Injectable hydrogel for treating periodontitis as well as preparation method and application of injectable hydrogel

Abstract

The invention discloses injectable hydrogel for treating periodontitis as well as a preparation method and application of the injectable hydrogel. The injectable hydrogel is prepared from the following raw materials: chitosan and derivatives thereof, oxidative modified natural polysaccharide and modified hydroxyapatite, the modified hydroxyapatite comprises hydroxyapatite, and the surface of the hydroxyapatite is modified with a metal polyphenol network. The modified hydroxyapatite has multiple functions of oxidation resistance, immunoregulation, osteogenesis promotion, migration promotion, tube formation promotion, antibiosis and the like, and can be combined with the injectable hydrogel with biological adhesion and self-healing performance to realize better in-vivo tissue healing. The injectable hydrogel of the composite functional hydroxyapatite nanoparticles synthesized by the invention has biocompatibility, oxidation resistance, immunoregulation performance, osteogenesis promotion performance and antibacterial performance, and can realize better alveolar bone regeneration and repair in a rat periodontitis model, and the effect of the injectable hydrogel is superior to that of clinically common minocycline.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of hydrogel, and particularly relates to an injectable hydrogel for treating periodontitis and a preparation method and application thereof. BACKGROUND

[0002] Periodontitis is a chronic inflammatory disease caused by plaque microorganisms, which can gradually destroy the periodontal support tissue (especially alveolar bone) and eventually lead to tooth loss. The established treatment strategy for periodontitis includes removal of pathogenic factors through tooth cleaning and root planing, and antibiotic antibacterial treatment, all of which are difficult to achieve periodontal tissue regeneration. During the entire progression of periodontitis, Porphyromonas gingivalis is considered to be the main pathogen, which exists in the periodontal pocket and produces an anaerobic and alkaline environment. In this unique bacterial microenvironment of periodontitis, immune cells produce excessive pro-inflammatory cytokines and reactive oxygen species (ROS), which hinder the bone regeneration process. During this process, the significantly higher proportion of M1 / M2 macrophages interacts with excessive ROS deposition and inflammatory microenvironment, leading to uncontrolled periodontal tissue damage. Today, a variety of biomaterials have been developed for the treatment of periodontitis, including antibacterial agents, ROS scavengers, and immunomodulatory biomaterials. However, most of the existing biomaterials and traditional treatment methods are single-function, which fail to meet the multifunctional requirements of periodontitis bone regeneration. Therefore, there is an urgent need to develop a new treatment strategy for periodontitis to achieve comprehensive intervention. SUMMARY

[0003] In order to overcome the problems existing in the prior art, one of the purposes of the present application is to provide an injectable hydrogel. The second purpose of the present application is to provide a preparation method of the injectable hydrogel. The third purpose of the present application is to provide an application of the injectable hydrogel.

[0004] Hydrogel scaffolds with injectability are one of the research hotspots of periodontal bone defect repair biomaterials. Injectable hydrogels have the characteristics of in-situ forming and controllable rheology in vivo. They have unique advantages in repairing periodontal bone defects: 1) injectable hydrogels are injected into the hydrogel through a syringe, which reflects minimally invasive in clinical application and reduces the risk of infection and complications; 2) improve patient compliance; 3) can adapt to the irregular anatomical structure of the periodontal pocket; 4) strong adhesion to bone tissue, resistant to gingival crevicular fluid flushing. When functional nanoparticles are added to these injectable hydrogel substrates, the problem of burst release of functional components is solved, achieving controlled release and enhancing the effect of composite hydrogel bone defect repair; the introduction of biologically active nanoparticles into the injectable hydrogel to a certain extent improves the problem of low mechanical strength and fast degradation of the injectable hydrogel.

[0005] Hydroxyapatite is the main mineral component of human bone tissue. It stands out in bone tissue engineering applications due to its excellent osteoconductive, osteoinductive and cell adhesion properties, as well as the potential for drug delivery. Hydroxyapatite nanoparticles maximally mimic the microstructure of human bone tissue, and significantly improve the fracture toughness and mechanical strength, showing enhanced bioactivity, better promoting cell adhesion and cell-matrix interaction. In recent years, hydroxyapatite nanoparticle-based biological composites have been widely used in the field of bone regeneration. The hydroxyapatite in natural bone tissue is mainly in the form of nanorod crystals, and some studies suggest that simulating such morphology can help regulate immune response, reduce inflammation, and thus promote stem cell osteogenic differentiation and bone tissue repair. Most biological composites based on nano-hydroxyapatite use a single morphology for modification and modification, mainly for self-comparison before and after modification, and there is a serious lack of research on the effect of modification strategy on different morphology hydroxyapatite substrates, which cannot provide a basis for the reasonable selection of nano-substrate material morphology.

