Performance screening method and application of magnetic mica-based colloidal gel

Abstract

The invention relates to the field of composite material preparation, in particular to a performance screening method and application of magnetic mica-based colloidal gels, according to the method, mica powder is magnetically functionalized and combined with gelatin nanoparticles, and the colloidal gel is prepared through electrostatic assembly. The injection performance, the magnetocaloric performance and the mechanical performance are represented by regulating and controlling the mass ratio of the assembly elements and the concentration of a gel solid solution. And performing three-dimensional synergistic performance screening by combining experimental data to obtain a preliminarily optimized gel formula, and further preparing the magnetic mica sheet colloidal gel to meet the requirements of a treatment preparation. According to the method, regulation and control parameters are clear, correlation between gel performance is established based on experimental data, an optimal gel formula can be effectively designed, explored and verified, and a thought is provided for preparation process optimization and functional material construction and application of the magnetic mica sheet colloidal gel.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of composite material preparation, in particular to a performance screening method of a magnetic mica-based colloidal gel and application. BACKGROUND

[0002] In recent years, injectable hydrogels have been widely concerned in tumor treatment due to their self-healing properties and adjustable mechanical properties suitable for minimally invasive treatment such as transcatheter arterial embolization. However, the commonly used embolic materials such as microspheres or iodized oil have defects such as easy recanalization of blood vessels or non-specific embolization. In contrast, injectable hydrogels have the ability to be delivered through clinical catheters and achieve complete embolization in different blood vessel shapes and sizes, while also having the ability to synergistically deliver multiple treatment methods, solving the problem of insufficient single embolization efficacy. Colloidal gels are formed by self-assembly of building blocks, and have good shear thinning and self-healing properties. However, the insufficient mechanical properties of colloidal gels cannot meet the requirements of injectability and high stability at the same time, limiting their practical application in vascular embolization therapy.

[0003] The bottom-up modular assembly strategy allows the overall performance of the colloidal gel to be precisely controlled by adjusting the assembly building blocks (such as size, roughness, etc.). Mica, as a natural two-dimensional non-metallic mineral, has a high aspect ratio, which helps to enhance the interfacial cross-linking density with gelatin nanoparticles when used as a negatively charged assembly building block. Mica nanosheets obtained by exfoliating mica powder exhibit a more excellent radius-thickness ratio and high specific surface area. At the same time, the mica sheets are modified with iron oxide in situ, which not only improves the roughness of the mica sheets, but also makes the colloidal gel magnetically functionalized to meet the combined therapy needs. The current magnetic mica sheet colloidal gel has relatively excellent performance, but its preparation process is complex, the preparation time is long, and the structure regulation parameters are complex, making it difficult to quickly adapt to the needs of clinical use. Based on the easily prepared magnetic mica powder colloidal gel, by constructing a clear performance screening process, the gel formula and parameter settings of the magnetic mica sheet colloidal gel are optimized, so as to shorten the material design and research cycle while obtaining a magnetic colloidal gel system with optimal comprehensive performance.

[0004] The present application proposes a construction path from mica powder to mica sheet and preparation of magnetic mica-based colloidal gel, which combines surface roughness regulation, assembly building block mass ratio and solid solution content in the gel, to systematically construct and screen high-performance composite gel materials suitable for magnetic hyperthermia combined with embolization therapy, providing a basis for the construction and application of functional gel materials. SUMMARY

[0005] The present application aims to solve the problems of long preparation period, ambiguous formula system and difficulty in realizing rapid construction and standardization of clinical application of the existing current magnetic mica sheet colloidal gel with excellent performance. A magnetic mica-based colloidal gel construction and performance screening method based on interface roughness regulation is provided, which improves the gel performance of the colloidal gel through the interface roughness strategy. Meanwhile, the mass ratio between the assembly units and the solid solute content in the gel are regulated to realize the comprehensive screening and optimization of the injection performance, magnetic heat performance and mechanical performance of the colloidal gel, and obtain a magnetic mica sheet colloidal gel suitable for magnetic heat therapy combined with embolization treatment.

[0006] To achieve the above-mentioned purpose, the present application discloses a performance screening method of a magnetic mica-based colloidal gel, which comprises the following steps:

[0007] S101, obtaining magnetic mica powder by magnetically functionalizing mica powder through high-temperature thermal decomposition method;

[0008] S102, preparing an organic-inorganic composite magnetic mica powder colloidal gel by taking gelatin nanoparticles as organic positive assembly units and the magnetic mica powder as inorganic negative assembly units, and regulating the concentrations of the organic positive assembly units and the inorganic negative assembly units through the detection results in the preparation process of the magnetic mica powder colloidal gel;

[0009] The concentration regulation of the magnetic mica powder is realized through a dynamic monitoring module, and the dynamic monitoring module comprises:

[0010] An injection performance monitoring unit is used for monitoring the flowability V1 of the mica powder colloidal gel under shear force and the structural stability V2 after shearing, and regulating the ratio of the gelatin nanoparticles according to V1 and V2;

[0011] A magnetic heat performance monitoring unit is used for monitoring the concentration N of the magnetic mica powder in the mica powder colloidal gel and the temperature T, and adjusting the content of the magnetic mica powder according to N and T;

[0012] A mechanical performance monitoring unit is used for monitoring the parameters of the injection performance monitoring unit and the magnetic heat performance monitoring unit;

[0013] The dynamic monitoring module compares the parameters monitored by the mechanical performance monitoring unit with preset standard environmental parameters, and if the obtained parameters exceed the threshold of the preset standard parameters, it is considered that the parameters are abnormal, and the concentration regulation of the organic positive assembly units and the inorganic negative assembly units is realized, wherein the mutual influence of the injection performance monitoring unit, the magnetic heat performance monitoring unit and the mechanical performance monitoring unit is as follows:

[0014] When the value N in the magnetic heat performance monitoring unit increases to cause the temperature T to rise, if the storage modulus of the mechanical performance monitoring unit abnormally decreases to <800 Pa, the value V1 of the injection performance monitoring unit decreases and the value V2 increases are triggered.

