Composite hydrosol and its preparation method and application

Abstract

The application discloses a composite hydrosol and a preparation method and application thereof, and belongs to the technical field of biological materials. The composite hydrosol is obtained by heating and dissolving a mixed dispersion liquid containing lipoic acid and lipoic acid salt and cooling, and has good biocompatibility, biodegradability and anti-inflammatory activity. The composite hydrosol can be used as a tissue adhesive for adhesion of defects of various tissues and can be used as a tissue filler for repairing irregular tissue defects. In addition, the composite hydrosol can be used as a carrier material to load various bioactive components and has application prospects in drug delivery and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biomaterials, and particularly relates to a composite hydrogel as well as a preparation method and application thereof. BACKGROUND

[0002] As a kind of viscous liquid formed by polymer and water, sol shows great application potential in tissue adhesion, filling and drug delivery. For example, cyanoacrylate biological glue is a kind of sol product widely used in clinical at present, which can replace traditional tissue suture to avoid the cumbersome process of tissue suture and the discomfort / pain brought to patients. However, the current hydrogel still has many defects, including poor biocompatibility, poor degradability, poor mechanical compatibility with soft tissue, and lack of biological activity, etc., which is difficult to meet the needs of clinical application. SUMMARY

[0003] In view of the above problems, the present application provides a novel composite hydrogel as well as a preparation method and application thereof. The composite hydrogel is prepared from raw materials containing lipoic acid and lipoic acid salt without adding any organic solvent and covalent crosslinking agent in the preparation process, and has good biocompatibility. The composite hydrogel is formed by dynamic disulfide bond crosslinking, and has good biodegradability in the body. The degradation product of the composite hydrogel is lipoic acid / lipoic acid salt small molecule, which has excellent anti-inflammatory activity, can promote the healing of tissue defects and effectively avoid the occurrence of scars after healing. The composite hydrogel can adhere to various tissues and organs under dry or wet conditions, and is used for adhesion of various tissue defects. The composite hydrogel can also be used as a tissue filler to fill various irregular tissue defects and promote rapid healing. The composite hydrogel can efficiently load various bioactive components, and has great application value in drug delivery.

[0004] The present application comprises the following technical solutions:

[0005] A composite hydrosol is a fluid, viscous liquid prepared from raw materials containing lipoic acid and lipoate. Lipoic acid alone cannot be prepared into a hydrosol due to its poor water solubility, while the fluid liquid formed by lipoate alone degrades rapidly, failing to meet the needs of biomedical applications. This invention successfully prepares a composite hydrosol with good biocompatibility, biodegradability, and bioactivity by combining lipoic acid and lipoate. The composite hydrosol can be prepared without the use of any organic solvents or covalent crosslinking agents, exhibiting excellent biocompatibility. It is biodegradable in vivo, and the degradation products are small molecules of lipoic acid / lipoate with anti-inflammatory activity, which is beneficial for accelerating tissue defect healing and preventing scar formation. Furthermore, the composite hydrosol can adhere to various tissues and organs under dry or humid conditions, enabling the adhesion of various tissue defects. In addition, under certain conditions, the composite hydrosol can transform into a gel, serving as a tissue filler to accelerate tissue repair and regeneration. This composite hydrosol can also efficiently load various bioactive components, showing significant application value in drug delivery.

[0006] The lipoic acid mentioned in this invention is a broad concept of lipoic acid, which can be lipoic acid molecules, lipoic acid derivatives, or a mixture of the two. The lipoic acid derivatives include modified products obtained by non-substantial modification of lipoic acid that does not affect its core function (including but not limited to grafting functional groups onto lipoic acid molecules).

[0007] Alternatively, in the aforementioned composite hydrosol, the thiocate salt can be sodium thiocate, potassium thiocate, or lithium thiocate. The metal ions contained in the thiocate salts selected in this scheme are all monovalent, and these monovalent metal ions can act as counter ions of the carboxylate group without chelating with thiocic acid.

[0008] Alternatively, in the aforementioned composite hydrosol, the molar ratio of lipoic acid to lipoate is 1:(2-100), and the water content is 55-90%. When the molar ratio of lipoic acid to lipoate is higher than 1:2, a hydrosol cannot be formed; when the molar ratio is 1:2, only a composite hydrosol with a water content of 80% is formed; when the molar ratio is 1:100, a composite hydrosol with a water content of 55-90% can be formed; when the molar ratio is lower than 1:100, the formed sol degrades rapidly, making it difficult to meet the requirements for clinical applications. Furthermore, the larger the molar ratio of lipoic acid to lipoate in the composite hydrosol, the narrower the water content range of the composite hydrosol; the smaller the molar ratio, the wider the water content range of the composite hydrosol.

