A PAM-AA-NHS-based multifunctional biomimetic polymer adhesive for wound repair

Abstract

The application discloses a PAM-AA-NHS-based multifunctional biomimetic polymer adhesive for wound repair and a preparation method thereof, and belongs to the field of biomaterial preparation and biomedical application. N-hydroxysuccinimide acrylate copolymerized polyacrylamide hydrogel is used as a substrate and as a main chain network, and functionalized materials tannic acid and phenolic hydroxyl chitosan containing o-diphenol groups are introduced, so that effective adhesion can be formed at a biological tissue interface, and cross-linking can be generated with the main chain network through hydrogen bond action to form a secondary network. In addition, aldehyde group-rich oxidized dextran side chains are introduced, which can form Schiff base cross-linking with the main chain network and amino groups in the biological tissue interface to form long-acting adhesion performance. The adhesive has good tissue adhesion, biocompatibility, antibacterial activity and wound healing promotion capacity, can replace sutures, has a positive effect on the formation of new tissues and tissue healing, and is expected to be applied in clinical treatment of wound surfaces.

Description

Technical Field

[0001] This invention belongs to the field of biomaterial preparation and biomedical applications, specifically relating to a PAM-AA-NHS-based multifunctional biomimetic polymer adhesive for wound repair and its preparation method. Background Technology

[0002] With the development of modern medicine and clinical technology, the quality of wound healing has a significant impact on patients' health and quality of life. Most adult skin injuries rarely recover to their optimal function like those of infants; the injured area often forms scar tissue accompanied by severe loss of skin tissue such as hair, sweat glands, and sebaceous glands. Currently, most wound treatments involve surgical suturing, which increases patient pain and can lead to additional scar hyperplasia. Various wound dressings, such as semi-permeable membranes, semi-permeable foams, hydrogels, and hydro-glues, have been developed. These dressings possess properties that prevent fluid leakage, restore tissue structure, and reduce scar hyperplasia, and can be used to promote wound repair. Among them, hydrogels have become the most competitive candidate materials for wound dressings due to their good hydrophilicity, biocompatibility, extracellular matrix and three-dimensional (3D) porous structure. In particular, in the last decade, many hydrophilic polymers, including natural chitosan, gelatin, hyaluronic acid, alginate and dextran, as well as artificially synthesized hydrophilic polymers such as polyethylene glycol and poloxamer, polyvinyl alcohol, olefin-containing polymer monomers such as polyacrylamide (PAM), polyacrylic acid and peptides, have been used to construct hydrogels through various chemical or physical crosslinking. However, current hydrogels have certain limitations in application, such as slow gelation speed, high cytotoxicity, poor tissue sealing, and the need for external equipment assistance (e.g., gelation by ultraviolet light or mixing of materials by fluid mixers). For example, a dopamine-grafted hyaluronic acid functionalized hydrogel that uses hydrogen peroxide / horseradish peroxidase polymerization and internally doped with reduced graphene oxide has extremely strong underwater adhesion. However, the cross-linking of these hydrogels requires strong oxidants such as sodium periodate and chelating agents such as ferric chloride, which makes the hydrogels potentially toxic and pose safety hazards.

[0003] In recent years, scientists have been dedicated to designing hydrogel materials with superior performance for widespread application in many fields. Inspired by nature, bioactive substances from marine mussels, including phenolic hydroxy chitosan, dopamine, tannic acid, gallic acid, and phenolic hydroxylated alanine, have been used as raw materials for many biomimetic hydrogels. These materials exhibit excellent biocompatibility and low cytotoxicity. For example, CN113975454A discloses a hemostatic material composed of inorganic mesoporous silica, adhesive tannic acid, and organic polyacrylamide. The swelling rate, mechanical properties, antibacterial properties, and hemostatic properties of the hemostatic material are optimized by adjusting the proportions of each component. However, an excessively high swelling rate can reduce the material's adhesive properties, preventing it from remaining at the wound site for an extended period, thus complicating subsequent treatment. Another example is CN114887110A, which discloses a material composed of two components (the first component consists of chitosan and grafted...). N- The first component is a polyacrylic acid-based hydroxysuccinimide ester; the second component consists of a non-aldehyde polysaccharide, a dialdehyde polysaccharide, and a cationic salt solution. Based on Schiff base reaction, it forms a hemostatic patch, dressing, or sponge with rapid hemostasis and adhesion through in-situ cross-linking. However, in-situ hydrogel formation has certain limitations, such as instability and easy liquid loss. For example, CN111748120A discloses a polydopamine-doped dextran hydrogel porous scaffold, its preparation method, and its application for in vitro 3D cell culture and wound repair. The dextran used in this invention is a highly water-soluble natural polysaccharide secreted by bacteria, possessing good biocompatibility and degradability. However, this invention uses sodium hydroxide solution to dissolve the dextran; the alkaline solution can irritate the skin and affect the healing of bleeding sites. CN112210091A discloses a method using natural polysaccharides as raw materials, modifying them with catechol functional groups to enhance their tissue adhesion, and adding magnesium oxide nanoparticles to shorten the gelation time and enhance the antibacterial effect. This invention modifies polysaccharides with catechol and aldehyde to enhance the water solubility of chitosan, reduce the viscosity of dextran solutions, shorten the gelation time of two-component gels, and improve tissue adhesion. However, the hydrogel has excessively high tissue viscosity, which can cause secondary damage to the wound when changing dressings.

