Body temperature responsive self-adhesive gel microsphere and preparation method and application thereof

Abstract

The invention discloses body temperature responsive self-adhesive gel microspheres as well as a preparation method and application thereof, and relates to the technical field of medicines. The body temperature responsive self-adhesive gel microspheres comprise a photocuring structure stabilizing unit material and a body temperature responsive self-adhesive unit material; the photocuring structure stable unit material comprises at least one of a natural polymer derivative material and a synthetic polymer material; the body temperature responsive self-adhesive unit material can be subjected to chain segment migration and re-entanglement at a physiological temperature. The gel microsphere has good temperature-controlled self-adhesion capability and interface adhesion property, and can be used as an embolism agent for treating vascular embolism.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a body temperature-responsive self-adhesive gel microsphere, its preparation method, and its application. Background Technology

[0002] Transcatheter arterial embolization (TAE) delivers embolic materials to target vessels to block blood supply to the lesion area, and is widely used in the clinical treatment of diseases such as hepatocellular carcinoma, acute hemorrhage, vascular malformations, and aneurysms. Microparticles were the earliest type of embolic agent developed. However, irregularly shaped particles are prone to interlocking, limiting injectability and flowability, which can lead to accidental occlusion of the catheter lumen or larger proximal vessels, hindering distal embolization. In contrast, calibrated spherical embolic agents offer advantages such as regular morphology, controllable particle size, and good flowability, allowing them to penetrate deeper into the vessel and distribute more evenly in the target area. Over the past few decades, microspheres such as DC Bead® (polyvinyl alcohol), HepaSphere® (sodium acrylate copolymer), and Embosphere® (gelatin acrylate) have been clinically applied in interventional therapy, representing an important direction in the development of current embolic agents.

[0003] Monodisperse microspheres, with their smooth, regular surface morphology, do not tend to aggregate, ensuring good injectability and low flow resistance in blood vessels, which is beneficial for improving the precision and safety of the procedure. However, in a real hemodynamic environment, individual microspheres are easily affected by shear forces, causing them to shift or migrate, or even be washed into non-target areas by blood flow, leading to the risk of misembolization or recanalization. In other words, most of the solid embolic agents currently used in clinical practice are monodisperse microspheres. Although they have good injectability, they cannot interact to form a structurally continuous physical occlusion. Once affected by blood flow shear forces, microspheres are easily dispersed, resulting in unstable or incomplete embolization.

[0004] Therefore, while maintaining good injection performance, improving the aggregation ability and occlusion stability of microspheres in target blood vessels, and developing novel microspheres with both good tissue adaptability and long-term embolization stability, remains a key technical challenge that urgently needs to be solved in this field.

[0005] Therefore, existing technologies still need to be improved and developed. Summary of the Invention

[0006] Based on the shortcomings of the prior art, the purpose of this invention is to provide a body temperature responsive self-adhesive gel microsphere, its preparation method and application, aiming to solve the problem that although existing monodisperse microspheres have good injectability, they are easily dispersed and cannot interact to form a structurally continuous physical sealing body.

[0007] The technical solution of the present invention is as follows: In a first aspect, the present invention provides a thermo-responsive self-adhesive gel microsphere, wherein the thermo-responsive self-adhesive gel microsphere comprises a photocurable structural stabilizing unit material and a thermo-responsive self-adhesive unit material; The photocurable structural stabilizing unit material includes at least one of natural polymer derivatives and synthetic polymers. The body temperature responsive self-adhesive unit material can undergo segment migration and re-entanglement at physiological temperatures.

[0008] Optionally, the body temperature responsive self-adhesive gel microspheres further include at least one of biocompatible nano-confining unit materials and interfacial adhesion unit materials; The biocompatible nanoconfined unit material includes nanomaterials with a two-dimensional layered structure; The interfacial adhesion unit material includes polyphenolic compounds with ortho-phenolic hydroxyl structures.

[0009] Optionally, the natural polymer derivative material includes at least one of the following: methacrylamide gelatin, methacrylamide hyaluronic acid, methacrylamide sodium alginate, methacrylamide chitosan, methacrylamide chondroitin sulfate, methacrylamide dextran, methacrylamide silk fibroin, methacrylamide collagen, methacrylamide agarose, and methacrylamide fiber. The synthetic polymer material includes at least one of polyethylene glycol diacrylate, multi-arm polyethylene glycol acrylate, polyethylene glycol acrylate, polycaprolactone acrylate, polyamino acid acrylate, polyacrylamide derivative, poly(N-isopropylacrylamide) derivative, and polymethyl methacrylate copolymer.

[0010] Optionally, the body temperature responsive self-adhesive unit material includes at least one of gelatin, gelatin derivatives, chitosan, chitosan derivatives, silk fibroin, elastin-like peptides, collagen-like peptides, polycaprolactone, poly-N-isopropylacrylamide, poly-N-isopropylacrylamide copolymer, polyethylene glycol-polylactic acid block copolymer, methylcellulose, and methylcellulose derivatives.

[0011] Optionally, the nanomaterial with a two-dimensional layered structure includes at least one of nanoclay, layered double hydroxide, black phosphorus, hexagonal boron nitride, expandable graphite, graphitic carbon nitride, graphene, graphene derivatives, transition metal disulfides, transition metal oxides, transition metal carbides, transition metal nitrides, metal-organic frameworks, and covalent organic frameworks.

[0012] Optionally, the polyphenolic compound having an ortho-hydroxyl structure includes at least one of dopamine, dopa, protocatechuic acid, gallic acid, pyrocyanic acid, chlorogenic acid, caffeic acid, tannic acid, ellagic acid, catechin, quercetin, rutin, proanthocyanidins, and epigallocatechin gallate.

[0013] Optionally, the body temperature responsive self-adhesive gel microspheres may further include a photoinitiator, photoinitiator-modified particles, or a crosslinking agent; The photoinitiators include lithium phenyl-2,4,6-trimethylbenzoylphosphine oxide, phenyl bis(2,4,6-trimethylbenzoyl)phosphine oxide, monoacylphosphine oxide, 2-hydroxy-2-methyl-1-phenyl-1-propanone, 1-hydroxycyclohexylphenyl ketone, 2-benzyl-2-dimethylamino-1-(4-morpholinobenzylphenyl)butanone, 2-methyl-1-(4-methylthiophenyl)-2-morpholino-1-propanone, 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylphenylpropanone, 2,2-dimethoxy-2-phenylacetophenone, ketoxime esters, and [Ru(bpy)3]. 2+ One of the following: persulfate system, riboflavin, riboflavin derivatives, chlorophyll, chlorophyll derivatives, Eosin Y / triethanolamine system, organometallic complexes, or organometallic complex derivatives; The photoinitiator-modified particles include photoinitiator-modified upconversion nanoparticles; The crosslinking agent includes at least one of glutaraldehyde and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

[0014] Optionally, the body temperature-responsive self-adhesive gel microspheres, by weight, comprise: The composition includes 1-50 parts of photocurable structural stabilizing unit material, 1-50 parts of body temperature responsive self-adhesive unit material, 0-3 parts of biocompatible nano-constraint unit material, 0-3 parts of interfacial adhesion unit material, and 0.1-10 parts of photoinitiator. And / or, The temperature-responsive self-adhesive microspheres have a particle size of 20 μm to 1000 μm.