[0009] Alternatively, in the above-mentioned composite hydrosol, the viscosity of the composite hydrosol is greater than or equal to 3 kPa. This is beneficial for forming effective adhesion with biological tissues.

[0010] Alternatively, in the aforementioned composite hydrosol, the composite hydrosol is a fluid, viscous liquid. The carboxyl groups on the thioctic acid molecules in the composite hydrosol enable it to interact with biological tissues at the interface, thereby achieving tissue adhesion. When used as an adhesive, especially for bonding moist interfaces of biological tissues, the composite hydrosol can overcome the adverse effects of moisture at the moist interface through the hydrophobic effect of thioctic acid, significantly improving the bonding effect. It can also effectively overcome the problems of poor biodegradability, exothermic bonding process, and soft tissue curing after bonding that exist with existing adhesives (such as cyanoacrylate). When used as a filler material and implanted into a predetermined tissue site, the composite hydrosol can effectively fill irregularly shaped gaps and effectively adhere and anchor to surrounding tissues, preventing flow and diffusion into non-target areas. When used as a carrier material, the composite hydrosol's good flow properties facilitate the uniform dispersion of the loaded substance and its smooth arrival at the target site. Furthermore, its gelling potential and viscosity can be used to fix it to the surrounding tissues of the target site, achieving targeted delivery.

[0011] Alternatively, in the aforementioned composite hydrosol, the lipoic acid and lipoate composite dispersion is heated to dissolve the lipoic acid and lipoate, and then cooled to form a flowable composite hydrosol. This method of preparing the sol via heating and crosslinking is simple and does not require the introduction of additional crosslinking agents, ensuring good biocompatibility and biosafety of the sol.

[0012] Alternatively, in the above-mentioned composite hydrosol, the composite hydrosol is prepared by reaction at a temperature greater than 60°C.

[0013] Alternatively, in the above-mentioned composite hydrosol, the carboxyl groups and / or carboxyl groups of thioctic acid and / or thiocate salt in the composite hydrosol can be functionalized by grafting or modification, thereby changing the properties of the composite hydrosol.

[0014] Alternatively, the aforementioned composite hydrosol may also contain other bioactive components. Specifically, these bioactive components may include growth factors, antibacterial agents, pharmaceutical active ingredients, hemostatic agents, etc. The introduction of these bioactive components can endow the sol with richer biological functions, enabling it to better meet the needs of clinical applications.

[0015] The present invention also provides a method for preparing the above-mentioned composite hydrosol, wherein a dispersion of thioctic acid and thiocate is dissolved by heating and then cooled to obtain a thioctic acid / thiocate composite hydrosol without using any organic solvents and covalent crosslinking agents.

[0016] Alternatively, the above preparation method may include the following steps:

[0017] Step A: Disperse lipoic acid and lipoic acid salt in water to obtain a uniform dispersion of lipoic acid and lipoic acid salt.

[0018] Step B: Dissolve the lipoic acid and lipoate dispersions from Step A by heating and then cooling to room temperature to obtain the lipoic acid / lipoate composite hydrosol.

[0019] Alternatively, in the above preparation method, other bioactive ingredients may be added in step A.

[0020] Alternatively, the above preparation method may include the following steps:

[0021] Step 1: Disperse the bioactive components, lipoic acid and lipoate in water to prepare a uniform lipoic acid and lipoate dispersion.

[0022] Step 2: Heat and dissolve the bioactive components, lipoic acid and lipoate dispersions from Step 1, and cool to room temperature to obtain a lipoic acid / lipoate composite hydrosol loaded with bioactive components.

[0023] The present invention also provides an application of the above-mentioned composite hydrosol, characterized in that it is used as a tissue defect adhesive, a tissue defect filler, and a drug delivery carrier.

[0024] The present invention also provides an adhesive, filler or carrier material made from the above-mentioned thioctic acid / thiocate composite hydrosol.

[0025] All features disclosed in this specification, or all steps in all disclosed methods or processes, may be combined in any way, except for mutually exclusive features and / or steps.

