A composite material for promoting repair of maxillofacial soft tissue defects and a preparation method thereof

Abstract

This invention belongs to the field of biomedical materials technology, specifically disclosing a composite material for promoting the repair of soft tissue defects in the maxillofacial region and its preparation method. The composite material comprises the following raw materials: oxidized hyaluronic acid, carboxymethyl chitosan, dopamine-functionalized hydroxyapatite nanoparticles, strontium salt, copper salt, glycerol, and deionized water. The preparation method includes: firstly, strontium salt and copper salt are hierarchically loaded onto the surface of dopamine-functionalized hydroxyapatite nanoparticles via a dual mechanism of "lattice substitution-surface coordination," and then, together with oxidized hyaluronic acid and carboxymethyl chitosan, construct a "dynamic covalent-hydrogen bond-coordination bond" triple synergistic network through Schiff base reaction, hydrogen bonding, and coordination bonds. This invention solves the technical problems of poor wet surface adhesion, low mechanical strength, single function, and easy burst release of ions in existing repair materials, exhibiting excellent effects such as sequential antibacterial and repair-promoting properties, high adhesion strength, and long-lasting sustained release.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, and relates to a composite material that promotes the repair of soft tissue defects in the maxillofacial region and its preparation method. Background Technology

[0002] Soft tissue defects of the maxillofacial region are often caused by trauma, surgical resection of tumors, or congenital malformations. Due to the complex anatomy of the maxillofacial region and its continuously moist and dynamic environment, traditional repair methods such as autologous skin grafting, while considered the gold standard, have limitations such as donor site damage, limited donor sources, and difficulty in fitting irregular wounds. Tissue-engineered scaffold materials offer a new solution to this problem.

[0003] In the prior art, the materials used for soft tissue repair mainly include collagen sponges, chitosan membranes and synthetic polymer scaffolds. However, these existing materials have the following significant defects when applied to the special environment of the oral and maxillofacial region: (1) poor adhesion to wet surfaces: There is saliva, blood and tissue fluid in the oral cavity. Traditional materials are prone to falling off or shifting in a moist environment and cannot adhere tightly to the wound, resulting in repair failure; (2) lack of dynamic adaptability: Existing preformed scaffolds are difficult to perfectly fill irregular defects of various shapes, and the material degradation rate does not match the rate of new tissue ingrowth; (3) single function: Most materials only play a physical filling role and lack active antibacterial, anti-inflammatory and vascularization-promoting biological activities. The repair effect is not good in contaminated wounds or areas with poor blood circulation (such as exposed bone surfaces).

[0004] Therefore, there is an urgent need to develop a multifunctional composite material that can be formed in situ, adapt to irregular wounds, and actively regulate the local microenvironment. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention provides a composite material for promoting the repair of soft tissue defects in the maxillofacial region and its preparation method. The innovation of the present invention lies in: utilizing Sr... 2+ isomorphic substitution mechanism with hydroxyapatite lattice and Cu 2+ The difference in coordination affinity with catechol groups enables the realization of Sr on dopamine-functionalized hydroxyapatite nanoparticles. 2 + Occupying the interior of the crystal lattice, Cu 2+ The material is chelated with catechol on its surface and then loaded in a partitioned manner. Simultaneously, this functional particle is introduced as a nano-crosslinking node into the Schiff base network of oxidized hyaluronic acid and carboxymethyl chitosan. Through hydrogen and coordination bonds, a dynamic covalent-hydrogen bond-coordination bond multi-layered synergistic network structure is constructed, enabling the prepared material to intelligently respond to pH changes in the wound microenvironment, preferentially releasing Cu under acidic conditions in the early stages of infection. 2+ Rapid antibacterial action, with sustained release of Sr under neutral conditions after inflammation subsides.2+ It continuously promotes repair, thus achieving the dual effects of "immediate antibacterial and long-lasting repair promotion".

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] This invention provides a composite material for promoting the repair of soft tissue defects in the maxillofacial region, which is prepared from the following raw materials in parts by weight: 3-8 parts of oxidized hyaluronic acid, 2-6 parts of carboxymethyl chitosan, 2-4 parts of dopamine-functionalized hydroxyapatite nanoparticles, 0.1-0.3 parts of strontium salt, 0.05-0.15 parts of copper salt, 1.5-2.5 parts of glycerol, and 70-90 parts of deionized water.

