A composite hydrogel, its preparation method and application

Abstract

This invention discloses a composite hydrogel, its preparation method, and its applications, belonging to the field of biomaterials technology. The composite hydrogel is prepared by dispersing lipoic acid and lipoate in water, then heating to dissolve and cross-linking the mixture before cooling. This composite hydrogel not only has a simple preparation process but also exhibits good biocompatibility and degradability. Furthermore, its water content, mechanical strength, and degradation rate can be controlled by adjusting the ratio of lipoic acid to lipoate in the composite hydrogel. This hydrogel shows great promise for applications in many fields of biomedical engineering, such as tissue engineering, disease treatment, and drug delivery.

Description

Technical Field

[0001] This invention belongs to the field of biomaterials technology, specifically relating to a composite hydrogel, its preparation method, and its application. Technical Background

[0002] Hydrogels are a class of soft materials with a three-dimensional network structure, high water content, and no flowability, formed by water-soluble or hydrophilic polymers through certain chemical and physical cross-linking processes. Due to their high water content, soft texture, and ability to simulate the three-dimensional microenvironment of the extracellular matrix, they show great promise for applications in many fields of biomedical engineering, such as tissue adhesion, skin tissue repair, bone / cartilage tissue repair, nerve tissue repair, and tumor and postoperative treatment.

[0003] Lipoic acid is a B vitamin synthesized by lipoic acid synthase in the mitochondria. It not only possesses good biocompatibility and safety but also exhibits anti-aging, fatigue-relieving, and anti-cancer effects. As a natural antioxidant, lipoic acid can effectively scavenge various free radicals in the body, with an antioxidant capacity approximately 400 times that of vitamin C.

[0004] In recent years, polymer bulk materials constructed from lipoic acid or lipoate have been increasingly reported, such as lipoic acid elastomers and thin film materials. However, because the network of elastomers does not contain water and thin film materials do not have a three-dimensional network structure, they cannot meet the application requirements in the field of biomedical engineering. Summary of the Invention

[0005] To address the above problems, this invention provides a thioctic acid / thiocate composite hydrogel. The composite hydrogel can be prepared without the use of any organic solvents and covalent crosslinking agents, exhibits good biocompatibility and degradation performance, and has controllable mechanical strength and degradation rate, which can well meet the application needs of the biomedical engineering field.

[0006] This invention includes the following technical solutions:

[0007] A composite hydrogel is a hydrogel material formed by combining raw materials containing lipoic acid and lipoate. Lipoic acid alone cannot be prepared into a hydrogel material due to its poor water solubility. Lipoate hydrogels degrade rapidly, failing to meet the specific application requirements in the biomedical field. The composite hydrogel described in this invention can be prepared without the use of any organic solvents or covalent crosslinking agents, exhibiting good biocompatibility and degradation performance, with controllable mechanical strength and degradation rate, thus well-suited for biomaterial applications. In this invention, lipoic acid is used in a broad sense, referring to lipoic acid molecules, lipoic acid derivatives, or mixtures of both. Lipoic acid derivatives include modified products obtained by non-substantial modifications to lipoic acid that do not affect its core function (including but not limited to grafting functional groups onto lipoic acid molecules).

[0008] Alternatively, in the above-mentioned composite hydrogel, the lipoate is sodium lipoate, potassium lipoate, or lithium lipoate. The metal ions contained in the lipoate selected in this scheme are all monovalent, and these monovalent metal ions can act as counter ions of the carboxylate group without chelating with lipoic acid.

[0009] Alternatively, the mechanical strength and degradation rate of the composite hydrogel can be controlled by adjusting the ratio of lipoic acid to lipoate. Preferably, the molar ratio of lipoic acid to lipoate in the composite hydrogel is 0.1–10:1. When the molar ratio of lipoic acid to lipoate is below 0.1:1, the resulting composite hydrogel has poor mechanical properties and a fast degradation rate, while a molar ratio above 10:1 prevents the formation of a composite hydrogel. More preferably, the molar ratio of lipoic acid to lipoate is 0.5–2:1.