[0026] The beneficial effects of this invention are:

[0027] 1. The composite hydrosol prepared by this invention is mainly composed of endogenous small molecule lipoic acid and does not contain any organic solvents or covalent crosslinking agents, thus exhibiting good biosafety and biocompatibility.

[0028] 2. The composite hydrosol prepared by this invention is formed by dynamic disulfide bond crosslinking and has good biodegradability in vivo.

[0029] 3. The degradation product of the composite hydrosol prepared in this invention in the body is lipoic acid, which has excellent anti-inflammatory activity. It can inhibit the inflammatory pathway NF-κB to prevent excessive collagen deposition, thereby avoiding the formation of scars during tissue defect repair.

[0030] 4. The composite hydrosol prepared by this invention does not cause tissue curing when bonding tissues and has good mechanical compatibility.

[0031] 5. The composite hydrosol prepared by this invention can also be used as a carrier for other bioactive components. After loading other bioactive components, it has richer biological functions and better meets the needs of clinical applications. Attached Figure Description

[0032] Figure 1 The following are the basic properties of the composite hydrosol. (a) The Tyndall effect of the composite hydrosol. (b) The adhesion of the composite hydrosol to fingers. (c) The injectability of the composite hydrosol. (d) The flow properties of the composite hydrosol.

[0033] Figure 2 The degradation performance of the composite hydrosol is shown in the following figures: (a) UV spectrum of the composite hydrosol extract; (b) degradation curves of the composite hydrosol and the liquid consisting only of sodium thiocate in PBS.

[0034] Figure 3 The adhesive properties of the composite hydrosol are shown in the following diagrams: (a) Schematic diagram of the adhesion mechanism of the composite hydrosol; (b) Adhesion of the composite hydrosol to different objects; (c) The composite hydrosol suspends a wide-mouth bottle (300g) containing ultrapure water by adhesion; (d) Actual images of the composite hydrosol adhering to biological tissues such as the heart, liver, spleen, lungs, and kidneys.

[0035] Figure 4 To illustrate the use of composite hydrosols for hemostasis of liver defects through adhesion. (a) Actual images of blood loss after liver adhesion using different materials. (b) Quantitative analysis of blood loss in different experimental groups.

[0036] Figure 5 The in vitro anti-inflammatory activity of the composite hydrosol.

[0037] Figure 6 This is a photograph of the actual skin tissue after the composite hydrosol has bonded the defective tissue.

[0038] Figure 7 The healing status of wounds at different time points after treatment with different materials (no treatment, surgical sutures, 3M-Glue and LA-Glue).

[0039] Figure 8 H&E staining and Masson staining of tissue sections from wound sites 7 days after wound treatment with different materials.

[0040] Figure 9 The image shows the physical samples of composite hydrosols prepared under different molar ratios of lipoic acid and sodium lipoate, and different water contents. Detailed Implementation

[0041] The following detailed description of specific embodiments further illustrates the above-described content of the present invention. However, this should not be construed as limiting the scope of the subject matter of the present invention to the following examples. Any modifications made without departing from the spirit and principles of the present invention, as well as equivalent substitutions or improvements made based on ordinary technical knowledge and common practice in the art, should be included within the scope of protection of the present invention.

[0042] Example 1:

[0043] (1) Preparation of thioctic acid / sodium thiocate composite hydrosol.

[0044] Step A: Disperse 93 mg of lipoic acid and 327 mg of sodium lipoate in 1 mL of aqueous solution to prepare a dispersion of lipoic acid and sodium lipoate.

[0045] Step B: Dissolve the dispersion obtained in Step A at 90°C, and after cooling, you can obtain the lipoic acid / sodium lipoate composite hydrosol (named LA-Glue).

[0046] (2) Performance characterization and results analysis of thioctic acid / sodium thioctic acid composite hydrosol.

[0047] The basic properties of LA-Glue. For example... Figure 1 As shown in figure a, the LA-Glue prepared in this embodiment is a fluid liquid and exhibits a significant Tyndall effect. Figure 1 As shown in b, LA-Glue adheres well to the thumb and forefinger after being coated, demonstrating its excellent skin adhesion properties. Figure 1 c and d demonstrate that LA-Glue was loaded into syringes and coated into different forms, indicating the good flowability of LA-Glue. The experimental results shown above indicate that LA-Glue is a flowable viscous liquid.