[0008] Further, the oxidation degree of the oxidized hyaluronic acid is 15%-35%, and its preparation method is as follows: (a) Sodium hyaluronate is dissolved in deionized water to prepare a solution with a mass fraction of 1%-2%, sodium periodate is added under light-protected conditions, the molar ratio of sodium hyaluronate to sodium periodate is 1:1-2, and the reaction is carried out at 25°C in the dark for 12-24 hours; (b) After the reaction is completed, ethylene glycol is added to terminate the reaction, and the mixture is stirred for 30 minutes to obtain the reaction solution; (c) The reaction solution is placed in a dialysis bag and dialyzed in purified water for 48-72 hours. After the dialysis is completed, the mixture is freeze-dried to obtain the oxidized hyaluronic acid.

[0009] Furthermore, the strontium salt is either strontium lactate or strontium gluconate, preferably strontium lactate; the copper salt is copper gluconate; and the glycerol is pharmaceutical grade glycerol.

[0010] Further, the preparation method of the dopamine-functionalized hydroxyapatite nanoparticles is as follows: (1) Disperse the hydroxyapatite nanoparticles in a 10mM Tris-HCl buffer solution at pH 8.5 to obtain a dispersion; (2) Then add dopamine hydrochloride to the dispersion, the weight ratio of dopamine hydrochloride to hydroxyapatite nanoparticles is 1:5, and stir magnetically at room temperature for 18 hours. Dissolved oxygen is used to initiate the oxidative self-polymerization of dopamine under weakly alkaline conditions. The generated polydopamine is firmly wrapped on the surface of hydroxyapatite nanoparticles through the synergistic effect of covalent and non-covalent bonds; (3) After the reaction is completed, centrifuge, wash with deionized water, freeze dry to obtain dopamine-functionalized hydroxyapatite nanoparticles with surface rich in catechol groups.

[0011] This invention also provides a method for preparing a composite material that promotes the repair of soft tissue defects in the maxillofacial region, comprising the following steps:

[0012] S1. Solution preparation: Divide the deionized water into three parts. Dissolve oxidized hyaluronic acid in the first part of the deionized water, which accounts for 40%-50% of the total deionized water volume. Stir magnetically at 4°C until completely dissolved to prepare solution A. Dissolve carboxymethyl chitosan in the second part of the deionized water, which accounts for 20%-30% of the total deionized water volume. Stir magnetically at room temperature until completely dissolved to prepare solution B. Add dopamine-functionalized hydroxyapatite nanoparticles to the remaining third part of the deionized water. Disperse ultrasonically in an ice-water bath for 30 minutes to obtain a uniform dispersion C.

[0013] S2. Ion Loading: Under continuous gentle stirring, the strontium salt is first dissolved in dispersion C, and the reaction is carried out at room temperature with stirring for 60-90 minutes. The strontium salt is then used to load the ions. 2+ Radius and Ca in the hydroxyapatite lattice 2+ The similar radius characteristics of Sr, through the isomorphic substitution mechanism, make Sr 2+ The nanoparticles are firmly bonded to the internal lattice and surface adsorption sites of the nanoparticle carrier. Then, copper salt is added, and the pH of the system is immediately adjusted to 5.5-6.0 with 0.1 mol / L dilute hydrochloric acid solution for stirring. Under this weakly acidic condition, the catechol groups on the surface of the dopamine-functionalized hydroxyapatite nanoparticles react with the Cu... 2+ It has a stronger coordination affinity, thus preferentially binding with Cu. 2+ Forming stable five-membered ring chelates, while Sr 2+ It mainly occupies lattice sites and some non-specific adsorption sites. After the reaction is completed, a functional particle dispersion D loaded with strontium / copper ions is obtained.

[0014] S3. Mixed crosslinking: Under stirring conditions, solution B is slowly added to solution A. After the addition is complete, stirring is continued for 10-15 minutes to allow the aldehyde groups on the oxidized hyaluronic acid chain to undergo a reversible Schiff base reaction with the amino groups on the carboxymethyl chitosan chain, forming a preliminary dynamic crosslinking network and obtaining a preliminary crosslinked mixed sol.