[0010] Optionally, the composite hydrogel has a water content of 5-80%. When the water content is below 5%, the formed composite hydrogel loses its flexibility; when the water content is above 80%, a composite hydrogel cannot be formed regardless of the molar ratio of lipoic acid to lipoate. More preferably, the composite hydrogel has a water content of 50-80%.

[0011] Alternatively, in the aforementioned composite hydrogel, the thioctic acid and thiocate composite dispersion is heated to the crosslinking temperature to dissolve and crosslink the thioctic acid and thiocate, and then cooled and molded to form a three-dimensional composite hydrogel. This method of preparing composite hydrogels through heating and crosslinking is simple and does not require the introduction of additional crosslinking agents, which helps ensure the good biocompatibility and biosafety of the composite hydrogel.

[0012] Alternatively, the composite hydrogel can be prepared by crosslinking at a temperature greater than 60°C.

[0013] As an alternative, in the above-mentioned composite hydrogel, the gelation time, degradation rate and mechanical strength of the final material can be adjusted by changing the preparation parameters such as the ratio of thioctic acid and thiocate, water content and heating temperature, so as to meet the specific needs of different application scenarios.

[0014] Alternatively, the aforementioned composite hydrogel may also contain metal ions capable of chelating with carboxyl or thiol groups. The chelation of metal ions with carboxyl or thiol groups serves as a physical cross-linking point in the hydrogel network, enhancing the mechanical strength of the hydrogel and prolonging its degradation time.

[0015] Alternatively, in the aforementioned composite hydrogel, the molar ratio of the metal ions to the total amount of lipoic acid / lipoate ranges from 1:10 to 10000. When the molar ratio of the metal ions to the total amount of lipoic acid / lipoate is less than 1:10000, the improvement of the mechanical properties and degradation properties of the composite hydrogel by the metal ions is very limited. When the molar ratio of the metal ions to the total amount of lipoic acid / lipoate exceeds 1:10, it is difficult to form a composite hydrogel material.

[0016] Optionally, the composite hydrogel also contains a Fenton-type metal. The introduction of the Fenton-type metal not only enhances the mechanical properties of the composite hydrogel through chelation with lipoic acid / lipoate, but also allows it to participate in Fenton / Fenton-like reactions. Lipoic acid / lipoate can induce tumor cell apoptosis by increasing the level of reactive oxygen species within tumor cells; however, the antitumor effect of simple lipoic acid / lipoate hydrogels is limited. The introduction of the Fenton-type metal can efficiently decompose hydrogen peroxide in tumor cells into highly toxic hydroxyl radicals through Fenton / Fenton-like reactions, achieving synergistic and efficient tumor treatment.

[0017] Alternatively, in the above-mentioned composite hydrogel, the Fenton-type metal is specifically one or more of iron ions, copper ions, manganese ions, nickel ions, cobalt ions, silver ions, or cadmium ions.

[0018] Alternatively, the aforementioned composite hydrogel may also contain bioactive components. Specifically, these bioactive components include growth factors, antibacterial agents, pharmaceutical active ingredients, and hemostatic agents. The introduction of these bioactive components endows the composite hydrogel with more biological properties, enabling it to better meet the needs of clinical applications.

[0019] The present invention also provides a method for preparing the above-mentioned composite hydrogel, wherein a dispersion of thioctic acid and thiocate is heated and dissolved and then cooled to obtain a thioctic acid / thiocate composite hydrogel without using any organic solvents and covalent crosslinking agents.

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

[0021] Step A: Disperse lipoic acid and lipoate uniformly in an aqueous solution to obtain a lipoic acid / lipoate composite dispersion;

[0022] Step B: The lipoic acid / lipoate composite dispersion prepared in Step A is heated and dissolved to obtain a lipoic acid / lipoate composite hydrogel prepolymer.