[0048] In vitro degradation performance of LA-Glue. The in vitro degradation performance of LA-Glue was determined by ultraviolet spectrophotometry. The procedure was as follows: LA-Glue (50 mg) was adhered between two pieces of pigskin, and then the entire material was immersed in 1 mL of PBS solution; finally, the extract after 1 h of immersion was diluted 3 times with PBS, and its ultraviolet absorption spectrum was measured by ultraviolet spectrophotometry. Figure 2 As shown in Figure a, the extract of LA-Glue exhibits a distinct UV absorption peak at 330 nm, consistent with the characteristic UV absorption peak of lipoic acid at 330 nm as described in the literature, indicating that LA-Glue possesses good in vitro degradability and that the degradation product is lipoic acid. Furthermore, Figure 2b. The degradation curves of LA-Glue and a liquid composed solely of sodium lipoate (LaNa-Liquid) prepared under the same conditions were compared in PBS. The results showed that LaNa-Liquid was completely degraded after immersion in PBS for 10 min. In contrast, LA-Glue showed a gradual degradation trend, with some LA-Glue remaining undegraded even after immersion for 1800 min. This indicates that the introduction of lipoic acid can regulate the degradation rate of the composite hydrogel, making it better suited to clinical applications.

[0049] LA-Glue exhibits excellent adhesive properties. Thanks to the carboxyl group in the lipoic acid molecule, which can interact with various biological tissues at the interface, LA-Glue demonstrates superior adhesive properties. Figure 3 a). For example Figure 3 As shown in b and c, LA-Glue can adhere not only to substrates such as plastic, glass, metal, wood, leaves, and stone, but also lift wide-mouthed bottles weighing over 300g through adhesion. Furthermore, LA-Glue can firmly adhere to the surfaces of various organ tissues in rats, including the heart, liver, spleen, lungs, and kidneys, and suspend them in the air. Figure 3 d). The above results indicate that LA-Glue can adhere to the surface of various biological tissues, demonstrating significant potential for biological applications.

[0050] Hemostatic properties of LA-Glue. The adhesive properties of LA-Glue were further evaluated using a Sprague Dawley rat liver hemostasis model. First, a tissue defect was constructed in the liver of Sprague Dawley rats. Then, the liver defect was bonded using LA-Glue and 3M-Glue. Finally, the blood loss and amount at the liver defect site were recorded. Figure 4 As shown in Figure a, the liver defect without any treatment showed significant blood loss. In contrast, the liver defect treated with LA-Glue showed only minimal blood loss, indicating that 3M-Glue can effectively bond liver defects and stop bleeding. Furthermore, the quantitative results of blood loss ( Figure 4 (b) The blood loss in the 3M-Glue group and the LA-Glue group was similar, significantly lower than that in the untreated liver defect group. In conclusion, LA-Glue can rapidly adhere liver defects and thus achieve hemostasis, and its hemostatic performance is close to that of commercially available 3M-Glue.

[0051] In vitro anti-inflammatory activity of LA-Glue. The in vitro anti-inflammatory activity of LA-Glue was evaluated by co-culturing LA-Glue extract with lipopolysaccharide (LPS)-stimulated mouse macrophages (RAW 264.7). The specific experimental steps were as follows: First, RAW 264.7 cells were co-incubated with LPS (1.5 μg / mL) for 12 h. Then, RAW 264.7 cells stimulated with LPS were co-incubated with LA-Glue extract for 24 h. Finally, the expression of pro-inflammatory genes (TNF-α, IL-1β, IL-6, and TGF-β1) in RAW 264.7 cells was detected by PCR. Figure 5 The cells stimulated with LPS showed a higher inflammatory response, with significantly higher expression levels of TNF-α, IL-1β, IL-6, and TGF-β1 compared to unstimulated cells. However, after treatment with LA-Glue, the expression of TNF-α, IL-1β, IL-6, and TGF-β1 decreased significantly, even approaching levels seen in unstimulated cells. These experimental results indicate that LA-Glue possesses excellent in vitro anti-inflammatory activity, primarily because the lipoic acid released during its degradation inhibits the inflammatory pathway NF-κB.