[0015] When the injection performance monitoring unit detects 40N < V1 < 50N, the mechanical performance monitoring unit synchronously checks whether the storage modulus is > 1500Pa, and if so, triggers a solid solution concentration or assembly unit mass ratio down-regulation instruction;

[0016] S103, injection performance characterization of the magnetic mica powder colloidal gel: the gel is passed through different diameter syringe needles and injection rates to evaluate its injection performance;

[0017] S104, magnetic heat performance characterization of the magnetic mica powder colloidal gel: the gel is placed under an alternating magnetic field, and its magnetic heat performance is evaluated by adjusting the magnetic field strength of the alternating magnetic field;

[0018] S105, mechanical performance characterization of the magnetic mica powder colloidal gel: the mechanical properties of the gel are measured by a rotational rheometer, mainly including the storage modulus and loss modulus obtained by frequency scanning, frequency-dependent index, and creep experiment, etc.

[0019] S201, based on the assembly unit mass ratio and the gel solid solution content of the magnetic mica powder colloidal gel in the above steps, the mica powder is exfoliated into mica sheets with higher specific surface area and magnetically functionalized to obtain a magnetic mica sheet colloidal gel under the same preparation conditions;

[0020] S202, repeat the performance tests of S103-S105 to determine whether the gel performance of the magnetic mica sheet colloidal gel meets the performance requirements of embolization preparations in magnetic hyperthermia combined with embolization therapy; if not, adjust the assembly unit mass ratio and the gel solid solution content of the magnetic mica powder colloidal gel, and repeat the steps of S102-S201;

[0021] S301, if the gel performance of the magnetic mica sheet colloidal gel meets the performance requirements, establish a rabbit ear tumor model and verify its therapeutic effect in magnetic hyperthermia combined with embolization therapy.

[0022] As a further improvement of the technical solution, the execution logic of the dynamic monitoring module includes the following cooperative control strategies:

[0023] When the magnetic heat performance monitoring unit detects T < 40℃, the magnetic mica powder concentration N is increased;

[0024] The mechanical performance monitoring unit checks whether the increased N value results in a storage modulus > 800Pa, and if lower than the value, the x:y = magnetic mica powder:gel nanoparticles ratio is increased to > 1:1;

[0025] The injection performance monitoring unit detects the V1 value after adjusting the ratio, and if V1 > 40N, the solid solution concentration or assembly unit mass ratio is down-regulated, and the down-regulation gradient is ≤ 3w / v%.

[0026] As a further improvement of the technical solution, the priority of the injection performance monitoring unit, the magnetic heat performance monitoring unit and the mechanical performance monitoring unit is:

[0027] The mechanical performance monitoring unit data is abnormal, and the priority is adjusted;

[0028] The injection performance monitoring unit and the magnetic heat performance monitoring unit are optimized in parallel, when V1>40N or T<42℃, the joint rebalancing of the assembly element mass ratio and the solid solution concentration is triggered.

[0029] As a further improvement of the technical solution, in step S102, the force between the assembly elements is an electrostatic interaction force.

[0030] As a further improvement of the technical solution, in steps S103-S105, the injection performance, the magnetic heat performance and the mechanical performance influence each other, and there is no test order requirement in the testing and screening process, and there is no requirement that all of them meet the requirements before entering the subsequent steps.

[0031] As a further improvement of the technical solution, the injection performance should be less than 50N through the 2.6F microcatheter, the magnetic heat performance should be heated to 40-45℃ in a short time, and the mechanical performance should be higher than 800Pa, which are all the minimum limits and should be met in the same gel formula.

[0032] As a further improvement of the technical solution, in step S202, if the gel performance of the magnetic mica sheet colloidal gel does not meet the performance requirements of the embolization preparation in the magnetic heat therapy combined with embolization treatment, the mass ratio of the assembly element of the magnetic mica powder colloidal gel and the solid solution content of the gel are adjusted, and the steps of S102-S201 are repeated.

[0033] As a further improvement of the technical solution, the performance enhancement strategy from the magnetic mica powder colloidal gel to the magnetic mica sheet colloidal gel is the synergistic result of the interface roughness and the specific surface area improvement, which respectively reduces the sliding of the assembly element in the gel and increases the crosslinking point position between the elements, thereby improving the performance of the magnetic mica-based colloidal gel.

[0034] To achieve the above purpose, the application also discloses the application of the screened and optimized magnetic mica sheet colloidal gel in the magnetic heat therapy combined with embolization treatment, which is applied to the rabbit ear tumor embolization model to verify the treatment effect of the magnetic heat therapy combined with embolization treatment.

[0035] As a further improvement of the technical solution, the treatment effect evaluation is comprehensively evaluated according to the actual treatment situation of the rabbit ear tumor, including the tumor growth situation and tumor tissue sections, if the performance does not meet the requirements and the treatment effect is poor, the screening can be performed again.

[0036] Compared with the prior art, the present application has the beneficial effects that:

[0037] 1. According to the key performance required for the gel material in the combined magnetic hyperthermia and embolization treatment, a comprehensive evaluation based on injection force (<50 N), storage modulus (>800 Pa) and magnetic heat warming performance is constructed, and a three-dimensional coordinated performance screening system of injection performance, magnetic heat performance and mechanical performance is established.

[0038] 2. By regulating the mass ratio of the assembly unit and the concentration of the gel solid solution, the influence of the component ratio on the gel performance is analyzed, the predictable optimization of the gel performance is realized, and the individual adjustment is facilitated. Meanwhile, from the mica powder to the mica sheet and then to the magnetic functionalization, the actual influence of the gel performance caused by the change of the unit structure is verified through the performance screening, so that the controllability and usability of the product at each stage are ensured, and the systematicness and scientificness of the material optimization are improved.

[0039] 3. The screening method is not only suitable for the magnetic mica-based colloidal gel in the present application, but also can be extended to other multifunctional and composite injection gel materials, thereby providing a general screening framework for the development of gel interventional therapy materials. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 It is a performance screening method flowchart of the magnetic mica-based colloidal gel in the present application;

[0041] Figure 2 It is a scanning diagram and a local enlarged view of the mica powder before a) iron oxide modification and b) iron oxide modification;

[0042] Figure 3 It is an atomic force microscope diagram of a) mica powder and b) magnetic mica powder, wherein the embedded diagram is a height curve diagram of the white line segment;

[0043] Figure 4 It is a real object diagram of the magnetic mica powder colloidal gel formed by assembling the negative assembly unit magnetic mica powder and the gel nanoparticles;

[0044] Figure 5 It is a mechanical property change diagram and a storage modulus statistical diagram of a) the mica powder colloidal gel and b) the magnetic mica powder colloidal gel before and after iron oxide modification;

[0045] Figure 6 It is a three-dimensional coordinated performance screening system of injection performance, magnetic heat performance and mechanical performance established in the present application;

[0046] Figure 7 It is a gel point diagram (inverted non-flowing gelation) of the magnetic mica powder colloidal gel prepared by different assembly unit mass ratios;

[0047] Figure 8 Frequency sweep plots of magnetic mica powder colloidal gels prepared with a) different gel solid solution contents and b) columnar statistics of storage modulus. c) Frequency sweep plots of magnetic mica powder colloidal gels prepared with different assembly unit mass ratios and d) columnar statistics of storage modulus;

[0048] Figure 9 Frequency dependence exponents of magnetic mica powder colloidal gels prepared with different assembly unit mass ratios.