[0023] Step C: Add the lipoic acid / lipoate composite hydrogel prepolymer from step B into the mold, and then cool to obtain the lipoic acid / lipoate composite hydrogel.

[0024] Alternatively, in the above preparation method, a metal ion capable of chelating with a carboxyl or thiol group is added in step A or step B.

[0025] Alternatively, the above preparation method may include the following steps:

[0026] Step 1: Metal ions, lipoic acid, and lipoate are uniformly dispersed in an aqueous solution to obtain a metal ion / lipoic acid / lipoate composite dispersion.

[0027] Step 2: The metal ion / lipoic acid / lipoate composite dispersion is heated and dissolved to form a metal ion / lipoic acid / lipoate hydrogel prepolymer.

[0028] Step 3: Add the metal ion / lipoic acid / lipoate hydrogel prepolymer from Step 2 into the mold, and then cool to obtain the metal ion / lipoic acid / lipoate composite hydrogel.

[0029] The present invention also provides an application of the above-mentioned composite hydrogel, characterized in that it is used as a tissue engineering material, a drug delivery system or an anti-tumor drug.

[0030] 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.

[0031] The beneficial effects of this invention are:

[0032] 1. The composite hydrogel of the present invention is prepared without the use of any organic solvents and covalent crosslinking agents. The process is simple, the mechanical strength and degradation rate are controllable, and it can well meet the application requirements of biomaterials.

[0033] 2. The mechanical strength and degradation properties of the composite hydrogel described in this invention are affected by the ratio of lipoic acid and thiocate in the composite hydrogel. Therefore, the mechanical strength and degradation properties of the composite hydrogel can be controlled by changing the ratio of lipoic acid and thiocate. Furthermore, metal ions can be introduced into the composite hydrogel, which can further regulate its mechanical strength and degradation properties.

[0034] 3. The degradation products of the composite hydrogel described in this invention are lipoic acid / lipoate small molecules, which not only have good biocompatibility, but also have excellent antioxidant and anti-inflammatory activities as well as certain anticancer activities. Attached Figure Description

[0035] Figure 1 The images show physical images of composite materials prepared under different molar ratios of lipoic acid and sodium lipoate, as well as different water contents.

[0036] Figure 2 Tensile strength of La / LaNa composite hydrogels with different La to LaNa ratios.

[0037] Figure 3 Degradation curves of La / LaNa composite hydrogels with different La to LaNa ratios in PBS.

[0038] Figure 4 The image shows physical images of La / LaNa composite hydrogels doped with different metal ions.

[0039] Figure 5 Tensile strength of La / LaNa composite hydrogels doped with different concentrations of copper ions.

[0040] Figure 6 Degradation curves of La / LaNa composite hydrogels doped with different concentrations of copper ions in PBS.

[0041] Figure 7 The toxicity of extracts of La / LaNa hydrogel and La / LaNa / Cu(1 / 50) hydrogel to melanoma cells.

[0042] Figure 8 The toxicity of extracts of La / LaNa hydrogel and La / LaNa / Cu(1 / 50) hydrogel to endothelial cells. Detailed Implementation

[0043] 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.

[0044] Example 1

[0045] Step A: Disperse 1g of lipoic acid in 1mL of NaOH solution (2.4mol / L) to obtain a composite dispersion of lipoic acid (La) and sodium lipoate (LaNa) with a molar ratio of 1:1.

[0046] Step B: Heat the above lipoic acid / sodium lipoate composite dispersion to 90°C and continue the reaction for 10 minutes to obtain a lipoic acid / sodium lipoate composite hydrogel prepolymer.

[0047] Step C: Add the lipoic acid / sodium lipoate composite hydrogel prepolymer from Step B into different molds, and then cool to obtain lipoic acid / sodium lipoate composite hydrogel (La / LaNa).

[0048] This embodiment yields a composite hydrogel with a tensile strength of approximately 15 kPa.

