Chitosan-polyethylene glycol-laponite composite hydrogel and application thereof

Abstract

According to the hydroxyethyl chitosan-polyethylene glycol-laponite composite hydrogel provided by the invention, polyethylene glycol, polyethylene glycol and laponite (LAPONITE) are introduced to form a mixed solution, and the prepared composite hydrogel is uniform and has good stability and mechanical properties; the compound can be clinically used as a tissue filling agent, a tissue engineering scaffold, a drug carrier, a sealing agent or an embolization agent.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a chitin-polyethylene glycol-laponite composite hydrogel which can be widely used in clinic as a tissue filler, a tissue engineering scaffold, a drug carrier, a sealing agent or an embolism agent. BACKGROUND

[0002] Hydroxyethyl deacetylated chitin is the only natural polysaccharide biomacromolecular compound with basic characteristics. Compared with chitin, there are more polar amino groups capable of protonation in the molecular structure of hydroxyethyl deacetylated chitin, so it has good biodegradability, biocompatibility and environmental friendliness, and also has better solubility in acidic medium and improved application performance. Hydroxyethyl deacetylated chitin can be combined with various antibacterial agents, antitumor drugs, photosensitizers and the like to form an amphiphilic complex, and can also form nanoparticles for cell imaging and drug delivery. Hydrogel is a high polymer material that can swell in water but is insoluble in water, and a complex three-dimensional network structure is formed through intermolecular interaction. Further preparation of hydroxyethyl deacetylated chitin into hydrogel can improve its mechanical properties and expand its application. High molecular weight hydrogel generally has two fatal weaknesses: low strength and toughness and slow response rate. In recent years, in order to improve the strength, the following new types of hydrogels have been studied and synthesized: nano-composite hydrogel, double network hydrogel, topological hydrogel and the like. Among them, nano-composite hydrogel has attracted widespread attention due to its simple preparation method.

[0003] The inorganic nanomaterials in the composite hydrogel can improve the biological and medical applications such as drug release effect, pH response drug delivery, photothermal therapy, etc. Among them, laponite material has a wide range of applications due to its unique electrostatic properties, uniform size and biological activity. Laponite (LAPONITE, magnesium lithium silicate (lithium magnesium silicate sodium salt) product, also known as laponite or laponite, LAPONITE has RD, RDS, XLG and LXS types, originally produced by ROCKWOOD company, now produced by BYK company) is a kind of artificial synthetic clay with laponite structure, which can be widely used as inorganic crosslinking agent to prepare nano-composite hydrogel to improve the mechanical strength of hydrogel. Because LAPONITE can be exfoliated and dispersed into sheet layer particles with a diameter of 25 nm and a thickness of 1 nm in water, and a large number of negative charges are present on the surface. Therefore, when ion type monomers are introduced into the Laponite dispersion or the pH and ionic strength of the dispersion are changed, the sheet layer particles will form a "card house" structure due to electrostatic attraction, thereby forming a weak gel, resulting in a non-uniform system, which seriously affects the optical properties and mechanical properties of the synthesized hydrogel.

[0004] How to improve the non-uniformity of the hydroxyethyl deacetylated chitin-laponite composite hydrogel is a problem that needs to be solved before the composite material is put into application. Summary of the Invention

[0005] This invention addresses the shortcomings of existing hydroxyethyl deacetylated chitosan hydrogels by providing a hydroxyethyl deacetylated chitosan-polyethylene glycol-lipoic acid composite hydrogel. By introducing polyethylene glycol, polyethylene glycol and lipoic acid (LAPONITE) form a mixed solution, and the resulting composite gel is uniform and has good stability and mechanical properties. It can be used clinically as a tissue filler, tissue engineering scaffold, drug carrier, sealing agent, or embolization agent.

[0006] To achieve the above-mentioned technical objectives, the present invention provides the following technical solution:

[0007] A hydroxyethyl deacetylated chitosan-polyethylene glycol-lithium diatomite composite hydrogel comprises hydroxyethyl deacetylated chitosan, polyethylene glycol, lithium diatomite, and a liquid phase. Hydroxyethyl deacetylated chitosan aqueous solution and polyethylene glycol-lithium diatomite mixed solution are prepared separately. The hydroxyethyl deacetylated chitosan aqueous solution and the polyethylene glycol-lithium diatomite mixed solution are mixed, and then solid lithium diatomite is added to obtain the chitosan-polyethylene glycol-lithium diatomite composite hydrogel.