[0049] Figure 10 a) Magnetic heating curves of magnetic mica powder colloidal gels with different magnetic particle concentrations and b) their corresponding thermal infrared images. c) Magnetic heating curves of magnetic mica powder colloidal gels under different magnetic field strengths and d) their corresponding thermal infrared images;

[0050] Figure 11 Injection profile of magnetic mica powder colloidal gels through a 2.6F microcatheter (n=3).

[0051] Figure 12 Preparation process of magnetic mica flakes with interface roughness promotion.

[0052] Figure 13 Scanning images and local magnified images of mica flakes before a) iron oxide modification and b) after iron oxide modification.

[0053] Figure 14 Atomic force microscope images of a) mica flakes and b) magnetic mica flakes, in which the inner embedded images are height profile plots of white line segments.

[0054] Figure 15 a) Specific surface area comparison plots and b) iron element content comparison plots of magnetic mica powder and magnetic mica flakes;

[0055] Figure 16 Real image of magnetic mica flakes assembled from negatively charged assembly units and gelatin nanoparticles to form magnetic mica flakes colloidal gels;

[0056] Figure 17 a) Mechanical property change plots and b) storage modulus statistics plots of mica flakes colloidal gels and magnetic mica flakes colloidal gels before and after iron oxide modification;

[0057] Figure 18 Gel point plots (inverted non-flowing as gelation) of magnetic mica flakes colloidal gels prepared with different assembly unit mass ratios;

[0058] Figure 19Frequency sweep plots of magnetic mica sheet gel colloidal gels prepared with a) different gel solid solution contents and b) columnar statistics of storage modulus. c) Frequency sweep plots of magnetic mica sheet gel colloidal gels prepared with different assembly unit mass ratios and d) columnar statistics of storage modulus;

[0059] Figure 20 Frequency dependence index statistics plots of magnetic mica sheet gel colloidal gels prepared with different assembly unit mass ratios;

[0060] Figure 21 Magnetocaloric heating curves of magnetic mica sheet gel colloidal gels with a) different magnetic particle concentrations and b) their corresponding thermal infrared images. c) Magnetocaloric heating curves of magnetic mica sheet gel colloidal gels under different magnetic field strengths and d) their corresponding thermal infrared images;

[0061] Figure 22 Injection profile of magnetic mica sheet gel colloidal gels through a 2.6F microcatheter (n=3);

[0062] Figure 23 a) Injection profile of magnetic mica sheet gel colloidal gels through different needle tube diameters and b) corresponding injection force columnar statistics;

[0063] Figure 24 Photos and corresponding infrared thermal images of rabbit ears during treatment: a) iodized oil group, b) magnetic mica sheet gel colloidal gel group, c) magnetic mica sheet gel colloidal gel + alternating magnetic field group. White circles represent embolized tumor areas;

[0064] Figure 25 Temperature change curves of rabbit ear tumor areas under different treatment methods during treatment;

[0065] Figure 26 Tumor volume change curves of rabbit ear tumor areas under different treatment methods during treatment;

[0066] Figure 27 Prussian blue (P&B) and hematoxylin-eosin (H&E) staining images of tumor tissue sections under different treatment methods and local magnification images. DETAILED DESCRIPTION

[0067] The above and other technical features and advantages of the present application will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

[0068] Example 1:

[0069] A performance screening method for a magnetic mica-based gel colloidal gel, the specific content of which is as follows:

[0070] 1. A magnetic mica powder is obtained by magnetically functionalizing mica powder through high-temperature thermal decomposition.

[0071] 2. Using gelatin nanoparticles as positively charged organic assembly units and magnetic mica powder as negatively charged inorganic assembly units, the concentrations of the organic positively charged assembly units and the inorganic negatively charged assembly units are regulated by the test results during the preparation of the magnetic mica powder colloidal gel to prepare an organic-inorganic composite magnetic mica powder colloidal gel. The concentration of the magnetic mica powder is also regulated by a dynamic monitoring module. The dynamic monitoring module includes:

[0072] The injection performance monitoring unit is used to monitor the fluidity V1 and structural stability V2 of the mica powder colloidal gel under shear force, and to adjust the ratio of gelatin nanoparticles based on V1 and V2;

[0073] The magnetothermal performance monitoring unit is used to monitor the concentration N and temperature T of the magnetic mica powder in the mica powder colloidal gel and adjust the content of the magnetic mica powder according to N and T;

[0074] Mechanical performance monitoring unit, which monitors the parameters of the injection performance monitoring unit and the magnetic thermal performance monitoring unit;

[0075] The dynamic monitoring module compares the monitoring parameters obtained by the mechanical performance monitoring unit with the preset standard environmental parameters. If the obtained parameters exceed the threshold of the preset standard parameters, the parameters are considered abnormal and the concentrations of organic positive assembly units and inorganic negative assembly units are regulated. The mutual influence between the injection performance monitoring unit, the magnetothermal performance monitoring unit, and the mechanical performance monitoring unit is manifested as follows:

[0076] When the N value in the magnetothermal performance monitoring unit increases, causing the temperature T to rise, if the storage modulus of the mechanical performance monitoring unit abnormally decreases to less than 800Pa, the V1 value of the injection performance monitoring unit will decrease and the V2 value will increase. In this case, the system has determined that it is in an "abnormal state";