[0004] Therefore, this invention provides a series of multifunctional biomimetic polymeric adhesives for wound repair (PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C) prepared by introducing TA, ODex, and CHI-C respectively, using AA-NHS and PAM as substrates. These PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C composite materials not only possess highly efficient in vivo hemostasis and good mechanical properties, effectively sealing wounds, but also exhibit excellent antibacterial properties and good biocompatibility, achieving both in vivo antibacterial activity and long-lasting adhesion at the wound site. Furthermore, results from a mouse full-thickness skin defect model demonstrate that this series of multifunctional biomimetic polymeric adhesives for wound repair can repair wounds and reduce scar hyperplasia. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention aims to provide a PAM-AA-NHS-based multifunctional biomimetic polymeric adhesive for wound repair and its preparation method. By mimicking the adhesion mechanism of mussels, a marine organism, and through a sophisticated design that induces non-covalent / covalent bonds in skin tissue, functionalized materials containing different tissue-reactive functional groups are introduced. This endows the series of biomimetic polymeric adhesives with excellent tissue adhesion, superior mechanical properties, antibacterial activity, and hemostatic properties. It is expected to become a novel biomedical adhesive that promotes the clinical application of wound repair.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for preparing a PAM-AA-NHS-based multifunctional biomimetic polymeric adhesive for wound repair includes the following steps:

[0008] (1) Mix acrylamide (AAm) and N AA-NHS ester powder was dissolved in deionized water and stirred at room temperature to obtain solution S1;

[0009] (2) Dissolve tannic acid (TA) in deionized water and stir at room temperature to obtain solution S2;

[0010] (3) Dissolve oxidized dextran (ODex) in deionized water and stir at room temperature to obtain solution S3;

[0011] (4) Dissolve phenolic hydroxy chitosan (CHI-C) in phosphate buffer solution and stir at room temperature to obtain solution S4;

[0012] (5) N,N - Methylenebisacrylamide (BIS) was dissolved in deionized water and stirred at room temperature to obtain solution S5;

[0013] (6) N,N,N',N' -Tetramethylethylenediamine (TEMED) was dissolved in deionized water and stirred at room temperature to obtain solution S6;

[0014] (7) Dissolve ammonium persulfate (APS) in deionized water and stir at room temperature to obtain solution S7;

[0015] (8) Mix solutions S2, S3 and S4 with solution S1 to obtain solutions S8, S9 and S10;

[0016] (9) Add solutions S5, S6, and S7 to solution S8 in sequence and mix thoroughly at room temperature; add solutions S5, S6, and S7 to solution S9 in sequence and mix thoroughly at room temperature; add solutions S5, S6, and S7 to solution S10 in sequence and mix thoroughly at room temperature; thus obtaining a series of PAM-AA-NHS-based multifunctional biomimetic polymer adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0017] Preferably, in the solution S1 of step (1), the mass fraction of AAM is 1.0~50.0 wt%, the mass fraction of AA-NHS ester is 0.1~10.0 wt%, the stirring temperature is 5~80 ℃, and the stirring time is 2~72 h.

[0018] Preferably, in the solution S2 of step (2), the mass fraction of TA is 0.2~20.0 wt%, the stirring temperature is 10~40℃, and the stirring time is 1~120 min.

[0019] Preferably, in the solution S3 of step (3), the mass fraction of ODex is 0.2~30.0 wt%, the stirring temperature is 10~50 ℃, and the stirring time is 2~120 min.

[0020] Preferably, in the solution S4 of step (4), the mass fraction of CHI-C is 0.1~30.0 wt%, the stirring temperature is 10~60 ℃, and the stirring time is 1~180 min.

[0021] Preferably, in solution S5 of step (5), the concentration of BIS is 0.001~0.1 g / mL; the stirring temperature is 5~45 ℃; and the stirring time is 2~150 min.

[0022] Preferably, in solution S6 of step (6), the concentration of TEMED is 0.001~1 g / mL; the stirring temperature is 5~45 ℃; and the stirring time is 2~150 min.

[0023] Preferably, in the solution S7 of step (7), the concentration of APS is 0.002~1 g / mL; the stirring temperature is 5~45℃; and the stirring time is 2~150 min.

[0024] Preferably, in step (8), the mass ratio of solution S1 to S2 in solution S8 is 100:1 to 1:100; in solution S9, the mass ratio of solution S1 to S3 is 100:1 to 1:100; in solution S10, the mass ratio of solution S1 to S4 is 100:1 to 1:100; the stirring temperature is 5 to 55 ℃ and the stirring time is 2 to 180 min.

[0025] Preferably, in step (9), the mass ratio of solution S5:S6:S7:S8 is 1:1:1:10~1:1:1:1000; the mass ratio of solution S5:S6:S7:S9 is 1:1:1:10~1:1:1:1000; the mass ratio of solution S5:S6:S7:S10 is 1:1:1:10~1:1:1:1000; the stirring temperature is 5~55 ℃ and the stirring time is 1~150 min.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] (1) The series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention exhibit strong adhesion to biological tissue interfaces. This invention uses a hydrogel formed by free radical polymerization of PAM and AA-NHS as a base and as the main chain network. Furthermore, functionalized materials TA and CHI-C containing catechol groups are introduced, which crosslink with the main chain network through hydrogen bonding to form a secondary network. These two adhesives mimic the adhesion mechanism of marine mussels, achieving effective adhesion at biological tissue interfaces. The introduced ODex side chains are rich in aldehyde groups, which can form a non-covalent crosslinked network with the amino groups on the PAM side chains via Schiff base bonding, and can also form Schiff base bonding with the amino groups on skin tissue, achieving adhesion at biological tissue interfaces. Moreover, based on the mechanism that the NHS ester groups in the adhesive can covalently couple with the primary amine groups on skin tissue within minutes, this series of multifunctional biomimetic polymeric adhesives for wound repair can achieve long-term stable adhesion within biological tissues.

[0028] (2) The series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention have high hemostatic efficiency. Due to their continuous, complete, and uniform porous structure, the series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention can rapidly absorb water from the blood, capture and activate red blood cells and platelets; their good tissue-sealing adhesion and stable mechanical properties endow the adhesives with the ability to quickly adhere to and close wounds. At the same time, the inherent hemostatic properties of the adhesives can stimulate the coagulation mechanism, thereby achieving efficient hemostasis at the wound site. In vitro and in vivo experiments have confirmed that the series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention have high and rapid hemostatic efficiency.

