Magnetic shear thinning embolism hydrogel and preparation method thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly discloses a preparation method of magnetic shear thinning embolism hydrogel, which comprises the following steps: S1, coating silicon dioxide (SiO2) with ferroferric oxide (Fe3O4), and carrying out surface treatment to prepare aminated SiO2-Fe3O4 ethanol dispersion liquid; s2, performing surface treatment on the magnesium lithium silicate to prepare epoxy modified magnesium lithium silicate dispersion liquid; s3, through amino-epoxy click chemistry, aminated SiO2 coated Fe3O4 is loaded on epoxy modified magnesium lithium silicate, and magnesium lithium silicate loaded with SiO2 coated Fe3O4 is prepared; and S4, uniformly mixing the magnesium lithium silicate loaded with SiO2 and Fe3O4, a high-molecular polymer, a developing agent and sterilized water for injection to prepare the magnetic shear thinning embolism hydrogel. The magnetic hydrogel-mediated liver cancer interventional embolism combined magnetic thermal therapy can be realized by the magnetic hydrogel-mediated liver cancer interventional embolism combined magnetic thermal therapy.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to a magnetic shear-thinning embolization hydrogel and a preparation method thereof. BACKGROUND

[0002] Hepatocellular carcinoma (HCC) is a strong invasive and high mortality primary liver cancer, which can be treated by surgery or transplantation in early stage. However, its symptoms are highly occult, and most patients have progressed to the middle and late stages at the time of diagnosis, at which time transarterial chemoembolization (TACE) becomes the cornerstone therapy.

[0003] Shear-thinning hydrogels show important value in the development of new embolic agents due to their excellent injectability and controllable mechanical properties. However, the reported hydrogel embolic agents still have two limitations: 1) the mechanical strength is insufficient, which easily leads to material fragmentation and causes ectopic embolization of gel fragments to normal blood vessels; 2) the single embolization effect is limited, and invasive auxiliary means such as radiofrequency ablation or radiotherapy are often required, which may induce radiation damage to liver tissue or bleeding at the puncture site.

[0004] Magnetic induction hyperthermia technology utilizes the conversion of magnetic energy into heat energy by magnetic materials under the action of alternating magnetic field (AMF), which makes the local temperature of the tumor break through the apoptosis threshold of 42℃, thereby achieving cancer cell killing. This technology has become a frontier in the field of tumor treatment with three advantages: 1) breaking through the limitation of tissue penetration depth of traditional hyperthermia; 2) having a significant tumor cell heat inactivation efficiency; 3) almost no systemic toxicity and extremely low invasiveness. It is recognized by the academic circle as a new strategy for liver cancer treatment with great clinical transformation potential.

[0005] Chinese invention patent CN115645635A discloses a liquid embolic agent and its preparation method and use. The liquid embolic agent is injected into the embolization site by shear thinning, and then returns to the gel state in the body after losing external force, achieving embolization effect. However, the hydrogel described in this patent has weak mechanical properties, low modulus and shear viscosity, and single embolization cannot achieve the best therapeutic effect.

[0006] Chinese invention patent CN108676111A discloses a preparation method of a magnetic field driven intelligent flexible material. The magnetic field driven intelligent flexible material is a hydrogel material obtained by simply mixing N,N-dimethyl acrylamide, iron oxide nanoparticles (Fe3O4), and nano wood pulp cellulose, and then free radical polymerization of N,N-dimethyl acrylamide. Although the materials are mixed under ultrasonic conditions, the mixed materials still need to be injected into a mold and left to stand for 24-26 hours for molding. During this process, the simply mixed Fe3O4 nanoparticles are easy to agglomerate and settle, and are also easy to be oxidized, thereby losing magnetism.

[0007] Chinese invention patent CN116196898B discloses a kind of nano four iron oxide cyclodextrin hydrogel adsorbent and preparation method, the nano Fe3O4 paste hydrogel adsorbent is generated by in-situ coprecipitation method, nano Fe3O4 is loaded and dispersed into cyclodextrin hydrogel matrix, and magnetic hydrogel adsorbent is obtained.However under this condition, nano Fe3O4 is not protected at all, and it is very easy to be oxidized and lose magnetism.

[0008] Chinese invention patent CN105796478B discloses a high-strength, self-repairing, injectable composite colloidal gel material assembled by nanocolloidal particles, and a preparation method and application thereof.Taking negatively charged silica nanoparticles and positively charged gelatin nanoparticles as basic structural units, the two-phase colloidal particles with opposite charges are uniformly blended in an alkaline environment, and then glucose acid lactone is added to induce the solution pH to restore to neutral, thereby triggering the electrostatic self-assembly between the two-phase colloidal particles to obtain a composite gel network.The shear thinning of the gel is due to the destruction of the electrostatic force by external force, temporary dissociation of particle-polymer chains, reduction of crosslinking points, and orientation of molecular chains along the shear direction, resulting in a decrease in viscosity.However, the volume of two-phase colloidal particles needs to account for more than 30% of the total volume of the gel, and the elastic modulus can only reach 2400Pa, and the high nanoparticle content can cause pipe blockage, which is not conducive to catheter delivery.

[0009] In summary, the embolization hydrogel in the prior art has the problems of easy sedimentation, easy oxidation and loss of magnetism, and high nanoparticle content causing pipe blockage, which is not conducive to catheter delivery. SUMMARY

[0010] The present application provides a magnetic shear thinning embolization hydrogel, which can solve the problems of easy sedimentation, easy oxidation and loss of magnetism, and high nanoparticle content causing pipe blockage, which is not conducive to catheter delivery in the prior art embolization hydrogel.

[0011] In a first aspect, the present application provides a preparation method of a magnetic shear thinning embolization hydrogel, comprising the following steps:

[0012] S1, Fe3O4 is coated with silica and surface treated to prepare an amino-modified SiO2@Fe3O4 ethanol dispersion;

[0013] S2, surface treatment of magnesium lithium silicate is performed to prepare an epoxy-modified magnesium lithium silicate dispersion;

[0014] S3, amino-modified SiO2@Fe3O4 is loaded on the epoxy-modified magnesium lithium silicate by amino-epoxy click chemistry to prepare SiO2@Fe3O4-loaded magnesium lithium silicate;

[0015] S4, uniformly mixing the SiO2@Fe3O4 loaded magnesium lithium silicate, the polymer, the developer and the sterile water for injection to prepare the magnetic shear-thinning embolus hydrogel.

[0016] Further, the step S1 specifically comprises the following steps:

[0017] S1.1, preparation of magnetic Fe3O4 nanoparticles

[0018] FeCl3·6H2O and FeCl2·4H2O are mixed in a molar ratio of (1.8-2):1 and dissolved in deoxygenated deionized water. Under vigorous stirring, dilute ammonia solution is slowly added dropwise, and the pH value is adjusted to 10-11. The reaction temperature is controlled at 60-80℃, and the reaction is continued for 30-60 minutes. The obtained black precipitate is centrifuged and washed repeatedly with deoxygenated deionized water until neutral to prepare magnetic Fe3O4 nanoparticles;

[0019] S1.2, preparation of activated Fe3O4 suspension

[0020] The magnetic Fe3O4 nanoparticles are dispersed in dilute hydrochloric acid and ultrasonically oscillated for 30-60 minutes. After acid washing, the supernatant is discarded by magnetic separation, and finally the activated Fe3O4 suspension is obtained by washing with ethanol / water mixture until the pH of the washing solution is 6-7;

[0021] S1.3, synthesis of SiO2@Fe3O4 ethanol dispersion

[0022] Ammonia water is added to the activated Fe3O4 suspension, and the final concentration of ammonia water is 0.16-0.18M. After ultrasonic mixing, tetraethyl orthosilicate is slowly added dropwise. After mechanical stirring at a speed of 700-900 rpm for 4-6 hours, centrifugal separation is performed, and then the product is washed with anhydrous ethanol and deionized water in sequence. Finally, the SiO2@Fe3O4 ethanol dispersion is obtained by uniformly dispersing in anhydrous ethanol.