[0049] Example 2

[0050] The operation in this embodiment is basically the same as in Example 1, except that the content of lipoic acid and the concentration of NaOH solution used in step A of Example 1 are changed to prepare composite materials with different water contents and different lipoic acid / sodium lipoate molar ratios. Figure 1 The results of the composite materials prepared through this embodiment are shown in Table 1.

[0051] Table 1: Experimental results of composite materials prepared under different water contents and different lipoic acid / sodium lipoate molar ratios

[0052]

[0053]

[0054] like Figure 1As shown, when the molar ratio of lipoic acid to sodium lipoate is 1:0, all resulting composite materials exhibit solid-liquid separation. When the molar ratio of lipoic acid to sodium lipoate is 10:1, composite materials with water contents of 90%, 80%, and 67% exhibit solid-liquid separation, while those with a water content of 50% form a gel. When the molar ratio of lipoic acid to sodium lipoate is 2:1, composite materials with water contents of 90% and 80% exhibit solid-liquid separation, while those with water contents of 67% and 50% form a gel. When the molar ratio of lipoic acid to sodium lipoate is 1:1, composite materials with a water content of 90% exhibit solid-liquid separation, while those with water contents of 80%, 67%, and 50% form a gel. When the molar ratio of lipoic acid to sodium lipoate is 1:2, composite materials with a water content of 90% exhibit solid-liquid separation, while those with water contents of 80%, 67%, and 50% form a gel. When the molar ratio of lipoic acid to sodium lipoate is 1:10, the composite materials formed with water contents of 90%, 80%, and 67% are liquids, while those with a water content of 50% form gels. These experimental results indicate that the larger or smaller the molar ratio of lipoic acid to sodium lipoate, the narrower the range of water content in the resulting composite hydrogels; conversely, the closer the contents of lipoic acid and sodium lipoate are to each other, the wider the range of water content in the resulting composite hydrogels. It is noteworthy that a gel can also be formed when the molar ratio of lipoic acid to sodium lipoate is 0:1 and the water content is ≤50%, but this gel degrades rapidly, making it difficult to meet the needs of clinical applications.

[0055] Figure 2 The tensile strength of composite hydrogels with different molar ratios of lipoic acid and sodium lipoate was demonstrated, and the results showed that the tensile strength of the composite hydrogels increased with the increase of lipoic acid. Figure 3 The degradation behavior of composite hydrogels formed by lipoic acid and sodium lipoate at different molar ratios was demonstrated. The results showed that the degradation rate of the composite hydrogel slowed down with increasing lipoic acid content, and the composite hydrogel containing only sodium lipoate was completely degraded within 1 hour. These experimental results indicate that the mechanical strength and degradation rate of the hydrogel can be controlled by adjusting the ratio of lipoic acid to sodium lipoate in the composite hydrogel.

[0056] Example 3

[0057] The water content of the composite hydrogel can also be controlled by heating to evaporate the water. For example, heating the composite hydrogel formed in Example 2 with a molar ratio of lipoic acid and sodium lipoate of 1:2 and a water content of 80% to remove some of the water can yield a composite hydrogel with a water content as low as 5%. When the water content is further reduced, the flexibility of the composite hydrogel is lost.

[0058] Example 4

[0059] Step A: Disperse 0.25g of lipoic acid and 0.27g of sodium lipoate evenly in an aqueous solution (1mL) to obtain a lipoic acid / sodium lipoate composite dispersion.

[0060] Step B: Heat the lipoic acid / lipoate composite dispersion prepared in Step A to 90°C and continue the reaction for 10 min to obtain the lipoic acid / sodium lipoate composite hydrogel prepolymer.

[0061] Step C: Add the lipoic acid / sodium lipoate composite hydrogel prepolymer from Step B into the mold, and then cool to obtain the lipoic acid / sodium lipoate composite hydrogel.

[0062] The composite hydrogel obtained in this embodiment has similar mechanical and degradation properties to the La / LaNa composite hydrogel prepared in Example 2 (with the same La to LaNa ratio and the same water content).