[0077] When the injection performance monitoring unit detects that V1 is greater than 40N (the injection force is high but does not reach the failure threshold of 50N), the mechanical performance monitoring unit will simultaneously check whether the storage modulus is greater than 1500Pa. At this time, the storage modulus may meet the performance requirements (greater than 800Pa) but has the risk of excessive cross-linking (less than 1500Pa). Therefore, it is necessary to verify the specific storage modulus value. If it is established, the solid solution concentration or the assembly unit mass ratio is triggered to reduce the instruction to avoid further increase in the modulus (for example, Figure 8 and Figure 19 shown);

[0078] The execution logic of the dynamic monitoring module includes the following collaborative control strategies:

[0079] When the magnetothermal performance monitoring unit detects that T is less than 40°C, the concentration N of magnetic mica powder is increased;

[0080] The mechanical performance monitoring unit checks whether the increased N value leads to a storage modulus > 800 Pa. If it is lower than this value, the ratio of x:y = magnetic mica powder:gelatin nanoparticles is increased to x:y≥1:1. The injection performance monitoring unit detects the V1 value after adjusting the ratio. If V1>40 N, the solid solution concentration or the assembly unit mass ratio is adjusted downward, and the adjustment gradient is ≤3 w / v%.

[0081] The priority of the injection performance monitoring unit, the magnetic heat performance monitoring unit and the mechanical performance monitoring unit is:

[0082] The mechanical performance monitoring unit data is adjusted first when it is abnormal;

[0083] The injection performance monitoring unit and the magnetic heat performance monitoring unit are optimized in parallel. When V1>40 N or T<42℃, the combined rebalancing of the assembly unit mass ratio and the solid solution concentration is triggered.

[0084] 3. Injection performance characterization of the magnetic mica powder colloidal gel: the gel is injected through different diameter syringe needles and injection rates to evaluate its injection performance.

[0085] 4. Magnetic heat performance characterization of the magnetic mica powder colloidal gel: the gel is placed in an alternating magnetic field, and the magnetic heat performance is evaluated by adjusting the magnetic field strength of the alternating magnetic field.

[0086] 5. Mechanical performance characterization of the magnetic mica powder colloidal gel: the mechanical properties of the gel are measured by a rotational rheometer, including storage modulus and loss modulus obtained by frequency scanning, frequency-dependent index and creep experiment, etc.

[0087] 6. Based on the assembly unit mass ratio and the gel solid solution content of the magnetic mica powder colloidal gel in the above steps, the mica powder is exfoliated into mica sheets with higher specific surface area and the iron oxide is modified to obtain a magnetic mica sheet colloidal gel under the same preparation conditions.

[0088] 7. Repeat the performance test to determine whether the gel performance of the magnetic mica sheet colloidal gel meets the performance requirements of embolization preparations in magnetic hyperthermia combined with embolization therapy. If not, adjust the assembly unit mass ratio and the gel solid solution content of the magnetic mica powder colloidal gel, and repeat the gel performance screening steps.

[0089] 8. If the gel performance of the magnetic mica sheet colloidal gel meets the performance requirements, a rabbit ear tumor model is established to verify its therapeutic effect in magnetic hyperthermia combined with embolization therapy.

[0090] Figure 1Flow chart of the performance screening method of the magnetic mica-based colloidal gel in the present application. In view of the good gel performance of the current magnetic mica sheet colloidal gel but the complex synthesis process, the method starts from the easily obtained mica powder as the raw material, analyzes the injection property, magnetic heat property and mechanical property of the gel and their correlation by regulating the mass ratio of the assembly unit and the concentration of the gel solid solution. The optimal performance of the colloidal gel is screened by using the preparation performance optimization process of the easily obtained magnetic mica powder colloidal gel, and the magnetic mica sheet colloidal gel is further prepared to meet the gel material requirements of the magnetic heat embolization therapy. The method has clear control parameters, repeatable performance, and can effectively shorten the preparation time of the material and the research time.

[0091] Example 2:

[0092] Preparation of the magnetic mica powder with improved surface roughness based on interface modification, the steps are as follows:

[0093] Accurately weigh 1 g of mica powder, 1 g of acetylacetone iron, and 250 mL of triethylene glycol, then fully stir to mix them evenly, and then add them to a 500 ml three-necked flask equipped with a high-temperature-resistant magnetic stirrer. Slowly stir the mixed solution and vacuum treat for 2 h. Then introduce nitrogen, and heat from 25℃ to 300℃ at a rate of 3℃ / min, and keep the mixed solution at 300℃ for 30 min. After the reaction is completed and it is naturally cooled to room temperature, the obtained precipitate is washed by centrifugation with ethanol three times, and the obtained precipitate is vacuum dried for standby use.

[0094] Figure 2 Scanning diagrams and local enlarged diagrams of the mica powder before a) iron oxide modification and b) after iron oxide modification. After the in-situ growth of iron oxide particles on the surface of the mica powder, the surface of the mica powder changes from relatively smooth to densely covered with particles, and the surface roughness is significantly improved.

[0095] Figure 3 Atomic force microscope diagrams of a) mica powder and b) magnetic mica powder, and the embedded diagram is the height curve diagram of the white line segment. Compared with the mica powder before modification of the iron oxide particles, the height of the magnetic mica powder is slightly increased due to the iron oxide particles on its surface, which proves that the iron oxide particles have changed the roughness.

[0096] Figure 4 A photograph of the magnetic mica powder colloidal gel formed by assembling the negatively charged assembly unit magnetic mica powder and gelatin nanoparticles. The gelatin nanoparticles are used as organic positively charged assembly units, and the magnetic mica powder is used as inorganic negatively charged assembly units, and the magnetic mica powder colloidal gel is prepared by electrostatic force assembly.

[0097] Figure 5Statistical diagram of a) mechanical property change and b) storage modulus of mica powder colloid gel before and after modification of iron oxide. Due to the iron oxide particles on the surface of the magnetic mica powder, when the gel is subjected to external force, the iron oxide particles can hinder the sliding between the gelatin and the magnetic mica powder, thereby improving the mechanical properties of the colloid gel.

[0098] Figure 6 The three-dimensional synergistic performance screening system of injection performance, magnetic heating performance and mechanical performance established in the present application. The present application constructs a three-dimensional synergistic performance screening system with injection performance, magnetic heating performance and mechanical performance as core indicators, which is used to evaluate and optimize the comprehensive performance of magnetic mica-based colloid gel to adapt to the clinical needs of magnetic heating therapy combined with embolization therapy. The screening system realizes balance and synergy between performances through multi-parameter quantitative testing and gel design feedback, based on the optimization and adjustment of assembly units, to screen out the optimal performance of the gel embolization preparation.

