then introduced into the receiving phase and cured by irradiation with 12W ultraviolet light (365nm) for 20 minutes.

[0064] S34 The solid-liquid mixture after solidification was collected, washed with isopropanol-water solution (1:1, by volume) for 3 times, centrifuged to remove the upper liquid paraffin, placed in a fume hood overnight to volatilize isopropanol, and finally freeze-dried to obtain soft-rigid double-layer gel microspheres with the shell layer crosslinked by the crosslinking agent and the core layer solidified by ultraviolet light, which were stored at -20°C.

[0065] Example 5: An interfacial self-assembly method for preparing soft-rigid double-layer gel microspheres according to the present disclosure, which is different from Example 4 in that PEGDA-600 is used instead of PEGDA-1000 in S2.

[0066] Example 6: An interfacial self-assembly method for preparing soft-rigid double-layer gel microspheres according to the present disclosure, which is different from Example 4 in that in S3, the oily continuous phase and the hydrogel pre-polymer dispersion phase are simultaneously introduced into the microfluidic chip at flow rates of 2 μL / min and 20 μL / min, respectively.

[0067] Example 7: An interfacial self-assembly method for preparing soft-rigid double-layer gel microspheres according to the present disclosure, which is different from Example 4 in that in S3, the microfluidic chip is replaced by a T-shaped chip.

[0068] Example 8: An interfacial self-assembly method for preparing soft-rigid double-layer gel microspheres according to the present disclosure, which is different from Example 4 in that in S3, the emulsion is prepared by homogenization, and the hydrogel pre-polymer dispersion phase and the oily continuous phase are prepared at a ratio of 1:10, and the homogenizer is rotated at a speed of 3000 rpm for 30 s to obtain the W / O primary emulsion.

[0069] Example 9: An interfacial self-assembly method for preparing soft-rigid double-layer gel microspheres according to the present disclosure, which is different from Example 4 in that in S3, the receiving phase is a 0.3 wt% aqueous solution of genipin and a 0.2 wt% aqueous solution of aspartic acid.

[0070] Example 10: An interfacial self-assembly method for preparing soft-rigid double-layer gel microspheres according to the present disclosure, which is different from Example 4 in that in S3, the receiving phase is a 10 wt% aqueous solution of tripolyphosphate, a 0.3 wt% aqueous solution of genipin, and a 0.2 wt% aqueous solution of aspartic acid.

[0071] Figure 2 The FT-IR spectrum of chitosan-arginine is as follows: Figure 2 It can be seen that arginine is successfully grafted onto chitosan. Figure 3 The FT-IR spectrum of chitosan-arginine is as follows: Figure 3 It can be further verified that the grafting is successful, and the grafting rate of chitosan is calculated to be 31.58%. Figure 4 The interfacial tension of chitosan before and after grafting and PEGDA is compared as follows:Figure 4 It can be seen that the interfacial tension of the modified chitosan is significantly reduced, showing amphiphilicity, and the upper interfacial rate and stability on the oil-water interface are higher than those of PEGDA.

[0072] Figure 5 To add the influence of aspartic acid content on the cross-linking strength of chitosan, from Figure 5 It can be seen that if the aspartic acid is 0.2wt%, the mechanical strength of the cross-linked chitosan-arginine is the largest. Figure 6 To add the influence of PEGDA concentration on the mechanical strength of the cross-linked gel, from Figure 6 It can be seen that when the PEGDA concentration is 15wt%, the mechanical strength can reach 6MPa, and the supporting ability is strong. Combined with Figure 5~6 , the outer chitosan-arginine of the prepared double-layer microspheres serves as an elastic part, and the soft surface can effectively dissipate external extrusion. The internal PEGDA is a rigid part, and the tough core can maintain the morphology of the microspheres and play a supporting effect.

[0073] Figure 7 To add the morphology of the microspheres under the optical microscope, from Figure 7 It can be seen that the microspheres are double-layered structures. Figure 8 To add the morphology of the microspheres prepared by labeling chitosan-arginine molecules with FITC under fluorescence confocal microscope, from Figure 8 It can be seen that the chitosan-arginine is distributed on the periphery of the microspheres, forming the outer shell of the microspheres.

[0074] Finally, it should be pointed out that the above examples are only used to illustrate the technical solutions of the present application and are not limiting. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the purpose and scope of the present application, and they should be covered in the scope of the claims of the present application.