[0063] Example 5

[0064] Step A: Disperse 0.25g of lipoic acid and 0.27g of sodium lipoate evenly in an aqueous solution (1mL) to obtain a lipoic acid / sodium lipoate composite dispersion.

[0065] Step B: Heat the lipoic acid / sodium lipoate composite dispersion prepared in Step A to 70°C and continue the reaction for 10 min to obtain the lipoic acid / sodium lipoate composite hydrogel prepolymer.

[0066] Step C: Add the lipoic acid / sodium lipoate composite hydrogel prepolymer from Step B into the mold, and then cool to obtain the lipoic acid / sodium lipoate composite hydrogel.

[0067] The composite hydrogel obtained in this embodiment has similar mechanical and degradation properties to the lipoic acid / sodium lipoate composite hydrogel prepared in Example 4.

[0068] Example 6

[0069] 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.

[0070] Step B: Disperse 0.25g of lipoic acid grafted with activated ester and 0.27g of sodium lipoate evenly in an aqueous solution (1mL) to obtain a composite dispersion of lipoic acid / sodium lipoate grafted with activated ester.

[0071] Step C: Heat the lipoic acid / sodium lipoate composite dispersion grafted with activated ester prepared in step B to 100°C and continue the reaction for 10 min to obtain the lipoic acid / sodium lipoate composite hydrogel prepolymer.

[0072] Step D: Add the prepolymerized lipoic acid / sodium lipoate composite hydrogel grafted with activated ester from Step C into the mold, and then cool to obtain the lipoic acid / sodium lipoate composite hydrogel grafted with activated ester.

[0073] The lipoic acid / sodium lipoate composite hydrogel with grafted activated ester obtained in this embodiment exhibits stronger adhesion compared to the lipoic acid / sodium lipoate composite hydrogel without grafted activated ester.

[0074] Example 7

[0075] Step 1: Disperse 16.56 mg of copper chloride dihydrate and 1 g of lipoic acid in 1 mL of NaOH solution (2.4 mol / L) to obtain a copper ion / lipoic acid / sodium lipoate composite dispersion (the molar ratio of copper ions to lipoic acid / sodium lipoate is 1:50).

[0076] Step 2: The copper ion / lipoic acid / sodium lipoate composite dispersion is heated to 100℃ and reacted for 20 minutes to form a copper ion / lipoic acid / sodium lipoate hydrogel prepolymer.

[0077] Step 3: Add the copper ion / lipoic acid / sodium lipoate hydrogel prepolymer from Step 2 into the mold, and then cool to obtain copper ion / lipoic acid / sodium lipoate composite hydrogel (named La / LaNa / Cu(1 / 50)).

[0078] The composite hydrogel prepared in this embodiment has a higher tensile strength than the composite hydrogel prepared in Example 1, and a slower degradation rate than the composite hydrogel prepared in Example 1.

[0079] Example 8

[0080] The operation in this example is basically the same as in Example 7, except that the copper chloride dihydrate used in Example 7 is replaced with an inorganic salt containing silver ions, iron ions, zinc ions, cobalt ions and manganese ions.

[0081] This embodiment yielded a series of composite hydrogels doped with different metal ions. Figure 4 Compared to composite hydrogels without metal ions, the mechanical properties of composite hydrogels increase and the degradation rate slows down after the introduction of metal ions.

[0082] Example 9

[0083] The operation in this example is basically the same as in Example 7, except that the amount of copper chloride dihydrate added in Example 7 is changed to obtain lipoic acid / sodium lipoate composite hydrogels with different copper ion contents (the molar ratios of copper ions and lipoic acid / sodium lipoate are 0 / 1, 1 / 10000, 1 / 1000 and 1 / 100, respectively).