[0015] S4. Molding and Curing: Add functional particle dispersion D to the mixed sol, stir gently to mix, then add glycerol, and adjust the pH of the system to 7.3-7.5 with 1M Tris-HCl buffer. Continue stirring to mix evenly, then transfer it to a mold and let it stand at room temperature for 20-40 minutes to obtain a hydrogel. During this process, the system undergoes multiple synergistic cross-linking: First, the aldehyde group of oxidized hyaluronic acid and the amino group of carboxymethyl chitosan undergo a Schiff base reaction to form the dynamic covalent backbone of the material; second, the catechol groups on the surface of the functional particles form a strong hydrogen bond network with the amino and hydroxyl groups on the polymer chain of the hydrogel, and some catechols form coordination bonds with metal ions, so that the functional particles are not only fillers, but also dispersed in the network as "nano-crosslinking nodes", which significantly improves the mechanical toughness and tissue adhesion of the hydrogel and constructs an interpenetrating network structure with synergistic enhancement of "dynamic covalent-hydrogen bond-coordination bond";

[0016] S5. Post-processing: Remove the hydrogel obtained in step S4 from the mold and immerse it in a phosphate buffer solution with a pH of 7.4. Change the buffer solution every 2 hours to fully remove unreacted small molecules, free ions, and possible byproducts. Place the washed hydrogel at -20°C for pre-freezing for 4 hours, then transfer it to a freeze dryer and freeze-dry it at -50°C and 10Pa for 24-48 hours. Subsequently, sterilize the material with ethylene oxide gas at low temperature to obtain a sterile final product, which is the composite material for promoting the repair of soft tissue defects in the maxillofacial region.

[0017] Compared with the prior art, the beneficial effects of the present invention are:

[0018] The core innovation of the composite material for promoting the repair of soft tissue defects in the maxillofacial region prepared by this invention lies in the spatial hierarchical loading and intelligent release of functional ions through a dual-mechanism design of "lattice substitution-surface coordination," and the synergistic enhancement of the material's mechanical properties and bioactivity through the construction of a triple network structure of "dynamic covalent-hydrogen bonds-coordination bonds." Specifically, it utilizes Sr... 2+ With Ca 2+ The similarity in radius allows it to enter the hydroxyapatite lattice for long-term anchoring, while the catechol groups on the dopamine surface utilize Cu... 2+ The high specific affinity of the material allows it to be chelated onto the surface of the nanoparticles, achieving a partitioned loading of "inner Sr and outer Cu". Furthermore, these functionalized nanoparticles are no longer just physical fillers, but rather "nano-crosslinking nodes" that deeply participate in the construction of the hydrogel network through hydrogen bonds between the catechol groups and the polymer chains, as well as metal-ligand coordination bonds, forming a stable multi-crosslinking system. This solves the problems of looseness, low strength, and easy burst release of ions in traditional physically mixed hydrogel networks.

[0019] Thanks to the unique graded loading structure and multiple cross-linking mechanism described above, the composite material of this invention exhibits excellent temporal therapeutic function and mechanical properties. Firstly, in terms of bioactivity, the spatially differentiated loading endows the material with pH-responsive "temporal release" characteristics: in the early stages of wound infection (slightly acidic environment), the surface Cu... 2+ Coordinate bonds are unstable, leading to rapid release of Cu. 2+ It exerts a strong antibacterial effect, eliminating the source of infection; as inflammation subsides and pH rises, Sr located inside the crystal lattice... 2+ Through slow, continuous ion exchange release, it effectively promotes angiogenesis and soft tissue remodeling. This "antibacterial first, repair later" intelligent mode precisely matches the healing pathological process of maxillofacial soft tissue defects. Secondly, in terms of mechanical properties, the introduction of nano-crosslinking nodes significantly enhances the toughness of the hydrogel framework, giving the material excellent tissue adhesion, enabling it to closely adhere to irregular defect surfaces, preventing bacterial invasion, while also possessing good injectability and self-healing capabilities, facilitating clinical operation. Furthermore, all raw materials are selected to medical-grade standards, combined with a gentle preparation process and a rigorous post-processing sterilization procedure, ensuring the material's excellent biocompatibility and safety for clinical application. Attached Figure Description

[0020] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below.