[0015] A second aspect of the present invention provides a method for preparing the body temperature-responsive self-adhesive gel microspheres of the present invention as described above, comprising the following steps: A prepolymer solution is obtained by mixing a photocurable structural stabilizing unit material, a body temperature responsive self-adhesive unit material, and a photoinitiator with water and heating the mixture. The prepolymer liquid is prepared into pregel droplets; The pregel droplets were subjected to cross-linking polymerization under preset temperature and preset wavelength irradiation conditions to obtain the body temperature responsive self-adhesive gel microspheres.

[0016] Optionally, the preset temperature is 30℃~80℃, and the preset wavelength is 300nm~900nm; and / or, The method for preparing the prepolymer liquid into pregel droplets includes one of the following: droplet microfluidics, mechanical stirring emulsification, membrane emulsification, gas-assisted spraying, electrospraying, high-pressure homogenization, and high-speed shearing.

[0017] A third aspect of the present invention provides the application of the thermoresponsive self-adhesive gel microspheres of the present invention as described above, or the thermoresponsive self-adhesive gel microspheres prepared by the preparation method of the present invention as described above, in the preparation of embolic agents, subcutaneous injection materials, ophthalmic gel materials, self-repairing gels for wound healing, tissue-engineered scaffolds for cartilage regeneration, or tissue-engineered scaffolds for skin regeneration.

[0018] Beneficial Effects: The synergistic effect of the various unit materials in this invention endows the gel microspheres with excellent temperature-controlled self-adhesion and interfacial adhesion properties, enabling them to be used as embolic agents for the treatment of vascular embolism. Specifically, the gel microspheres remain dispersed in vitro and have good injectability; after entering the body, triggered by physiological temperature, the movement and entanglement of polymer chains drive the formation of self-adhesive connections between the gel microspheres, allowing the dispersed gel microspheres to achieve dynamic interfacial reconstruction within the blood vessel, forming a structurally continuous occluder (i.e., welding the gel microspheres into a whole), effectively solving the problem that existing microspheres are loosely structured and easily dispersed in blood flow, failing to achieve effective occlusion. In addition, the gel microspheres have good tissue adhesion ability, which can significantly reduce the risk of reflux and distal migration. This invention achieves a triple functional synergy of "injectability-temperature-responsive self-adhesion-tissue adhesion" through a dual stabilization mechanism of self-adhesion between gel microspheres and adhesion between gel microspheres and vascular tissue, inhibiting microsphere slippage and migration, and reducing the risk of complications caused by non-targeted embolization of microspheres. Attached Figure Description

[0019] Figure 1 This is a microscopic image of the body temperature responsive self-adhesive gel microspheres prepared in Example 1.

[0020] Figure 2 This is a diagram showing the results of verifying the self-adhesive properties of the body temperature-responsive self-adhesive gel microspheres in vitro in Example 2.

[0021] Figure 3 The particle size distribution diagram is shown for the body temperature responsive self-adhesive gel microspheres prepared in Example 3.

[0022] Figure 4 The image shows the adhesion strength results of the hydrogel sheets prepared under different dopamine contents in Example 4.

[0023] Figure 5The graph shows the adhesion strength results of hydrogel sheets prepared with different Laponite contents in Example 5.

[0024] Figure 6 This is a diagram showing the verification results of the self-adhesion performance of the body temperature responsive self-adhesive gel microspheres in animals in Example 6.

[0025] Figure 7 This is a diagram showing the results of verifying the adhesion performance of the body temperature-responsive self-adhesive gel microspheres to skin tissue in Example 7.

[0026] Figure 8 This is a diagram showing the verification results of the adhesion performance between the body temperature-responsive self-adhesive gel microspheres and the inner wall of blood vessels in Example 8.

[0027] Figure 9 The image shows the adhesion strength results of the hydrogel sheet prepared in Example 9.

[0028] Figure 10 The image shows the adhesion strength results of the hydrogel sheet prepared in Example 10.

[0029] Figure 11 The graph shows the adhesion strength of hydrogel sheets prepared under different ratios of gelatin and methacrylamide gelatin in Examples 11 to 13.

[0030] Figure 12 The graph shows the adhesion strength results of the hydrogel sheets prepared in Examples 14 to 17. Detailed Implementation

[0031] This invention provides a body temperature-responsive self-adhesive gel microsphere, its preparation method, and its application. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0033] Existing embolic microsphere designs primarily focus on particle size control, drug loading, and release properties, resulting in limited material functional integration. Currently, most clinically used solid embolic agents are monodisperse microspheres. While they offer good injectability, they cannot interact to form a structurally continuous physical occluder. Under blood flow shear forces, microspheres are easily dispersed, leading to unstable or incomplete embolization. Furthermore, existing embolic microspheres typically exhibit non-specific physical embedding with vascular tissue, resulting in weak interfacial bonding and insufficient adhesion for stable anchoring. Under continuous blood flow perfusion, they are prone to overall slippage, backflow, or distal migration, potentially leading to non-target embolism or vascular recanalization risks. Moreover, microspheres migrating to non-target organs (such as the lungs or brain) may cause vascular occlusion, inducing pulmonary embolism, cerebral infarction, and other multi-organ dysfunctions, even causing irreversible tissue failure and medical accidents. Therefore, simultaneously achieving good injectability, aggregation at physiological temperatures, and adhesion to vascular tissue remains a critical technical challenge that urgently needs to be addressed in this field.

[0034] Based on this, embodiments of the present invention provide a body temperature responsive self-adhesive gel microsphere, wherein the body temperature responsive self-adhesive gel microsphere comprises a photocurable structural stabilizing unit material and a body temperature responsive self-adhesive unit material.

[0035] This invention also provides a thermoresponsive self-adhesive gel microsphere, wherein the thermoresponsive self-adhesive gel microsphere comprises a photocurable structural stabilizing unit material, a thermoresponsive self-adhesive unit material, and a biocompatible nano-constraint unit material.

[0036] This invention also provides a thermoresponsive self-adhesive gel microsphere, wherein the thermoresponsive self-adhesive gel microsphere comprises a photocurable structural stabilizing unit material, a thermoresponsive self-adhesive unit material, and an interfacial adhesion unit material.