[0052] Mechanical compatibility of LA-Glue. The mechanical compatibility of LA-Glue was evaluated by observing the flexibility of the skin tissue after it was bonded to a skin defect. First, a skin defect was constructed on the back of a Sprague Dawley rat. Then, the skin defect was sutured using surgical sutures, and bonded with LA-Glue and 3M-Glue, respectively. Finally, the mechanical compatibility of the material with the skin tissue was evaluated by observing indicators such as the flexibility of the skin tissue. Figure 6 As shown, while 3M-Glue can replace traditional surgical sutures to bond damaged skin tissue together, the skin tissue becomes significantly harder after bonding with 3M-Glue, indicating poor biocompatibility between 3M-Glue and skin tissue. In contrast, LA-Glue not only achieves a similar bonding effect to 3M-Glue, but also maintains the flexibility of the bonded skin tissue. These results demonstrate that compared to 3M-Glue, LA-Glue has better biocompatibility with skin tissue and does not cause significant side effects during use, showing good potential for clinical application.

[0053] The ability of LA-Glue to promote wound healing. This study used a Sprague Dawley rat dorsal skin defect repair experiment to verify the wound healing ability of LA-Glue. The general experimental steps were as follows: First, a linear skin tissue defect was constructed on the back of Sprague Dawley rats. Second, the skin tissue defect was sutured using surgical sutures and then bonded with LA-Glue and 3M-Glue. Untreated tissue defects served as a blank control group. Finally, the wound healing ability of the material was evaluated by observing the repair status of the skin defect at different time points and examining histological sections (H&E and Masson staining). Figure 7 As shown, the skin defect healing rate in the LA-Glue group was significantly faster than that in the control group, the surgical suture group, and the 3M-Glue group. Specifically, 7 days after implantation, the control group, the surgical suture group, and the 3M-Glue treatment group still had noticeable scars, while the scars in the LA-Glue treatment group completely disappeared. The quality of the regenerated skin tissue was further analyzed by H&E and Masson staining. Figure 8 The experimental results showed that obvious tissue defects were observed in the sections of the surgical suture group and the 3M-Glue group, while no obvious tissue defects were observed in the sections of the Control group, but the newly formed tissue was not yet mature. In contrast, no obvious tissue defects were observed in the tissue sections of the LA-Glue group, and structures such as hair follicles appeared in the regenerated tissue (similar to normal skin tissue), indicating that the regenerated tissue had gradually matured. All the above experimental results indicate that LA-Glue can not only adhere tissue defects but also accelerate the repair of these tissue defects.

[0054] Example 2:

[0055] The operation in this embodiment is basically the same as in Example 1, except that the amounts of lipoic acid, sodium lipoate, and water in step A of Example 1 are changed to prepare composite materials with different water contents and different molar ratios of lipoic acid and sodium lipoate. Figure 9 The composition, water content, and viscosity of the composite material prepared in this embodiment are shown in Table 1.

[0056] Table 1: Composition, water content, and viscosity of composite materials prepared with different amounts of lipoic acid, sodium lipoate, and water.

[0057]

[0058]

[0059] like Figure 9As shown, when the molar ratio of lipoic acid to sodium lipoate in step A is 1:0, the resulting composite material exhibits a solid-liquid separation state and does not form a hydrogel. When the molar ratio of lipoic acid to sodium lipoate in step A is 1:1, the resulting composite material is either solid-liquid separated or solid, and again, no hydrogel is formed. When the molar ratio of lipoic acid to sodium lipoate in step A is 1:2, and the water content is 90%, the composite material exhibits solid-liquid separation. The composite materials formed at water contents of 77%, 67%, and 50% are solid, and only at a water content of 83% does a hydrogel form (viscosity: 15.2 kPa). When the molar ratio of lipoic acid to sodium lipoate in step A is 1:4, and the water content is 90%, the resulting composite material exhibits solid-liquid separation. The composite materials formed at water contents of 67% and 50% are solid, and at water contents of 83% and 77% do a sol (viscosities: 10.4 kPa and 16.2 kPa, respectively). When the molar ratio of lipoic acid to sodium lipoate in step A is 1:10 and the water content is 90%, the resulting composite material exhibits solid-liquid separation. When the water content is 50%, the composite material is solid. When the water content is 83%, 77%, and 67%, a sol is formed (with viscosities of 7.9 kPa, 9.3 kPa, and 14.7 kPa, respectively). When the molar ratio of lipoic acid to sodium lipoate in step A is 1:100 and the water content is 50%, the resulting composite material is solid. When the water content is 90%, 83%, 77%, and 67%, a sol is formed (with viscosities of 3.0 kPa, 4.2 kPa, 5.6 kPa, and 11.9 kPa, respectively). These results indicate that a higher molar ratio of lipoic acid to sodium lipoate results in a narrower range of water content in the formed composite hydrosol; conversely, a lower molar ratio results in a wider range of water content in the formed composite hydrosol. When the molar ratio of lipoic acid to sodium lipoate is less than 1:100, the resulting composite hydrosol degrades rapidly, making it difficult to meet the needs of clinical applications.