[0006] Metal-polyphenol network is constructed by coordination bond between natural polyphenols (tannic acid, tea polyphenol, dopamine) and metal ions (such as Zn 2+ , Fe 3+ , Cu 2+ , Ce 3+ ). Natural polyphenols are rich in ortho-diphenol groups, have high antioxidant performance, and can form a stable functional coating through metal coordination, and can be flexibly applied to nano-substrate materials of different morphologies. Metal ions have antibacterial, immune regulation, pro-vascular and bone regeneration effects. Therefore, a multifunctional coating can be constructed on the surface of nano-hydroxyapatite using metal-polyphenol network to remove ROS in the microenvironment of periodontitis, inhibit inflammatory response and promote bone tissue repair. In the present application, the metal-polyphenol network is modified on the surface of nano-hydroxyapatite substrates with various morphologies, the influence of substrate morphology on modification efficiency is compared in multiple dimensions, the most suitable substrate morphology is selected, and the modified nano-hydroxyapatite is introduced into the injectable hydrogel system. The obtained injectable hydrogel has good repair effect on soft and hard tissue defects caused by periodontitis, and has the effects of promoting collagen fiber regeneration and promoting alveolar bone regeneration.

[0007] In order to achieve the above purpose, the technical scheme adopted by the present application is: The first aspect of the present application provides an injectable hydrogel, which is prepared from the following raw materials: chitosan and its derivatives, oxidized natural polysaccharide and modified hydroxyapatite nanoparticles. The modified hydroxyapatite nanoparticles comprise hydroxyapatite nanoparticles, and the surface of the hydroxyapatite nanoparticles is modified with a metal-polyphenol network; the metal-polyphenol network is constructed by coordination bond between natural polyphenols and metal ions.

[0008] Preferably, the hydroxyapatite nanoparticles have a geometric shape that is one of spherical, short rod-shaped, long rod-shaped, dendritic, petal-shaped, or hollow.

[0009] More preferably, the spherical modified hydroxyapatite nanoparticles have a diameter of about 30-100 nm; the short rod-shaped modified hydroxyapatite nanoparticles have a major diameter of about 30-100 nm; and the long rod-shaped modified hydroxyapatite nanoparticles have a major diameter of about 50-150 nm.

[0010] Preferably, the oxidized modified natural polysaccharide includes at least one of oxidized sodium hyaluronate, oxidized sodium alginate, oxidized sodium carboxymethyl cellulose, oxidized starch, or oxidized dextran.

[0011] More preferably, the method for preparing the oxidized sodium alginate includes the following steps: oxidizing sodium alginate with sodium periodate to obtain the oxidized sodium alginate.

[0012] Preferably, the chitosan and its derivatives include at least one of chitosan, carboxymethyl chitosan, thiolated chitosan, quaternary ammonium salt chitosan, or amphiphilic chitosan.

[0013] Preferably, the natural polyphenols are selected from at least one of tannic acid, tea polyphenols, dopamine, or quercetin.

[0014] Preferably, the metal ion is selected from at least one of zinc ions, iron ions, copper ions, manganese ions, or cobalt ions.

[0015] Preferably, the preparation method of the modified hydroxyapatite nanoparticles includes the following steps: Hydroxyapatite nanoparticles, natural polyphenols, and metal ion salts were mixed in water, and the pH of the resulting reaction solution was adjusted to 8-10. The reaction was then carried out to obtain the modified hydroxyapatite nanoparticles.

[0016] More preferably, the mixing method is ultrasonic dispersion.

[0017] More preferably, the reaction time is 8-24 h.

[0018] More preferably, the reaction time is 10-16 h.

[0019] More preferably, the reaction is carried out under stirring conditions.

[0020] More preferably, the stirring speed is 100-500 rpm.

[0021] Preferably, the mass ratio of the hydroxyapatite nanoparticles to natural polyphenols is 1:(0.1-0.3).

[0022] More preferably, the mass ratio of the hydroxyapatite nanoparticles to natural polyphenols is 1:(0.15-0.25).

[0023] Preferably, the mass ratio of the hydroxyapatite nanoparticles to the metal ion salt is 1:(0.1-0.5).