[0029] (3) The series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention have excellent antibacterial properties. These adhesives can interact with bacterial cell membranes and cell walls, affecting the expression of functional proteins in bacteria, hindering cell signal transduction, and inhibiting the biosynthesis of cellular components, thus exhibiting good antibacterial activity against microorganisms. Furthermore, these adhesives can also adhere to the phosphate groups of cell membrane phospholipids through electrostatic interactions, influencing the denaturation of microbial proteins and the replication of DNA, thereby inhibiting surrounding bacteria and achieving an antibacterial effect.

[0030] (4) The series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention can promote wound healing. While rapidly stopping bleeding, the series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention can form a physical barrier membrane to protect the wound through good adhesion and sealing between the adhesive and tissue. Simultaneously, due to the excellent antioxidant properties of the catechol groups, they can capture reactive oxygen species, playing a protective role in reducing oxidative stress during the wound healing stage, thereby contributing to the formation of epithelial tissue. Furthermore, the synergistic effect of the antibacterial activity and hemostatic ability of this series of multifunctional biomimetic polymeric adhesives for wound repair can protect the wound from bacterial infection and promote fibroblast migration and vascular remodeling.

[0031] In summary, the series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention possess excellent tissue adhesion, biocompatibility, antibacterial activity, and wound healing promotion capabilities. These multifunctional biomimetic polymeric adhesives combine adhesion, closure, hemostasis, antibacterial, and repair-promoting functions, rapidly repairing tissue and reducing scar hyperplasia after timely hemostasis, while maintaining antibacterial activity during the recovery of the main wound to its original skin state. This new generation of multifunctional biomimetic polymeric adhesives for wound repair, which can replace sutures, technically solves the problems of wound tearing and bleeding, as well as scar hyperplasia, caused by improper postoperative care. It plays a positive role in the formation of new tissue and tissue healing, and is expected to be applied in the clinical treatment of wounds. Attached Figure Description

[0032] Figure 1 Structural characterization of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 and Comparative Example 1. A. UV-Vis absorption spectra of ODex and Dex. B. Fourier transform infrared (FTIR) spectra of ODex and Dex. C. UV-Vis absorption spectra of CHI-C and CHI. D. Fourier transform infrared (FTIR) spectra of CHI-C and CHI. E. Fourier transform infrared (FTIR) spectra of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive.

[0033] Figure 2 Morphology and contact angle characterization of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1. A. Scanning electron microscope image of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive. B. Pore size distribution of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive. C. Contact angle of the surface of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive.

[0034] Figure 3 Quantitative analysis of the mechanical properties of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1. A. Tensile stress-strain curve of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive. B. Tensile strength of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive. C. Tensile Young's modulus of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive. D. Compressive stress-strain curve of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive. E. Compressive strength of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive. F. Compressive Young's modulus of the functionalized PAM-AA-NHS-based biomimetic polymer adhesive.

[0035] Figure 4The adhesion strength of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1 to wet pigskin.

[0036] Figure 5 The antibacterial activity of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 and Comparative Example 1 is shown in the figures. A. Plate count diagrams of Escherichia coli and Staphylococcus aureus co-cultured with the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive. B. Inhibition rate of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive against Escherichia coli. C. Inhibition rate of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive against Staphylococcus aureus.

[0037] Figure 6 Biocompatibility and coagulation dynamics characterization of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 and Comparative Example 1. A. Live / dead staining images of NIH / 3T3 cells co-cultured with the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive for 1, 3, and 7 days. B. Coagulation dynamics evaluation of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive at 37 °C. C. Cell proliferation capacity of NIH / 3T3 cells co-cultured with the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive for 1, 3, and 7 days.

[0038] Figure 7 Characterization of the hemostatic properties of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 and Comparative Example 1 in mice. A. Treatment of mouse liver and heart hemorrhage models using the blank group, gauze group, and functionalized PAM-AA-NHS-based biomimetic polymeric adhesive (dashed lines represent bleeding area, arrows represent treatment materials). B. Schematic diagrams of mouse liver and heart hemorrhage models. C. Blood loss in mouse liver hemorrhage treated with functionalized PAM-AA-NHS-based biomimetic polymeric adhesive. D. Blood loss in mouse heart hemorrhage model treated with functionalized PAM-AA-NHS-based biomimetic polymeric adhesive.

[0039] Figure 8 Evaluation of the therapeutic effect of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive prepared in Example 7 and Comparative Example 1 on full-thickness skin wound defects in mice. A. Schematic diagram of full-thickness wound defect modeling in mice. B. The therapeutic effect of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive at different time points. C. Simulated wound healing area treated with the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive. D. The mechanism of wound healing treated with the functionalized PAM-AA-NHS-based biomimetic polymeric adhesive. Detailed Implementation

[0040] To make the content of this invention easier to understand, the technical solution of this invention will be further described below with reference to specific embodiments, but this invention is not limited thereto.

[0041] This invention discloses a series of PAM-AA-NHS-based multifunctional biomimetic polymer adhesives for wound repair, comprising the following steps:

[0042] (1) Mix acrylamide (AAm) and N AA-NHS ester powder was dissolved in deionized water and stirred at room temperature to obtain solution S1;

[0043] (2) Dissolve tannic acid (TA) in deionized water and stir at room temperature to obtain solution S2;

[0044] (3) Dissolve oxidized dextran (ODex) in deionized water and stir at room temperature to obtain solution S3;

[0045] (4) Dissolve phenolic hydroxy chitosan (CHI-C) in phosphate buffer solution and stir at room temperature to obtain solution S4;

[0046] (5) N,N - Methylenebisacrylamide (BIS) was dissolved in deionized water and stirred at room temperature to obtain solution S5;

[0047] (6) N,N,N',N' -Tetramethylethylenediamine (TEMED) was dissolved in deionized water and stirred at room temperature to obtain solution S6;

[0048] (7) Dissolve ammonium persulfate (APS) in deionized water and stir at room temperature to obtain solution S7;

[0049] (8) Mix solutions S2, S3 and S4 with solution S1 to obtain solutions S8, S9 and S10;

[0050] (9) Add solutions S5, S6, and S7 to solution S8 in sequence and mix thoroughly at room temperature; add solutions S5, S6, and S7 to solution S9 in sequence and mix thoroughly at room temperature; add solutions S5, S6, and S7 to solution S10 in sequence and mix thoroughly at room temperature; thus obtaining a series of PAM-AA-NHS-based multifunctional biomimetic polymer adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0051] In this invention, deionized water is first added to AAm and AA-NHS ester powder, and stirred at room temperature to form an aqueous solution S1. More preferably, the concentration of AAm is 1.0~50.0 wt%, the concentration of AA-NHS ester is 0.1~10.0 wt%, the stirring temperature is 5~80 ℃, and the stirring time is 2~72 h.