[0008] Specifically:

[0009] 1. Add hydroxyethyl deacetylated chitosan to water and stir to dissolve, obtaining an aqueous solution of hydroxyethyl deacetylated chitosan;

[0010] 2. Add polyethylene glycol and lithium diatomaceous earth to water and stir to obtain a polyethylene glycol-lithium diatomaceous earth mixed solution;

[0011] 3. Mix the aqueous solution of hydroxyethyl deacetylated chitosan and the polyethylene glycol-lithium diatomaceous earth mixed solution;

[0012] 4. Add a certain mass of solid lithium diatomaceous earth to the mixed solution in step 3 to form a composite hydrogel.

[0013] Preferably, the liquid phase is water or a buffer solution (pH = 7.4). This includes deionized water, water for injection, or phosphate buffer solution.

[0014] Preferably, the mass percentage concentration of hydroxyethyl deacetylated chitosan in the gel is 0.2%-3%.

[0015] Preferably, the mass percentage concentration of lithium diatomite in the gel is 0.6%-15%, and more preferably, the mass percentage concentration of lithium diatomite is 1%-5%.

[0016] Preferably, the molecular weight of polyethylene glycol is 0.3k-4 million Da, and more preferably, the molecular weight of polyethylene glycol is 6000 Da.

[0017] Preferably, the mass percentage concentration of polyethylene glycol in the gel is 0.1%-2.5%, and more preferably, the mass percentage concentration of polyethylene glycol in the gel is 1%-2%.

[0018] Preferably, the lithium diatomite is LAPONITE RD, LAPONITE RDS, LAPONITE XLG, or LAPONITE LXS.

[0019] This invention prepares a gel material by precisely adjusting the concentration and dosage ratio of hydroxyethyl deacetylated chitosan, polyethylene glycol, and lithium diatomite. The gel material forms a spatial network structure under body temperature conditions and slowly degrades. As time goes on, the rigidity of the gel decreases and it gradually loses its original spatial network structure, making it a bio-absorbable composite hydrogel.

[0020] The hydroxyethyl deacetylated chitosan-polyethylene glycol-lithium diatomaceous earth composite hydrogel prepared by this invention can be used clinically as a tissue filler, tissue engineering scaffold, drug carrier, sealing agent or embolizing agent.

[0021] The beneficial effects of this invention are:

[0022] (1) The present invention uses a combination of hydroxyethyl deacetylated chitosan, polyethylene glycol and lithium diatomite (clay) to prepare a composite hydrogel with high mechanical properties and stability.

[0023] (2) The composite hydrogel prepared by the present invention has a high viscosity and uniform system, and is non-toxic, non-irritating and biocompatible.

[0024] (3) The composite hydrogel material prepared by the present invention forms a spatial network structure and slowly degrades under body temperature conditions. As time goes on, the rigidity of the gel decreases and it gradually loses its original spatial network structure. It is a composite hydrogel with bio-absorbability. Attached Figure Description

[0025] Figure 1 Gel morphology at different time points in Example 7.

[0026] Figure 2 Hydrogel degradation in Example 8. Detailed Implementation

[0027] The specific steps of the present invention are illustrated below through examples, but are not limited to these examples.

[0028] Unless otherwise stated, the terms used in this invention generally have the meanings commonly understood by those skilled in the art.

[0029] The present invention will now be described in further detail with reference to specific embodiments and data. It should be understood that these embodiments are merely illustrative of the invention and are not intended to limit the scope of the invention in any way.

[0030] In the following embodiments, various processes and methods, not described in detail, are conventional methods known in the art.

[0031] Example 1: Study on the gelling properties of hydroxyethyl deacetylated chitosan, polyethylene glycol, and lithium diatomaceous earth.

[0032] Solution preparation:

[0033] 1. Dissolve 0.6g of hydroxyethyl deacetylated chitosan in 49.4g of deionized water and stir to obtain an aqueous solution of hydroxyethyl deacetylated chitosan.

[0034] 2. Dissolve 0.5g of LAPONITE XLG in 49.5g of deionized water and stir to disperse to obtain LAPONITE dispersion.

[0035] 3. Dissolve 1g of polyethylene glycol (molecular weight 6000 Da) in 49g of deionized water and stir to obtain a PEG-6K solution. Experiment 1: Mix 2g of hydroxyethyl deacetylated chitosan aqueous solution and 3g of LAPONITE dispersion and stir to obtain a homogeneous solution without gel formation.