[0037] This invention also provides a thermoresponsive self-adhesive gel microsphere, wherein the thermoresponsive self-adhesive gel microsphere comprises a photocurable structural stabilizing unit material, a thermoresponsive self-adhesive unit material, a biocompatible nano-constraint unit material, and an interface adhesion unit material.

[0038] In the above embodiments, the photocurable structural stabilizing unit material includes at least one of natural polymer derivative materials and synthetic polymer materials; The body temperature responsive self-adhesive unit material can undergo segment migration and re-entanglement at physiological temperatures; The biocompatible nanoconfined unit material includes nanomaterials with a two-dimensional layered structure; The interfacial adhesion unit material includes polyphenolic compounds with ortho-phenolic hydroxyl structures.

[0039] In this embodiment of the invention, the synergistic effect of the various unit materials endows the gel microspheres with excellent temperature-controlled self-adhesion and interfacial adhesion properties, enabling the gel microspheres to be used for the treatment of vascular embolism. Specifically, the gel microspheres remain dispersed in vitro and have good injection performance; after entering the body, triggered by physiological temperature, the movement and entanglement of polymer chains can drive the formation of self-adhesive connections between the gel microspheres, allowing the dispersed gel microspheres to achieve dynamic interfacial reconstruction within the blood vessel, forming a structurally continuous occluder (i.e., welding the gel microspheres into a whole), effectively solving the problem that existing microspheres are loosely structured and easily dispersed in blood flow, failing to achieve effective occlusion. The ortho-phenolic hydroxyl structure endows the gel microspheres with excellent tissue adhesion ability, that is, the ortho-phenolic hydroxyl groups in the gel microspheres can form hydrogen bonds and covalent interactions with specific functional groups on the vascular wall (such as amino, hydroxyl, carboxyl, and thiol groups contained in proteins and polysaccharides on the vascular wall), significantly reducing the risk of reflux and distal migration. The embodiments of the present invention achieve a triple synergistic effect of "injectability-temperature-responsive self-adhesion-tissue adhesion" through a dual stabilization mechanism of self-adhesion between gel microspheres and adhesion between gel microspheres and vascular tissue, thereby inhibiting the sliding and migration of microspheres and reducing the risk of complications caused by non-targeted embolization of microspheres.

[0040] In this embodiment, the photocurable structural stabilizing unit material can form a three-dimensional network structure through free radical polymerization or photoinduced crosslinking reaction under specific wavelength light irradiation conditions. The thermoresponsive self-adhesive unit material is temperature sensitive and can undergo chain segment migration and re-entanglement at physiological temperature (approximately 37°C) to achieve thermoresponsive self-adhesion of the gel microspheres. The thermoresponsive self-adhesive unit material works synergistically with other dynamic crosslinking units in the hydrogel system (such as hydrogen bonds, metal coordination bonds, imine bonds, etc.) to achieve multi-mechanism coupling and regulation of self-adhesion response, improving the interfacial self-adhesion efficiency and overall stability between microspheres.

[0041] Polyphenolic compounds with ortho-hydroxyl groups can adhere to various substrate materials through covalent interactions (such as Schiff base reactions and Michael addition) and non-covalent interactions (such as hydrogen bonds and π-π stacking) due to the presence of their catechol functional groups. However, the process of functionalizing them to further improve adhesion is very complex and may require the introduction of exogenous initiators, while exogenous oxidants may weaken adhesion performance. Therefore, this invention eliminates the need for exogenous oxidants by utilizing the limited space of nanomaterials with two-dimensional layered structures (such as synthetic lithium magnesium silicate, montmorillonite, and Hectolith) to achieve controlled oxidative polymerization of polyphenolic compounds with ortho-hydroxyl groups (such as dopamine) under mild conditions, thereby improving the adhesion performance of gel microspheres and thus enhancing their tissue anchoring and anti-migration properties. Furthermore, utilizing the limited space between layers of nanomaterials with two-dimensional layered structures (such as synthetic lithium magnesium silicate, montmorillonite, and Hectolith) not only maintains sufficient catechol groups as adhesion units, but also preserves the polymer's dynamic bond exchange and segment diffusion capabilities, which is beneficial for constructing hydrogel networks with self-adhesion and adhesion functions.

[0042] In some embodiments, the natural polymer derivative material includes, but is not limited to, at least one of the following: methacrylamide gelatin, methacrylamide hyaluronic acid, methacrylamide sodium alginate, methacrylamide chitosan, methacrylamide chondroitin sulfate, methacrylamide dextran, methacrylamide silk fibroin, methacrylamide collagen, methacrylamide agarose, and methacrylamide fiber.

[0043] In some embodiments, the synthetic polymer material includes, but is not limited to, at least one of polyethylene glycol diacrylate, multi-arm polyethylene glycol acrylate, polyethylene glycol acrylate, polycaprolactone acrylate, polyamino acid acrylate, polyacrylamide derivatives, poly(N-isopropylacrylamide) derivatives, and polymethyl methacrylate copolymers.

[0044] In some embodiments, the body temperature responsive self-adhesive unit material includes, but is not limited to, at least one of gelatin, gelatin derivatives, chitosan, chitosan derivatives, silk fibroin, elastin-like peptides (ELPs), collagen peptides, polycaprolactone (PCL), poly-N-isopropylacrylamide (PNIPAM), poly-N-isopropylacrylamide copolymer, polyethylene glycol-polylactic acid block copolymer (PEG-PLA), methylcellulose, and methylcellulose derivatives.

[0045] In some embodiments, the nanomaterials having a two-dimensional layered structure include, but are not limited to, nanoclay, layered double hydroxides (LDHs), black phosphorus (BP), hexagonal boron nitride (h-BN), expandable graphite, graphitic carbon nitride (g-C3N4), graphene and its derivatives (such as GO, rGO), transition metal disulfides (TMDs, such as MoS2, WS2, etc.), transition metal oxides (such as MnO2, TiO2 nanosheets, etc.), transition metal carbon / nitrides (MXenes), metal-organic frameworks (MOFs), and covalent organic frameworks (COFs).

[0046] For example, the nano-clay includes, but is not limited to, kaolinite, montmorillonite (MMT), hectorite, vermiculite, and synthetic layered silicates (such as Laponite, i.e., synthetic lithium magnesium silicate).

[0047] In some embodiments, the polyphenolic compounds having an ortho-hydroxyl structure include, but are not limited to, at least one of dopamine, dopa, protocatechuic acid, gallic acid, pyrocyanic acid, chlorogenic acid, caffeic acid, tannic acid, ellagic acid, catechin, quercetin, rutin, proanthocyanidins, and epigallocatechin gallate.

