A thioctic acid-based deep eutectic supramolecular polymer adhesive, its preparation method and application

Abstract

This invention discloses a thioctic acid-based deep eutectic supramolecular polymer adhesive, its preparation method, and its applications. It is obtained by one-step heating of a mixture of thioctic acid and thiocate. During heating, multiple strong hydrogen bonds form between the terminal carboxyl groups of thioctic acid and the terminal carboxylate structure of sodium thiocate, promoting deep eutectic melting of the mixture and transforming it from a powder state to a viscous liquid state. After eutectic melting, the sulfur-containing five-membered rings of thioctic acid and sodium thiocate undergo spontaneous ring-opening and copolymerization to form a supramolecular polymer. The adhesive of this invention can achieve stable and high-strength adhesion to various matrices and can be used as a hot melt adhesive, providing anti-inflammatory, bactericidal, and antioxidant effects.

Description

Technical Field

[0001] This invention belongs to the field of polymer materials, specifically relating to the preparation and application research of a thioctic acid-based deep eutectic supramolecular polymer adhesive. Background Technology

[0002] Lipoic acid, due to its terminal carboxyl radical, is often used to prepare adhesives. When heated, lipoic acid monomers spontaneously undergo ring-opening to form polylipoic acid (PPA). However, due to the presence of the terminal sulfur radical in PPA, it becomes unstable upon cooling or solvent evaporation, undergoing reversible spontaneous depolymerization into PPA oligomers or small lipoic acid molecules. The final product is an opaque, semi-crystalline state and lacks any tissue adhesion properties. Although there are reports of stabilizing PPA by introducing monomers with multiple double bonds, polyvalent metal ions, and ionic liquids into the lipoic acid system, the resulting materials exhibit significantly reduced biocompatibility, making them unsuitable for biomedical applications. Furthermore, the tight cross-linking in these materials and the inherent hydrophobic properties of lipoic acid molecules make it difficult to release small molecules, thus greatly diminishing the bioactivity of the lipoic acid monomer. Additionally, the melting temperature of lipoic acid, far exceeding body temperature, also limits its in vivo application.

[0003] Epidermal injuries are common in daily life, and severe cases often require suturing. However, traditional surgical sutures are not only time-consuming and non-biodegradable, but they can also cause secondary damage to tissues, increasing patient suffering. Furthermore, surgical sutures often leave scars at the healed site, adding to the patient's psychological stress. To overcome these shortcomings of traditional surgical sutures, bio-tissue adhesives have been designed to replace them and accelerate wound healing. However, traditional tissue adhesives, such as bio-adhesives or fibrin adhesives, have low adhesion strength to tissues and cannot effectively seal skin wounds. While cyanoacrylate-based adhesives can achieve rapid and high-strength adhesion to tissues, the hardening of the adhesive after adhesion and the toxic degradation products can easily cause infection at the wound site, which is detrimental to tissue healing. Therefore, the development of tissue adhesives with good biocompatibility and excellent tissue adhesion is urgently needed. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a thioctic acid-based deep eutectic supramolecular polymer adhesive, its preparation method, and its application. Using thioctic acid monomer and sodium thiocate monomer as raw materials, the two powders are thoroughly mixed and ground at different mass ratios, followed by a one-step heating and melting process to obtain a thioctic acid-based hot melt adhesive. In this adhesive, the strong electron-withdrawing properties of the carboxylate structure at the end of sodium thiocate allow it to form strong hydrogen bonds with the carboxyl groups at the end of thioctic acid, thus effectively reducing the melting temperature of the mixture. By adjusting the ratio between the two, the melting temperature of the mixture can be lowered to near body temperature, thereby enabling in vivo application. This is completely different from the aqueous solution reaction described in our previous invention application, "A Sodium Polythiocate-Polythiocate Composite Adhesive Patch and its Preparation Method and Application" (Application No. 2023103748352, Application Date: April 10, 2023), and the resulting product and performance are also completely different.

[0005] The technical objective of this invention is achieved through the following technical solution.

[0006] A thioctic acid-based deep eutectic supramolecular polymer adhesive and its preparation method are disclosed. The method involves mixing and grinding thioctic acid and sodium thiocate, heating to melt, and then cooling to room temperature of 20-25 degrees Celsius to obtain the thioctic acid-based deep eutectic supramolecular polymer adhesive.

[0007] The mass ratio of lipoic acid to sodium lipoate is (0.5-3):1, preferably (0.5-2):1.