[0023] S1.4, 3-aminopropyltriethoxysilane silanization

[0024] 3-aminopropyltriethoxysilane is added to the SiO2@Fe3O4 ethanol dispersion, and after ultrasonic mixing, water bath reflux is carried out under nitrogen protection. The water bath reflux temperature is 50-75℃, and the water bath reflux is carried out for 4-6 hours. After magnetic separation and washing with anhydrous ethanol, the amino-functionalized SiO2@Fe3O4 ethanol dispersion is obtained by dispersing in ethanol.

[0025] Further, in step S1.1, the deoxygenated deionized water is deoxygenated deionized water by inert gas;

[0026] In step S1.2, the concentration of dilute hydrochloric acid is 0.1-0.12M, and the concentration of the activated Fe3O4 suspension is 10-20mg / ml;

[0027] In step S1.3, the mass ratio of tetraethyl orthosilicate to Fe3O4 in the activated Fe3O4 suspension is (1.8-1.9):1, the dropping speed of the tetraethyl orthosilicate is 0.01-0.05ml / min, and the concentration of the SiO2@Fe3O4 ethanol dispersion is 20-30mg / ml;

[0028] In step S1.4, the mass ratio of SiO2@Fe3O4 in the SiO2@Fe3O4 ethanol dispersion to 3-aminopropyl triethoxysilane is 1:(2.8-2.9), and the concentration of the aminated SiO2@Fe3O4 ethanol dispersion is 50-60mg / ml.

[0029] Further, the step S2 specifically comprises the following steps:

[0030] S2.1, exfoliation of magnesium lithium silicate sheets

[0031] The magnesium lithium silicate is added into a Na4P2O7 aqueous solution, and is subjected to ice-bath ultrasonic treatment for 30-60min. After stepwise centrifugation, the obtained precipitate is resuspended in N2-saturated deionized water to obtain a magnesium lithium silicate monolayer dispersion;

[0032] S2.2, epoxy modification of magnesium lithium silicate

[0033] The magnesium lithium silicate monolayer dispersion is taken, glycidyl ether oxypropyl trimethoxysilane is added, and the mixture is subjected to magnetic stirring under a water bath at 60-70℃ for 2-3h. After dialysis to remove free glycidyl ether oxypropyl trimethoxysilane, an epoxy-modified magnesium lithium silicate is obtained.

[0034] Further, in step S2.1, the mass ratio of the magnesium lithium silicate to Na4P2O7 is 1:(0.01-0.012);

[0035] In step S2.1, the stepwise centrifugation specifically comprises the following steps: first centrifugation at a speed of 2000-4000rpm for 5-10min, and then centrifugation at a speed of 10000-12000rpm for 20-30min after discarding the precipitate and the supernatant;

[0036] In step S2.1, the concentration of the magnesium lithium silicate monolayer dispersion is 10-15mg / ml;

[0037] In step S2.2, the mass ratio of the magnesium lithium silicate in the magnesium lithium silicate monolayer dispersion to glycidyl ether oxypropyl trimethoxysilane is 1:(1-1.1);

[0038] In step S2.2, the magnetic stirring rate is 200-300 rpm.

[0039] Further, the step S3 specifically comprises the following steps:

[0040] S3.1, click chemistry condensation gelation

[0041] The amino-functionalized SiO2@Fe3O4 ethanol dispersion is mixed with the epoxy-modified magnesium lithium silicate dispersion, and the pH is adjusted to 8.0 using Tris buffer to obtain a mixed solution. The mixed solution is mechanically stirred at 200-300 rpm in a 37°C water bath under N2 protection for 36-48 hours. Then, a sodium citrate solution is added to a final concentration of 0.01 M, and stirring is continued for 20-30 min. After centrifugal separation and deionized water washing, a gel product is obtained.

[0042] S3.2, preparation of SiO2@Fe3O4-loaded magnesium lithium silicate

[0043] After the gel product is quickly frozen using liquid nitrogen, it is freeze-dried in a freeze dryer to prepare SiO2@Fe3O4-loaded magnesium lithium silicate.

[0044] Further, in step S3.1, the mass ratio of amino-functionalized SiO2@Fe3O4 in the amino-functionalized SiO2@Fe3O4 ethanol dispersion to epoxy-modified magnesium lithium silicate in the epoxy-modified magnesium lithium silicate dispersion is 1:(4-13).

[0045] In step S3.2, the freeze-drying time is 24-60 h.

[0046] Further, the step S4 specifically comprises the following steps:

[0047] The following raw materials are weighed according to the weight ratio: SiO2@Fe3O4-loaded magnesium lithium silicate 1.5%-4.5%, high molecular polymer 1%-10%, developer 10%-40%, and the rest is sterile water for injection. The sterile water for injection is divided into 1# sterile water and 2# sterile water. The 1# sterile water is mixed with the high molecular polymer to prepare a high molecular polymer aqueous solution. The SiO2@Fe3O4-loaded magnesium lithium silicate, high molecular polymer aqueous solution, developer, and 2# sterile water are placed in a vacuum stirring defoaming machine and stirred at 1000-1800 rpm for 1-5 minutes to prepare a magnetic shear-thinning embolism hydrogel.

[0048] Further, the high molecular polymer is a natural high molecular polymer and / or an artificially synthesized high molecular polymer.

[0049] In a second aspect, the present application provides a magnetic shear-thinning embolization hydrogel, which is prepared by the preparation method of the magnetic shear-thinning embolization hydrogel provided in the first aspect of the present application.

[0050] Compared with the prior art, the present application has the following beneficial effects:

[0051] 1. The present application provides a preparation method of a magnetic shear-thinning embolization hydrogel, which comprises the following steps: coating Fe3O4 with SiO2 and surface treatment, surface treatment of magnesium lithium silicate, and amino-epoxy click chemistry to load SiO2@Fe3O4 on magnesium lithium silicate, thereby preparing a magnetic response shear-thinning hydrogel embolic agent; specifically, in the preparation method, the Fe3O4 nanoparticles are loaded on the magnesium lithium silicate by forming a covalent bond through click reaction, and the magnetic heating performance is improved and the oxidation demagnetization time is prolonged by magnetic core protection (SiO2 isolation layer + acid washing activation + citric acid passivation). At the same time, the loading ratio is optimized, which can significantly enhance the shear-thinning performance.

[0052] 2. The magnetic shear-thinning embolization hydrogel provided by the present application makes up for the single function of the existing hydrogel embolic agent, realizes magnetic hydrogel-mediated liver cancer interventional embolization combined with magnetic hyperthermia, and can also be used for local magnetic hyperthermic prevention and treatment of liver cancer recurrence after surgery.

[0053] 3. In the present application, Fe3O4 is coated with SiO2 and surface treated, and magnesium lithium silicate is surface treated, and then amino-epoxy click chemistry is used to load SiO2@Fe3O4 on magnesium lithium silicate, which makes up for the shortcomings of simple mixing of Fe3O4 nanoparticles and magnesium lithium silicate, which is prone to sedimentation and oxidation and loss of magnetism.

[0054] 4. In the present application, by loading SiO2@Fe3O4 on magnesium lithium silicate and adjusting the ratio of Fe3O4 loaded on magnesium lithium silicate, the shear-thinning properties of magnesium lithium silicate can be improved. DETAILED DESCRIPTION

[0055] The specific embodiments of the present application are described in detail below, but it should be understood that the protection scope of the present application is not limited by the specific embodiments.