[0021] Figure 1 This is a flowchart illustrating the preparation of the composite material according to an embodiment of the present invention;

[0022] Figure 2 The figures show the test tube inversion test results of the composite materials prepared in Examples 1-3 and Comparative Examples 1-4 of this invention. Detailed Implementation

[0023] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0025] Unless otherwise specified, all materials used in the following implementation are pharmaceutical-grade materials purchased from the market.

[0026] Example 1: This example provides a composite material for promoting the repair of soft tissue defects in the maxillofacial region, which is prepared from the following raw materials in parts by weight: 3 parts oxidized hyaluronic acid, 2 parts carboxymethyl chitosan, 2 parts dopamine-functionalized hydroxyapatite nanoparticles, 0.1 parts strontium lactate, 0.05 parts copper gluconate, 1.5 parts glycerol, and 70 parts deionized water.

[0027] The oxidation degree of the oxidized hyaluronic acid is 15%, and its preparation method is as follows: (a) 10g of sodium hyaluronate is weighed and dissolved in 990mL of deionized water to prepare a solution with a mass fraction of 1%. 5.35g of sodium periodate is added under light-protected conditions, and the reaction is carried out at 25℃ under light-protected conditions for 24 hours; (b) after the reaction is completed, 2mL of ethylene glycol is added to terminate the reaction, and the mixture is stirred for 30 minutes to obtain the reaction solution; (c) the reaction solution is placed in a dialysis bag with a molecular weight cutoff of 3500Da, and dialyzed in purified water for 72 hours. After dialysis, the solution is freeze-dried to obtain the oxidized hyaluronic acid.

[0028] The preparation method of the dopamine-functionalized hydroxyapatite nanoparticles is as follows: (1) 10g of hydroxyapatite nanoparticles are weighed and dispersed in 1000mL of 10mM Tris-HCl buffer solution with pH 8.5 to obtain a dispersion; (2) 2g of dopamine hydrochloride is added to the dispersion solution and the mixture is magnetically stirred at room temperature for 18 hours; (3) After the reaction is completed, the mixture is centrifuged at 8000rpm for 10 minutes, washed three times with deionized water, and freeze-dried to obtain dopamine-functionalized hydroxyapatite nanoparticles with catechol groups on the surface.

[0029] This embodiment also provides a method for preparing a composite material that promotes the repair of soft tissue defects in the maxillofacial region, including the following steps:

[0030] S1. Solution preparation: Dissolve oxidized hyaluronic acid in 28 parts of deionized water and stir magnetically at 4°C until completely dissolved to prepare solution A. Dissolve carboxymethyl chitosan in 14 parts of deionized water and stir magnetically at room temperature until completely dissolved to prepare solution B. Add dopamine-functionalized hydroxyapatite nanoparticles to the remaining deionized water and ultrasonically disperse in an ice-water bath for 30 minutes to obtain a uniform dispersion C.

[0031] S2. Ion loading: Strontium lactate was first dissolved in dispersion C under continuous gentle stirring and stirred at room temperature for 90 minutes. Then, copper gluconate was added and the pH of the system was immediately adjusted to 5.5 with 0.1 mol / L dilute hydrochloric acid solution and stirred. After the reaction was completed, functional particle dispersion D loaded with strontium / copper dual ions was obtained.

[0032] S3. Mixed crosslinking: Under stirring conditions, solution B is slowly added to solution A. After the addition is complete, stirring is continued for 15 minutes to obtain a mixed sol with preliminary crosslinking.

[0033] S4. Molding and curing: Add functional particle dispersion D to the mixed sol, stir gently to mix, then add glycerol, and adjust the pH of the system to 7.3 with 1M Tris-HCl buffer. Continue to stir and mix evenly, then transfer it to a mold and let it stand at room temperature for 40 minutes to obtain hydrogel.