[0099] Example 3:

[0100] The performance screening of the magnetic mica powder colloid gel based on the interface roughness improvement is as follows:

[0101] 1. In order to prepare magnetic mica powder colloid gels with different assembly unit mass ratios or gel solid sol contents, the gelatin nanoparticle concentration is 6, 9, 12 and 15 w / v%, and the magnetic mica powder concentration is 6, 9, 12 and 15 w / v%. The two kinds of particles are mixed in a centrifuge tube and vortexed uniformly at pH≈12. Glucono-delta-lactone is added and the system pH is adjusted to induce gelation, and the gel situation is observed.

[0102] 2. The mechanical properties of the magnetic mica powder colloid gel were characterized by frequency sweep test with a frequency of 0.1-100 Hz and a constant stress of 1%. The main test object is different assembly unit mass ratio or gel solid sol content. The frequency-dependent index (FDI) is defined as the slope of the frequency sweep curve of the colloid gel.

[0103] 3. The magnetic mica powder colloid gels synthesized in different proportions are placed in a centrifuge tube, and the magnetic heating performance is tested under magnetic field intensity of 20, 25 and 30 kA / m. The thermal infrared imager is used to record the heating situation.

[0104] 4. Combined with the universal mechanical testing machine, the 2.6F microcatheter is selected for the test of the injection force of the colloid gel, and the size of the injection force of each group is recorded in real time. Then different needle tube diameters are selected to test the injection load of the colloid gel during injection.

[0105] Figure 7Gel point plot of magnetic mica powder colloidal gels prepared with different assembly unit mass ratios (inverted not flowing is gelled). This test intuitively shows the gelling of magnetic mica powder colloidal gels under different assembly unit mass ratios and gel sol contents, which is beneficial to the preliminary analysis and screening of colloidal gels.

[0106] Figure 8 a) Frequency sweep plots of magnetic mica powder colloidal gels prepared with different gel sol contents and b) columnar statistics of storage modulus. c) Frequency sweep plots of magnetic mica powder colloidal gels prepared with different assembly unit mass ratios and d) columnar statistics of storage modulus. Based on the analysis of rheological test results, the storage modulus of magnetic mica powder colloidal gels gradually increases with the increase of gel sol concentration, but its storage modulus can only meet the demand at 20 w / v%. At the same time, the storage modulus of colloidal gels gradually increases with the increase of the proportion of gelatin nanoparticles in the assembly unit mass ratio, and its storage modulus meets the demand after 1:2. On the other hand, the higher mechanical properties limit the injection performance of the gel, and the appropriate assembly unit and gel sol content need to be considered comprehensively, and 15 w / v% sol is selected for subsequent magneto-thermal tests here.

[0107] Figure 9 Frequency dependence index of magnetic mica powder colloidal gels prepared with different assembly unit mass ratios. As shown in the figure, the lower the frequency dependence index, the more stable the material is at high frequency, which provides a reference basis for the screening and optimization of magnetic mica powder colloidal gels.

[0108] Figure 10 a) Magnetic heating curves of magnetic mica powder colloidal gels with different magnetic particle concentrations and b) their corresponding thermal infrared images. c) Magnetic heating curves of magnetic mica powder colloidal gels under different magnetic field strengths and d) their corresponding thermal infrared images. As shown in figures a-b, with the increase of magnetic particle concentration, the magnetic heating temperature (plateau) of colloidal gels reaches gradually within 10 min, but all cannot meet the demand of magnetic hyperthermia. Since the mechanical properties of 1:1, 15 w / v% colloidal gels are weak, 1:2, 15 w / v% magnetic mica powder colloidal gels are subsequently selected for magnetic heating under different field strengths. As shown in figures c-d, with the increase of alternating magnetic field strength, the magnetic heating trend of colloidal gels is the same as above, indicating that the magnetic mica powder colloidal gels under the above gel sol content and various assembly unit ratios do not meet the performance requirements.

[0109] Figure 11Injection force profile of magnetic mica powder hydrogel through 2.6F microcatheter (n=3). The injection force rises rapidly in the process of injection as the gel is pressed to overcome the static yield stress; then the injection force fluctuates up and down in the shear thinning region, showing an unstable state. The average injection force is maintained between 25-30 N, indicating that the material is injectable but the injection force is high, making it difficult to inject manually.

[0110] Based on the above performance screening method and experimental data, first, the formation ability of magnetic mica powder hydrogel is evaluated by the gel point diagram. Then the mechanical properties are evaluated based on the storage modulus and gel network stability, and the mechanical properties of different gel preparation ratios are obtained. At the same time, the magnetic heat performance and magnetic heat response efficiency are evaluated by adjusting the assembly unit and gel solid solution content. The formula of the magnetic mica powder hydrogel selected by the comprehensive consideration of the two performances is tested for injection force. In the process of three-dimensional coordinated performance screening system, the magnetic mica powder hydrogel should be tested for three performances at a fixed ratio or gel solid solution. Then the data are collected and compared based on the data. The optimal performance of the magnetic mica powder hydrogel is considered comprehensively to prepare the magnetic mica sheet hydrogel.

[0111] Example 4:

[0112] The performance screening of the magnetic mica sheet hydrogel based on the interface roughness improvement is as follows:

[0113] 1. The mica powder is first exfoliated into mica nanosheets, and then the magnetic mica nanosheets are prepared after magnetic functionalization;

[0114] 2. In order to prepare magnetic mica sheet hydrogel with different assembly unit mass ratios or gel solid solution contents, the gelatin nanoparticle concentration is 6, 9, 12, and 15 w / v%, and the magnetic mica powder concentration is 6, 9, 12, and 15 w / v%. The two kinds of particles are mixed in a centrifuge tube and vortexed uniformly at pH≈12. Glucono-δ-lactone is added and the system pH is adjusted to induce gelation, and the gelation situation is observed.

[0115] 2. The mechanical properties of the magnetic mica sheet hydrogel are characterized by frequency sweep test with a frequency of 0.1-100 Hz and a constant stress of 1%. The main test object is different assembly unit mass ratio or gel solid solution content. The frequency-dependent index (FDI) is defined as the slope of the frequency sweep curve of the hydrogel.