[0084] This embodiment yielded lipoic acid / sodium lipoate composite hydrogels with different copper ion contents. Figure 5 The tensile strength of lipoic acid / sodium lipoate composite hydrogels with different copper ion doping contents was demonstrated. The results show that the tensile strength of the hydrogel gradually increases with increasing copper ion content. Furthermore, Figure 6 The degradation behavior of lipoic acid / sodium lipoate composite hydrogels with different copper ion doping contents was demonstrated. The results showed that the higher the copper ion content in the composite hydrogel, the slower its degradation rate. These findings indicate that the introduction of copper ions can enhance the mechanical strength of the hydrogel and delay its degradation.

[0085] Example 10

[0086] Extracts of the La / LaNa / Cu (1 / 50) hydrogel prepared in Example 7 and the La / LaNa hydrogel prepared in Example 1 were co-cultured with mouse melanoma cells (B16 cells) and endothelial cells (HUVECs), respectively, to evaluate the in vitro antitumor activity and toxicity to normal cells of the composite hydrogels. The steps were as follows: First, the composite hydrogels were extracted using PBS solution as the extraction medium to prepare hydrogel extracts containing different concentrations of lipoic acid. Then, the hydrogel extracts of different concentrations were co-cultured with B16 cells and HUVECs for 48 hours, respectively. Finally, the absorbance of each experimental group at 490 nm was measured using the MTT assay, and the cell viability of each experimental group was calculated.

[0087] like Figure 7 As shown, the survival rate of B16 cells gradually decreased with increasing lipoic acid content in the La / LaNa composite hydrogel extract. When the lipoic acid content in the La / LaNa composite hydrogel extract reached 2000 μM, the survival rate of B16 cells dropped below 50%, indicating that the La / LaNa composite hydrogel has certain antitumor activity. Compared with the extract of the La / LaNa composite hydrogel, the extract of the La / LaNa / Cu(1 / 50) composite hydrogel showed significantly enhanced cytotoxicity to tumor cells, indicating that the introduction of copper ions can enhance the antitumor effect of the composite hydrogel.

[0088] Figure 8The cytotoxicity of extracts from La / LaNa and La / LaNa / Cu(1 / 50) composite hydrogels to normal cells was demonstrated. Experimental results showed that even when the concentration of lipoic acid in the La / LaNa composite hydrogel extract reached 5000 μM, the endothelial cell survival rate remained above 60%. Furthermore, at the same dosage, the cytotoxicity of the La / LaNa / Cu(1 / 50) composite hydrogel extract to endothelial cells was similar to that of the La / LaNa composite hydrogel extract. These results indicate that the La / LaNa composite hydrogel exhibits low cytotoxicity to normal cells, and the introduction of copper ions does not enhance the cytotoxicity of the composite hydrogel to normal cells.

[0089] Example 11

[0090] Step 1: Disperse 10 mg of chitosan oligosaccharide and 0.5 g of lipoic acid in 1 mL of NaOH solution (1.2 mol / L) to obtain a chitosan oligosaccharide / lipoic acid / sodium lipoate composite dispersion.

[0091] Step 2: Heat the chitosan oligosaccharide / lipoic acid / sodium lipoate composite dispersion to 100℃ and continue the reaction for 10 minutes to form a chitosan oligosaccharide / lipoic acid / sodium lipoate hydrogel prepolymer.

[0092] Step 3: Add the prepolymerized solution of chitosan oligosaccharide / lipoic acid / sodium lipoate hydrogel from Step 2 into the mold, and then cool to obtain chitosan oligosaccharide / lipoic acid / sodium lipoate composite hydrogel.

[0093] The chitosan oligosaccharide composite hydrogel and the composite hydrogel without chitosan oligosaccharide prepared in this embodiment were co-cultured with Escherichia coli and Staphylococcus aureus, respectively. The results showed that the composite hydrogel loaded with chitosan oligosaccharide had better antibacterial activity than the composite hydrogel without chitosan oligosaccharide, and could effectively kill Escherichia coli and Staphylococcus aureus.