[0048] In addition, natural polymer-based hydrogels contain abundant reactive groups such as amino and carboxyl groups, which synergistically interact with the phenolic hydroxyl and quinone groups in polydopamine to form multiple interfacial bonding reactions (such as hydrogen bonds and covalent bonds), further endowing the gel microspheres with excellent tissue adhesion ability, thereby increasing their stability in vivo.

[0049] In some embodiments, the body temperature responsive self-adhesive gel microspheres further include a photoinitiator, photoinitiator-modified particles, or a crosslinking agent.

[0050] In some embodiments, the photoinitiator includes ultraviolet light-responsive photoinitiators, visible light-responsive photoinitiators, and near-infrared light-responsive photoinitiators.

[0051] Specifically, the photoinitiators include, but are not limited to, lithium phenyl-2,4,6-trimethylbenzoylphosphine oxide (LAP), phenyl bis(2,4,6-trimethylbenzoyl)phosphine oxide (BAPO), monoacylphosphine oxide (MAPO), 2-hydroxy-2-methyl-1-phenyl-1-propanone (Darocur 1173), 1-hydroxycyclohexylphenyl methyl ketone (Irgacure 184), 2-benzyl-2-dimethylamino-1-(4-morpholinobenzylphenyl)butanone (Irgacure 369), 2-methyl-1-(4-methylthiophenyl)-2-morpholino-1-propanone (Irgacure 907), 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylphenylpropanone (Irgacure 2959), 2,2-dimethoxy-2-phenylacetophenone (DMPA), ketoxime esters, [Ru(bpy)3]² + One of the following: persulfate system, riboflavin, riboflavin derivatives, chlorophyll, chlorophyll derivatives, Eosin Y / triethanolamine (TEA) system, organometallic complexes (visible or near-infrared responsive, such as iridium complexes and platinum complexes), or organometallic complex derivatives.

[0052] In some embodiments, the photoinitiator-modified particles include, but are not limited to, photoinitiator-modified upconversion nanoparticles (such as composites of UCNPs@LAP and UCNPs@Irgacure2959).

[0053] In some embodiments, the crosslinking agent includes, but is not limited to, at least one of glutaraldehyde and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

[0054] In some embodiments, the body temperature-responsive self-adhesive gel microspheres comprise: The composition includes 1-50 parts of photocurable structural stabilizing unit material, 1-50 parts of body temperature responsive self-adhesive unit material, 0-3 parts of biocompatible nano-constraint unit material, 0-3 parts of interfacial adhesion unit material, and 0.1-10 parts of photoinitiator.

[0055] In some embodiments, the body temperature-responsive self-adhesive gel microspheres comprise: The composition includes 1-50 parts of photocurable structural stabilizing unit material, 1-50 parts of body temperature responsive self-adhesive unit material, 0-3 parts of biocompatible nano-constraint unit material, 0-3 parts of interfacial adhesion unit material, 0.1-10 parts of photoinitiator, and 100 parts of water.

[0056] In some embodiments, the body temperature-responsive self-adhesive gel microspheres comprise: The mixture consists of 5-10 parts of photocurable structural stabilizing unit material, 5-10 parts of body temperature responsive self-adhesive unit material, 0.1-3 parts of biocompatible nano-constraint unit material, 0.1-3 parts of interfacial adhesion unit material, 5-10 parts of photoinitiator, and 100 parts of water.

[0057] In some embodiments, the particle size of the body temperature responsive self-adhesive microspheres is 20 μm to 1000 μm (e.g., it can be 20 μm, 50 μm, 80 μm, 100 μm, 200 μm, 300 μm, 500 μm, 800 μm or 1000 μm, etc.).

[0058] This invention also provides a method for preparing the body temperature-responsive self-adhesive gel microspheres as described above, comprising the following steps: A prepolymer solution is obtained by mixing a photocurable structural stabilizing unit material, a body temperature responsive self-adhesive unit material, and a photoinitiator with water and heating the mixture. The prepolymer liquid is prepared into pregel droplets; The pregel droplets were subjected to cross-linking polymerization under preset temperature and preset wavelength irradiation conditions to obtain the body temperature responsive self-adhesive gel microspheres.

[0059] The preparation method provided by this invention is simple, and the prepared gel microspheres have good temperature-controlled self-adhesion ability and interfacial adhesion properties. When used as an embolizing agent, they can form an effective blockage in blood vessels and have strong adhesion to blood vessels. This effectively solves the problem that existing microspheres have a loose structure in blood flow, poor adhesion stability to blood vessels, are easily dispersed, and cannot achieve effective blockage.

[0060] This invention also provides a method for preparing the body temperature-responsive self-adhesive gel microspheres described above, characterized by comprising the following steps: S1. Mix at least one of the biocompatible nano-confined unit material and the interfacial adhesion unit material with water to obtain a dispersion; S2. Add photocurable structural stabilizing unit material, body temperature responsive self-adhesive unit material and photoinitiator to the dispersion, and heat to obtain prepolymer liquid; S3. Prepare the prepolymer liquid into pregel droplets; S4. The pregel droplets are placed under preset temperature and preset wavelength irradiation conditions to carry out cross-linking polymerization reaction to obtain the body temperature responsive self-adhesive gel microspheres.

[0061] The preparation method provided by this invention is simple, and the prepared gel microspheres have good temperature-controlled self-adhesion ability and interfacial adhesion properties. When used as an embolizing agent, they can form an effective blockage in blood vessels and have strong adhesion to blood vessels. This effectively solves the problem that existing microspheres have a loose structure in blood flow, poor adhesion stability to blood vessels, are easily dispersed, and cannot achieve effective blockage.

[0062] In step S1, the biocompatible nano-confined unit material can be mixed with water to obtain a dispersion.

[0063] Alternatively, the interfacial adhesion unit material can be mixed with water and subjected to oxidative polymerization (adjusting the pH to 8.5) to obtain a dispersion.

[0064] Biocompatible nano-confined unit materials and interfacial adhesion unit materials can also be mixed with water and subjected to oxidative polymerization to obtain a dispersion. The oxidative polymerization reaction of the interfacial adhesion unit materials (such as dopamine) can proceed spontaneously under alkaline conditions, while the ions dissolved in the biocompatible nano-confined unit materials after being added to the water can provide an alkaline environment.

[0065] In some embodiments, the step of mixing biocompatible nano-confined unit materials and interfacial adhesion unit materials with water, followed by oxidative polymerization to obtain a dispersion specifically includes: Biocompatible nano-confined unit materials are added to water and ultrasonically treated for 5 to 60 minutes (e.g., 5, 10, 20, 30, 40, 50, or 60 minutes). Then, interfacial adhesion unit materials are added and magnetically stirred at room temperature for 6 to 36 hours (e.g., 6, 10, 8, 12, 15, 18, 20, 22, 25, 28, 30, 32, 34, or 36 hours) to carry out an oxidative polymerization reaction and obtain a dispersion.