[0036] Experiment 2: Add 3g of PEG-6K solution to the mixed solution from Experiment 1, stir to obtain a homogeneous solution, and no gel formation is observed. Experiment 3: Mix 3g of LAPONITE dispersion and 1g of PEG-6K solution, add 1g of polyhydroxyethyl deacetylated chitosan aqueous solution to the mixed solution, stir to obtain a viscous solution, and no gel formation is observed.

[0037] Experiment 4: Add 0.03g LAPONITE XLG to the mixed solution of Experiment 1, stir, and the solution forms a precipitate but cannot form a gel.

[0038] Experiment 5: Add 0.03g LAPONITE XLG to the mixed solution of Experiment 2 and stir to obtain a gel with heterogeneous colloidal structure. Experiment 6: Add 0.03g LAPONITE XLG to the mixed solution of Experiment 3 and stir to obtain a hydrogel with homogeneous colloidal structure.

[0039] The above research results show that:

[0040] 1. Hydroxyethyl deacetylated chitosan and LAPONITE cannot form a gel (Experiment 1). Adding solid LAPONITE to the solution twice does not promote gel formation (precipitation occurs, Experiment 4).

[0041] 2. Although polyethylene glycol could not promote the gel formation of the mixed solution of hydroxyethyl deacetylated chitosan and LAPONITE (Experiment 2), the gel-forming properties of the mixed solution varied depending on the mixing order. The viscosity of the solution increased after mixing the LAPONITE and polyethylene glycol solution with the hydroxyethyl deacetylated chitosan solution (Experiment 3).

[0042] 3. The secondary addition of LAPONITE XLG solid is crucial for gel formation, and the order of solution mixing has a significant impact on the uniformity of the gel.

[0043] Example 2: Effect of the amount of lithium diatomite added twice on the properties of the hydrogel

[0044] Solution preparation:

[0045] 1. Dissolve 0.6g of hydroxyethyl deacetylated chitosan in 49.4g of deionized water and stir to obtain an aqueous solution of hydroxyethyl deacetylated chitosan.

[0046] 2. Dissolve 0.5g of LAPONITE XLG in 49.5g of deionized water and stir to disperse to obtain LAPONITE dispersion.

[0047] 3. Dissolve 1g of polyethylene glycol (molecular weight 6000Da) in 50mL of deionized water and stir to obtain a PEG-6K solution.

[0048] Mix 3g of LAPONITE dispersion and 6g of PEG-6K solution, add 2g of polyhydroxyethyl deacetylated chitosan aqueous solution to the mixture, and add LAPONITE XLG according to the table below to prepare hydrogel and observe the gel state.

[0049]

[0050] The above research results show that when the mass ratio of LAPONITE XLG added to the prepared solution to that of LAPONITE XLG added in the second step is 1:5 to 1:10, a uniform hydrogel can be formed.

[0051] Example 3: The effect of lithium diatomite concentration in the gel on the mechanical properties of the composite hydrogel

[0052] (1) Add hydroxyethyl deacetylated chitosan to water, stir to dissolve, and prepare an aqueous solution of hydroxyethyl deacetylated chitosan with a mass percentage concentration of 1.2%.

[0053] (2) Add 6K molecular weight polyethylene glycol and a certain amount of LAPONITE XLG to water and stir to obtain polyethylene glycol-LAPONITE composite solution. The mass percentage concentration of polyethylene glycol in the solution is 2%.

[0054] (3) Take 10g of hydroxyethyl deacetylated chitosan aqueous solution and 10g of polyethylene glycol-LAPONITE composite solution and mix them. (4) Add a certain mass of LAPONITE XLG to 20g of the solution in step (3) under shaking conditions, let it stand for 30min to form a composite hydrogel.

[0055] (5) Tensile testing was conducted: Preload force: 0.05N; Preload speed: 2.5mm / min.

[0056] The specific process parameters are shown in the table below:

[0057]

[0058] The results showed that, with the concentrations of hydroxyethyl deacetylated chitosan and polyethylene glycol remaining constant, the mechanical strength of the hydrogel could be freely adjusted by changing the concentration of lithium diatomite in the gel to between 0.6% and 15%.