[0052] TA is dissolved by stirring at room temperature to form solution S2. More preferably, the mass fraction of the TA solution is 0.2~20.0 wt%, the stirring temperature is 10~40 °C, and the stirring time is 1~120 min. ODex is dissolved by stirring in PBS at pH 7.4 at room temperature to form solution S3. More preferably, the mass fraction of ODex is 0.2~30.0 wt%, the stirring temperature is 10~50 °C, and the stirring time is 2~120 min. CHI-C is dissolved in PBS at pH 7.4 to form solution S4. More preferably, the mass fraction of CHI-C is 0.1~30.0 wt%, the stirring temperature is 10~60 °C, and the stirring time is 1~180 min.

[0053] BIS, TEMED, and APS were dissolved in deionized water and stirred to obtain solutions S5, S6, and S7. More preferably, the concentration of BIS was 0.001~0.1 g / mL; the concentration of TEMED was 0.001~1 g / mL; and the concentration of APS was 0.002~1 g / mL. The stirring temperature was 5~45 ℃ and the stirring time was 2~150 min.

[0054] Solutions S2, S3, and S4 are mixed evenly with solution S1 to obtain solutions S8, S9, and S10. More preferably, in solution S8, the mass ratio of solution S1 to S2 is 100:1 to 1:100; in solution S9, the mass ratio of solution S1 to S3 is 100:1 to 1:100; and in solution S10, the mass ratio of solution S1 to S4 is 100:1 to 1:100. The stirring temperature is 5 to 55 °C, and the stirring time is 2 to 180 min. Finally, solutions S5, S6, and S7 are added to solution S8 in sequence and mixed evenly at room temperature; solutions S5, S6, and S7 are added to solution S9 in sequence and mixed evenly at room temperature; and solutions S5, S6, and S7 are added to solution S10 in sequence and mixed thoroughly to form three different types of biomimetic polymer composite materials with hemostatic, antibacterial, and wound repair properties. More preferably, the mass ratio of solutions S5:S6:S7:S8 is 1:1:1:10~1:1:1:1000; the mass ratio of solutions S5:S6:S7:S9 is 1:1:1:10~1:1:1:1000; the mass ratio of solutions S5:S6:S7:S10 is 1:1:1:10~1:1:1:1000; the stirring temperature is 5~55 ℃ and the stirring time is 1~150 min.

[0055] Table 1 shows a series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair, their preparation methods, the experimental reagents used, and their manufacturers.

[0056]

[0057] Example 1

[0058] Dextran (100 kDa, 10 g, 61.60 mmol glucose monomer) was dissolved in 400.0 mL of deionized water. Then, 13.19 g of sodium periodate (61.60 mmol) was dissolved in 100.0 mL of deionized water and added to the dextran solution. The mixture was stirred at room temperature in the dark for 24 h. The reaction was quenched with an equimolar amount of diethylene glycol and stirred for 2 h. The resulting mixture was then dialyzed against pure water for more than 3 days using a dialysis membrane. The dextran solution was removed from the dialysis bag and freeze-dried to form a white ODex powder.

[0059] Chitosan (1.0 g, 11.81 mmol) was dissolved in 10.0 mL of 1 mol / L HCl solution, then 90.0 mL of deionized water was added. The pH of the solution was then adjusted using 5 mol / L NaOH solvent until it reached pH = 5.0. Dihydrocaffeic acid (HCA, 1.184 g, 6.49 mmol) was dissolved in 10.0 mL of deionized water. 1 -Ethyl-3 -( 3 (-Dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 1.2805 mg, 6.50 mmol) was dissolved in 200.0 mL of a mixed solution (water:ethanol = 1:1). V / V The solution was added dropwise to the prepared chitosan solution and stirred continuously at room temperature for 12 h, during which the pH was monitored and maintained at pH = 5. Then, the solution after 12 h of stirring was dialyzed using a dialysis membrane (cutoff molecular weight 3500). The reactant solution was purified by dialyzing in acidified secondary water (pH 5.0, HCl) for 2 days, in phosphate buffered saline (PBS, pH 7.4) for 4 h, and in secondary water for 4 h. Finally, the product was freeze-dried in a vacuum freeze dryer to obtain CHI-C, and the freeze-dried product was stored at 4 °C.

[0060] 100 mL of deionized water was added to 10.0 g of AAm and 2.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all powders were dissolved. Then, TA, ODex, and CHI-C were dissolved in water and PBS at pH 7.4, respectively, until completely dissolved to form 2.0 wt% TA, ODex, and CHI-C solutions. After the AAm and AA-NHS ester powders were completely dissolved, 50 mL of the mixed solution was taken, and 2.0 wt% TA, ODex, and CHI-C solutions were added, while stirring continuously. Subsequently, BIS, TEMED, and APS were added sequentially during stirring to form a series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0061] Example 2

[0062] Dextran (100 kDa, 10 g, 61.60 mmol glucose monomer) was dissolved in 400.0 mL of deionized water. Then, 13.19 g of sodium periodate (61.60 mmol) was dissolved in 100.0 mL of deionized water and added to the dextran solution. The mixture was stirred at room temperature in the dark for 24 h. The reaction was quenched with an equimolar amount of diethylene glycol and stirred for 2 h. The resulting mixture was then dialyzed against pure water for more than 3 days using a dialysis membrane. The dextran solution was removed from the dialysis bag and freeze-dried to form a white ODex powder.