[0066] Step S2, which involves adding a photocurable structural stabilizing unit material, a body temperature responsive self-adhesive unit material, and a photoinitiator to the dispersion and heating it to obtain a prepolymer solution, specifically includes: Photocurable structural stabilizing unit material, body temperature responsive self-adhesive unit material and photoinitiator are added to the dispersion and dissolved by heating in a water bath at 40℃~90℃ (e.g., 40℃, 50℃, 60℃, 70℃, 80℃ or 90℃, etc.) to obtain a prepolymer solution.

[0067] In step S3, in some embodiments, the method for preparing the prepolymer liquid into pregel droplets includes, but is not limited to, droplet microfluidics, mechanical stirring emulsification, membrane emulsification, gas-assisted spraying, electrospraying, high-pressure homogenization, and high-speed shearing.

[0068] In some implementations, the droplet shear position structure in the microfluidic device used in the droplet microfluidic method can be set according to actual needs. For example, the droplet shear position structure includes one of T-type, Y-type, and cross-type.

[0069] In step S4, the photocurable structural stabilizing unit material undergoes chemical cross-linking in the presence of a photoinitiator and light of a specific wavelength, and there are hydrogen bonds and chemical bonds between the body temperature responsive self-adhesive unit material and the interfacial adhesion unit material.

[0070] In some embodiments, the preset temperature is 30℃~80℃ (e.g., it can be 30℃, 40℃, 50℃, 60℃, 70℃ or 80℃, etc.), and the preset wavelength is 300nm~900nm, specifically 300nm~400nm (near ultraviolet light), 400nm~700nm (visible light), 700nm~900nm (near infrared light). The appropriate wavelength can be flexibly selected according to different crosslinking monomers, photoinitiator systems and application scenarios to achieve effective response and control under various optical conditions.

[0071] In steps S3 and S4, in some embodiments, a droplet microfluidic method is used to prepare the prepolymer liquid into pregel droplets, and the pregel droplets are placed under preset temperature and preset wavelength irradiation conditions to carry out a crosslinking polymerization reaction to obtain the body temperature responsive self-adhesive gel microspheres. The specific steps include the following: Using the prepolymer as the dispersed phase solution and soybean oil as the continuous phase solution (i.e., the microsphere collection medium), soybean oil and prepolymer are separately loaded into syringes and injected into the microfluidic chip at a flow rate ratio of (1~10):1 using a micro-injection pump. The temperature of the reaction zone is controlled at 30℃~80℃ (e.g., 30℃, 40℃, 50℃, 60℃, 70℃, or 80℃, etc.). Pregel droplets are formed through shear force and hydrophobic interaction. After being discharged from the microfluidic channel, the pregel droplets enter a beaker for collection and are subjected to 300nm~900nm wavelength light at a temperature of 30℃~80℃ (e.g., 30℃, 40℃, 50℃, 60℃, 70℃, or 80℃, etc.) for cross-linking, gradually solidifying into a gel state to obtain the body temperature responsive self-adhesive gel microspheres.

[0072] In this embodiment, as an example, the flow rate ratio of soybean oil to prepolymer liquid can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, etc.

[0073] The present invention also provides the application of the body temperature responsive self-adhesive gel microspheres of the present invention as described above, or the body temperature responsive self-adhesive gel microspheres prepared by the preparation method of the present invention as described above, in the preparation of embolic agents, subcutaneous injection materials, ophthalmic gel materials, self-repairing gels for wound healing, tissue engineering scaffolds for cartilage regeneration, or tissue engineering scaffolds for skin regeneration.

[0074] The present invention will be further described below through specific embodiments.

[0075] Unless otherwise specified, the raw materials used in the following embodiments are all commercially available products.

[0076] Example 1 This embodiment provides a body temperature responsive self-adhesive gel microsphere and its preparation method, wherein the body temperature responsive self-adhesive gel microsphere includes a photocurable structural stabilizing unit material, a body temperature responsive self-adhesive unit material, a biocompatible nano-constraint unit material, an interfacial adhesion unit material, and a photoinitiator; The photocurable structural stabilizing unit material is methacrylamide gelatin, the body temperature responsive self-adhesive unit material is gelatin, the biocompatible nano-constraint unit material is Laponite, the interfacial adhesion unit material is dopamine hydrochloride, and the photoinitiator is lithium phenyl (2,4,6-trimethylbenzoyl)phosphate (LAP).

[0077] The preparation of body temperature-responsive self-adhesive gel microspheres based on droplet microfluidics includes the following steps: (1) Based on the mass of water, 0.6 wt% Laponite and 1.2 wt% dopamine hydrochloride were mixed with water and stirred at room temperature for 24 hours to carry out an oxidative polymerization reaction to form a dispersion. Subsequently, 10 wt% gelatin, 7.5 wt% methacrylamide gelatin and 7.5 wt% lithium phenyl (2,4,6-trimethylbenzoyl)phosphate were added to the dispersion and stirred under a water bath heating condition of 60°C until completely dissolved to form a homogeneous dispersed phase solution. Furthermore, analytical grade soybean oil was used as the continuous phase solution and the microsphere collection medium (0.6 wt% Laponite means 0.6% of the water mass, i.e., the mass of Laponite is 0.6% of the water mass; 1.2 wt% dopamine hydrochloride means 1.2% of the water mass, i.e., the mass of dopamine hydrochloride is 1.2% of the water mass, and the meaning of the amounts of other components in the gel microspheres is similar. In the examples below, the amounts of each component in the gel microspheres or hydrogel sheets are also based on the mass of water, and the meaning of the amounts of each component is similar).

[0078] (2) The continuous phase and the dispersed phase were loaded into syringes and injected into a microfluidic chip with a channel diameter of 400 μm at a flow rate ratio of 3:1 (the flow rate ratio of the continuous phase to the dispersed phase is 3:1) using a microinjection pump. The temperature of the reaction zone was controlled at 60 °C. Pregel droplets were formed through shear force and hydrophobic interaction. After being discharged from the microfluidic channel, the pregel droplets entered a beaker for collection and were cross-linked by irradiation with 405 nm wavelength light at room temperature, gradually solidifying into a gel state.

[0079] (3) After preparation, after the microspheres have settled naturally in the beaker, they are transferred to a centrifuge tube and washed three times in sequence with PBS buffer, acetone, and PBS buffer to remove residual oil phase and unreacted monomers. Finally, the microspheres (i.e., thermoresponsive self-adhesive gel microspheres) are stored in PBS buffer at 4°C for later use.