[0094] Example 12

[0095] The operation in this example is basically the same as in Example 11, except that the chitosan oligosaccharide used in Example 11 is replaced with organic / inorganic materials with other biological functions, such as tannic acid (10mg), doxorubicin (1mg), and hydroxyapatite (20mg).

[0096] This embodiment prepared three composite hydrogels loaded with different active ingredients, including tannic acid / lipoic acid / sodium lipoate composite hydrogel, doxorubicin / lipoic acid / sodium lipoate composite hydrogel, and hydroxyapatite / lipoic acid / sodium lipoate composite hydrogel.

[0097] The composite hydrogels of tannic acid / lipoic acid / sodium lipoate and those without tannic acid were co-cultured with Escherichia coli and Staphylococcus aureus, respectively. The results showed that the composite hydrogel loaded with tannic acid had better antibacterial activity than the composite hydrogel without tannic acid and could effectively kill Escherichia coli and Staphylococcus aureus.

[0098] The doxorubicin / lipoic acid / sodium lipoate composite hydrogel and the doxorubicin-free composite hydrogel were co-cultured with tumor cells (A549 cells, HeLa cells, and B16 cells). The experimental results showed that the doxorubicin-loaded composite hydrogel had superior anti-tumor activity compared with the doxorubicin-free composite hydrogel, and could effectively kill a variety of tumor cells.

[0099] The composite hydrogels loaded with hydroxyapatite and those without hydroxyapatite were co-cultured with bone marrow mesenchymal stem cells. The results showed that the composite hydrogel loaded with hydroxyapatite had a stronger ability to induce bone marrow mesenchymal stem cells to differentiate into osteoblasts than the composite hydrogel without hydroxyapatite.

[0100] The above description is merely a preferred embodiment of the present invention and is illustrative rather than restrictive. Those skilled in the art will understand that many changes, modifications, and even equivalent alterations can be made within the spirit and scope defined by the claims of the present invention, but all such changes will fall within the protection scope of the present invention.

Claims

1. A composite hydrogel, characterized in that, It is a hydrogel material formed by combining raw materials containing lipoic acid and lipoate. The composite hydrogel is prepared without the use of any organic solvents and covalent crosslinking agents. The molar ratio of lipoic acid to lipoate is 0.1 to 10:1, and the water content of the composite hydrogel is 5 to 80%. The metal ions contained in the lipoate are all monovalent. These monovalent metal ions can act as counter ions of carboxylate groups and will not chelate with lipoic acid.

2. The composite hydrogel according to claim 1, characterized in that, The lipoic acid is a lipoic acid molecule and / or a lipoic acid derivative, and the lipoic acid derivative includes modified products obtained by non-substantial modification of lipoic acid that does not affect its core function.

3. The composite hydrogel according to claim 1, characterized in that, The composite hydrogel also contains metal ions that can chelate with carboxyl or thiol groups.

4. The composite hydrogel according to claim 1, characterized in that, The composite hydrogel also contains a Fenton-type metal, which can participate in the Fenton reaction or a Fenton-like reaction.

5. The composite hydrogel 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.

6. The composite hydrogel according to claim 1, characterized in that, The composite hydrogel also contains bioactive components.

7. A method for preparing the composite hydrogel as described in claim 1, characterized in that, Includes the following steps: Step A: Prepare a composite dispersion of lipoic acid / lipoate; Step B: After heating and dissolving the lipoic acid / lipoate composite dispersion prepared in Step A, continue heating to the crosslinking temperature to obtain the lipoic acid / lipoate composite hydrogel prepolymer. Step C: Add the lipoic acid / lipoate composite hydrogel prepolymer from step B into the mold, and then cool to obtain the lipoic acid / lipoate composite hydrogel.

8. The preparation method according to claim 7, characterized in that, The composite dispersion in step A is prepared by adding thioctic acid to an alkaline solution.

9. An application of the composite hydrogel as described in claim 1, characterized in that, It can be used to prepare tissue engineering materials, drug delivery systems, or anti-tumor drugs.

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