[0063] Chitosan (1.0 g, 11.81 mmol) was dissolved in 10.0 mL of 1 mol / L HCl solution, then 90.0 mL of deionized water was added. The pH of the solution was then adjusted using 5 mol / L NaOH solvent until it reached pH = 5.0. Dihydrocaffeic acid (HCA, 1.184 g, 6.49 mmol) was dissolved in 10.0 mL of deionized water. 1 -Ethyl- 3 -( 3 (-Dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 1.2805 mg, 6.50 mmol) was dissolved in 200.0 mL of a mixed solution (water:ethanol = 1:1). V / V The solution was added dropwise to the prepared chitosan solution and stirred continuously at room temperature for 12 h, during which the pH was monitored and maintained at pH = 5. Then, the solution after 12 h of stirring was dialyzed using a dialysis membrane (cutoff molecular weight 3500). The reactant solution was purified by dialyzing in acidified secondary water (pH 5.0, HCl) for 2 days, in phosphate buffered saline (PBS, pH 7.4) for 4 h, and in secondary water for 4 h. Finally, the product was freeze-dried in a vacuum freeze dryer to obtain CHI-C, and the freeze-dried product was stored at 4 °C.

[0064] 100 mL of deionized water was added to 20.0 g of AAm and 2.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all powders were dissolved. Then, TA, ODex, and CHI-C were dissolved in water and PBS at pH 7.4, respectively, until completely dissolved to form 2.0 wt% TA, ODex, and CHI-C solutions. After the AAm and AA-NHS ester powders were completely dissolved, 50 mL of the mixed solution was taken, and 2.0 wt% TA, ODex, and CHI-C solutions were added, while stirring continuously. Subsequently, BIS, TEMED, and APS were added sequentially during stirring to form a series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0065] Example 3

[0066] Dextran (100 kDa, 10 g, 61.60 mmol glucose monomer) was dissolved in 400.0 mL of deionized water. Then, 13.19 g of sodium periodate (61.60 mmol) was dissolved in 100.0 mL of deionized water and added to the dextran solution. The mixture was stirred at room temperature in the dark for 24 h. The reaction was quenched with an equimolar amount of diethylene glycol and stirred for 2 h. The resulting mixture was then dialyzed against pure water for more than 3 days using a dialysis membrane. The dextran solution was removed from the dialysis bag and freeze-dried to form a white ODex powder.

[0067] Chitosan (1.0 g, 11.81 mmol) was dissolved in 10.0 mL of 1 mol / L HCl solution, then 90.0 mL of deionized water was added. The pH of the solution was then adjusted using 5 mol / L NaOH solvent until it reached pH = 5.0. Dihydrocaffeic acid (HCA, 1.184 g, 6.49 mmol) was dissolved in 10.0 mL of deionized water. 1 -Ethyl- 3 -( 3 (-Dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 1.2805 mg, 6.50 mmol) was dissolved in 200.0 mL of a mixed solution (water:ethanol = 1:1). V / V The solution was added dropwise to the prepared chitosan solution and stirred continuously at room temperature for 12 h, during which the pH was monitored and maintained at pH = 5. Then, the solution after 12 h of stirring was dialyzed using a dialysis membrane (cutoff molecular weight 3500). The reactant solution was purified by dialyzing in acidified secondary water (pH 5.0, HCl) for 2 days, in phosphate buffered saline (PBS, pH 7.4) for 4 h, and in secondary water for 4 h. Finally, the product was freeze-dried in a vacuum freeze dryer to obtain CHI-C, and the freeze-dried product was stored at 4 °C.

[0068] 100 mL of deionized water was added to 30.0 g of AAm and 2.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all powders were dissolved. Then, TA, ODex, and CHI-C were dissolved in water and PBS at pH 7.4, respectively, until completely dissolved to form 2.0 wt% TA, ODex, and CHI-C solutions. After the AAm and AA-NHS ester powders were completely dissolved, 50 mL of the mixed solution was taken, and 2.0 wt% TA, ODex, and CHI-C solutions were added, while stirring continuously. Subsequently, BIS, TEMED, and APS were added sequentially during stirring to form a series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0069] Example 4

[0070] Dextran (100 kDa, 10 g, 61.60 mmol glucose monomer) was dissolved in 400.0 mL of deionized water. Then, 13.19 g of sodium periodate (61.60 mmol) was dissolved in 100.0 mL of deionized water and added to the dextran solution. The mixture was stirred at room temperature in the dark for 24 h. The reaction was quenched with an equimolar amount of diethylene glycol and stirred for 2 h. The resulting mixture was then dialyzed against pure water for more than 3 days using a dialysis membrane. The dextran solution was removed from the dialysis bag and freeze-dried to form a white ODex powder.

[0071] Chitosan (1.0 g, 11.81 mmol) was dissolved in 10.0 mL of 1 mol / L HCl solution, then 90.0 mL of deionized water was added. The pH of the solution was then adjusted using 5 mol / L NaOH solvent until it reached pH = 5.0. Dihydrocaffeic acid (HCA, 1.184 g, 6.49 mmol) was dissolved in 10.0 mL of deionized water. 1 -Ethyl- 3 -( 3 (-Dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 1.2805 mg, 6.50 mmol) was dissolved in 200.0 mL of a mixed solution (water:ethanol = 1:1). V / VThe solution was added dropwise to the prepared chitosan solution and stirred continuously at room temperature for 12 h, during which the pH was monitored and maintained at pH = 5. Then, the solution after 12 h of stirring was dialyzed using a dialysis membrane (cutoff molecular weight 3500). The reactant solution was purified by dialyzing in acidified secondary water (pH 5.0, HCl) for 2 days, in phosphate buffered saline (PBS, pH 7.4) for 4 h, and in secondary water for 4 h. Finally, the product was freeze-dried in a vacuum freeze dryer to obtain CHI-C, and the freeze-dried product was stored at 4 °C.