[0008] The melting temperature is 180-42 degrees Celsius, preferably 180-49 degrees Celsius.

[0009] The application of the thioctic acid-based deep eutectic supramolecular polymer adhesive of the present invention in the preparation of wound adhesion / repair materials.

[0010] During preparation, the raw materials lipoic acid and sodium lipoate, as well as the product lipoic acid-based deep eutectic supramolecular polymer adhesive, are sterilized, for example, by ethylene oxide sterilization, before in vivo use or experiments.

[0011] The supramolecular polymer adhesive of the present invention can be obtained by one-step heating of a mixture of lipoic acid and lipoate (sodium lipoate). During the heating process, multiple strong hydrogen bonds are formed between the carboxyl groups at the ends of lipoic acid and the carboxylate structures at the ends of sodium lipoate, promoting deep eutectic melting of the mixture and transforming the powder state of the mixture into a viscous liquid state. After eutectic melting, the sulfur-containing five-membered rings of lipoic acid and sodium lipoate undergo spontaneous ring-opening and copolymerization to form a supramolecular polymer. The random copolymerization between lipoic acid and sodium lipoate effectively quenches the sulfur free radicals at the ends of polylipoic acid, and the strong hydrogen bonds formed between polylipoic acid and sodium lipoate effectively reduce the potential energy of the system. Therefore, the supramolecular polymer formed by deep eutectic melting remains stable at room temperature. Based on the in-situ curing properties and the abundant adhesive carboxyl groups on the polymer backbone, this supramolecular polymer can achieve stable and high-strength adhesion to various matrices, including wet structures. Therefore, it can be used as a hot melt adhesive. Furthermore, the strong hydrogen bonding between sodium polythiooctanoate and polythioctic acid effectively reduces the dissociation rate of sodium polythiooctanoate in a humid environment. This allows the supramolecular polymer adhesive to gradually dissociate and release bioactive small molecules of sodium thiooctanoate when used in a humid environment, thereby exerting anti-inflammatory, bactericidal, and antioxidant effects and accelerating wound healing. By replacing surgical sutures with this adhesive for rapid sealing of skin wounds, its effect on accelerating wound healing was demonstrated to be superior to traditional surgical sutures.

[0012] The preparation method of this invention is simple, the materials are widely available, and it has strong practicality. The thermal ring-opening polymerization of lipoic acid is actually a deep eutectic phenomenon, which is mainly driven by multiple hydrogen bonds between the carboxyl groups at the ends of the lipoic acid monomers. Therefore, inspired by the deep eutectic mechanism, introducing stronger hydrogen bond interactions into the lipoic acid system may significantly reduce the melting temperature of the system, bringing it closer to body temperature and increasing its application in the biomedical field. Attached Figure Description

[0013] Figure 1 This is a bar chart showing the melting temperature test results of mixtures of lipoic acid and sodium lipoate in different mass ratios in this invention.

[0014] Figure 2 These are macroscopic images of a mixture of lipoic acid and sodium lipoate in different mass ratios before and after heating, as described in this invention.

[0015] Figure 3 These are infrared spectra of thioctic acid, sodium thiocate, and adhesives with different compositions in this invention, where a is the spectrum and b is a partially enlarged view of the infrared spectra of adhesives with different compositions.

[0016] Figure 4These are XRD patterns of thioctic acid monomers and polymers with different compositions in this invention, where a is the XRD curve of thioctic acid monomers and b is the XRD curve of adhesives with different compositions.

[0017] Figure 5 These are Raman spectra of thioctic acid and sodium thiocate monomers and polymers with different compositions in this invention.

[0018] Figure 6 This is a bar chart showing the tensile stress and strain results of adhesives with different compositions in this invention.

[0019] Figure 7 This is a bar chart showing the test results of the adhesion strength of different adhesive components to different substrates in this invention.

[0020] Figure 8 This is a bar chart showing the monomer release efficiency test results of LA-DESP-2 in this invention.

[0021] Figure 9 This is a bar chart showing the DPPH removal efficiency test results of the LA-DESP-2 adhesive in this invention.

[0022] Figure 10 This is a bar chart showing the test results of the bactericidal efficiency of the LA-DESP-2 adhesive in this invention against Staphylococcus aureus and Escherichia coli.

[0023] Figure 11 These are photos showing the healing effects of skin wounds treated in different ways. Detailed Implementation

[0024] The technical solution of the present invention will be further illustrated below with specific examples. However, these examples are not intended to limit the present invention.