[0059] Example 4: Effect of hydroxyethyl deacetylated chitosan concentration on the mechanical properties of the composite hydrogel

[0060] (1) Add hydroxyethyl deacetylated chitosan to water, stir to dissolve, and prepare aqueous solutions of hydroxyethyl deacetylated chitosan of different concentrations.

[0061] (2) Polyethylene glycol with a molecular weight of 6K and LAPONITE XLG were added to water and stirred to obtain a polyethylene glycol-LAPONITE composite solution with a mass percentage concentration of 1% for LAPONITE XLG.

[0062] (3) Mix 10g of hydroxyethyl deacetylated chitosan aqueous solution and 10g of polyethylene glycol-lithium diatomite composite solution;

[0063] (4) Add 1g LAPONITE XLG to 20g of solution from step (3) under shaking conditions, let stand for 30min to form a composite hydrogel.

[0064] (5) Tensile testing was conducted: Preload force: 0.05N; Preload speed: 2.5mm / min.

[0065] Specific process parameters are shown in the table below (the concentrations in the table are the concentrations of each component in the gel):

[0066]

[0067] The results showed that, with constant polyethylene glycol and clay concentrations, adjusting the concentration of hydroxyethyl deacetylated chitosan (0.2%-3%) allowed for flexible adjustment of the mechanical strength of the hydrogel.

[0068] Example 5: Control of the mechanical properties of composite hydrogels by the molecular weight and concentration of polyethylene glycol.

[0069] (1) Add hydroxyethyl deacetylated chitosan to water, stir to dissolve, and prepare an aqueous solution of hydroxyethyl deacetylated chitosan;

[0070] (2) Select polyethylene glycol and LAPONITE XLG of different molecular weights and add them to water, stir to obtain polyethylene glycol-LAPONITE XLG composite solution, and prepare composite solutions of polyethylene glycol-LAPONITE XLG of different concentrations.

[0071] (3) Mix 5g of hydroxyethyl deacetylated chitosan aqueous solution and 5g of polyethylene glycol-LAPONITE XLG composite solution and stir.

[0072] (4) Add 0.5g LAPONITE XLG to 10g of the solution from step (3) under shaking conditions, let stand for 30min to form a composite hydrogel;

[0073] (5) Tensile testing was conducted using a tensile testing machine: Preload force: 0.05N; Preload speed: 2.5mm / min

[0074] Specific process parameters are shown in the table below (the concentrations in the table are the mass percentage concentrations of each component in the gel):

[0075]

[0076] The results showed that, with constant concentrations of hydroxyethyl deacetylated chitosan and LAPONITE, adjusting the molecular weight and concentration of polyethylene glycol (PEG) between 300 and 4,000,000 Da allowed for convenient adjustment of the hydrogel's mechanical strength. Furthermore, the mechanical strength of the hydrogel could be freely adjusted when the PEG concentration was between 0.1% and 2.5%.

[0077] Example 6: Effect of the ratio of hydroxyethyl deacetylated chitosan and lithium diatomaceous earth to polyethylene glycol on the mechanical properties of the composite hydrogel.

[0078] (1) Add hydroxyethyl deacetylated chitosan to water, stir to dissolve, and prepare an aqueous solution of hydroxyethyl deacetylated chitosan with a mass percentage concentration of 1.2%.

[0079] (2) Select polyethylene glycol with a molecular weight of 6K and add it to water and stir to obtain a polyethylene glycol-LAPONITE composite solution, wherein the mass percentage concentration of polyethylene glycol is 2% and the mass percentage concentration of LAPONITE XLG is 1%.

[0080] (3) Mix the aqueous solution of hydroxyethyl deacetylated chitosan and the polyethylene glycol-LAPONITE XLG composite solution according to different mass ratios.

[0081] (4) Add 0.5g LAPONITE XLG to 10g of solution from step (3) under shaking conditions, let stand for 30min to form a composite hydrogel.

[0082] (5) Tensile testing was conducted: Preload force: 0.05N; Preload speed: 2.5mm / min.

[0083] Specific process parameters are shown in the table below (the concentrations in the table are the concentrations of each component in the gel):

[0084]

[0085] The results showed that when the concentration of hydroxyethyl deacetylated chitosan was 0.3%-0.6%, the concentration of clay was 5.5-5.8%, the molecular weight of polyethylene glycol was 6k, and the concentration of polyethylene glycol was 1%-1.5%, the mechanical strength of the hydrogel could be freely adjusted by controlling the mass ratio of hydroxyethyl deacetylated chitosan and lithium diatomite to polyethylene glycol. When the mass ratio of hydroxyethyl deacetylated chitosan and LAPONITE to polyethylene glycol was between 3:1 and 1:5, the mechanical strength of the hydrogel could be freely adjusted.