[0034] S5. Post-processing: Remove the hydrogel obtained in step S4 from the mold and immerse it in a phosphate buffer solution with a pH of 7.4. Change the buffer solution every 2 hours for a total of 5 times. Place the washed hydrogel at -20°C for 4 hours to pre-freeze, and then transfer it to a freeze dryer to freeze dry at -50°C and 10Pa for 48 hours. Subsequently, sterilize the material with ethylene oxide gas at low temperature to obtain a sterile final product, which is the composite material for promoting the repair of soft tissue defects in the maxillofacial region.

[0035] Example 2: This example provides a composite material for promoting the repair of soft tissue defects in the maxillofacial region, which is prepared from the following raw materials in parts by weight: 5.5 parts of oxidized hyaluronic acid, 4 parts of carboxymethyl chitosan, 3 parts of dopamine-functionalized hydroxyapatite nanoparticles, 0.2 parts of strontium gluconate, 0.1 parts of copper gluconate, 2.0 parts of glycerol, and 80 parts of deionized water.

[0036] The oxidation degree of the oxidized hyaluronic acid is 25%, and its preparation method is as follows: (a) Dissolve 10g of sodium hyaluronate in 490mL of deionized water to prepare a 2% solution by mass, add 10.7g of sodium periodate under light-protected conditions, and react at 25℃ in the dark for 18 hours; (b) After the reaction is completed, add 2mL of ethylene glycol to terminate the reaction, stir for 30 minutes, and obtain the reaction solution; (c) Put the reaction solution into a dialysis bag, dialyze in purified water for 60 hours, and freeze-dry after dialysis to obtain the oxidized hyaluronic acid.

[0037] The preparation method of the dopamine-functionalized hydroxyapatite nanoparticles is the same as that in Example 1.

[0038] This embodiment also provides a method for preparing a composite material that promotes the repair of soft tissue defects in the maxillofacial region, including the following steps:

[0039] S1. Solution preparation: Dissolve oxidized hyaluronic acid in 36 parts of deionized water and stir magnetically at 4°C until completely dissolved to prepare solution A. Dissolve carboxymethyl chitosan in 20 parts of deionized water and stir magnetically at room temperature until completely dissolved to prepare solution B. Add dopamine-functionalized hydroxyapatite nanoparticles to the remaining deionized water and ultrasonically disperse in an ice-water bath for 30 minutes to obtain a uniform dispersion C.

[0040] S2. Ion loading: Strontium gluconate was first dissolved in dispersion C under continuous gentle stirring and stirred at room temperature for 75 minutes. Then, copper gluconate was added and the pH of the system was immediately adjusted to 5.8 with 0.1 mol / L dilute hydrochloric acid solution and stirred. After the reaction was completed, functional particle dispersion D loaded with strontium / copper dual ions was obtained.

[0041] S3. Mixed crosslinking: Under stirring conditions, solution B is slowly added to solution A. After the addition is complete, stirring is continued for 13 minutes to obtain a mixed sol with preliminary crosslinking.

[0042] S4. Molding and curing: Add functional particle dispersion D to the mixed sol, stir gently to mix, then add glycerol, and adjust the pH of the system to 7.4 with 1M Tris-HCl buffer. Continue to stir and mix evenly, then transfer it to a mold and let it stand at room temperature for 30 minutes to obtain hydrogel.

[0043] S5. Post-processing: Remove the hydrogel obtained in step S4 from the mold and soak it in a phosphate buffer solution with a pH of 7.4. Change the buffer solution every 2 hours for a total of 5 times. Place the washed hydrogel at -20°C for 4 hours to pre-freeze, and then transfer it to a freeze dryer to freeze dry at -50°C and 10Pa for 36 hours. Subsequently, sterilize the material with ethylene oxide gas at low temperature to obtain a sterile final product, which is the composite material for promoting the repair of soft tissue defects in the maxillofacial region.

[0044] Example 3: This example provides a composite material for promoting the repair of soft tissue defects in the maxillofacial region, which is prepared from the following raw materials in parts by weight: 8 parts oxidized hyaluronic acid, 6 parts carboxymethyl chitosan, 4 parts dopamine-functionalized hydroxyapatite nanoparticles, 0.3 parts strontium lactate, 0.15 parts copper gluconate, 2.5 parts glycerol, and 90 parts deionized water.