[0080] Microscopic image of thermoresponsive self-adhesive gel microspheres as shown below Figure 1 As shown in the figure (scale bar: 250μm), the microspheres are uniform in size, with a diameter of approximately 500μm, and are in a dispersed state.

[0081] Example 2 This embodiment verifies the body temperature-responsive self-adhesive gel microspheres in vitro, specifically including the following steps: The body temperature-responsive self-adhesive gel microspheres prepared in Example 1 were placed in a sterile petri dish and then placed on a heating platform set at approximately 37°C, ensuring slight contact between the gel microspheres without external pressure. The interfacial bonding behavior of the gel microspheres under heating conditions was observed. Figure 2 As shown (scale bar: 100 μm), approximately one minute after heating begins, multiple gel microspheres fuse at the interface through thermally induced movement and entanglement of gelatin segments, forming a stable and irreversible monolithic structure, exhibiting typical thermoresponsive self-adhesive behavior. This confirms that the gel microspheres prepared in Example 1 can achieve rapid interfacial adhesion under physiological conditions without external stimulation, providing strong support for their construction of continuous occlusion structures within blood vessels, and demonstrating their key function of automatically assembling and forming a monolithic structure at physiological temperatures.

[0082] Example 3 The preparation method of the body temperature-responsive self-adhesive gel microspheres in this embodiment is basically the same as that in Example 1, except that the microfluidic chip with a channel diameter of 400 μm is replaced with a microfluidic chip with a channel diameter of 300 μm, and the flow rate ratio of the continuous phase to the dispersed phase is changed from 3:1 to 9:2. Its particle size distribution is as follows: Figure 3 As shown, the results indicate that body temperature responsive self-adhesive gel microspheres with different particle size ranges can be prepared by adjusting the channel diameter of the microfluidic chip and the flow rate ratio of the continuous phase to the dispersed phase.

[0083] Example 4 In this embodiment, five rectangular thermoresponsive self-adhesive hydrogel sheets were prepared using polytetrafluoroethylene (PTFE) templates, denoted as hydrogel sheet a, hydrogel sheet b, hydrogel sheet c, hydrogel sheet d, and hydrogel sheet e, respectively. The only difference between these and the microspheres in Example 1 is the amount of dopamine used. The composition and amount of each hydrogel sheet in Example 4 are shown in Table 1.

[0084] Table 1. Composition of each hydrogel sheet in Example 4 and the percentage of each component by water mass.

[0085] Example 4 (in which the thickness of the prepared hydrogel sheets was 1 mm) aimed to investigate the effect of changes in dopamine hydrochloride content on the adhesion properties of the hydrogel sheets. The adhesion test was conducted using the overlap-shear method. To control for variables, only the amount of added dopamine hydrochloride was adjusted. Figure 4 As shown, the adhesion strength of the hydrogel increases significantly with increasing dopamine hydrochloride content.

[0086] Example 5 In this embodiment, five rectangular thermoresponsive self-adhesive hydrogel sheets were prepared using a polytetrafluoroethylene template. These sheets are designated as hydrogel sheet f, hydrogel sheet e, hydrogel sheet g, hydrogel sheet h, and hydrogel sheet i. Their composition differs from the microspheres in Example 1 only in the amount of Laponite used. The composition and amount of each hydrogel sheet in Example 5 are shown in Table 2.

[0087] Table 2. Composition of each hydrogel sheet in Example 5 and the percentage of each component by water mass.

[0088] Example 5 (in which the thickness of the prepared hydrogel sheets was 1 mm) aimed to evaluate the effect of changes in Laponite content on the adhesion properties of the hydrogel sheets. Adhesion tests were conducted using the overlap-shear method. To control for variables, only the amount of added Laponite was adjusted. The test results are as follows: Figure 5 As shown, the adhesion strength of the hydrogel sheet exhibits a non-linear trend of first increasing and then decreasing with the change in Laponite content. Therefore, the Laponite content needs to be controlled within an appropriate range to achieve the best interfacial adhesion effect.

[0089] Example 6 This embodiment verifies the temperature-responsive self-adhesive gel microspheres' self-adhesive behavior in vivo (under the influence of blood flow shear forces), specifically including the following steps: Male New Zealand rabbits weighing 2.5-3.5 kg were selected as experimental animals. The body temperature-responsive self-adhesive gel microspheres (60 mg / kg, i.e., 60 mg of body temperature-responsive self-adhesive gel microspheres per kg of rabbit) prepared in Example 1 were injected into the central auricular artery of the rabbits with physiological saline. After 28 days, the rabbits were euthanized, and the area containing the gel microspheres in the rabbit's ear was surgically removed and fixed by soaking in 4% paraformaldehyde. A segment of self-adhesive gel microsphere was removed from the blood vessel at the site of the ear embolism. Microscopic images are shown below. Figure 6 As shown (scale bar: 500 μm), the boundaries of the gel microspheres merge with each other, indicating that the gel microspheres can also self-adhere to form a whole when there is blood flow in the blood vessels.

[0090] Example 7 This embodiment verifies the adhesion behavior between body temperature-responsive self-adhesive gel microspheres and skin tissue, specifically including the following steps: Rectangular thermo-responsive self-adhesive hydrogel sheets (1 mm thick) were prepared using a polytetrafluoroethylene template. Their composition was the same as that of the microspheres in Example 1. When the hydrogel sheet was placed between two fingers and gently pressed at body temperature for about one minute, adhesion between the hydrogel sheet and the skin tissue of the fingers was observed upon slow separation of the fingers. The experimental results are as follows: Figure 7 As shown.

[0091] Example 8 This embodiment verifies the adhesion behavior between body temperature-responsive self-adhesive gel microspheres and blood vessels, specifically including the following steps: A segment of blood vessel was removed from the neck of a New Zealand rabbit and longitudinally dissected to expose the inner wall of the vessel. The body temperature-responsive self-adhesive gel microspheres prepared in Example 1 were placed on the blood vessel. After one minute, the blood vessel with the adhered gel microspheres was picked up with tweezers and placed directly under a faucet. Figure 8 As shown, the gel microspheres can still adhere to the inner wall of blood vessels under continuous water flow, demonstrating excellent tissue adhesion properties.

[0092] Example 9 In this embodiment, four rectangular thermoresponsive self-adhesive hydrogel sheets (1 mm thick) were prepared using a polytetrafluoroethylene template, denoted as hydrogel sheet j, hydrogel sheet k, hydrogel sheet l, and hydrogel sheet m, respectively. Their composition is basically the same as the microspheres in Example 1, with the only differences being: Laponite was replaced with montmorillonite (hydrogel sheet j), Laponite was replaced with Hectolith (hydrogel sheet k), methacryloyl gelatin was replaced with methacryloyl hyaluronic acid (hydrogel sheet l), and methacryloyl gelatin was replaced with chondroitin sulfate (hydrogel sheet m). Adhesion tests were conducted using the overlap-shear method, and the adhesion strength of each hydrogel sheet is as follows: Figure 9 As shown.