[0086] Example 7: Control of the mechanical properties of composite hydrogels by reaction time

[0087] (1) Add hydroxyethyl deacetylated chitosan to water, stir to dissolve, and prepare an aqueous solution of hydroxyethyl deacetylated chitosan with a concentration of 1.2%.

[0088] (2) Select polyethylene glycol with a molecular weight of 6K and LAPONITE XLG and add them to water. Stir to obtain a polyethylene glycol-LAPONITE composite solution. Prepare a polyethylene glycol solution with a mass percentage concentration of 2% and a LAPONITE concentration of 1%.

[0089] (3) Mix the aqueous solution of hydroxyethyl deacetylated chitosan and the polyethylene glycol-LAPONITE composite solution at a mass ratio of 1:3 and stir.

[0090] (4) Add 0.4g LAPONITE XLG to 8g of the solution from step (3) under shaking conditions, and let it stand for a certain period of time to form a composite hydrogel.

[0091] (5) Tensile testing was conducted: Preload force: 0.05N; Preload speed: 2.5mm / min.

[0092] The specific process parameters are shown in the table below:

[0093]

[0094]

[0095] The results showed that when preparing a composite gel with a concentration of 0.3% hydroxyethyl deacetylated chitosan, 5.75% LAPONITE XLG, and 1.5% polyethylene glycol (6k molecular weight), different reaction times resulted in variations in the mechanical properties of the prepared hydrogel. The mechanical properties of the hydrogel gradually increased with increasing reaction time, indicating that the mechanical strength of the hydrogel could be freely adjusted by controlling the reaction time. The gel morphology at different time points is shown in the figure. Figure 1 As shown.

[0096] Example 8: Stability Study of Hydroxyethyl Deacetylated Chitosan-Polyethylene Glycol-Lithium Diatomite Composite Hydrogel

[0097] 0.6 g of hydroxyethyl deacetylated chitosan was dissolved in 49.4 g of deionized water and stirred to obtain an aqueous solution of hydroxyethyl deacetylated chitosan. 0.5 g of LAPONITE XLG and 1 g of polyethylene glycol (molecular weight 6000) were dissolved in 48.5 g of deionized water and stirred to obtain a PEG-LAPONITE solution. 2 g of the hydroxyethyl deacetylated chitosan aqueous solution and 6 g of the PEG-LAPONITE 6K solution were mixed to form a solution. 0.4 g of LAPONITE XLG was then added, and after shaking for several seconds, a hydroxyethyl deacetylated chitosan-polyethylene glycol-lithium diatomaceous earth composite hydrogel was obtained.

[0098] Take 1g of the above hydrogel and place it in a centrifuge tube. Add 10mL of phosphate buffer solution with a pH of 7.4 and conduct a stability test in a constant temperature water bath shaker at 37℃ or 60℃. The sample is removed at regular intervals to observe its condition; the degradation endpoint is reached when no obvious gel can be removed. Calculate the degree of swelling at different times (mass of swollen gel / initial gel mass × 100%). The results are shown in the table below:

[0099]

[0100] The results show that the hydroxyethyl deacetylated chitosan-polyethylene glycol-lithium diatomaceous earth composite hydrogel described in this invention can remain stable for ≥27 days at 37℃, indicating its application value. The degradation of the hydrogel at 37℃ is as follows: Figure 2 As shown.

[0101] Example 9 investigated the effect of polysaccharide or clay type on gel formation.

[0102] 1. Sodium hyaluronate is selected as the polysaccharide.

[0103] 0.6 g of sodium hyaluronate was dissolved in 49.5 g of deionized water and stirred to obtain an aqueous solution of sodium hyaluronate. 0.5 g of LAPONITE XLG and 1 g of polyethylene glycol (molecular weight 6000) were dissolved in 48.5 g of deionized water and stirred to obtain a LAPONITE-PEG 6K solution. 2 g of the sodium hyaluronate aqueous solution and 6 g of the LAPONITE-PEG 6K solution were mixed to form a solution. 0.4 g of LAPONITE XLG was then added, and the solution was shaken to obtain a solution. No stable, homogeneous hydrogel was formed.