[0116] 3. The magnetic mica sheet hydrogel synthesized at different ratios is placed in a centrifuge tube, and the magnetic heat warming performance is tested under magnetic field intensity of 20, 25, and 30 kA / m. The thermal infrared imager is used to record the warming situation.

[0117] 4. Combined with the universal testing machine, 2.6F microcatheter was selected for the test of colloidal gel injection force, and the injection force of each group was recorded in real time. Then, different needle tube diameters were selected to test the injection load of colloidal gel injection.

[0118] Figure 12 The preparation process diagram of the magnetic mica sheet for interface roughness enhancement. As shown in the figure, compared with mica powder, the magnetic mica sheet not only has a higher specific surface area to provide more binding sites, but also can synergistically enhance the gel performance with the enhanced roughness.

[0119] Figure 13 The scanning diagram and local enlarged view of the mica sheet before a) iron oxide modification and b) after iron oxide modification. As can be seen from the figure, the mica sheet has a high aspect ratio and a nanoscale thickness, and the surface of the mica sheet is covered with particles after the successful modification of iron oxide particles, and the surface roughness is significantly improved.

[0120] Figure 14 The atomic force microscope diagram of a) mica sheet and b) magnetic mica sheet, and the height curve diagram of the white line segment is embedded. For the mica sheet without modification of iron oxide particles, the height is ~1 nm, while the surface height of the magnetic mica sheet is increased to ~20 nm, which indicates that the successful modification of iron oxide particles effectively improves the surface roughness.

[0121] Figure 15 The a) specific surface area comparison diagram and b) iron element content comparison diagram of the magnetic mica powder and the magnetic mica sheet. By exfoliating the mica into mica sheets, the specific surface area of the two-dimensional material is significantly improved, so when the magnetic particles are modified, the magnetic mica sheet has nearly three times the iron content compared to the magnetic mica powder. Therefore, based on the same interface enhancement strategy, the magnetic mica sheet as an inorganic assembly unit has a higher specific surface area and more iron oxide particles, and is expected to exhibit more excellent gel performance.

[0122] Figure 16 The real object diagram of the magnetic mica sheet colloidal gel assembled by the negative assembly unit magnetic mica sheet and the gelatin nanoparticles. The gelatin nanoparticles are used as organic positive assembly units, and the magnetic mica sheet is used as inorganic negative assembly units. The magnetic mica sheet colloidal gel is prepared by electrostatic force assembly.

[0123] Figure 17 The a) mechanical property change and b) storage modulus statistical diagram of the mica sheet colloidal gel and the magnetic mica sheet colloidal gel before and after modification of iron oxide. The results show that the structural stability of the magnetic mica sheet colloidal gel with enhanced interface roughness is significantly enhanced, showing higher storage modulus and stronger deformation recovery ability, which indicates that the modification of iron oxide effectively hinders the sliding degree of particles between gels under external force, thereby improving the mechanical properties of the material.

[0124] Figure 18 Gel point plot of magnetic mica platelet colloidal gels prepared with different assembly unit mass ratios (inverted not flowing is gelled). With the adjustment of assembly unit mass ratio, the magnetic mica platelet colloidal gels show a clear gelation window, when the content of magnetic mica platelets is too low, the network support skeleton is insufficient to form a gel, indicating that the assembly mass ratio has a significant regulatory effect on the colloidal gel.

[0125] Figure 19 a) Frequency sweep plots of magnetic mica platelet colloidal gels prepared with different gel solute contents and b) columnar statistics of storage modulus. c) Frequency sweep plots of magnetic mica platelet colloidal gels prepared with different assembly unit mass ratios and d) columnar statistics of storage modulus (x:y=magnetic mica platelet:gelatin nanoparticles). As shown in the figure, with the increase of gel solute content and assembly unit mass ratio, the storage modulus of the gel is significantly enhanced, and in the whole test frequency range, the storage modulus is higher than the loss modulus, indicating that the system is always in a gel state. The storage modulus shown is positively correlated with the material solid content and the mass ratio of the assembly unit, indicating that increasing the material concentration or adjusting the mass ratio of the assembly unit can significantly enhance the mechanical properties of the gel, thereby improving the mechanical properties.

[0126] Figure 20 Frequency dependence index of magnetic mica platelet colloidal gels prepared with different assembly unit mass ratios. The frequency dependence index quantifies the degree of network structure response to external frequency disturbance, indicating that through assembly ratio regulation, not only can the storage modulus and other macroscopic mechanical parameters be optimized, but also the network disturbance resistance can be improved at the microscopic level. This index as a sensitive evaluation dimension in the performance screening system provides a more accurate structure performance evaluation method for the ratio optimization of gel materials.

[0127] Figure 21 a) Magnetic heating curves of magnetic mica platelet colloidal gels with different magnetic particle concentrations and b) their corresponding thermal infrared images. c) Magnetic heating curves of magnetic mica platelet colloidal gels under different magnetic field strengths and d) their corresponding thermal infrared images. As shown in figures a-b, with the increase of magnetic particle concentration, the heating rate and final temperature of the colloidal gel are significantly increased, showing concentration dependence. At the same time, as shown in figures c-d, with the increase of alternating magnetic field strength, the heating rate and overall temperature of the colloidal gel increase significantly. From the two dimensions of magnetic particle concentration and magnetic field strength, the controllable magnetic heating and efficient heating capacity of the magnetic mica platelet colloidal gel are verified, which provides strong performance support for its clinical application in magnetic heating combined with embolization therapy.

[0128] Figure 22Injection profile of magnetic mica flake colloidal gel through 2.6F microcatheter (n=3). As shown in the figure, low injection load injection can be smoothly achieved through 2.6F microcatheter, which indicates that the magnetic mica flake colloidal gel prepared at this ratio can adapt to the clinical use conditions, with low and smooth injection load.

[0129] Figure 23 a) Injection profile of magnetic mica flake colloidal gel through different needle diameters and b) corresponding injection force column chart. As shown in the figure, all injection profiles show the characteristics of rapid initiation-plateau stability, indicating that the magnetic mica flake colloidal gel has good shear thinning and flow recovery ability. Although the fine needle diameter (24G) increases the injection resistance, the injection force under all test conditions is controlled below 3N, which is far below the clinical operation threshold.