Claims

1. A method for preparing soft-rigid bilayer gel microspheres through interfacial self-assembly, characterized in that: Includes the following steps, Under weakly acidic solvent conditions, S1 undergoes a grafting reaction between the main chain polymer and the activated branched material. After the reaction is completed, post-treatment is performed to obtain an amphiphilic grafted polymer. S2 disperses and dissolves the amphiphilic grafted polymer, the non-amphiphilic photocrosslinked polymer, and the photoinitiator obtained in S1 in a solvent to obtain a hydrogel prepolymer dispersion phase; S3 mixes the hydrogel prepolymer dispersion phase obtained in S2 with an oily continuous phase stabilized by an emulsifier to prepare an emulsion. After the interface is distributed for a predetermined time to obtain gel droplets, the emulsion is passed into a receiving phase containing a crosslinking agent for ultraviolet light curing to obtain a soft and rigid bilayer gel microsphere with a shell layer crosslinked by a crosslinking agent and a core layer cured by ultraviolet light.

2. The method for preparing a soft-rigid bilayer gel microsphere through interfacial self-assembly according to claim 1, characterized in that: In S1, the grafting rate of the branched material onto the main-chain polymer is 30-50%.

3. The method for preparing soft-rigid bilayer gel microspheres by interfacial self-assembly according to claim 2, characterized in that: In S1, the main chain polymer is one or a combination of several of the following: polylactic acid-glycolic acid copolymer, chitosan, alginate, hyaluronic acid, cellulose and its derivatives, starch, agarose, collagen, gelatin, silk fibroin, fibroin, polyethylene glycol and its derivatives, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol, poly(N-isopropylacrylamide), poly(2-hydroxyethyl methacrylate), clay, silica nanoparticles, carbon nanomaterials, and hydroxyapatite.

4. The method for preparing a soft-rigid bilayer gel microsphere through interfacial self-assembly according to claim 2, characterized in that: In S1, the branched material is one or a combination of several of the following: polyethylene glycol and its derivatives, polylactic acid-glycolic acid copolymer, polycaprolactone, poloxamer, poloxamine, 2-methacryloyloxyethylphosphatidylcholine, chitosan, hyaluronic acid, sodium alginate, albumin, glycine, arginine, serine, threonine, tyrosine, histidine, aspartic acid, lysine, glutamic acid, alanine, leucine, valine phosphatidylcholine, dodecanoic acid, stearic acid, and polydopamine.

5. The method for preparing a soft-rigid bilayer gel microsphere through interfacial self-assembly according to claim 1, characterized in that: In S2, the hydrogel prepolymer dispersion phase consists of 1.0 to 3.0 parts of amphiphilic grafted polymer, 5.0 to 25.0 parts of non-amphiphilic photocrosslinking polymer, 0.5 to 2.0 parts of photoinitiator, and 67.5 to 91.0 parts of water.

6. The method for preparing soft-rigid bilayer gel microspheres by interfacial self-assembly according to claim 5, characterized in that: In S2, the non-amphiphilic photocrosslinking polymer is one or a combination of several of polyethylene glycol diacrylate, polyurethane acrylate, epoxy acrylate, polyester acrylate, acrylated polyacrylate, and epoxy resin.

7. The method for preparing soft-rigid bilayer gel microspheres by interfacial self-assembly according to claim 1, characterized in that: In S3, the oily continuous phase consists of 5-20 wt% emulsifier and oily solvent.

8. The method for preparing soft-rigid bilayer gel microspheres by interfacial self-assembly according to claim 1, characterized in that: In S3, the receiving phase consists of 0.1 to 30.0 wt% crosslinking agent, 0.1 to 1.0 wt% aspartic acid, and water.

9. The method for preparing soft-rigid bilayer gel microspheres by interfacial self-assembly according to claim 8, characterized in that: In S3, the crosslinking agent is one or a combination of several of the following: glutaraldehyde, genipin, N-hydroxysuccinimide, calcium ions, and tripolyphosphate.

10. The method for preparing soft-rigid bilayer gel microspheres by interfacial self-assembly according to claim 1, characterized in that: In S3, the interface distribution time is controlled to be 1~60 min, the flow rate ratio of the hydrogel prepolymer dispersed phase to the oily continuous phase is 1:(1~50), the crosslinking time is 3 min~2 h, and the ultraviolet wavelength is 200~400 nm.

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