[0056] In a first aspect, the present application provides a preparation method of a magnetic shear-thinning embolization hydrogel, which comprises the following steps:

[0057] S1, coating Fe3O4 with SiO2 and surface treatment to prepare an aminoized SiO2@Fe3O4 ethanol dispersion;

[0058] In step S1, the following steps are included:

[0059] S1.1, preparation of magnetic Fe3O4 nanoparticles

[0060] FeCl3-6H2O and FeCl2-4H2O were mixed in a molar ratio of (1.8-2):1 and dissolved in deoxygenated deionized water. Under vigorous stirring, a dilute ammonia solution was slowly added dropwise, and the pH value was adjusted to 10-11. The reaction temperature was controlled at 60-80°C, and the reaction was continued for 30-60 minutes. The black precipitate obtained was separated by centrifugation and washed repeatedly with deoxygenated deionized water until neutral to prepare magnetic Fe3O4 nanoparticles;

[0061] Specifically, the deoxygenated deionized water is deoxygenated deionized water by an inert gas; the inert gas is any one of helium (He), neon (Ne), argon (Ar), and nitrogen (N2); more specifically, the inert gas is preferably nitrogen (N2);

[0062] S1.2, preparation of activated Fe3O4 suspension

[0063] The magnetic Fe3O4 nanoparticles were dispersed in dilute hydrochloric acid and ultrasonically oscillated for 30-60 minutes. After acid washing to remove the oxide layer, the supernatant was discarded by magnetic separation, and finally the activated Fe3O4 suspension was obtained by washing with an ethanol / water mixture for 3 times until the pH of the washing solution was 6-7;

[0064] In this step S1.2, the concentration of dilute hydrochloric acid is 0.1-0.12M, and the concentration of the prepared activated Fe3O4 suspension is 10-20mg / ml;

[0065] S1.3, synthesis of SiO2@Fe3O4 ethanol dispersion

[0066] Ammonia was added to the activated Fe3O4 suspension, and the final concentration of ammonia was 0.16-0.18M. After ultrasonic mixing, tetraethyl orthosilicate was slowly added dropwise. After mechanical stirring at a speed of 700-900rpm for 4-6 hours, centrifugal separation was performed, and then the product was washed with anhydrous ethanol and deionized water for 3 times each. Finally, the product was uniformly dispersed in anhydrous ethanol to obtain SiO2@Fe3O4 ethanol dispersion;

[0067] In step S1.3, the mass ratio of tetraethyl orthosilicate to Fe3O4 in the activated Fe3O4 suspension is (1.8-1.9):1, the dropwise addition rate of tetraethyl orthosilicate is 0.01-0.05ml / min, and the concentration of SiO2@Fe3O4 ethanol dispersion is 20-30mg / ml;

[0068] S1.4, 3-aminopropyltriethoxysilane silanization

[0069] The SiO2@Fe3O4 ethanol dispersion liquid is added with 3-aminopropyl triethoxysilane (APTES), and after ultrasonic mixing, water bath reflux is carried out under nitrogen protection, the water bath reflux temperature is 50-75℃, and after water bath reflux for 4-6 hours, magnetic separation is carried out, and then the obtained product is washed with anhydrous ethanol for 6 times until no oily residue is left in the washing liquid, and then the product is dispersed in ethanol to obtain an amino-modified SiO2@Fe3O4 ethanol dispersion liquid;

[0070] In step S1.4, the mass ratio of SiO2@Fe3O4 in the SiO2@Fe3O4 ethanol dispersion liquid to APTES is 1:(2.8-2.9), and the concentration of the amino-modified SiO2@Fe3O4 ethanol dispersion liquid is 50-60 mg / ml.

[0071] S2, surface treatment of magnesium lithium silicate is carried out to prepare an epoxy-modified magnesium lithium silicate dispersion liquid;

[0072] Step S2 specifically includes the following steps:

[0073] S2.1, exfoliation of magnesium lithium silicate layers

[0074] The magnesium lithium silicate is added into a Na4P2O7 aqueous solution, ice bath ultrasonic treatment is carried out for 30-60 min, and after stepwise centrifugation, the obtained precipitate is resuspended in N2-saturated deionized water to obtain a magnesium lithium silicate monolayer dispersion liquid;

[0075] Specifically, in step S2.1, the N2-saturated deionized water refers to deionized water in which dissolved oxygen is removed by nitrogen gas, which combines the low ionic impurity characteristics of deionized water and the low dissolved oxygen characteristics of nitrogen saturation;

[0076] In step S2.1, the mass ratio of magnesium lithium silicate to Na4P2O7 in the Na4P2O7 aqueous solution is 1:(0.01-0.012), and the concentration of the Na4P2O7 aqueous solution is 0.1±0.02 mM;

[0077] In step S2.1, the stepwise centrifugation specifically includes the following steps: first centrifugation at a speed of 2000-4000 rpm for 5-10 min, and then centrifugation at a speed of 10000-12000 rpm for 20-30 min after the precipitate is discarded;

[0078] In step S2.1, the prepared magnesium lithium silicate monolayer dispersion liquid has a concentration of 10-15 mg / ml;

[0079] S2.2, epoxy modification of magnesium lithium silicate

[0080] The magnesium lithium silicate monolayer dispersion liquid is taken, glycidyl ether propyltrimethoxysilane (GPTMS) is added, and after magnetic stirring at 60-70°C water bath for 2-3 hours, free GPTMS is removed by dialysis to obtain an epoxy-modified magnesium lithium silicate dispersion liquid;

[0081] In step S2.2, the mass ratio of magnesium lithium silicate in the magnesium lithium silicate monolayer dispersion liquid to GPTMS is 1:(1-1.1);

[0082] In step S2.2, the magnetic stirring rate is 200-300 rpm.

[0083] S3, by amino-epoxy click chemistry, amino-SiO2@Fe3O4 is loaded on the epoxy-modified magnesium lithium silicate to prepare SiO2@Fe3O4-loaded magnesium lithium silicate;

[0084] Step S3 specifically includes the following steps:

[0085] S3.1, click chemistry condensation gelation

[0086] The amino-SiO2@Fe3O4 ethanol dispersion liquid is mixed with the epoxy-modified magnesium lithium silicate dispersion liquid, a 0.1M Tris buffer solution is used to adjust the pH to 8.0±0.2 to obtain a mixed solution, the mixed solution is mechanically stirred at 200-300 rpm in a 37°C water bath under N2 protection for 36-48 hours, then a sodium citrate solution is added to a final concentration of 0.01M, and the stirring is continued for 20-30 minutes, then the gel crude product is prepared by centrifugal separation, and the gel product is obtained after the gel crude product is washed with deionized water for 3 times;

[0087] Specifically, in step S3.1, the mass ratio of amino-SiO2@Fe3O4 in the amino-SiO2@Fe3O4 ethanol dispersion liquid to epoxy-modified magnesium lithium silicate in the epoxy-modified magnesium lithium silicate dispersion liquid is 1:(4-13), more specifically, the mass ratio of amino-SiO2@Fe3O4 in the amino-SiO2@Fe3O4 ethanol dispersion liquid to epoxy-modified magnesium lithium silicate in the epoxy-modified magnesium lithium silicate dispersion liquid is preferably 1:(7-13);

[0088] S3.2, preparation of SiO2@Fe3O4-loaded magnesium lithium silicate

[0089] After the gel product is quickly frozen with liquid nitrogen, it is placed in a freeze dryer for freeze-drying for 24-60h to prepare SiO2@Fe3O4-loaded magnesium lithium silicate.