[0072] 100 mL of deionized water was added to 20.0 g of AAm and 3.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all powders were dissolved. Then, TA, ODex, and CHI-C were dissolved in water and PBS at pH 7.4, respectively, until completely dissolved to form 2.0 wt% TA, ODex, and CHI-C solutions. After the AAm and AA-NHS ester powders were completely dissolved, 50 mL of the mixed solution was taken, and 2.0 wt% TA, ODex, and CHI-C solutions were added, while stirring continuously. Subsequently, BIS, TEMED, and APS were added sequentially during stirring to form a series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0073] Example 5

[0074] Dextran (100 kDa, 10 g, 61.60 mmol glucose monomer) was dissolved in 400.0 mL of deionized water. Then, 13.19 g of sodium periodate (61.60 mmol) was dissolved in 100.0 mL of deionized water and added to the dextran solution. The mixture was stirred at room temperature in the dark for 24 h. The reaction was quenched with an equimolar amount of diethylene glycol and stirred for 2 h. The resulting mixture was then dialyzed against pure water for more than 3 days using a dialysis membrane. The dextran solution was removed from the dialysis bag and freeze-dried to form a white ODex powder.

[0075] Chitosan (1.0 g, 11.81 mmol) was dissolved in 10.0 mL of 1 mol / L HCl solution, and then 90.0 mL of deionized water was added. The pH of the solution was then adjusted using 5 mol / L NaOH solvent until it reached pH = 5.0. Dihydrocaffeic acid (HCA, 1.184 g, 6.49 mmol) was then dissolved in 10.0 mL of deionized water. 1 -Ethyl- 3 -(3 (-Dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 1.2805 mg, 6.50 mmol) was dissolved in 200.0 mL of a mixed solution (water:ethanol = 1:1). V / V The solution was added dropwise to the prepared chitosan solution and stirred continuously at room temperature for 12 h, during which the pH was monitored and maintained at pH = 5. Then, the solution after 12 h of stirring was dialyzed using a dialysis membrane (cutoff molecular weight 3500). The reactant solution was purified by dialyzing in acidified secondary water (pH 5.0, HCl) for 2 days, in phosphate buffered saline (PBS, pH 7.4) for 4 h, and in secondary water for 4 h. Finally, the product was freeze-dried in a vacuum freeze dryer to obtain CHI-C, and the freeze-dried product was stored at 4 °C.

[0076] 100 mL of deionized water was added to 30.0 g of AAm and 3.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all powders were dissolved. Then, TA, ODex, and CHI-C were dissolved in water and PBS at pH 7.4, respectively, until completely dissolved to form 2.0 wt% TA, ODex, and CHI-C solutions. After the AAm and AA-NHS ester powders were completely dissolved, 50 mL of the mixed solution was taken, and 2.0 wt% TA, ODex, and CHI-C solutions were added, while stirring continuously. Subsequently, BIS, TEMED, and APS were added sequentially during stirring to form a series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0077] Example 6

[0078] Dextran (100 kDa, 10 g, 61.60 mmol glucose monomer) was dissolved in 400.0 mL of deionized water. Then, 13.19 g of sodium periodate (61.60 mmol) was dissolved in 100.0 mL of deionized water and added to the dextran solution. The mixture was stirred at room temperature in the dark for 24 h. The reaction was quenched with an equimolar amount of diethylene glycol and stirred for 2 h. The resulting mixture was then dialyzed against pure water for more than 3 days using a dialysis membrane. The dextran solution was removed from the dialysis bag and freeze-dried to form a white ODex powder.

[0079] Chitosan (1.0 g, 11.81 mmol) was dissolved in 10.0 mL of 1 mol / L HCl solution, then 90.0 mL of deionized water was added. The pH of the solution was then adjusted using 5 mol / L NaOH solvent until it reached pH = 5.0. Dihydrocaffeic acid (HCA, 1.184 g, 6.49 mmol) was dissolved in 10.0 mL of deionized water. 1 -Ethyl- 3 -( 3 (-Dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 1.2805 mg, 6.50 mmol) was dissolved in 200.0 mL of a mixed solution (water:ethanol = 1:1). V / V The solution was added dropwise to the prepared chitosan solution and stirred continuously at room temperature for 12 h, during which the pH was monitored and maintained at pH = 5. Then, the solution after 12 h of stirring was dialyzed using a dialysis membrane (cutoff molecular weight 3500). The reactant solution was purified by dialyzing in acidified secondary water (pH 5.0, HCl) for 2 days, in phosphate buffered saline (PBS, pH 7.4) for 4 h, and in secondary water for 4 h. Finally, the product was freeze-dried in a vacuum freeze dryer to obtain CHI-C, and the freeze-dried product was stored at 4 °C.

[0080] 100 mL of deionized water was added to 20.0 g of AAm and 3.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all powders were dissolved. Then, TA, ODex, and CHI-C were dissolved in water and PBS at pH 7.4, respectively, until completely dissolved to form 3.0 wt% TA, ODex, and CHI-C solutions. After the AAm and AA-NHS ester powders were completely dissolved, 50 mL of the mixed solution was taken, and 3.0 wt% TA, ODex, and CHI-C solutions were added, while stirring continuously. Subsequently, BIS, TEMED, and APS were added sequentially during stirring to form a series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0081] Example 7

[0082] Dextran (100 kDa, 10 g, 61.60 mmol glucose monomer) was dissolved in 400.0 mL of deionized water. Then, 13.19 g of sodium periodate (61.60 mmol) was dissolved in 100.0 mL of deionized water and added to the dextran solution. The mixture was stirred at room temperature in the dark for 24 h. The reaction was quenched with an equimolar amount of diethylene glycol and stirred for 2 h. The resulting mixture was then dialyzed against pure water for more than 3 days using a dialysis membrane. The dextran solution was removed from the dialysis bag and freeze-dried to form a white ODex powder.