[0024] More preferably, the mass ratio of the hydroxyapatite nanoparticles to the metal ion salt is 1:(0.2-0.4).

[0025] Preferably, the mass ratio of the modified hydroxyapatite nanoparticles to chitosan and its derivatives is 1:(0.3-2).

[0026] More preferably, the mass ratio of the modified hydroxyapatite nanoparticles to chitosan and its derivatives is 1:(0.3-2).

[0027] Preferably, the mass ratio of the modified hydroxyapatite nanoparticles to the oxidized modified natural polysaccharide is 1:(0.7-3).

[0028] More preferably, the mass ratio of the modified hydroxyapatite nanoparticles to chitosan and its derivatives is 1:(0.3-2).

[0029] The second aspect of the present invention provides a method for preparing the injectable hydrogel described in the first aspect, comprising the following steps: mixing chitosan and its derivatives, oxidized modified natural polysaccharides and modified hydroxyapatite nanoparticles in water to obtain the injectable hydrogel.

[0030] Preferably, the injectable hydrogel is prepared by mixing an aqueous solution of chitosan and its derivatives, an aqueous solution of oxidized modified natural polysaccharides, and an aqueous solution of modified hydroxyapatite nanoparticles.

[0031] The third aspect of this invention provides for the application of the injectable hydrogel described in the first aspect in any of the following aspects: A) Application in the preparation of drugs for treating chronic inflammation; B) Applications in the preparation of antibacterial drugs; C) Applications in the preparation of antioxidant drugs; D) Applications in the preparation of immunomodulatory drugs; E) Application in the preparation of osteogenic drugs; F) Application in the preparation of drugs that promote angiogenesis. Preferably, the chronic inflammation is periodontitis.

[0032] The beneficial effects of this invention are: This invention provides an injectable hydrogel. The base hydrogel comprises chitosan and its derivatives, and oxidized polysaccharides. The hydrogel prepared using these two materials possesses injectability, self-healing properties, shape adaptability, adhesion, hemostasis, and antibacterial properties. The surface of the hydroxyapatite nanoparticles used in the hydrogel is modified with a metal polyphenol network. These modified hydroxyapatite nanoparticles possess multiple functions, including antioxidant, immunomodulatory, osteopromoting, migration-promoting, vascularization-promoting, and antibacterial properties. Modification efficiency is selected based on these functional effects, and nanoparticles with the optimal modification efficiency are combined with the injectable hydrogel possessing bioadhesiveness and self-healing properties to achieve better in vivo tissue healing. The injectable hydrogel of composite functional hydroxyapatite nanoparticles synthesized in this invention exhibits biocompatibility, antioxidant properties, immunomodulatory properties, osteopromoting properties, and antibacterial properties. Furthermore, it can achieve good alveolar bone regeneration and repair in a rat periodontitis model, with effects superior to commonly used minocycline.

[0033] In addition, the injectable hydrogel of the composite functional hydroxyapatite nanoparticles described in this invention has low cytotoxicity, and no obvious inflammatory infiltrating cells or abnormal tissue proliferation were observed in the pathological sections of the heart, liver, spleen, lungs, and kidneys of rats, indicating that it has low toxicity and good biocompatibility. Attached Figure Description

[0034] Figure 1 The gelation process of the hydrogel in Example 3; Figure 2 Transmission electron microscopy images of nanoparticles with different geometric shapes in Examples 1-3; Figure 3 Images of the injectable hydrogel used in Example 3 being applied to different items; Figure 4 The therapeutic effects of injectable hydrogels in Examples 1-3 and Comparative Examples 1-4 on experimental rat periodontitis were studied. Detailed Implementation

[0035] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials used in the following embodiments can be obtained from conventional commercial channels or prepared and isolated through simple synthesis; unless otherwise specified, the processes employed are conventional processes in the art.

[0036] Example 1 This embodiment provides a zinc ion tannic acid-spherical nano-hydroxyapatite (S-HA@TZ) and its hydrogel, the specific preparation method of which is as follows: 1. Preparation of zinc ion tannic acid-spherical nano-hydroxyapatite (S-HA@TZ) 40 mg of spherical hydroxyapatite nanoparticles (S-HA) were dissolved in 40 mL of deionized water. Then, 200 μL of pre-prepared TA solution (40 mg / mL) and 3 mL of ZnCl2 solution (3.5 mg / mL) were added sequentially to the tube. The nanoparticles were dispersed by ultrasonication. After 1 minute, the pH of the reaction solution was adjusted to 8 using 1 M NaOH solution. The mixture was stirred at 200 rpm for 12 hours. The nanoparticles were collected by centrifugation and washed three times with deionized water. After vacuum drying overnight, pure S-HA@TZ nanoparticles were obtained.