[0025] Powder mixtures of lipoic acid and sodium lipoate in mass ratios of 0.5, 1, 1.5, 2, 2.5, and 3 were prepared, thoroughly ground, and then heated at different temperatures (42–180°C) until completely melted to obtain hot melt adhesives. In this preparation method, the mass of sodium lipoate remained constant, while varying the mass ratio of lipoic acid to sodium lipoate yielded adhesives with different proportions. The resulting adhesives were named LA-DESP-x, where x represents the mass ratio of lipoic acid to sodium lipoate. For example, LA-DESP-1.5 (or LA / LA-Na-1.5) is an adhesive obtained through deep eutectic melting when the mass ratio of lipoic acid to sodium lipoate is 1.5. The prepared lipoic acid-based deep eutectic supramolecular polymer adhesives were used for characterizing material structures, adhesion, and testing of basic in vitro and in vivo properties. In this invention, the comprehensive performance of the thioctic acid-based deep eutectic supramolecular polymer adhesive is demonstrated through the thermodynamic properties of the mixed powder and the structure, adhesion properties, biocompatibility, and in vivo application effects of the obtained adhesive.

[0026] like Figure 1 As shown, the thermodynamic properties of mixtures of lipoic acid (LA) and sodium lipoate (LA-Na) with different compositions are presented. The results show that the melting temperature of pure lipoic acid is approximately 65°C. When the carboxyl groups at the terminal of lipoic acid are deprotonated to obtain sodium lipoate, it does not exhibit melting even when heated to 200°C, indicating that the multiple hydrogen bonds between the terminal carboxyl groups of lipoic acid are crucial for achieving monomer melting. However, when lipoic acid and sodium lipoate are mixed, the melting temperature of the mixture decreases significantly with increasing lipoic acid content. When the mass ratio of lipoic acid to sodium lipoate is 0.5, the melting temperature is around 180°C. Further increasing the mass ratio of lipoic acid to 2 results in a significantly lower melting temperature of around 49°C, exhibiting a clear deep eutectic phenomenon. When the mass ratio of lipoic acid to sodium lipoate was further increased to 3, the melting temperature of the mixture decreased by about 42°C, which was significantly lower than the melting temperature of lipoic acid and sodium lipoate alone, further demonstrating that deep eutectic melting occurred between the two.

[0027] like Figure 2 As shown, macroscopic images of a mixture of lipoic acid and sodium lipoate powders in different mass ratios after a single step of heating and cooling are presented. Figure 1The melting point was tested, and a melting temperature higher than the melting point was chosen to achieve melting. As can be seen from the image, while pure lipoic acid can melt upon heating to its melting point, the molten material immediately depolymerizes upon cooling to room temperature, transforming into an opaque oligomer. Pure polylipoic acid, even when heated to 200℃, cannot melt. However, when the ratio of lipoic acid to sodium lipoate is 0.5, 1, 1.5, and 2, it remains stable after melting and cooling to room temperature, indicating that the random copolymerization between sodium lipoate and lipoic acid, and the strong hydrogen bonds between them, contribute to the stability of polylipoic acid. However, when the lipoic acid content continues to increase to 2.5 and 3, the polymer formed after melting and cooling to room temperature also depolymerizes. This is because when the lipoic acid content is too high, the sodium lipoate in the system is insufficient to stabilize all polylipoic acid components, thus causing partial depolymerization.

[0028] like Figure 3 As shown in the figure, this is the infrared spectrum of the reacting monomer and the obtained polymer. The results show that, compared with pure lipoic acid monomer, sodium lipoate exhibits a higher infrared spectrum at 1249 cm⁻¹. -1 The -OH peak disappears at 1700 cm⁻¹, and the -C=O peak in the carboxyl group drops from 1700 cm⁻¹. -1 It was moved to 1545cm -1 This indicates that the carboxyl groups on the sodium thiooctanoate structure have been completely deprotonated. Furthermore, the adhesive obtained exhibits both carboxyl groups and carboxylates in its structure, suggesting that polythioctic acid and sodium polythiooctanoate coexist in the adhesive. Figure 3 As shown in Figure a, in the adhesive, the -C=O peak of the carboxylate on the sodium polythiooctanoate backbone exhibits a significant red shift, indicating that the -C=OO peak on the sodium polythiooctanoate backbone... - Strong hydrogen bonds are formed between the structure and the -COOH groups on the polythiooctanoic acid backbone, such as Figure 3 As shown in b.