[0083] Chitosan (1.0 g, 11.81 mmol) was dissolved in 10.0 mL of 1 mol / L HCl solution, then 90.0 mL of deionized water was added. The pH of the solution was then adjusted using 5 mol / L NaOH solvent until it reached pH = 5.0. Dihydrocaffeic acid (HCA, 1.184 g, 6.49 mmol) was dissolved in 10.0 mL of deionized water. 1 -Ethyl- 3 -( 3 (-Dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 1.2805 mg, 6.50 mmol) was dissolved in 200.0 mL of a mixed solution (water:ethanol = 1:1). V / V The solution was added dropwise to the prepared chitosan solution and stirred continuously at room temperature for 12 h, during which the pH was monitored and maintained at pH = 5. Then, the solution after 12 h of stirring was dialyzed using a dialysis membrane (cutoff molecular weight 3500). The reactant solution was purified by dialyzing in acidified secondary water (pH 5.0, HCl) for 2 days, in phosphate buffered saline (PBS, pH 7.4) for 4 h, and in secondary water for 4 h. Finally, the product was freeze-dried in a vacuum freeze dryer to obtain CHI-C, and the freeze-dried product was stored at 4 °C.

[0084] 100 mL of deionized water was added to 30.0 g of AAm and 3.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all powders were dissolved. Then, TA, ODex, and CHI-C were dissolved in water and PBS at pH 7.4, respectively, until completely dissolved to form 3.0 wt% TA, ODex, and CHI-C solutions. After the AAm and AA-NHS ester powders were completely dissolved, 50 mL of the mixed solution was taken, and 3.0 wt% TA, ODex, and CHI-C solutions were added, while stirring continuously. Subsequently, BIS, TEMED, and APS were added sequentially during stirring to form a series of PAM-AA-NHS-based multifunctional biomimetic polymeric adhesives for wound repair, namely PAM-AA-NHS / TA, PAM-AA-NHS / ODex, and PAM-AA-NHS / CHI-C.

[0085] Comparative Example 1

[0086] 100 mL of deionized water was added to 30.0 g of AAm and 3.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all the powders were dissolved to obtain mixed solution A. Then, 60 mL of mixed solution A was taken, and BIS, TEMED and APS were added in sequence to form PAM-AA-NHS hydrogel.

[0087] Comparative Example 2

[0088] 100 mL of deionized water was added to 30.0 g of AAm and 3.0 g of AA-NHS ester powder to form an aqueous solution. The solution was stirred for at least 12 h until all the powders were dissolved to obtain mixed solution A. Then, 70 mL of mixed solution A was taken, and BIS, TEMED and APS were added in sequence to form PAM-AA-NHS hydrogel.

[0089] The structural characterization of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1 is as follows: Figure 1 As shown, the introduction of functionalized materials mainly involves physical crosslinking through intermolecular forces during the crosslinking process with the substrate adhesive, without any chemical reaction.

[0090] The morphology and contact angle characterization of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1 are as follows: Figure 2As shown, the average pore size of the PAM-AA-NHS polymeric adhesive prepared in Comparative Example 1 was 50.84 ± 31.46 µm, while the average pore sizes of the series of functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 were 68.06 ± 22.43, 52.03 ± 14.77, and 55.59 ± 15.48 µm, respectively. The series of functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared by introducing functionalized materials exhibited a more uniform and continuous pore size distribution and a smaller gap range.

[0091] The quantitative analysis of the mechanical properties of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1 are shown in the figure below. Figure 3 As shown. The PAM-AA-NHS / CHI-C in the series of functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 exhibited the best tensile (55.64 ± 3.71 kPa) and compressive (525.07 ± 13.80 kPa) mechanical strengths. The tensile and compressive strengths of the PAM-AA-NHS polymer adhesive prepared in Comparative Example 1 were 32.97 ± 1.20 kPa and 172.56 ± 3.12 kPa, respectively. The introduction of semi-rigid CHI-C material can form hydrogen bonds and amide bonds with the main chain network. The presence of multiple cross-linking mechanisms increases the degree of cross-linking of the internal network, which is beneficial to improving the mechanical properties of the adhesive and helps to resist external forces and prevent secondary damage to skin tissue.

[0092] The adhesion strength of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1 to wet pigskin is as follows: Figure 4 As shown. The adhesion strength of the PAM-AA-NHS polymeric adhesive prepared in Comparative Example 1 was 4.77 ± 0.84 kPa. The average pore sizes of the series of functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 were 11.87 ± 2.77 kPa, 5.19 ± 0.95 kPa, and 8.26 ± 1.03 kPa, respectively. The two groups of adhesives with biomimetic mussel adhesion protein derivative functionalized materials exhibited higher adhesion strength, indicating that the series of multifunctional biomimetic polymeric adhesives for wound repair provided by this invention have the ability to be used as wound dressings, which can quickly close wounds in practical applications, facilitating hemostasis and repair.

[0093] The antibacterial activity of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1 is as follows: Figure 5 As shown, the series of multifunctional biomimetic polymer adhesives for wound repair prepared in this invention have a better inhibitory effect on Escherichia coli and Staphylococcus aureus compared with the adhesive prepared in Comparative Example 1.

[0094] Biocompatibility and coagulation dynamics characterization of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 and Comparative Example 1 are as follows: Figure 6 As shown in the diagram. First, mouse embryonic fibroblasts (NIH / 3T3) were seeded onto four different adhesive materials and co-cultured for different numbers of days. Live and dead cells were simultaneously stained with fluorescence using a live / dead cell dual staining kit, and the live and dead cells were monitored under a fluorescence microscope. Second, cytotoxicity was tested using the CCK-8 assay, and the absorbance of the solution at 450 nm was measured using a microplate reader after different time intervals. Both test methods demonstrate that the series of multifunctional biomimetic polymeric adhesives for wound repair prepared in this invention have excellent biocompatibility. Furthermore, in vitro coagulation kinetic experiments confirmed that the series of functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 have a high hemostatic rate.