[0090] S4, after the SiO2@Fe3O4-loaded magnesium lithium silicate, the high molecular polymer, the developer and the sterile water for injection are uniformly mixed, a magnetic shear-thinning embolism hydrogel is prepared;

[0091] Step S4 specifically comprises the following steps:

[0092] S4.1, the following raw materials are weighed according to the percentage by weight: SiO2@Fe3O4 loaded magnesium lithium silicate 1.5%-4.5%, high molecular polymer 1%-10%, developer 10%-40%, and the rest is sterile water for injection; wherein the sterile water for injection is divided into 1# sterile water and 2# sterile water, the 1# sterile water is mixed with the high molecular polymer to prepare a high molecular polymer aqueous solution;

[0093] Preferably, the following raw materials are weighed according to the percentage by weight: SiO2@Fe3O4 loaded magnesium lithium silicate 1.5%-4.5%, high molecular polymer 1%-5%, developer 10%-40%, and the rest is sterile water for injection; wherein the sterile water for injection is divided into 1# sterile water and 2# sterile water, the 1# sterile water is mixed with the high molecular polymer to prepare a high molecular polymer aqueous solution;

[0094] S4.2, the SiO2@Fe3O4 loaded magnesium lithium silicate, the high molecular polymer aqueous solution and the developer are placed in a vacuum stirring defoaming machine, and the 2# sterile water is added, and vacuum stirring is carried out at 1000-1800 rpm for 1-5 minutes to prepare a magnetic shear thinning embolism hydrogel;

[0095] S4.3, the prepared magnetic shear thinning embolism hydrogel is vacuum filled in a 1ml syringe for sterilization.

[0096] Specifically, the temperature of the sterile water for injection is 2-8℃;

[0097] The high molecular polymer is a natural high molecular polymer and / or an artificially synthesized high molecular polymer;

[0098] More specifically, the high molecular polymer is preferably gelatin; and the developer is preferably tantalum powder.

[0099] In a second aspect, the present application provides a magnetic shear thinning embolism hydrogel prepared by the preparation method of the magnetic shear thinning embolism hydrogel provided in the first aspect of the present application.

[0100] Example 1

[0101] The present embodiment provides a preparation method of aminoized SiO2@Fe3O4 ethanol dispersion liquid and a preparation method of epoxy modified magnesium lithium silicate dispersion liquid, and the preparation method of aminoized SiO2@Fe3O4 ethanol dispersion liquid comprises the following steps:

[0102] S1, FeCl3-6H2O and FeCl2-4H2O were dissolved in deoxygenated deionized water with a molar ratio of 2:1. Under vigorous stirring, a dilute ammonia solution was slowly added to the solution until the pH was about 10.5, and the reaction temperature was controlled at 80°C. The reaction was continued for 30 minutes. The black precipitate was separated by centrifugation and washed repeatedly with deoxygenated deionized water until neutral to obtain magnetic Fe3O4 nanoparticles;

[0103] S2, the synthesized magnetic Fe3O4 nanoparticles were dispersed in 0.1M HCl (the solid-liquid ratio was 1g:50ml, i.e., the ratio of the amount of magnetic Fe3O4 nanoparticles to 0.1M HCl was 1g:50ml), and ultrasonic oscillation was performed for 30min. The oxide layer was removed by acid washing, and the supernatant was discarded by magnetic separation. The activated Fe3O4 suspension (concentration of 10mg / ml) was obtained by washing with an ethanol / water mixture (4:1, v / v) for 3 times until the pH of the washing solution was about 6.5.

[0104] S3, 100ml of the activated Fe3O4 suspension was taken, 28% ammonia water was added, and the final concentration of the ammonia water was about 0.17M. After ultrasonic mixing (50°C), 2ml of tetraethyl orthosilicate was slowly added at a rate of 0.05ml / min, and mechanical stirring was performed at a speed of 900rpm for 6 hours. Then, the mixture was centrifuged, washed with anhydrous ethanol and deionized water for 3 times respectively, and uniformly dispersed in 50ml of anhydrous ethanol to obtain a SiO2@Fe3O4 ethanol dispersion (concentration of 20mg / ml).

[0105] S4, 50ml of the SiO2@Fe3O4 ethanol dispersion was taken, and 3ml of APTES (3-aminopropyltriethoxysilane) was added and ultrasonically mixed. After refluxing in a 65°C water bath for 4 hours under the protection of nitrogen atmosphere, the mixture was magnetically separated, washed with anhydrous ethanol for 6 times until no oily residue was left in the washing solution, and dispersed in 20ml of ethanol to obtain an amino-functionalized SiO2@Fe3O4 dispersion (concentration of 50mg / ml).

[0106] The preparation method of the epoxy-modified magnesium lithium silicate dispersion liquid comprises the following steps:

[0107] S1, 5g of magnesium lithium silicate was added to 2000ml of deionized water containing 0.1mM Na4P2O7, and ice-bath ultrasonic treatment was performed for 30min. Stepwise centrifugation was performed: first segment: 4000rpm centrifugation for 5min, and the precipitate was discarded; second segment: the supernatant was centrifuged at 12000rpm for 20min, and the supernatant was discarded (the precipitate was reserved); the precipitate was resuspended in N2-saturated deionized water to obtain a single-layer dispersion liquid of magnesium lithium silicate (concentration of 10mg / ml).

[0108] S2, take 100 ml of the magnesium lithium silicate monolayer dispersion solution (10 mg / ml), add 1% (v / v) glycidyl ether propyltrimethoxysilane (GPTMS), the mass ratio of magnesium lithium silicate in the magnesium lithium silicate monolayer dispersion solution to GPTMS is 1:1. 70℃ water bath magnetic stirring for 2 hours, the magnetic stirring rate is 300 rpm. Dialysis to remove free GPTMS (MWCO 8000 dialysis bag, deionized water is changed for 3 times), to obtain an epoxy modified magnesium lithium silicate dispersion solution (concentration is 10 mg / ml).

[0109] Example 2

[0110] The present embodiment provides a preparation method of SiO2@Fe3O4 loaded magnesium lithium silicate, which comprises the following steps:

[0111] The amino-functionalized SiO2@Fe3O4 ethanol dispersion solution (50 mg / ml) prepared in Example 1 is mixed with the epoxy modified magnesium lithium silicate dispersion solution (10 mg / ml) prepared in Example 1, wherein the mass ratio of amino-functionalized SiO2@Fe3O4 in the amino-functionalized SiO2@Fe3O4 ethanol dispersion solution to epoxy modified magnesium lithium silicate in the epoxy modified magnesium lithium silicate dispersion solution is 1:7. Adjust the pH to 8.0 with 0.1M Tris buffer. 300 rpm mechanical stirring reaction for 48 hours in a 37℃ water bath, protected by N2. Add 0.1M sodium citrate (final concentration 10mM), continue to stir for 30 min. Prepare a gel crude product, and after washing the gel crude product with deionized water for 3 times, a gel product is obtained. The gel product is quickly frozen with liquid nitrogen, and then freeze-dried in a freeze dryer for 48 hours to prepare SiO2@Fe3O4 loaded magnesium lithium silicate.

[0112] Example 3

[0113] The present embodiment provides a preparation method of SiO2@Fe3O4 loaded magnesium lithium silicate, which comprises the following steps:

[0114] The amino-functionalized SiO2@Fe3O4 ethanol dispersion (50 mg / ml) prepared in Example 1 was mixed with the epoxy-modified magnesium silicate lithium dispersion (10 mg / ml) prepared in Example 1, wherein the mass ratio of the amino-functionalized SiO2@Fe3O4 in the amino-functionalized SiO2@Fe3O4 ethanol dispersion to the epoxy-modified magnesium silicate lithium in the epoxy-modified magnesium silicate lithium dispersion was 1:9. The pH was adjusted to 8.0 with 0.1 M Tris buffer. The reaction was carried out in a 37 °C water bath with mechanical stirring at 300 rpm for 48 hours under N2protection. 0.1 M sodium citrate was added (final concentration 10 mM), and stirring was continued for 30 min. The crude gel product was prepared, and the crude gel product was washed with deionized water three times to obtain the gel product. The gel product was quickly frozen with liquid nitrogen and then lyophilized in a freeze dryer for 48 hours to prepare the SiO2@Fe3O4-loaded magnesium silicate lithium.