[0029] like Figure 4 The image shows the XRD patterns of lipoic acid monomers and polymers with different compositions. It can be seen from the image that the lipoic acid monomer alone is highly crystalline, as shown... Figure 4As shown in Figure a, the crystallization peaks of thioctic acid monomers completely disappeared in the structures of LA-DESP-1 and LA-DESP-1.5, indicating that polythioctic acid did not depolymerize in these two polymers. However, a small diffraction peak appeared in a smaller diffraction region, indicating that a highly ordered structure appeared in LA-DESP-1 and LA-DESP-1.5, which was caused by the regular arrangement of sodium polythiocate in the system. With further increasing the thioctic acid content, the intensity of this diffraction peak gradually decreased until it disappeared, indicating that the introduction of thioctic acid monomers could disrupt the regular arrangement of sodium polythiocate, causing it to change from an ordered crystalline structure to an amorphous structure. Further increasing the thioctic acid content revealed the appearance of thioctic acid monomer diffraction peaks in the LA-DESP-2.5 and LA-DESP-3 polymers, further demonstrating that when the thioctic acid content is too high, the formed polythioctic acid is unstable in the system and will undergo further depolymerization, such as... Figure 4 As shown in b.

[0030] like Figure 5 The image shows the Raman spectra of lipoic acid and sodium lipoate monomers, as well as polymers with different compositions. It can be seen from the image that when the mass ratio of lipoic acid to sodium lipoate is 1 and 2, the lipoic acid in the adhesive obtained has a wavelength of 511 cm⁻¹. -1 The characteristic peak at that location was split into 493 cm. -1 and 515cm -1 The two peaks at [value missing] indicate that the sulfur-containing five-membered ring underwent ring-opening and is stable after ring-opening without depolymerization. When the mass ratio of lipoic acid to sodium lipoate is 3, lipoic acid [value missing] at 511 cm⁻¹. -1 The peak at that location did not split but broadened, indicating that some of the polythioctic acid in the adhesive underwent depolymerization.

[0031] The mechanical property testing method involved cutting the prepared composite adhesive patches of different compositions into dumbbell shapes using a cutter, performing tensile tests using a tensile testing machine, and recording the tensile stress and tensile strain. The tensile speed was 50 mm / min. Detailed tensile process steps can be found in the reference Chunyan Cui, Tengling Wu, Fei Gao, Chuanchuan Fan, Ziyang Xu, Hongbo Wang, Bo Liu, Wenguang Liu*, An Autolytic High Strength Instant Adhesive Hydrogel for Emergency Self-Rescue, Advanced Functional Materials, 2018, 28, 1804925. Figure 6As shown, the tensile stress and strain results of adhesives with different compositions are presented. The results show that as the lipoic acid content increases, the tensile stress of the adhesive first decreases and then increases, while the strain shows the opposite trend of first increasing and then decreasing. This is because the internal structure of the adhesive changes from crystalline to amorphous and then back to crystalline.

[0032] The adhesion strength test method used in this experiment was the overlap shear method. The adhesive patch was cut into 10mm*10mm square samples, one side of which was adhered to a damp pigskin surface, and the other side was adhered to another piece of pigskin. After gently pressing for 10 seconds, the test was immediately conducted. During the test, the two pieces of pigskin were fixed to a tensile testing machine and stretched at a certain speed. The stretching speed was 50mm / min. Detailed stretching procedures can be found in the reference Chunyan Cui, Chuanchuan Fan, Yuanhao Wu, Meng Xiao, Tengling Wu, Dongfei Zhang, Xinyu Chen, Bo Liu, Ziyang Xu, Bo Qu, Wenguang Liu *Water-Triggered Hyperbranched Polymer Universal Adhesives: From Strong Underwater Adhesion to Rapid Sealing Hemostasis, Advanced Materials, 2019, 31, 1905761. Figure 7 As shown, the adhesion strength of adhesives with different compositions to different matrices shows that the adhesion strength of the adhesive to the solid matrix first decreases and then increases with the increase of thioctic acid content. This is consistent with the trend of the bulk strength of the adhesive. Figure 7 As shown in Figures a-e, the bulk strength of the adhesive is crucial to its adhesive properties. Since LA-DESP-2 remains stable at room temperature and its melting temperature is close to body temperature, it was selected as a tissue adhesive to test its adhesion to tissues. The results show that it can adhere to various tissues, with the highest adhesion strength reaching 55 kPa on pigskin. Figure 7 As shown in f.