[0060] Example 3:

[0061] The water content of the composite hydrosol can also be controlled by adjusting the heating time to evaporate the water. In Example 2, the composite hydrosol formed with a 1:100 molar ratio of lipoic acid and sodium lipoate and a water content of 90% was heated continuously to remove some of the water, resulting in a composite hydrosol with a water content as low as 55%. When the water content is further reduced, the material becomes solid.

[0062] Example 4:

[0063] The operation of this embodiment is basically the same as that of Embodiment 1, except that the temperature in Embodiment 1 is adjusted from 90°C to 100°C.

[0064] The fluid viscous composite hydrosol obtained in this embodiment has similar adhesion, degradation and anti-inflammatory activity to the composite hydrosol obtained in Example 1.

[0065] Example 5:

[0066] Step A: First, disperse 420 mg of lipoic acid and 63.5 mg of sodium hydroxide in 1 mL of aqueous solution to prepare a dispersion of lipoic acid and sodium lipoate.

[0067] Step B: Dissolve the dispersion obtained in Step A at 90°C, and after cooling, obtain a thioctic acid / sodium thiocate composite hydrosol.

[0068] The fluid viscous composite hydrosol obtained in this embodiment has similar adhesion, degradation and anti-inflammatory activity to the composite hydrosol obtained in Example 1.

[0069] Example 6:

[0070] Step A: Dissolve 2.06 g of lipoic acid and 1.37 g of N-hydroxysuccinimide in tetrahydrofuran (80 mL) and stir in an ice bath for 12 h. After the reaction is complete, lipoic acid grafted with the activated ester can be obtained by rotary evaporation.

[0071] Step B: Disperse 93 mg of lipoic acid grafted with activated ester and 327 mg of sodium lipoate in 1 mL of aqueous solution to obtain a dispersion of lipoic acid and sodium lipoate grafted with activated ester.

[0072] Step C: Dissolve the dispersion obtained in step B at 90°C, and after cooling, obtain a lipoic acid / sodium lipoate composite hydrosol with grafted activated ester.

[0073] The composite hydrosol with grafted activated ester obtained in this embodiment exhibits stronger adhesion compared to the composite hydrosol in Example 1, while its degradation properties and anti-inflammatory activity remain largely unchanged.

[0074] Example 7:

[0075] Step 1: Disperse 93 mg of lipoic acid, 327 mg of sodium lipoate and 30 mg of tannic acid in 1 mL of aqueous solution to prepare a dispersion of lipoic acid, sodium lipoate and tannic acid.

[0076] Step 2: Dissolve the dispersion obtained in step A at 90°C, and after cooling, a fluid viscous composite hydrosol loaded with tannic acid can be obtained.

[0077] The tannic acid-loaded fluid viscous composite hydrosol obtained in this embodiment exhibits similar adhesion, degradation properties, and anti-inflammatory activity to the composite hydrosol obtained in Example 1. Furthermore, co-culturing the composite hydrosol obtained in Example 1 and the tannic acid-loaded composite hydrosol with *Escherichia coli* and *Staphylococcus aureus*, respectively, showed that the tannic acid-loaded composite hydrosol possessed superior antibacterial activity compared to the composite hydrosol obtained in Example 1, effectively killing both *Escherichia coli* and *Staphylococcus aureus*.

[0078] Example 8:

[0079] The operation of this embodiment is basically the same as that of Example 7, except that the tannic acid (30mg) in step 1 of Example 7 is replaced with hydroxyapatite (10mg), doxorubicin (1mg) and chitosan oligosaccharide (10mg), respectively.

[0080] This embodiment yielded three composite hydrosols loaded with different bioactive components, including a composite hydrosol loaded with hydroxyapatite, a composite hydrosol loaded with doxorubicin, and a composite hydrosol loaded with chitosan oligosaccharide.