[0037] 2. Preparation of sodium alginate oxide Dissolve 5 g of sodium alginate in 100 mL of deionized water and stir magnetically until completely dissolved. Add 3.25 g of sodium periodate and react at room temperature in the dark for 8 hours. Stop the reaction by adding 2 mL of ethylene glycol for 2 hours. Dialyze the product in a dialysis bag (Mw=3500) for 3 days, changing the water 3-4 times daily. Then freeze-dry the product to obtain white oxidized sodium alginate.

[0038] 3. Solution preparation Weigh out the freeze-dried sodium alginate and dissolve it fully in deionized water to prepare a 5 mg / mL solution.

[0039] Weigh out carboxymethyl chitosan and dissolve it fully in deionized water to prepare a 6 mg / mL solution.

[0040] 4. Preparation of Injectable Hydrogels Weigh the obtained S-HA@TZ nanoparticles and ultrasonically disperse them in deionized water to prepare a 10 mg / mL solution. Mix the above solution with the 6 mg / mL carboxymethyl chitosan solution and the 5 mg / mL sodium alginate solution from step (3) in a 1:1:2 ratio, stir thoroughly at room temperature, and obtain a composite injectable hydrogel after 1 minute, denoted as GS-HA@TZ.

[0041] Example 2 This embodiment provides a zinc ion tannic acid-short rod-shaped nano-hydroxyapatite (SR-HA@TZ) and its hydrogel, the specific preparation method of which is as follows: 1. Preparation of zinc ion tannic acid-short rod-shaped nano-hydroxyapatite (SR-HA@TZ) 40 mg of short rod-shaped hydroxyapatite nanoparticles (SR-HA) were dissolved in 40 mL of deionized water. Then, 200 μL of pre-prepared TA solution (40 mg / mL) and 3 mL of ZnCl2 solution (3.5 mg / mL) were added sequentially to the tube. The nanoparticles were dispersed by ultrasonication. After 1 minute, the pH of the reaction solution was adjusted to 8 using 1 M NaOH solution. The mixture was stirred at 200 rpm for 12 hours. The nanoparticles were collected by centrifugation and washed three times with deionized water. After vacuum drying overnight, pure SR-HA@TZ nanoparticles were obtained.

[0042] Steps 2 and 3 are the same as in Example 1.

[0043] 4. Preparation of Injectable Hydrogels Weigh the obtained SR-HA@TZ nanoparticles and ultrasonically disperse them in deionized water to prepare a 10 mg / mL solution. Mix the above solution with the 6 mg / mL carboxymethyl chitosan solution and the 5 mg / mL sodium alginate solution from step (3) in a 1:1:2 ratio. Stir thoroughly at room temperature for 1 minute to obtain a composite injectable hydrogel, denoted as G-SR-HA@TZ.

[0044] Example 3 This embodiment provides a zinc ion tannic acid-long rod-shaped nano-hydroxyapatite (LR-HA@TZ) and its hydrogel, the specific preparation method of which is as follows: 1. Preparation of zinc ion tannic acid-long rod-shaped nano-hydroxyapatite (LR-HA@TZ) 40 mg of long rod-shaped hydroxyapatite nanoparticles (LR-HA) were dissolved in 40 mL of deionized water. Then, 200 μL of pre-prepared TA solution (40 mg / mL) and 3 mL of ZnCl2 solution (3.5 mg / mL) were added sequentially to the tube. The nanoparticles were dispersed by ultrasonication. After 1 minute, the pH of the reaction solution was adjusted to 8 using 1 M NaOH solution. Stirring was continued at 200 rpm for 12 hours. The mixture was collected by centrifugation and washed three times with deionized water. After vacuum drying overnight, pure LR-HA@TZ nanoparticles were obtained.

[0045] Steps 2 and 3 are the same as in Example 1.

[0046] 4. Preparation of Injectable Hydrogels Weigh the obtained LR-HA@TZ nanoparticles and ultrasonically disperse them in deionized water to prepare a 10 mg / mL solution. Mix the above solution with the 6 mg / mL carboxymethyl chitosan solution and the 5 mg / mL sodium alginate solution from step (3) in a 1:1:2 ratio. Stir thoroughly at room temperature for 1 minute to obtain a composite injectable hydrogel, denoted as G-LR-HA@TZ.