[0115] Example 4

[0116] The present example provides a method for preparing SiO2@Fe3O4-loaded magnesium silicate lithium, which comprises the following steps:

[0117] The amino-functionalized SiO2@Fe3O4 ethanol dispersion (50 mg / ml) prepared in Example 1 was mixed with the epoxy-modified magnesium silicate lithium dispersion (10 mg / ml) prepared in Example 1, wherein the mass ratio of the amino-functionalized SiO2@Fe3O4 in the amino-functionalized SiO2@Fe3O4 ethanol dispersion to the epoxy-modified magnesium silicate lithium in the epoxy-modified magnesium silicate lithium dispersion was 1:9. The pH was adjusted to 8.0 with 0.1 M Tris buffer. The reaction was carried out in a 37 °C water bath with mechanical stirring at 300 rpm for 48 hours under N2protection. 0.1 M sodium citrate was added (final concentration 10 mM), and stirring was continued for 30 min. The crude gel product was prepared, and the crude gel product was washed with deionized water three times to obtain the gel product. The gel product was quickly frozen with liquid nitrogen and then lyophilized in a freeze dryer for 48 hours to prepare the SiO2@Fe3O4-loaded magnesium silicate lithium.

[0118] Example 5

[0119] The present example provides a method for preparing a magnetic shear-thinning embolization hydrogel, which comprises the following steps:

[0120] In a stirring tank, 253.45 g of sterilized water cooled to 2 °C, 13.21 g of SiO2@Fe3O4-loaded magnesium silicate lithium powder, 80 g of tantalum powder, and 53.34 g of a 7.6% gelatin aqueous solution were added, and vacuum stirring was carried out in a vacuum stirring defoaming machine at 1800 rpm for 5 minutes to obtain a magnetic shear-thinning embolization hydrogel. The magnetic shear-thinning embolization hydrogel was vacuum filled into a 1 ml syringe, and after moist heat sterilization, it was ready for use.

[0121] In this embodiment, the SiO2@Fe3O4-loaded lithium magnesium silicate powder is prepared by Example 2.

[0122] The gelatin aqueous solution with a concentration of 7.6% is prepared by uniformly mixing gelatin and sterile water for injection.

[0123] Example 6

[0124] The embodiment provides a preparation method of a magnetic shear-thinning embolus hydrogel, and the preparation method comprises the following steps:

[0125] In a stirring tank, 253.45 g of sterile water for injection cooled to 2 ℃, 13.21 g of SiO2@Fe3O4-loaded lithium magnesium silicate powder, 80 g of tantalum powder and 53.34 g of a gelatin aqueous solution with a concentration of 7.6% are added, vacuum stirring is performed in a vacuum stirring defoaming machine at 1800 rpm for 5 minutes to obtain a magnetic shear-thinning embolus hydrogel, the magnetic shear-thinning embolus hydrogel is vacuum filled in a 1 ml syringe, and the magnetic shear-thinning embolus hydrogel is reserved after moist heat sterilization.

[0126] In this embodiment, the SiO2@Fe3O4-loaded lithium magnesium silicate powder is prepared by Example 3.

[0127] The gelatin aqueous solution with a concentration of 7.6% is prepared by uniformly mixing gelatin and sterile water for injection.

[0128] Example 7

[0129] The embodiment provides a preparation method of a magnetic shear-thinning embolus hydrogel, and the preparation method comprises the following steps:

[0130] In a stirring tank, 253.45 g of sterile water for injection cooled to 2 ℃, 13.21 g of SiO2@Fe3O4-loaded lithium magnesium silicate powder, 80 g of tantalum powder and 53.34 g of a gelatin aqueous solution with a concentration of 7.6% are added, vacuum stirring is performed in a vacuum stirring defoaming machine at 1800 rpm for 5 minutes to obtain a magnetic shear-thinning embolus hydrogel, the magnetic shear-thinning embolus hydrogel is vacuum filled in a 1 ml syringe, and the magnetic shear-thinning embolus hydrogel is reserved after moist heat sterilization.

[0131] In this embodiment, the SiO2@Fe3O4-loaded lithium magnesium silicate powder is prepared by Example 4.

[0132] The gelatin aqueous solution with a concentration of 7.6% is prepared by uniformly mixing gelatin and sterile water for injection.

[0133] Example 8

[0134] The embodiment provides a preparation method of a magnetic shear-thinning embolus hydrogel, and the preparation method comprises the following steps:

[0135] In a stirring tank, 253.45 g of sterilized water cooled to 2℃, 12 g of SiO2@Fe3O4-loaded lithium magnesium silicate powder, 80 g of tantalum powder, and 53.34 g of a 7.6% gelatin aqueous solution were added, and a magnetic shear-thinning embolus hydrogel was obtained by stirring at 1800 rpm for 5 minutes in a vacuum stirring defoaming machine. The magnetic shear-thinning embolus hydrogel was vacuum-filled in a 1 ml syringe, and after wet heat sterilization, it was ready for use.

[0136] In this embodiment, the SiO2@Fe3O4-loaded lithium magnesium silicate powder was prepared according to Example 3.

[0137] The 7.6% gelatin aqueous solution was prepared by uniformly mixing gelatin and sterilized water.

[0138] Example 9

[0139] The present embodiment provides a preparation method of a magnetic shear-thinning embolus hydrogel, which comprises the following steps:

[0140] In a stirring tank, 253.45 g of sterilized water cooled to 2℃, 12 g of SiO2@Fe3O4-loaded lithium magnesium silicate powder, 80 g of tantalum powder, and 53.34 g of a 7.6% gelatin aqueous solution were added, and a magnetic shear-thinning embolus hydrogel was obtained by stirring at 1800 rpm for 5 minutes in a vacuum stirring defoaming machine. The magnetic shear-thinning embolus hydrogel was vacuum-filled in a 1 ml syringe, and after wet heat sterilization, it was ready for use.

[0141] In this embodiment, the SiO2@Fe3O4-loaded lithium magnesium silicate powder was prepared according to Example 3.

[0142] The 7.6% gelatin aqueous solution was prepared by uniformly mixing gelatin and sterilized water.

[0143] Example 10

[0144] The present embodiment provides a preparation method of a magnetic shear-thinning embolus hydrogel, which comprises the following steps:

[0145] In a stirring tank, 253.45 g of sterilized water cooled to 2℃, 12 g of SiO2@Fe3O4-loaded lithium magnesium silicate powder, 80 g of tantalum powder, and 53.34 g of a 7.6% gelatin aqueous solution were added, and a magnetic shear-thinning embolus hydrogel was obtained by stirring at 1800 rpm for 5 minutes in a vacuum stirring defoaming machine. The magnetic shear-thinning embolus hydrogel was vacuum-filled in a 1 ml syringe, and after wet heat sterilization, it was ready for use.

[0146] In this embodiment, the SiO2@Fe3O4-loaded lithium magnesium silicate powder was prepared according to Example 3.

[0147] The gelatin aqueous solution with a concentration of 7.6% was prepared by uniformly mixing 10 g of gelatin and 121.58 g of sterilized water for injection.

[0148] Example 11

[0149] The present example provides a preparation method of a magnetic shear-thinning embolization hydrogel, which comprises the following steps:

[0150] In a stirring tank, 90.84 g of sterilized water for injection cooled to 2°C, 6 g of SiO2@Fe3O4-loaded lithium magnesium silicate powder, 40 g of tantalum powder, and 263.16 g of gelatin aqueous solution with a concentration of 7.6% were added, and vacuum stirring was performed in a vacuum stirring defoaming machine at 1800 rpm for 5 minutes to obtain a magnetic shear-thinning embolization hydrogel. The magnetic shear-thinning embolization hydrogel was vacuum filled in a 1 ml syringe, and after moist heat sterilization, it was ready for use.

[0151] In the present example, the SiO2@Fe3O4-loaded lithium magnesium silicate powder was prepared according to Example 3.

[0152] The gelatin aqueous solution with a concentration of 7.6% was prepared by uniformly mixing 20 g of gelatin and 243.16 g of sterilized water for injection.