[0093] Figure 9 The results show that the rectangular body temperature responsive self-adhesive hydrogel sheets in Example 9 all have good adhesion properties.

[0094] Example 10 In this embodiment, three types of rectangular thermo-responsive self-adhesive hydrogel sheets (1 mm thick) were prepared using a polytetrafluoroethylene template.

[0095] The preparation method of hydrogel sheet n includes the following steps: based on the mass of water, 10wt% gelatin, 7.5wt% methacrylamide gelatin and 7.5wt% phenyl (2,4,6-trimethylbenzoyl) lithium phosphate are mixed with water, heated to dissolve, and then subjected to light with a wavelength of 405nm to crosslink into a gel state.

[0096] The preparation method of hydrogel sheet f includes the following steps: Based on the mass of water, 1.2 wt% dopamine hydrochloride is mixed with water (adjusting the pH to 8.5) and stirred at room temperature for 24 hours to carry out an oxidative polymerization reaction to form a dispersion. Subsequently, 10 wt% gelatin, 7.5 wt% methacryloyl gelatin, and 7.5 wt% lithium phenyl (2,4,6-trimethylbenzoyl)phosphate are added to the dispersion, heated to dissolve, and then irradiated with light at a wavelength of 405 nm to crosslink it into a gel state.

[0097] The preparation method of hydrogel sheet O includes the following steps: based on the mass of water, 0.6wt% Laponite, 10wt% gelatin, 7.5wt% methacrylamide gelatin and 7.5wt% phenyl (2,4,6-trimethylbenzoyl) lithium phosphate are mixed with water, heated to dissolve, and then subjected to light with a wavelength of 405nm to crosslink into a gel state.

[0098] Adhesion tests were conducted using the overlap-shear method, and the adhesion strength of each hydrogel sheet was as follows: Figure 10 As shown.

[0099] Figure 10 The results show that although the rectangular body temperature responsive self-adhesive hydrogel sheet in Example 10 has certain adhesion properties, they are all significantly lower than the adhesion strength of the hydrogel sheet g in Example 5 when dopamine hydrochloride and Laponite are present at the same time.

[0100] Example 11 This embodiment utilizes a polytetrafluoroethylene template to prepare a rectangular thermo-responsive self-adhesive hydrogel sheet. Based on the mass of water, the process includes the following steps: 0.3 wt% Laponite and 0.3 wt% dopamine hydrochloride are mixed with water and stirred at room temperature for 24 hours to undergo oxidative polymerization to form a dispersion. Subsequently, 10 wt% gelatin, 5 wt% methacryloyl gelatin, and 5 wt% lithium phenyl (2,4,6-trimethylbenzoyl)phosphate are added to the dispersion, and the mixture is stirred until completely dissolved under a 60°C water bath. Finally, the mixture is irradiated with 405 nm light to crosslink and form a gel state.

[0101] Example 12 This embodiment utilizes a polytetrafluoroethylene template to prepare a rectangular thermo-responsive self-adhesive hydrogel sheet. Based on the mass of water, the process includes the following steps: 0.3 wt% Laponite and 0.3 wt% dopamine hydrochloride are mixed with water and stirred at room temperature for 24 hours to undergo oxidative polymerization to form a dispersion. Subsequently, 7.5 wt% gelatin, 7.5 wt% methacryloyl gelatin, and 7.5 wt% lithium phenyl (2,4,6-trimethylbenzoyl)phosphate are added to the dispersion, and the mixture is stirred until completely dissolved under a 60°C water bath. Finally, the mixture is irradiated with 405 nm light to crosslink and form a gel state.

[0102] Example 13 This embodiment utilizes a polytetrafluoroethylene template to prepare a rectangular thermo-responsive self-adhesive hydrogel sheet. Based on the mass of water, the process includes the following steps: 0.3 wt% Laponite and 0.3 wt% dopamine hydrochloride are mixed with water and stirred at room temperature for 24 hours to undergo oxidative polymerization to form a dispersion. Subsequently, 5 wt% gelatin, 10 wt% methacrylamide gelatin, and 10 wt% lithium phenyl (2,4,6-trimethylbenzoyl)phosphate are added to the dispersion, and the mixture is stirred until completely dissolved under a 60°C water bath. Finally, the mixture is irradiated with 405 nm light to crosslink and form a gel state.

[0103] Examples 11 to 13 (each example yielded a hydrogel sheet with a thickness of 1 mm) aimed to evaluate the effect of the ratio of gelatin to methacrylamide gelatin on the adhesion properties of the hydrogel sheets. Adhesion tests were conducted using the overlap-shear method. The test results are as follows: Figure 11 As shown, reducing the gelatin content while increasing the methacrylamide gelatin content will reduce the adhesion strength of the hydrogel sheet.

[0104] Example 14 In this embodiment, a rectangular thermoresponsive self-adhesive hydrogel sheet (1 mm thick) was prepared using a polytetrafluoroethylene template. Its composition was essentially the same as the microspheres in Example 1, except that 0.1 wt% Laponite and 0.1 wt% dopamine hydrochloride were mixed with water. Adhesion testing was performed using the overlap-shear method. The adhesion strength of the hydrogel sheet was as follows: Figure 12 As shown.

[0105] Example 15 In this embodiment, a rectangular thermoresponsive self-adhesive hydrogel sheet (1 mm thick) was prepared using a polytetrafluoroethylene template. Its composition was essentially the same as the microspheres in Example 1, except that 0.1 wt% Laponite and 3 wt% dopamine hydrochloride were mixed with water. Adhesion testing was performed using the overlap-shear method. The adhesion strength of the hydrogel sheet was as follows: Figure 12 As shown.

[0106] Example 16 In this embodiment, a rectangular thermoresponsive self-adhesive hydrogel sheet (1 mm thick) was prepared using a polytetrafluoroethylene template. Its composition was essentially the same as the microspheres in Example 1, except that 3 wt% Laponite and 0.1 wt% dopamine hydrochloride were mixed with water. Adhesion testing was performed using the overlap-shear method. The adhesion strength of the hydrogel sheet was as follows: Figure 12 As shown.

[0107] Example 17 In this embodiment, a rectangular thermo-responsive self-adhesive hydrogel sheet (1 mm thick) was prepared using a polytetrafluoroethylene template. Its composition is basically the same as that of the microspheres in Example 1, except that 3 wt% Laponite and 3 wt% dopamine hydrochloride were mixed with water.