[0130] Based on the test results of magnetic mica powder colloidal gel, the magnetic mica flake colloidal gel has more excellent gel performance, which verifies the effectiveness of morphology optimization on the improvement of gel performance. First, the gel formation ability of the magnetic mica flake colloidal gel is preliminarily evaluated by the gel dot diagram. Subsequently, the mechanical performance is evaluated, based on the storage modulus and gel network stability, combined with the regulation of assembly units and gel solid sol content, and the magnetic heating performance and its magnetic heating response efficiency are evaluated, to obtain the preliminarily optimized gel formula. Finally, the injectability of the gel is evaluated based on the injection force test to adapt to clinical use. The statistical results of the experimental results show that, in the regulation of gel solid sol content of 5-15w / v% and assembly unit mass ratio from 4:1-1:4, the magnetic mica flake colloidal gel with magnetic mica flake: gelatin nanoparticles = 1:2 has good mechanical stability, excellent magnetic heating performance and smooth low load injection performance, and is expected to be used as a new embolic agent for magnetic heating therapy combined with embolization therapy.

[0131] Example 5

[0132] The magnetic mica flake colloidal gel after performance optimization screening is used to evaluate the treatment effect in a rabbit ear tumor embolization model, and the steps are as follows:

[0133] 1) The tumor tissue suspension is injected into the central marginal artery of the rabbit ear to establish a rabbit ear tumor embolization model.

[0134] 2) The tumor-bearing rabbits were randomly divided into 3 groups (n=3), including iodized oil group (control group), magnetic mica sheet colloidal gel group (embolization group), magnetic mica sheet colloidal gel + alternating magnetic field group (magnetic heat embolization combined group). After the rabbits were anesthetized, the above three treatment methods were applied to the tumor by injecting materials into the main blood supply artery of the tumor using a syringe. Subsequently, for the magnetic heat embolization combined group, the rabbit ears were placed in an alternating magnetic field for 10 min of magnetic heat therapy, and the temperature changes were recorded using an infrared thermal imager. The rabbit ear tumors were photographed and sampled on day 0, day 1, day 5, and day 10, and the tumor growth was recorded.

[0135] 3) After day 10, all rabbits were sacrificed and the tumors were removed, and the tumor tissues were stained with hematoxylin-eosin (H&E) and Prussian blue (P&B) for analysis.

[0136] Figure 24 The photos of the rabbit ears during treatment and the corresponding infrared thermal images: a) iodized oil group, b) magnetic mica sheet colloidal gel group, c) magnetic mica sheet colloidal gel + alternating magnetic field group. The white circles represent the embolized tumor area. As shown in the figure, compared to the iodized oil group, which recanalized rapidly after embolization on day 1, the tumor growth in the magnetic mica sheet colloidal gel group and the magnetic mica sheet colloidal gel + alternating magnetic field group was significantly inhibited. However, as shown in the thermal infrared data, the magnetic mica sheet colloidal gel group showed a significant temperature rise in the blood supply on day 10, while the magnetic mica sheet colloidal gel + alternating magnetic field group showed no significant temperature change in the blood vessels.

[0137] Figure 25 The temperature change curve of the rabbit ear tumor area under different treatment methods during treatment. In the magnetic mica sheet colloidal gel group, the tumor area temperature decreased from about 35°C to about 32°C. In the magnetic mica sheet colloidal gel + alternating magnetic field group, the distal arterial blood flow disappeared on day 1, resulting in a temperature drop (the lowest temperature was about 30°C). Combined with the data, after 10 days, the rabbit ear tissue turned black and scabbed, and the tumor site significantly reduced, indicating that compared to single embolization treatment, embolization and magnetic heat therapy combined treatment induced more severe local necrosis effect. Figure 24

[0138] Figure 26 The tumor volume change curve of the rabbit ear tumor area under different treatment methods during treatment. In the iodized oil group, the tumor volume continued to grow, and the curve showed an upward trend, indicating that the embolization effect of iodized oil on the tumor was limited. For the magnetic mica sheet colloidal gel group, the tumor volume growth was significantly inhibited, indicating that the colloidal gel had good embolization blocking effect; the magnetic mica sheet colloidal gel + alternating magnetic field group showed significant inhibition of tumor, and achieved magnetic heat synergistic treatment effect under the action of alternating magnetic field, which not only completed the blood supply blockage but also achieved magnetic heat therapy, thereby completely inhibiting the growth of the tumor.

[0139] ​Figure 27 The Prussian blue (P&B) and hematoxylin-eosin (H&E) staining images and local magnification images of tumor tissue sections under different treatment methods are shown in the figure. As shown in the figure, a large number of cancer cells still survive in the iodized oil group. In the embolism group and the magnetic embolism combined group, the blue magnetic mica colloidal gel in the pathological section is clearly visible, which proves that the embolism treatment of the magnetic mica colloidal gel can effectively block the blood vessels supplying the tumor. As shown in the H&E staining magnification analysis chart, the magnetic mica colloidal gel + alternating magnetic field group appears obvious cancer cell necrosis, while the magnetic mica colloidal gel group still has part of the tumor cells surviving, and still has a risk of recurrence. These results show that the magnetic heat therapy combined with embolism treatment has better treatment effect than single treatment, and the magnetic mica colloidal gel has the potential as a new embolism preparation.

[0140] The above experimental results prove that the performance screening method constructed by the present application not only realizes the optimal balance of the magnetic mica colloidal gel in the injection performance, mechanical performance and magnetic heat performance, and the colloidal gel screened by the method verifies the synergistic anti-tumor treatment effect of the colloidal gel in the embolism treatment and the magnetic heat treatment in the in vivo experiment. By precisely controlling the mass ratio of the assembly unit and the content of the gel solid solution, not only the material design research period is shortened, but also the magnetic colloidal gel system with optimal comprehensive performance is obtained, which provides a thinking for the preparation and functional material construction application of the magnetic mica colloidal gel.