[0153] Comparative Example 1

[0154] The present comparative example provides a preparation method of a hydrogel embolization agent, which comprises the following steps:

[0155] In a flask, gelatin and sterilized water for injection (mass ratio of gelatin to sterilized water for injection was 4.5:25) were added, and stirring was performed at 70°C and a stirring speed of 400 rpm for 30 min to obtain a gelatin pre-solution with a concentration of 7.6%, which was kept at 70°C for standby. In a stirring tank, 253.45 g of sterilized water for injection cooled to 2°C, 80 g of tantalum powder, 13.21 g of nano lithium magnesium silicate, and 53.34 g of the gelatin pre-solution were added, and vacuum stirring was performed in a vacuum stirring defoaming machine at 1800 rpm for 5 min to obtain a hydrogel embolization agent, which was vacuum filled in a 1 ml syringe and subjected to moist heat sterilization.

[0156] Comparative Example 2

[0157] The present comparative example provides a preparation method of Fe3O4-loaded lithium magnesium silicate, which comprises the following steps:

[0158] S1. Under nitrogen protection, FeCl2·4H2O and mol FeCl3·6H2O were dissolved in deoxygenated deionized water at a molar ratio of 1:2. An iron salt mixed solution was prepared by heating at 80°C and magnetic stirring.

[0159] S2. Take 14 g of magnesium lithium silicate and disperse it in 500 ml of deoxygenated deionized water to form a stable colloid, i.e., a magnesium lithium silicate dispersion. Add the magnesium lithium silicate dispersion to the hot iron salt mixture solution under vigorous stirring (1000 rpm) and N2protection. Ensure that the system temperature is maintained at 80°C. After the addition of the magnesium lithium silicate, continue stirring for 15-30 minutes to allow the magnesium lithium silicate flakes to disperse uniformly in the iron ion environment and to begin adsorbing iron ions.

[0160] S3. Prepare a 1 M NaOH solution and quickly add the NaOH solution to the above-mentioned vigorously stirred mixture. Upon reaching a pH of 9-11, Fe3O4 rapidly nucleates and precipitates. The newly formed Fe3O4 nanoparticles nucleate and grow on the surface of the magnesium lithium silicate flakes or between the layers of the magnesium lithium silicate flakes.

[0161] S4. Maintain the temperature at 60-80°C and vigorous stirring (1000 rpm) and continue the reaction for 30 minutes under N2protection. The Fe3O4 crystallizes and matures. Cool to room temperature under N2protection. Centrifuge to collect the black Fe3O4 / magnesium lithium silicate precipitate. Wash the precipitate repeatedly with deoxygenated deionized water until the washings are neutral and free of Cl ions (no white precipitate is detected using AgNO3solution). Centrifuge to collect the solid after each washing. Freeze-dry in a freeze-dryer for 48 h to obtain a Fe3O4-loaded magnesium lithium silicate powder, wherein the mass ratio of Fe3O4 to magnesium lithium silicate in the Fe3O4-loaded magnesium lithium silicate powder is 1:7.

[0162] Comparative Example 3

[0163] This comparative example provides a method for preparing a Fe3O4-loaded magnesium lithium silicate, which comprises the following steps:

[0164] S1. Dissolve FeCl2-4H2O and mol FeCl3-6H2O in a molar ratio of 1:2 in deoxygenated deionized water under nitrogen protection. Prepare an iron salt mixture solution by heating at 80°C with magnetic stirring.

[0165] S2. Take 14 g of magnesium lithium silicate and disperse it in 500 ml of deoxygenated deionized water to form a stable colloid, i.e., a magnesium lithium silicate dispersion. Add the magnesium lithium silicate dispersion to the hot iron salt mixture solution under vigorous stirring (1000 rpm) and N2protection. Ensure that the system temperature is maintained at 80°C. After the addition of the magnesium lithium silicate, continue stirring for 15-30 minutes to allow the magnesium lithium silicate flakes to disperse uniformly in the iron ion environment and to begin adsorbing iron ions.

[0166] S3. Prepare a 1 M NaOH solution and quickly add the NaOH solution to the above-mentioned vigorously stirred mixture. Upon reaching a pH of 9-11, Fe3O4 rapidly nucleates and precipitates. The newly formed Fe3O4 nanoparticles nucleate and grow on the surface of the magnesium lithium silicate flakes or between the layers of the magnesium lithium silicate flakes.

[0167] S4, maintain the temperature at 60-80 °C and vigorous stirring (1000 rpm) for 30 minutes under N2protection, Fe3O4crystallization mature. Cool to room temperature under N2protection. Centrifugal collection of black Fe3O4 / magnesium lithium silicate precipitate. The precipitate is washed repeatedly with deoxygenated deionized water until the washing liquid is neutral and does not contain Cl-ions (no white precipitate is detected with AgNO3solution). The solid is collected by centrifugation after each washing. Freeze-drying in a freeze dryer for 48 h to obtain Fe3O4-loaded magnesium lithium silicate powder, wherein the mass ratio of Fe3O4to magnesium lithium silicate in the Fe3O4-loaded magnesium lithium silicate powder is 1:9.

[0168] Comparative Example 4

[0169] The present comparative example provides a preparation method of Fe3O4-loaded magnesium lithium silicate, which comprises the following steps:

[0170] S1, dissolve FeCl2*4H2O and mol FeCl3*6H2O in a molar ratio of 1:2 in deoxygenated deionized water under nitrogen protection. Prepare a mixed iron salt solution by heating and magnetic stirring at 80 °C.

[0171] S2, 26 g of magnesium lithium silicate is dispersed in 500 ml of deoxygenated deionized water to form a stable colloid, i.e. magnesium lithium silicate dispersion. Add the magnesium lithium silicate dispersion to the hot mixed iron salt solution under vigorous stirring (1000 rpm) and N2protection. Ensure that the temperature of the system is maintained at 80 °C. After the addition of magnesium lithium silicate, continue stirring for 15-30 minutes to allow the magnesium lithium silicate flakes to disperse uniformly in the iron ion environment and begin to adsorb iron ions.

[0172] S3, prepare a 1M NaOH solution, and quickly add the NaOH solution to the above-mentioned vigorously stirred mixture. When the pH is 9-11, Fe3O4nucleates and precipitates rapidly. The newly formed Fe3O4nanoparticles nucleate and grow on the surface of the magnesium lithium silicate flakes or between the layers.

[0173] S4, maintain the temperature at 60-80 °C and vigorous stirring (1000 rpm) for 30 minutes under N2protection, Fe3O4crystallization mature. Cool to room temperature under N2protection. Centrifugal collection of black Fe3O4 / magnesium lithium silicate precipitate. The precipitate is washed repeatedly with deoxygenated deionized water until the washing liquid is neutral and does not contain Cl-ions (no white precipitate is detected with AgNO3solution). The solid is collected by centrifugation after each washing. Freeze-drying in a freeze dryer for 48 h to obtain Fe3O4-loaded magnesium lithium silicate powder, wherein the mass ratio of Fe3O4to magnesium lithium silicate in the Fe3O4-loaded magnesium lithium silicate powder is 1:13.

[0174] Comparative Example 5

[0175] The present comparative example provides a preparation method of a hydrogel embolic agent, which comprises the following steps:

[0176] Into a stirring tank, 253.45 g of sterilized water cooled to 2°C, 13.21 g of the Fe3O4-loaded lithium magnesium silicate powder provided by Comparative Example 2, 80 g of tantalum powder, and 53.34 g of a gelatin aqueous solution with a concentration of 7.6% were added. The mixture was stirred in a vacuum stirring and defoaming machine at 1800 rpm for 5 minutes to obtain a hydrogel embolic agent. The hydrogel embolic agent was vacuum-filled into 1 ml syringes and sterilized by moist heat for standby use.