[0045] The oxidation degree of the oxidized hyaluronic acid is 35%, and its preparation method is as follows: (a) 10g of sodium hyaluronate is weighed and dissolved in 665mL of deionized water to prepare a solution with a mass fraction of 1.5%. 10.7g of sodium periodate is added under light-protected conditions, and the reaction is carried out at 25℃ under light-protected conditions for 12 hours; (b) after the reaction is completed, 2mL of ethylene glycol is added to terminate the reaction, and the mixture is stirred for 30 minutes to obtain the reaction solution; (c) the reaction solution is placed in a dialysis bag with a molecular weight cutoff of 3500Da, and dialyzed in purified water for 48 hours. After the dialysis is completed, the oxidized hyaluronic acid is freeze-dried to obtain the oxidized hyaluronic acid.

[0046] The preparation method of the dopamine-functionalized hydroxyapatite nanoparticles is the same as that in Example 1.

[0047] This embodiment also provides a method for preparing a composite material that promotes the repair of soft tissue defects in the maxillofacial region, including the following steps:

[0048] S1. Solution preparation: Dissolve oxidized hyaluronic acid in 45 parts of deionized water and stir magnetically at 4°C until completely dissolved to prepare solution A. Dissolve carboxymethyl chitosan in 27 parts of deionized water and stir magnetically at room temperature until completely dissolved to prepare solution B. Add dopamine-functionalized hydroxyapatite nanoparticles to the remaining deionized water and ultrasonically disperse in an ice-water bath for 30 minutes to obtain a uniform dispersion C.

[0049] S2. Ion loading: Strontium lactate was first dissolved in dispersion C under continuous gentle stirring and stirred at room temperature for 60 minutes. Then, copper gluconate was added and the pH of the system was immediately adjusted to 6.0 with 0.1 mol / L dilute hydrochloric acid solution and stirred. After the reaction was completed, functional particle dispersion D loaded with strontium / copper dual ions was obtained.

[0050] S3. Mixed crosslinking: Under stirring conditions, solution B is slowly added to solution A. After the addition is complete, stirring is continued for 10 minutes to obtain a mixed sol with preliminary crosslinking.

[0051] S4. Molding and curing: Add functional particle dispersion D to the mixed sol, stir gently to mix, then add glycerol, and adjust the pH of the system to 7.5 with 1M Tris-HCl buffer. Continue to stir and mix evenly, then transfer it to a mold and let it stand at room temperature for 20 minutes to obtain hydrogel.

[0052] S5. Post-processing: Remove the hydrogel obtained in step S4 from the mold and soak it in a phosphate buffer solution with a pH of 7.4. Change the buffer solution every 2 hours for a total of 5 times. Place the washed hydrogel at -20°C for 4 hours to pre-freeze, and then transfer it to a freeze dryer to freeze dry at -50°C and 10Pa for 24 hours. Subsequently, sterilize the material with ethylene oxide gas at low temperature to obtain a sterile final product, which is the composite material for promoting the repair of soft tissue defects in the maxillofacial region.

[0053] Comparative Example 1: The difference between this comparative example and Example 2 is that the dopamine-functionalized hydroxyapatite nanoparticles are replaced with unfunctionalized hydroxyapatite nanoparticles, and the coordination reaction step of "adjusting the pH value to 5.5-6.0" in step S2 is omitted in the preparation method, and only simple physical adsorption mixing is performed; the remaining raw material ratios and methods are the same as in Example 2.

[0054] Comparative Example 2: The difference between this comparative example and Example 2 is that the raw materials do not contain copper gluconate, that is, they do not contain copper salts. In step S2 of the preparation method, only the loading of strontium salts is carried out, and the subsequent steps of adding copper salts and adjusting pH are omitted. The other raw material ratios and methods are the same as those in Example 2.

[0055] Comparative Example 3: The difference between this comparative example and Example 2 is that the raw materials do not contain strontium lactate, that is, they do not contain strontium salt. In step S2 of the preparation method, the addition of strontium lactate is omitted, and copper gluconate is directly added to the dispersion C. The proportions and methods of the remaining raw materials are the same as those in Example 2.