[0033] Different compositions of adhesives were weighed into PBS, maintaining a material concentration of 10 mg / ml. The prepared solutions were placed in a 37°C oven, and their UV absorption was measured at different time points, within the range of 200-500 nm. The release amounts of different compositions of the materials in artificial saliva at different time points were calculated using a standard curve of sodium thiocate's UV absorption in artificial saliva. The monomer release efficiency was calculated as: monomer release amount at different time points / total monomer content in the material. Figure 8 The figure shows the monomer release efficiency of LA-DESP-2. Because sodium polythiooctanoate is water-sensitive, it spontaneously dissociates into sodium thiooctanoate monomers upon contact with water. Sodium thiooctanoate has excellent antioxidant and antibacterial effects; therefore, the effective release of sodium thiooctanoate monomers is crucial for the in vivo application of the adhesive. The sodium thiooctanoate content in saliva was measured after the adhesive was soaked in artificial saliva for different times. Figure 8 As shown, sodium thioctic acid can be continuously released in each component of the patch. The release efficiency decreases slightly with the increase of thioctic acid content, which overcomes the defect of excessively rapid release of sodium thioctic acid alone.

[0034] Based on the excellent antioxidant capacity of sodium thiocate, a small molecule, it exhibited a good effect in scavenging free radicals. The results are as follows... Figure 9 As shown, due to the efficient release of small molecules, LA-DESP-2 exhibits excellent DPPH radical scavenging effects, laying the foundation for its in vivo application. The testing procedure can be found in the published literature: Yang Liu, Xiaoping Zhang, Tengling Wu, Bo Liu, Jianhai Yang, Wenguang Liu*, Chinese herb-crosslinked hydrogel bearing rBMSCs-laden polyzwitterion microgels: Self-adaptive manipulation of micromilieu and stemness maintenance for restoring infarcted myocardium, Nano Today, 2021, 41, 101306.

[0035] Based on the excellent antibacterial properties of alpha-lipoic acid small molecules, we tested the bactericidal effect of LA-DESP-2 against Escherichia coli and Staphylococcus aureus. The results are as follows: Figure 10As the incubation time with bacteria increased, the small molecules of sodium thioctic acid in the patch were gradually released, thus exhibiting a bactericidal effect. Even after 48 hours of co-culturing with bacteria, the bactericidal rate remained above 80%. The testing process can be found in the published literature: Xinyu Bian, Chunyan Cui, Ying Qi, Yage Sun, Zhuodan Zhang, and Wenguang Liu*, Amino Acid Surfactant-Induced Superfast Gelation of Silk Fibroin for Treating Noncompressible Hemorrhage, Advanced Functional Materials, 2022, 32, 2207349.

[0036] Based on the excellent tissue adhesion and viability of LA-DESP-2, it was developed as a tissue adhesive to replace surgical sutures and accelerate skin wound healing. In a rat dorsal skin injury model, we found that using thioctic acid-based adhesives could quickly adhere to and seal the wound, accelerating wound healing, and the repair effect was superior to traditional surgical sutures. Figure 11 As shown.

[0037] By adjusting the process parameters according to the present invention, the preparation of bio-adhesives can be achieved, and tests have shown that they exhibit performance substantially consistent with that of the present invention. The present invention has been described above as exemplary. It should be noted that any simple modifications, alterations, or other equivalent substitutions that can be made by those skilled in the art without creative effort, without departing from the core of the present invention, fall within the protection scope of the present invention.

Claims

1. A thioctic acid-based deep eutectic supramolecular polymer adhesive, characterized in that, After mixing and grinding lipoic acid and sodium lipoate, heat to melt and then cool to room temperature. The mass ratio of lipoic acid to sodium lipoate is (0.5-2):1, and the melting temperature is 49-180 degrees Celsius.

2. A method for preparing a thioctic acid-based deep eutectic supramolecular polymer structure adhesive, characterized in that, After mixing and grinding lipoic acid and sodium lipoate, heat to melt and then cool to room temperature. The mass ratio of lipoic acid to sodium lipoate is (0.5-2):1, and the melting temperature is 49-180 degrees Celsius.

3. The application of the thioctic acid-based deep eutectic supramolecular polymer tissue adhesive as described in claim 1 in the preparation of wound adhesive materials.

4. The application according to claim 3, characterized in that, The raw materials lipoic acid and sodium lipoate, as well as the product lipoic acid-based deep eutectic supramolecular polymer tissue adhesive, are sterilized.

Images