[0177] Comparative Example 6

[0178] The present comparative example provides a preparation method of a hydrogel embolic agent, which comprises the following steps:

[0179] Into a stirring tank, 253.45 g of sterilized water cooled to 2°C, 13.21 g of the Fe3O4-loaded lithium magnesium silicate powder provided by Comparative Example 2, 80 g of tantalum powder, and 53.34 g of a gelatin aqueous solution with a concentration of 7.6% were added. The mixture was stirred in a vacuum stirring and defoaming machine at 1800 rpm for 5 minutes to obtain a hydrogel embolic agent. The hydrogel embolic agent was vacuum-filled into 1 ml syringes and sterilized by moist heat for standby use.

[0180] Comparative Example 7

[0181] The present comparative example provides a preparation method of a hydrogel embolic agent, which comprises the following steps:

[0182] Into a stirring tank, 253.45 g of sterilized water cooled to 2°C, 13.21 g of the Fe3O4-loaded lithium magnesium silicate powder provided by Comparative Example 2, 80 g of tantalum powder, and 53.34 g of a gelatin aqueous solution with a concentration of 7.6% were added. The mixture was stirred in a vacuum stirring and defoaming machine at 1800 rpm for 5 minutes to obtain a hydrogel embolic agent. The hydrogel embolic agent was vacuum-filled into 1 ml syringes and sterilized by moist heat for standby use.

[0183] Comparative Example 8

[0184] The present comparative example provides a preparation method of a hydrogel embolic agent, which comprises the following steps:

[0185] Into a stirring tank, 253.45 g of sterilized water cooled to 2°C, 13.21 g of the Fe3O4-loaded lithium magnesium silicate powder provided by Comparative Example 2, 80 g of tantalum powder, and 53.34 g of a gelatin aqueous solution with a concentration of 7.6% were added. The mixture was stirred in a vacuum stirring and defoaming machine at 1800 rpm for 5 minutes to obtain a hydrogel embolic agent. The hydrogel embolic agent was vacuum-filled into 1 ml syringes and sterilized by moist heat for standby use.

[0186] Comparative Example 9

[0187] The present comparative example provides a preparation method of a hydrogel embolic agent, comprising the following steps:

[0188] Into a stirring tank, add sterilized water 253.45 g cooled to 2℃, Fe3O4-loaded lithium magnesium silicate powder 15.85 g provided by Comparative Example 3, tantalum powder 80 g, and gelatin aqueous solution with a concentration of 7.6% 53.34 g, and vacuum stir for 5 minutes at 1800 rpm in a vacuum stirring defoaming machine to obtain a hydrogel embolic agent. The hydrogel embolic agent is vacuum filled into a 1 ml syringe, and is ready for use after moist heat sterilization.

[0189] Performance test

[0190] The magnetic shear-thinning embolic hydrogels prepared in Examples 5-9, the hydrogel embolic agent prepared in Comparative Example 1, and the hydrogel embolic agents prepared in Comparative Examples 5-9 are tested according to the following test methods:

[0191] 1. Extrusion force test

[0192] Prepare a microcatheter with a length of 130 cm and a diameter of 2.8F, and inject the hydrogel embolic material to be tested into the microcatheter before testing. Connect the microcatheter filled with the vascular embolic agent through a luer connector to the head end of a syringe, and fix the syringe with a clamp. Set the pushing speed to 30 mm / min, and the test distance to 20 mm. Record the maximum and average values of the pushing force of the syringe handle during the test, accurate to 0.1 N.

[0193] 2. Modulus test

[0194] Strain 1%, 0.02-100 Hz frequency scanning mode, test the loss modulus and storage modulus of the sample.

[0195] 3. Shear viscosity test

[0196] At (25±0.2)℃, perform peristalsis scanning at a shear rate from 0.001 s -1 -1000 s -1 to obtain the shear viscosity at a shear rate of 0.01 s-1and 10 s-1, with the unit of: millipascal·second (mPa·s).

[0197] 4. Magnetic heating effect test

[0198] Place the sample (Fe concentration 1 mg / mL) in N2-deoxygenated normal saline, apply an alternating magnetic field (370 kHz, 20 kA / m) in a constant temperature environment of 37℃, and use an infrared thermal imager to record the temperature rise curve in real time (sampling rate 30 Hz).

[0199] The obtained extrusion force test results are shown in Table 1:

[0200] Table 1

[0201]

[0202]

[0203] The obtained modulus test results and shear viscosity test results are shown in Table 2:

[0204] Table 2

[0205]

[0206] The obtained magnetocaloric effect test results are shown in Table 3:

[0207] Table 3

[0208] Performance indicators Example 6 Comparative Example 6 Initial temperature rise rate 4.21 ± 0.15 °C / min 2.85 ± 0.22 °C / min Temperature rise ΔT over 5 minutes 18.6±0.8℃ 12.7±1.1℃ Equilibrium temperature 55.3±0.6℃ 49.8±1.2℃

[0209] Based on the results of the above Tables 1, 2 and 3, it can be seen from the data of Examples 5-7 that by optimizing the ratio of SiO2@Fe3O4 or Fe3O4 loaded by lithium magnesium silicate (i.e. changing the mass ratio of aminated SiO2@Fe3O4 to epoxy-modified lithium magnesium silicate), the shear thinning performance of the hydrogel can be enhanced;

[0210] Based on the results of the above Tables 1, 2 and 3, the syringe push force and shear viscosity under high shear of Examples 5-7 are all less than those of Comparative Example 1 without loading, and the optimal loading ratio is about 10% (i.e. the mass ratio of aminated SiO2@Fe3O4 to epoxy-modified lithium magnesium silicate is 1:9), and the extrusion force and shear viscosity under high shear rate of Example 6 are less than those of Examples 5 and 7;

[0211] Based on the results of the above Tables 1, 2 and 3, the syringe push force and shear viscosity under high shear of Comparative Examples 5-7 are all less than those of Comparative Example 1 without loading, and the optimal loading ratio is about 10% (i.e. the mass ratio of Fe3O4 to lithium magnesium silicate is 1:9), and the extrusion force and shear viscosity under high shear rate of Comparative Example 6 are less than those of Comparative Examples 5 and 7, thus indicating that when the ratio of SiO2@Fe3O4 or Fe3O4 loaded by lithium magnesium silicate is 10%, the prepared hydrogel has better performance;

[0212] Based on the results of the above Tables 1, 2 and 3, Examples 8-9 and Comparative Examples 8-9 show that by adjusting the content of lithium magnesium silicate in the embolization agent, the push force, shear viscosity and modulus of the embolization agent can be controlled, thus being suitable for different occasions.

[0213] Based on the results of Table 1, Table 2 and Table 3 above, the comprehensive data of Comparative Examples 10-11 and Example 6 show that the optimal loading ratio (mass ratio of aminated SiO2@Fe3O4 to epoxy-modified magnesium lithium silicate is 1:9) is 10%.

[0214] Comparative Examples 5-9 synthesize Fe3O4 in situ in the magnesium lithium silicate solution by the coprecipitation method, which precipitates and grows between the layers of magnesium lithium silicate. Compared with Examples 5-9, Fe3O4 is directly bonded between the layers of magnesium lithium silicate. Comparative Examples 5-9 have the disadvantages of easy sedimentation and uneven dispersion of Fe3O4, which leads to a larger pushing force than the data of Examples under the same formula, and a higher shear viscosity than the data of Examples under high shear, which is not conducive to the use of embolization agents.

[0215] Based on the data in Table 3, it can be seen that the chemically bonded Fe3O4 has increased oxidation resistance due to the protection of the SiO2 barrier on the magnetic core integrity. Therefore, the initial temperature rise rate, 5-minute temperature rise ΔT and equilibrium temperature of Example 6 are higher than those of Comparative Example 6, and the performance is superior.

[0216] The above disclosure is only a few specific embodiments of the present application, but the embodiments of the present application are not limited thereto, and any changes that can be thought of by those skilled in the art shall fall within the scope of the present application.