[0056] Comparative Example 4: The difference between this comparative example and Example 2 is that the raw materials do not contain oxidized hyaluronic acid, but are replaced with the same amount of unoxidized hyaluronic acid (i.e., sodium hyaluronate). The "mixing and crosslinking" step in step S3 is omitted in the preparation method, and the hyaluronic acid solution is directly mixed with the carboxymethyl chitosan solution. The remaining raw material ratios and methods are the same as in Example 2.

[0057] To verify the performance of the composite material of the present invention, the materials obtained in Examples 1-3 and Comparative Examples 1-4 were subjected to the following tests:

[0058] Morphological observation: The composite materials prepared in Examples 1-3 and Comparative Examples 1-4 were subjected to an inverted test tube experiment to observe their gelation state. The sample results are as follows: Figure 2 As shown.

[0059] Mechanical property testing: The prepared hydrogel sample was made into a cylinder with a diameter of 10 mm and a height of 5 mm. Unrestrained compression test was performed using a universal testing machine at a compression rate of 5 mm / min. The compressive stress at 70% of the compressive strain was recorded. According to ASTM F2255 standard, fresh pigskin was used as the adhesion substrate. The hydrogel was placed between two pieces of pigskin tissue (contact area 10 mm × 10 mm) and stretched at a speed of 10 mm / min. The overlap shear strength was measured. The results are shown in Table 1.

[0060] In vitro ion release performance test: 0.5 g of each freeze-dried sample was immersed in 20 mL of PBS buffer (pH 7.4) and placed in a 37°C constant temperature shaker. Samples were taken on days 1, 3, 5, 7, and 14, and the Sr content in the release medium was determined using inductively coupled plasma optical emission spectrometry (ICP-OES). 2+ and Cu 2+ The concentration.

[0061] In vitro antibacterial test: The sample was cut into 10 mm diameter discs using the film adhesion method and attached to a solid culture medium inoculated with Staphylococcus aureus or Porphyromonas gingivalis. After incubation at 37°C for 24 hours, the diameter of the inhibition zone was measured.

[0062] Table 1 Mechanical performance test results

[0063]

[0064] Table 2 Results of in vitro ion sustained-release performance test (cumulative release rate (%))

[0065]

[0066] Table 3. Results of in vitro antibacterial performance test (diameter of inhibition zone (mm))

[0067]

[0068] Test tube inversion experiment results: The samples of Examples 1-3 maintained their shape and did not flow after the test tubes were inverted, proving that a stable self-supporting hydrogel was formed. The samples of Comparative Examples 1 and 4 had strong flowability and obvious slippage after inversion, indicating that their cross-linking network was incomplete or insufficient in strength. The gel state of Comparative Examples 2 and 3 was good, but the texture was slightly softer compared with the examples. As can be seen from the data in Table 1, the composite materials prepared in Examples 1-3 exhibited excellent comprehensive performance. Due to the lack of dopamine functionalization modification, Comparative Example 1 lacked strong interactions (such as hydrogen bonds and coordination bonds) between nanoparticles and polymer chains, resulting in a significant decrease in its mechanical strength and adhesion strength, which proved the importance of dopamine interface modification. The mechanical properties of Comparative Examples 2 and 3 were lower than those of Example 2, indicating that Sr 2+and Cu 2+ The coexistence of these components is not a simple superposition, but rather they optimize the function of the "nano-crosslinking nodes" by forming coordination bonds of varying strengths with dopamine, thereby achieving synergistic enhancement of the hydrogel network structure.

[0069] As shown in Table 2, Examples 1-3 all exhibited stable sustained-release characteristics without burst release, and could sustain release for more than 14 days, demonstrating the excellent controlled-release ability of the multi-crosslinked network for ions. The experimental data of Comparative Example 1 further illustrates that the dopamine functionalization treatment of this invention can achieve sustained-release control of ions through the coordination of catechol groups with metal ions, avoiding burst release effects. This is of great significance for maintaining long-term repair-promoting effects. Observing the in vitro antibacterial performance test results, it can be found that Examples 1-3 all showed obvious inhibition zones, and with Cu... 2+ With increasing content, the diameter of the inhibition zone gradually increased, proving that the material has excellent antibacterial activity. Comparative Example 1, although showing a slight inhibition zone, had indistinct boundaries and a small diameter. Based on its ion release results, it is speculated that its antibacterial effect originates from the early, rapidly released, and loosely bound Cu. 2+ However, it cannot achieve long-lasting antibacterial effects and may cause local ion toxicity, which highlights the superiority of the functionalized particles in this invention in achieving controlled release.