[0081] Compared to the composite hydrosol obtained in Example 1, the hydroxyapatite-loaded composite hydrosol exhibited reduced adhesion, slower degradation, and similar anti-inflammatory activity. Furthermore, co-culturing the composite hydrosol obtained in Example 1 and the hydroxyapatite-loaded composite hydrosol with bone marrow mesenchymal stem cells, respectively, showed that the hydroxyapatite-loaded composite hydrosol had a stronger ability to induce bone marrow mesenchymal stem cells to differentiate into osteoblasts than the composite hydrosol obtained in Example 1.

[0082] Compared to the composite hydrosol obtained in Example 1, the doxorubicin-loaded composite hydrosol exhibited similar adhesion, degradation properties, and anti-inflammatory activity. Furthermore, co-culturing the composite hydrosol obtained in Example 1 and the doxorubicin-loaded composite hydrosol with tumor cells (A549 cells, HeLa cells, and B16 cells) showed that the doxorubicin-loaded composite hydrosol possessed superior antitumor activity compared to the composite hydrosol obtained in Example 1, effectively killing various tumor cell types.

[0083] Compared to the composite hydrosol obtained in Example 1, the composite hydrosol loaded with chitosan oligosaccharides showed reduced adhesion, slower degradation rate, and similar anti-inflammatory activity. Furthermore, co-culturing the composite hydrosol obtained in Example 1 and the composite hydrosol loaded with chitosan oligosaccharides with *Escherichia coli* and *Staphylococcus aureus*, respectively, revealed that the composite hydrosol loaded with chitosan oligosaccharides exhibited superior antibacterial activity compared to the composite hydrosol obtained in Example 1, effectively killing both *Escherichia coli* and *Staphylococcus aureus*.

[0084] Example 9:

[0085] Step A: Disperse 110 mg of lipoic acid and 350 mg of sodium lipoate in 1 mL of aqueous solution to prepare a dispersion of lipoic acid and sodium lipoate.

[0086] Step B: Dissolve the dispersion obtained in Step A at 90°C, and after cooling, you can obtain the thioctic acid / sodium thiocate composite hydrosol.

[0087] This embodiment yields a composite hydrosol that can be used for filling skin tissue defects. The freshly prepared composite hydrosol is a fluid, viscous liquid that can flow and fill large areas of skin tissue defects. After filling the skin tissue defect, the composite hydrosol rapidly solidifies to form a gel, which acts as a tissue repair material to induce skin tissue regeneration.

Claims

1. A composite hydrosol, characterized in that, It is a fluid, viscous liquid formed from raw materials containing thioctic acid and thiocate. The composite hydrosol is formed by dynamic disulfide crosslinking and does not contain organic solvents or covalent crosslinking agents. The metal ions contained in the thiocate are all monovalent. The molar ratio of thioctic acid to thiocate is 1:(2-100), and the water content is 55-90%. By adjusting the molar ratio of thioctic acid to thiocate and the water content, the product can form a fluid, viscous liquid.

2. The composite hydrosol according to claim 1, characterized in that, The thiocate is at least one of sodium thiocate, potassium thiocate, and lithium thiocate.

3. The composite hydrosol according to claim 1, characterized in that, The viscosity of the composite hydrosol is greater than or equal to 3.0 kPa.

4. The composite hydrosol according to claim 1, characterized in that, The carboxyl and / or carboxylate groups of the lipoic acid and / or lipoate are functionalized by grafting or modification.

5. The composite hydrosol according to claim 1, characterized in that, The composite hydrosol also contains other bioactive components.

6. A method for preparing the composite hydrosol as described in claim 1, characterized in that... Includes the following steps: Step A: Disperse lipoic acid and lipoate in water to prepare a uniform dispersion of lipoic acid and lipoate; Step B: Heat the dispersion from Step A to dissolve it, and then cool it to room temperature to obtain a flowing viscous liquid.

7. The preparation method according to claim 6, characterized in that, The thioctic acid and thiocate dispersion in step A can be prepared by adding an alkaline solution to thioctic acid.

8. An application of the composite hydrosol as described in claim 1, characterized in that, It is used to prepare at least one of tissue defect adhesives, tissue defect fillers, and delivery carriers for bioactive ingredients.

9. An adhesive, filler, or carrier material made using the composite hydrosol of claim 1.

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