[0108] The adhesion test was conducted using the overlap shear method. The adhesion strength of the hydrogel sheet was as follows: Figure 12 As shown.

[0109] Figure 12 The results show that the rectangular body temperature responsive self-adhesive hydrogel sheets in Examples 14 to 17 all have certain adhesion properties.

[0110] In summary, this invention provides a thermoresponsive self-adhesive gel microsphere, its preparation method, and its application. The gel microsphere can spontaneously achieve interfacial self-adhesion at physiological temperatures, realizing the integration of injectability, self-adhesion, and adhesion, and can form a continuous sealing structure in blood vessels.

[0111] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A thermoresponsive self-adhesive gel microsphere, characterized in that, The body temperature responsive self-adhesive gel microspheres include photocurable structural stabilizing unit materials and body temperature responsive self-adhesive unit materials; The photocurable structural stabilizing unit material includes at least one of natural polymer derivatives and synthetic polymers. The body temperature responsive self-adhesive unit material can undergo segment migration and re-entanglement at physiological temperatures.

2. The body temperature-responsive self-adhesive gel microspheres according to claim 1, characterized in that, The body temperature responsive self-adhesive gel microspheres also include at least one of biocompatible nano-confined unit materials and interfacial adhesion unit materials; The biocompatible nanoconfined unit material includes nanomaterials with a two-dimensional layered structure; The interfacial adhesion unit material includes polyphenolic compounds with ortho-phenolic hydroxyl structures.

3. The body temperature-responsive self-adhesive gel microspheres according to claim 1 or 2, characterized in that, The natural polymer derivative material includes at least one of the following: methacrylamide gelatin, methacrylamide hyaluronic acid, methacrylamide sodium alginate, methacrylamide chitosan, methacrylamide chondroitin sulfate, methacrylamide dextran, methacrylamide silk fibroin, methacrylamide collagen, methacrylamide agarose, and methacrylamide fiber. The synthetic polymer material includes at least one of polyethylene glycol diacrylate, multi-arm polyethylene glycol acrylate, polyethylene glycol acrylate, polycaprolactone acrylate, polyamino acid acrylate, polyacrylamide derivative, poly(N-isopropylacrylamide) derivative, and polymethyl methacrylate copolymer.

4. The body temperature-responsive self-adhesive gel microspheres according to claim 1 or 2, characterized in that, The body temperature responsive self-adhesive unit material includes at least one of gelatin, gelatin derivatives, chitosan, chitosan derivatives, silk fibroin, elastin-like peptides, collagen-like peptides, polycaprolactone, poly-N-isopropylacrylamide, poly-N-isopropylacrylamide copolymer, polyethylene glycol-polylactic acid block copolymer, methylcellulose, and methylcellulose derivatives.

5. The body temperature-responsive self-adhesive gel microspheres according to claim 2, characterized in that, The nanomaterials with a two-dimensional layered structure include at least one of nanoclay, layered double hydroxides, black phosphorus, hexagonal boron nitride, expandable graphite, graphitic carbon nitride, graphene, graphene derivatives, transition metal disulfides, transition metal oxides, transition metal carbides, transition metal nitrides, metal-organic frameworks, and covalent organic frameworks.

6. The body temperature-responsive self-adhesive gel microspheres according to claim 2, characterized in that, The polyphenolic compounds having an ortho-hydroxyl structure include at least one of dopamine, dopa, protocatechuic acid, gallic acid, pyrocyanic acid, chlorogenic acid, caffeic acid, tannic acid, ellagic acid, catechin, quercetin, rutin, proanthocyanidins, and epigallocatechin gallate.

7. The body temperature-responsive self-adhesive gel microspheres according to claim 1 or 2, characterized in that, The body temperature responsive self-adhesive gel microspheres also include photoinitiators, photoinitiator-modified particles, or crosslinking agents; The photoinitiators include lithium phenyl-2,4,6-trimethylbenzoylphosphine oxide, phenyl bis(2,4,6-trimethylbenzoyl)phosphine oxide, monoacylphosphine oxide, 2-hydroxy-2-methyl-1-phenyl-1-propanone, 1-hydroxycyclohexylphenyl ketone, 2-benzyl-2-dimethylamino-1-(4-morpholinobenzylphenyl)butanone, 2-methyl-1-(4-methylthiophenyl)-2-morpholino-1-propanone, 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylphenylpropanone, 2,2-dimethoxy-2-phenylacetophenone, ketoxime esters, and [Ru(bpy)3]. 2+ One of the following: persulfate system, riboflavin, riboflavin derivatives, chlorophyll, chlorophyll derivatives, Eosin Y / triethanolamine system, organometallic complexes, or organometallic complex derivatives; The photoinitiator-modified particles include photoinitiator-modified upconversion nanoparticles; The crosslinking agent includes at least one of glutaraldehyde and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

8. The body temperature-responsive self-adhesive gel microspheres according to claim 1, characterized in that, By weight, the body temperature responsive self-adhesive gel microspheres comprise: The composition includes 1-50 parts of photocurable structural stabilizing unit material, 1-50 parts of body temperature responsive self-adhesive unit material, 0-3 parts of biocompatible nano-constraint unit material, 0-3 parts of interfacial adhesion unit material, and 0.1-10 parts of photoinitiator. And / or, The temperature-responsive self-adhesive microspheres have a particle size of 20 μm to 1000 μm.

9. A method for preparing body temperature-responsive self-adhesive gel microspheres according to any one of claims 1-8, characterized in that, Includes the following steps: A prepolymer solution is obtained by mixing a photocurable structural stabilizing unit material, a body temperature responsive self-adhesive unit material, and a photoinitiator with water and heating the mixture. The prepolymer liquid is prepared into pregel droplets; The pregel droplets were subjected to cross-linking polymerization under preset temperature and preset wavelength irradiation conditions to obtain the body temperature responsive self-adhesive gel microspheres.

10. The preparation method according to claim 9, characterized in that, The preset temperature is 30℃~80℃, and the preset wavelength is 300nm~900nm; and / or, The method for preparing the prepolymer liquid into pregel droplets includes one of the following: droplet microfluidics, mechanical stirring emulsification, membrane emulsification, gas-assisted spraying, electrospraying, high-pressure homogenization, and high-speed shearing.

11. The use of the thermoresponsive self-adhesive gel microspheres according to any one of claims 1-8 or the thermoresponsive self-adhesive gel microspheres prepared by the preparation method according to any one of claims 9-10 in the preparation of embolic agents, subcutaneous injection materials, ophthalmic gel materials, self-repairing gels for wound healing, tissue-engineered scaffolds for cartilage regeneration, or tissue-engineered scaffolds for skin regeneration.

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