[0070] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

[0071] The present invention and its embodiments have been described above. This description is not restrictive, and the accompanying drawings are only one embodiment of the present invention. The actual application is not limited to this. In conclusion, if those skilled in the art are inspired by this description and design similar methods and embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A composite material for promoting the repair of soft tissue defects in the maxillofacial region, characterized in that, It is prepared from the following raw materials in parts by weight: 3-8 parts of oxidized hyaluronic acid, 2-6 parts of carboxymethyl chitosan, 2-4 parts of dopamine-functionalized hydroxyapatite nanoparticles, 0.1-0.3 parts of strontium salt, 0.05-0.15 parts of copper salt, 1.5-2.5 parts of glycerol, and 70-90 parts of deionized water; the preparation method of the dopamine-functionalized hydroxyapatite nanoparticles is as follows: (1) Disperse the hydroxyapatite nanoparticles in Tris-HCl buffer to obtain a dispersion; (2) Then add dopamine hydrochloride to the dispersion and perform magnetic stirring reaction; (3) After the reaction is completed, centrifuge, wash, and freeze dry to obtain the dopamine-functionalized hydroxyapatite nanoparticles.

2. The composite material for promoting the repair of soft tissue defects in the maxillofacial region according to claim 1, characterized in that, The oxidation degree of the oxidized hyaluronic acid is 15%-35%, and its preparation method is as follows: (a) dissolve sodium hyaluronate in deionized water, and then add sodium periodate to react; (b) after the reaction is completed, add ethylene glycol to terminate the reaction, stir for 30 minutes to obtain the reaction solution; (c) dialyze the reaction solution and freeze dry to obtain the oxidized hyaluronic acid.

3. The composite material for promoting the repair of soft tissue defects in the maxillofacial region according to claim 1, characterized in that, In the preparation method of dopamine-functionalized hydroxyapatite nanoparticles, the weight ratio of dopamine hydrochloride to hydroxyapatite nanoparticles is 1:

5.

4. The composite material for promoting the repair of soft tissue defects in the maxillofacial region according to claim 2, characterized in that, In the method for preparing oxidized hyaluronic acid, the molar ratio of sodium hyaluronate to sodium periodate is 1:1-2.

5. The composite material for promoting the repair of soft tissue defects in the maxillofacial region according to claim 1, characterized in that, The strontium salt is either strontium lactate or strontium gluconate.

6. The composite material for promoting the repair of soft tissue defects in the maxillofacial region according to claim 1, characterized in that, The copper salt is copper gluconate; the glycerol is pharmaceutical grade glycerol.

7. A method for preparing a composite material for promoting the repair of soft tissue defects in the maxillofacial region according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Solution preparation: Divide the deionized water into three parts. Then, dissolve the oxidized hyaluronic acid in the first part of the deionized water to prepare solution A. Dissolve the carboxymethyl chitosan in the second part of the deionized water to prepare solution B. Add the dopamine-functionalized hydroxyapatite nanoparticles to the third part of the deionized water and ultrasonically disperse to obtain a uniform dispersion C. S2. Ion loading: First, dissolve the strontium salt in dispersion C, stir and react, then add the copper salt, and adjust the pH of the system to 5.5-6.0 with dilute hydrochloric acid solution to obtain functional particle dispersion D loaded with strontium / copper dual ions; S3. Mixed crosslinking: Slowly add solution B to solution A. After the addition is complete, stir to obtain a mixed sol with preliminary crosslinking. S4. Molding and curing: Add functional particle dispersion D to the mixed sol, stir gently to mix, then add glycerol, and adjust the pH of the system to 7.3-7.5 with Tris-HCl buffer, continue to stir and mix evenly, then transfer it to a mold and let it stand to obtain hydrogel; S5. Post-processing: The hydrogel is removed, washed by immersion in phosphate buffer, then frozen and dried, and subsequently sterilized to obtain the composite material that promotes the repair of soft tissue defects in the maxillofacial region.

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