Claims

1. A method for preparing a magnetic shear-thinning embolic hydrogel, characterized in that, Includes the following steps: S1. An aminated SiO2@Fe3O4 ethanol dispersion was prepared by coating Fe3O4 with silica and then subjecting it to surface treatment. S2. Surface treatment of lithium magnesium silicate was performed to prepare an epoxy-modified lithium magnesium silicate dispersion. S3. By using amino-epoxy click chemistry, aminated SiO2@Fe3O4 is loaded onto epoxy-modified lithium magnesium silicate to prepare lithium magnesium silicate loaded with SiO2@Fe3O4. S4. After uniformly mixing SiO2@Fe3O4-loaded lithium magnesium silicate, polymer, developer, and sterile water for injection, a magnetic shear-thinning embolic hydrogel is prepared.

2. The method for preparing a magnetic shear-thinning embolic hydrogel according to claim 1, characterized in that, Step S1 specifically includes the following steps: Preparation of S1.1 Magnetic Fe3O4 Nanoparticles FeCl3·6H2O and FeCl2·4H2O were mixed and dissolved in deoxygenated deionized water at a molar ratio of (1.8-2):

1. Under vigorous stirring, dilute ammonia solution was slowly added dropwise to adjust the pH value to 10-11. The reaction temperature was controlled at 60-80℃ and the reaction was continued for 30-60 minutes. The resulting black precipitate was separated by centrifugation and repeatedly washed with deoxygenated deionized water until neutral to prepare magnetic Fe3O4 nanoparticles. S1.2 Preparation of activated Fe3O4 suspension First, the magnetic Fe3O4 nanoparticles were dispersed in dilute hydrochloric acid and ultrasonically vibrated for 30-60 min. After acid washing, they were magnetically separated, the supernatant was discarded, and finally the mixture was washed with an ethanol / water mixture until the pH of the washing solution was 6-7 to obtain an activated Fe3O4 suspension. S1.3, Synthesis of SiO2@Fe3O4 ethanol dispersion Ammonia water was added to the activated Fe3O4 suspension, with a final concentration of 0.16-0.18M. After ultrasonic mixing, tetraethyl orthosilicate was slowly added dropwise. The mixture was mechanically stirred at 700-900 rpm for 4-6 hours and then centrifuged. The mixture was washed successively with anhydrous ethanol and deionized water, and then uniformly dispersed in anhydrous ethanol to obtain SiO2@Fe3O3 ethanol dispersion. S1,4,3-aminopropyltriethoxysilane silanization 3-Aminopropyltriethoxysilane was added to the SiO2@Fe3O4 ethanol dispersion, and after ultrasonic mixing, the mixture was refluxed in a water bath under nitrogen protection at a temperature of 50-75°C for 4-6 hours. After magnetic separation, the mixture was washed with anhydrous ethanol and then dispersed in ethanol to obtain an aminated SiO2@Fe3O4 ethanol dispersion.

3. The method for preparing a magnetic shear-thinning embolic hydrogel according to claim 2, characterized in that, In step S1.1, the deoxygenated deionized water is deionized water that has been deoxygenated by an inert gas; In step S1.2, the concentration of dilute hydrochloric acid is 0.1-0.12M, and the concentration of the activated Fe3O4 suspension is 10-20 mg / ml; In step S1.3, the mass ratio of tetraethyl orthosilicate to Fe3O4 in the activated Fe3O4 suspension is (1.8-1.9):1, the dropping rate of the tetraethyl orthosilicate is 0.01-0.05 ml / min, and the concentration of the SiO2@Fe3O4 ethanol dispersion is 20-30 mg / ml. In step S1.4, the mass ratio of SiO2@Fe3O4 to 3-aminopropyltriethoxysilane in the SiO2@Fe3O4 ethanol dispersion is 1:(2.8-2.9), and the concentration of the aminated SiO2@Fe3O4 ethanol dispersion is 50-60 mg / ml.

4. The method for preparing a magnetic shear-thinning embolic hydrogel according to claim 1, characterized in that, Step S2 specifically includes the following steps: S2.1 Lithium magnesium silicate sheet peeling Lithium magnesium silicate was added to an aqueous solution of Na4P2O7, sonicated in an ice bath for 30-60 min, and after step centrifugation, the precipitate was resuspended in N2 saturated deionized water to obtain a monolayer dispersion of lithium magnesium silicate. S2.2, Lithium Magnesium Silicate Epoxy Modification Take a monolayer dispersion of lithium magnesium silicate, add glycidoxypropyltrimethoxysilane, and stir magnetically in a water bath at 60-70℃ for 2-3 hours. Then, dialyze to remove free glycidoxypropyltrimethoxysilane to obtain epoxy-modified lithium magnesium silicate.

5. The method for preparing a magnetic shear-thinning embolic hydrogel according to claim 4, characterized in that, In step S2.1, the mass ratio of lithium magnesium silicate to Na4P2O7 is 1:(0.01-0.012); In step S2.1, the step centrifugation specifically includes the following steps: first centrifuge at 2000-4000 rpm for 5-10 min, discard the precipitate, and then centrifuge at 10000-12000 rpm for 20-30 min, discard the supernatant. In step S2.1, the concentration of the lithium magnesium silicate monolayer dispersion is 10-15 mg / ml; In step S2.2, the mass ratio of lithium magnesium silicate to glycidyl etheroxypropyltrimethoxysilane in the lithium magnesium silicate monolayer dispersion is 1:(1-1.1); In step S2.2, the magnetic stirring speed is 200-300 rpm.

6. The method for preparing a magnetic shear-thinning embolic hydrogel according to claim 1, characterized in that, Step S3 specifically includes the following steps: S3.1, Click chemical condensation gelation Aminated SiO2@Fe3O4 ethanol dispersion was mixed with epoxy-modified magnesium lithium silicate dispersion, and the pH was adjusted to 8.0 using Tris buffer to obtain a mixture. Under N2 protection, the mixture was mechanically stirred at 200-300 rpm in a 37°C water bath for 36-48 hours. Then, sodium citrate solution was added to a final concentration of 0.01M, and stirring was continued for 20-30 minutes. After centrifugation and washing with deionized water, the gel product was obtained. S3.2 Preparation of lithium magnesium silicate supported on SiO2@Fe3O4 After the gel product was rapidly frozen with liquid nitrogen, it was freeze-dried in a freeze dryer to prepare lithium magnesium silicate loaded with SiO2@Fe3O4.

7. The method for preparing a magnetic shear-thinning embolic hydrogel according to claim 6, characterized in that, In step S3.1, the mass ratio of aminated SiO2@Fe3O4 in the aminated SiO2@Fe3O4 ethanol dispersion to epoxy-modified magnesium silicate in the epoxy-modified magnesium silicate dispersion is 1:(4-13). In step S3.2, the freeze-drying time is 24-60 hours.

8. The method for preparing a magnetic shear-thinning embolic hydrogel according to claim 1, characterized in that, Step S4 specifically includes the following steps: Weigh the following raw materials according to the following weight ratio: 1.5%-4.5% lithium magnesium silicate loaded with SiO2@Fe3O4, 1%-10% polymer, 10%-40% developer, and the remainder is sterile water for injection. Divide the sterile water for injection into two parts: sterile water #1 and sterile water #2. Mix sterile water #1 with the polymer to prepare a polymer aqueous solution. Place the lithium magnesium silicate loaded with SiO2@Fe3O4, the polymer aqueous solution, the developer, and sterile water #2 in a vacuum stirrer and stir under vacuum at 1000-1800 rpm for 1-5 minutes to prepare a magnetic shear thinning embolic hydrogel.

9. The method for preparing a magnetic shear-thinning embolic hydrogel according to claim 1, characterized in that, The polymer is a natural polymer and / or a synthetic polymer.

10. A magnetic shear-thinning embolic hydrogel, characterized in that, It was prepared by the method for preparing magnetic shear-thinning embolic hydrogel according to any one of claims 1-9.

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