[0141] The above description of disclosed embodiments enables one of ordinary skill in the art to make or use the application. Various modifications to these embodiments will be readily apparent to those of ordinary skill in the art, and the generic principles defined herein can be applied to other embodiments without departing from the spirit or scope of the application. Accordingly, the application is not to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for screening properties of magnetic mica-based colloidal gel, characterized in that: The method comprises the following steps: S101, magnetically functionalizing mica powder by a high-temperature thermal decomposition method to obtain magnetic mica powder; S102, using gelatin nanoparticles as organic positive assembly units and magnetic mica powder as inorganic negative assembly units, and regulating the concentrations of the organic positive assembly units and the inorganic negative assembly units according to the test results during the preparation of the magnetic mica powder colloidal gel, to prepare an organic-inorganic composite magnetic mica powder colloidal gel; The concentration of magnetic mica powder is controlled by a dynamic monitoring module, which includes: The injection performance monitoring unit is used to monitor the fluidity V1 and structural stability V2 of the mica powder colloidal gel under shear force, and to adjust the ratio of gelatin nanoparticles based on V1 and V2; The magnetothermal performance monitoring unit is used to monitor the concentration N and temperature T of the magnetic mica powder in the mica powder colloidal gel and adjust the content of the magnetic mica powder according to N and T; Mechanical performance monitoring unit, which monitors the parameters of the injection performance monitoring unit and the magnetic thermal performance monitoring unit; The dynamic monitoring module compares the monitoring parameters obtained by the mechanical performance monitoring unit with the preset standard environmental parameters. If the obtained parameters exceed the threshold of the preset standard parameters, the parameters are considered abnormal and the concentrations of organic positive assembly units and inorganic negative assembly units are regulated. The mutual influence between the injection performance monitoring unit, the magnetothermal performance monitoring unit, and the mechanical performance monitoring unit is manifested as follows: When the N value in the magnetothermal performance monitoring unit increases, causing the temperature T to rise, if the storage modulus of the mechanical performance monitoring unit abnormally decreases to <800Pa, it triggers the V1 value of the injection performance monitoring unit to decrease and the V2 value to increase; When the injection performance monitoring unit detects that 40N<V1<50N, the mechanical performance monitoring unit will simultaneously check whether the storage modulus is greater than 1500Pa. If so, it will trigger a command to reduce the solid solution concentration or the mass ratio of the assembly unit. S103. Characterization of the injectability of magnetic mica powder colloidal gel: The gel was injected through syringe needles of different diameters and at different injection rates to evaluate its injectability. S104. Characterizing the magnetocaloric properties of the magnetic mica powder colloidal gel; placing the gel in an alternating magnetic field and evaluating its magnetocaloric properties by adjusting the magnetic field strength of the alternating magnetic field; S105. Characterization of the mechanical properties of magnetic mica powder colloidal gel: The mechanical properties of the gel were measured using a rotational rheometer, including storage modulus and loss modulus obtained by frequency sweep, frequency dependence index, and creep experiments; S201, based on the mass ratio of assembly units and the solid solution content of the magnetic mica powder colloidal gel in the above step, exfoliating the mica powder into mica flakes with a higher specific surface area and magnetically functionalizing them to obtain a magnetic mica flake colloidal gel prepared under the same preparation conditions; S202, repeating the performance tests of S103-S105 to determine whether the gel properties of the magnetic mica sheet colloidal gel meet the performance requirements of the embolic preparation in magnetic hyperthermia combined with embolization therapy; if not, adjusting the assembly unit mass ratio and gel solid solution content of the magnetic mica powder colloidal gel, and repeating the steps of S102-S201; S301. If the gel properties of the magnetic mica sheet colloidal gel meet the performance requirements, a rabbit ear tumor model is established and its therapeutic effect in magnetic hyperthermia combined with embolization therapy is verified.

2. The method for screening properties of magnetic mica-based colloidal gel according to claim 1, wherein: The execution logic of the dynamic monitoring module includes the following collaborative control strategies: When the magnetothermal performance monitoring unit detects that T is less than 40°C, the concentration N of magnetic mica powder is increased; The mechanical property monitoring unit verifies whether the increased N value results in a storage modulus greater than 800 Pa. If it is lower than this value, the ratio of x:y = magnetic mica powder: gelatin nanoparticles is increased to ≥ 1:1; The injection performance monitoring unit detects the V1 value after adjusting the ratio. If V1>40N, it triggers a reduction in the solid solution concentration or the mass ratio of the assembly unit, with a reduction gradient of ≤3w / v%.

3. The method for screening properties of magnetic mica-based colloidal gel according to claim 1, wherein: The priorities of the injection performance monitoring unit, magnetothermal performance monitoring unit and mechanical performance monitoring unit are as follows: Prioritize adjustment when the mechanical performance monitoring unit data is abnormal; The injection performance monitoring unit and the magnetothermal performance monitoring unit are optimized in parallel. When V1>40N or T<42℃, the joint rebalancing of the mass ratio of assembly units and the concentration of solid solution is triggered.

4. The method for screening properties of magnetic mica-based colloidal gel according to claim 1, wherein: In step S102 , the force between the assembly units is an electrostatic interaction force.

5. The method for screening properties of magnetic mica-based colloidal gel according to claim 1, wherein: In steps S103-S105, the injection performance, magnetocaloric performance and mechanical performance affect each other. There is no test order requirement for the three during the testing and screening process, and there is no requirement that all three meet the requirements before entering the subsequent steps.

6. The method for screening properties of magnetic mica-based colloidal gel according to claim 5, wherein: The injection performance should be that the injection force is less than 50N when passing through a 2.6F microcatheter, and the magnetothermal heating performance should be that the temperature rises to 40-45°C in a short time; the mechanical performance is that the storage modulus is higher than 800Pa. These performance standards are the minimum limits and should be met on the same gel formula.

7. The method for screening properties of magnetic mica-based colloidal gel according to claim 1, wherein: In step S202, if the gel properties of the magnetic mica sheet colloidal gel do not meet the performance requirements of the embolic preparation in magnetic hyperthermia combined with embolic therapy, the assembly unit mass ratio and gel solid solution content of the magnetic mica powder colloidal gel are adjusted, and steps S102-S201 are repeated.

8. The application of the screened and optimized magnetic mica sheet colloidal gel in magnetic hyperthermia combined with embolization therapy is characterized by: The screened and optimized magnetic mica sheet colloidal gel was applied to the rabbit ear tumor embolization model to verify the therapeutic effect of magnetic hyperthermia combined with embolization therapy.

9. The use of the screened and optimized magnetic mica flake colloidal gel according to claim 8 in magnetic hyperthermia combined with embolization therapy, characterized in that: The therapeutic effect evaluation is comprehensively evaluated based on the actual treatment of rabbit ear tumors, including tumor growth and tumor tissue sections. If the performance does not meet the requirements and the therapeutic effect is poor, re-screening can be performed until the magnetic mica sheet colloidal gel with suitable gel properties is optimized.

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