[0104] 2. Sodium alginate is selected as the polysaccharide.

[0105] Dissolve 0.6 g of sodium alginate in 49.5 g of deionized water and stir to obtain an aqueous sodium alginate solution. Dissolve 0.5 g of LAPONITE XLG and 1 g of polyethylene glycol (molecular weight 6000) in 48.5 g of deionized water and stir to obtain a LAPONITE-PEG 6K solution. Mix 2 g of the sodium alginate aqueous solution and 6 g of the LAPONITE-PEG 6K solution to form a solution. Add 0.4 g of LAPONITE XLG, shake to obtain a solution, and no stable hydrogel was formed.

[0106] 3. Bentonite is selected as the clay.

[0107] 0.6 g of hydroxyethyl deacetylated chitosan was dissolved in 49.5 g of deionized water and stirred to obtain an aqueous solution of hydroxyethyl deacetylated chitosan. 0.5 g of bentonite and 1 g of polyethylene glycol (molecular weight 6000) were dissolved in 48.5 g of deionized water and stirred to obtain a bentonite-PEG 6K solution. 2 g of the hydroxyethyl deacetylated chitosan aqueous solution and 6 g of the bentonite-PEG 6K solution were mixed to form a solution. 0.4 g of bentonite was then added, and the solution was shaken to obtain a solution that did not form a stable hydrogel.

[0108] Performance testing methods

[0109] 1. Stability Test

[0110] Take the hydroxyethyl deacetylated chitosan-polyethylene glycol-lithium diatomaceous earth composite hydrogel, place it in a centrifuge tube, add 10 times the mass of phosphate buffer solution with a pH of 7.4, and conduct a stability test in a constant temperature water bath shaker controlled at 37℃ or 60℃.

[0111] The sample is removed at regular intervals to observe its condition; the degradation endpoint is reached when no obvious gel can be removed.

[0112] 2. Mechanical property testing

[0113] Equipment: Tensile tester

[0114] Equipment parameter settings: Preload force: 0.05N; Preload speed: 2.5mm / min

[0115] Tensile test: Tensile tests were performed on the composite hydrogel membranes prepared in each embodiment.

Claims

1. A chitosan-polyethylene glycol-lithium diatomaceous earth composite hydrogel, characterized in that, The gel comprises chitosan, polyethylene glycol, lithium diatomaceous earth, and a liquid phase. The chitosan is hydroxyethyl deacetylated chitosan, with a mass percentage concentration of 0.2%-3%. The lithium diatomaceous earth has a mass percentage concentration of 0.6%-15%, and the polyethylene glycol has a mass percentage concentration of 0.1%-2.5% with a molecular weight of 0.3-4 million Da. The liquid phase is water or a buffer solution. The gel is prepared using the following method: Hydroxyethyl deacetylated chitosan aqueous solution and polyethylene glycol-lithium diatomaceous earth mixed solution were prepared separately. The hydroxyethyl deacetylated chitosan aqueous solution and polyethylene glycol-lithium diatomaceous earth mixed solution were mixed, and then solid lithium diatomaceous earth was added to obtain chitosan-polyethylene glycol-lithium diatomaceous earth composite hydrogel.

2. The composite hydrogel according to claim 1, characterized in that, The mass percentage concentration of lithium diatomite in the gel is 1%-5%.

3. The composite hydrogel according to claim 1, characterized in that, The molecular weight of polyethylene glycol is 6000 Da.

4. The composite hydrogel according to claim 1, characterized in that, The mass percentage concentration of polyethylene glycol in the gel is 1%-2%.

5. The composite hydrogel according to claim 1, characterized in that, The mass ratio of lithium diatomite used to prepare the polyethylene glycol-lithium diatomite mixed solution to the solid lithium diatomite added in the second step is 1:5 to 1:

10.

6. The composite hydrogel according to claim 1, characterized in that, The volume ratio of the aqueous solution of hydroxyethyl deacetylated chitosan to the mixed solution of polyethylene glycol-lithium diatomaceous earth is 3:1 to 1:

5.

7. The composite hydrogel according to claim 1, characterized in that, The lithium diatomite is LAPONITE RD, LAPONITE RDS, LAPONITE XLG or LAPONITE LXS.

8. The application of the composite hydrogel according to claim 1 in the preparation of tissue fillers, tissue engineering scaffolds, drug carriers, sealing agents or embolizing agents.

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