[0095] The hemostatic properties of the functionalized PAM-AA-NHS-based biomimetic polymer adhesives prepared in Example 7 and Comparative Example 1 in mice were characterized as follows: Figure 7 As shown, bleeding was simulated by creating wounds in the liver and heart of mice, and hemostasis was achieved using the polymeric adhesives prepared in Example 7 and Comparative Example 1. The blood loss in the two bleeding models demonstrates that the series of functionalized PAM-AA-NHS-based biomimetic polymeric adhesives provided in Example 7 of this invention have better hemostatic effects.

[0096] Evaluation of the functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 and Comparative Example 1 in the treatment of full-thickness skin wound defects in mice. Figure 8 As shown. After 15 days of treatment, the wound healing rate of the PAM-AA-NHS polymeric adhesive prepared in Comparative Example 1 was 91.56% ± 0.96%, and the wound healing rates of the series of functionalized PAM-AA-NHS-based biomimetic polymeric adhesives prepared in Example 7 were 96.97% ± 0.39%, 90.34% ± 1.13%, and 97.15% ± 0.32%, respectively. The experimental results demonstrate that the series of multifunctional biomimetic polymeric adhesives for wound repair provided by this invention can promote wound healing.

[0097] Table 2 shows the complete blood loss in two bleeding models. Medical gauze, Comparative Example 1, Comparative Example 2, and the series of multifunctional biomimetic polymeric adhesives for wound repair prepared in Examples 1-7 were used in hemostasis experiments on mouse liver and heart. Table 2 shows that the series of multifunctional biomimetic polymeric adhesives for wound repair provided in Examples 1-7 of this invention resulted in lower blood loss in both bleeding models compared to the gauze group, Comparative Example 1, and Comparative Example 2, significantly shortening the hemostasis time. Furthermore, the prepared adhesive materials can adhere to moist environments such as the liver, and are expected to replace traditional surgical sutures, becoming a new generation of biomedical adhesive materials.

[0098]

[0099] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should be included in the scope of the present invention.

Claims

1. A method for preparing a PAM-AA-NHS-based multifunctional biomimetic polymeric adhesive for wound repair, characterized in that: Includes the following steps: (1) Mix acrylamide and N 1-Hydroxysuccinimide acrylate was dissolved in deionized water and stirred evenly at room temperature to obtain solution S1. (2) Dissolve tannic acid in deionized water and stir evenly at room temperature to obtain solution S2; (3) Dissolve the oxidized dextran in deionized water and stir until homogeneous at room temperature to obtain solution S3; (4) Dissolve the phenolic hydroxyl-modified chitosan in phosphate buffer solution and stir evenly at room temperature to obtain solution S4; (5) N,N -Methylenebisacrylamide was dissolved in deionized water and stirred evenly at room temperature to obtain solution S5; (6) N,N,N',N' -Tetramethylethylenediamine was dissolved in deionized water and stirred until homogeneous at room temperature to obtain solution S6; (7) Dissolve ammonium persulfate in deionized water and stir evenly at room temperature to obtain solution S7; (8) Mix solutions S2, S3 and S4 with solution S1 to obtain solutions S8, S9 and S10; (9) Add solutions S5, S6, and S7 to solution S8 in sequence and mix thoroughly at room temperature to obtain PAM-AA-NHS / TA multifunctional biomimetic polymer adhesive for wound repair; add solutions S5, S6, and S7 to solution S9 in sequence and mix thoroughly at room temperature to obtain PAM-AA-NHS / ODex multifunctional biomimetic polymer adhesive for wound repair; add solutions S5, S6, and S7 to solution S10 in sequence and mix thoroughly at room temperature to obtain PAM-AA-NHS / CHI-C multifunctional biomimetic polymer adhesive for wound repair.

2. The method according to claim 1, characterized in that: In solution S1 described in step (1), the mass fraction of acrylamide is 1.0~50.0 wt%. N The mass fraction of 2-hydroxysuccinimide acrylate is 0.1~10.0 wt%; the temperature is 5~80 ℃; and the stirring time is 2~72 h.

3. The method according to claim 1, characterized in that: In solution S2 described in step (2), the mass fraction of tannic acid is 0.2~20.0 wt%; the temperature is 10~40 ℃; and the stirring time is 1~120 min.

4. The method according to claim 1, characterized in that: In solution S3 described in step (3), the mass fraction of oxidized dextran is 0.2~30.0 wt%; the temperature is 10~50 ℃; and the stirring time is 2~120 min.

5. The method according to claim 1, characterized in that: In solution S4 described in step (4), the mass fraction of phenolic hydroxyl modified chitosan is 0.1~30.0 wt%; the temperature is 10~60 ℃; and the stirring time is 1~180 min.

6. The method according to claim 1, characterized in that: In solution S5 described in step (5), N,N The concentration of methylenebisacrylamide is 0.001~0.1 g / mL; the temperature is 5~45 ℃, and the stirring time is 2~150 min; in the solution S6 described in step (6), N,N,N',N' The concentration of tetramethylethylenediamine is 0.001~1 g / mL; the temperature is 5~45 ℃; the stirring time is 2~150 min; in the solution S7 described in step (7), the concentration of ammonium persulfate is 0.002~1 g / mL; the temperature is 5~45 ℃; and the stirring time is 2~150 min.

7. The method according to claim 1, characterized in that: In step (8), the mass ratio of solution S1 to S2 in solution S8 is 100:1 to 1:100; the mass ratio of solution S1 to S3 in solution S9 is 100:1 to 1:100; the mass ratio of solution S1 to S4 in solution S10 is 100:1 to 1:100; the temperature is 5 to 55 °C and the mixing time is 2 to 180 min.

8. The method according to claim 1, characterized in that: In step (9), the mass ratio of solutions S5:S6:S7:S8 is 1:1:1:10~1:1:1:1000; the mass ratio of solutions S5:S6:S7:S9 is 1:1:1:10~1:1:1:1000; the mass ratio of solutions S5:S6:S7:S10 is 1:1:1:10~1:1:1:1000; the temperature is 5~55 ℃ and the mixing time is 1~150 min.

9. The application of a polymeric adhesive prepared by the method according to any one of claims 1-8 in the preparation of wound repair materials.

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