[0047] Figure 1 The gelation process of the hydrogel in Example 3 is illustrated in the following images: oxidized sodium alginate (OSA) solution, a mixed solution of carboxymethyl chitosan (CMCS) and LR-HA@TZ, and physical samples of G-LR-HA@TZ. Figure 1 It can be seen that the aldehyde and amino groups of carboxymethyl chitosan and sodium alginate react to form a chemical cross-linking network, and the resulting hydrogel G-LR-HA@TZ is composed of these two compounds.

[0048] Comparative Example 1 This comparative example provides a hydrogel, the specific preparation method of which is as follows: Spherical hydroxyapatite nanoparticles (S-HA) were weighed and ultrasonically dispersed in deionized water to prepare a 10 mg / mL solution. The above solution was mixed with the 6 mg / mL carboxymethyl chitosan solution and the 5 mg / mL sodium alginate solution from step (3) of Example 1 in a 1:1:2 ratio. The mixture was stirred thoroughly at room temperature, and after 1 minute, a composite injectable hydrogel was obtained, denoted as GS-HA.

[0049] Comparative Example 2 This comparative example provides a hydrogel, the specific preparation method of which is as follows: Short rod-shaped hydroxyapatite nanoparticles (SR-HA) were weighed and ultrasonically dispersed in deionized water to prepare a 10 mg / mL solution. The above solution was mixed with the 6 mg / mL carboxymethyl chitosan solution and the 5 mg / mL sodium alginate solution from step (3) of Example 1 in a 1:1:2 ratio. The mixture was stirred thoroughly at room temperature, and after 1 minute, a composite injectable hydrogel was obtained, denoted as G-SR-HA.

[0050] Comparative Example 3 This comparative example provides a hydrogel, the specific preparation method of which is as follows: Weigh out long rod-shaped hydroxyapatite nanoparticles (LR-HA), and ultrasonically disperse them in deionized water to prepare a 10 mg / mL solution. Mix the above solution with the 6 mg / mL carboxymethyl chitosan solution and the 5 mg / mL sodium alginate solution from step (3) of Example 1 in a 1:1:2 ratio, stir thoroughly at room temperature, and obtain a composite injectable hydrogel after 1 minute, denoted as G-LR-HA.

[0051] Comparative Example 4 This comparative example provides a hydrogel, the specific preparation method of which is as follows: The 6 mg / mL carboxymethyl chitosan solution and the 5 mg / mL sodium alginate solution from step (3) of Example 1 were mixed at a ratio of 1:2 and stirred thoroughly at room temperature. After 1 minute, a composite injectable hydrogel was obtained, denoted as G.

[0052] Hydrogel characterization 1. Material Characterization Transmission electron microscopy was used to characterize the various functional hydroxyapatite nanoparticles, such as... Figure 2 As shown, three types of nanoparticles with different geometric shapes were prepared: S-HA@TZ with a diameter of about 50 nm, SR-HA@TZ with a major diameter of about 70 nm, and LR-HA@TZ with a major diameter of about 100 nm.

[0053] 2. Testing of the Adhesion Properties of Injectable Hydrogels The injectable hydrogel of Example 3 was injected into a circular mold using a syringe. After demolding, the hydrogel was used to adhere to glass, plastic, metal, rubber, and pigskin, and pictures were taken.

[0054] Test results: such as Figure 3 As shown, G-LR-HA@TZ hydrogel can adhere firmly to glass, plastic, metal, rubber, and pigskin surfaces, and can be used as an adhesive. The same effect can be achieved using GS-HA and G-SR-HA@TZ.

[0055] 3. The therapeutic effect of injectable hydrogel on experimental periodontitis in rats. Subjects: 54 male SD rats (8 weeks old, 400-450 g) were obtained from the Experimental Animal Center of Southern Medical University, and a bilateral molar periodontitis model was established based on previous studies. Specifically, 2-0 silk sutures were tied to the maxillary second molars of the rats for 2 weeks to induce periodontitis.

[0056] Experimental grouping: All rats were randomly divided into 9 groups: (1) No periodontitis group, i.e., no ligation treatment (Control); (2) Periodontitis treated with PBS; (3) Periodontitis treated with G; (4) Periodontitis treated with GS-HA injectable hydrogel; (5) Periodontitis treated with GS-HA@TZ injectable hydrogel; (6) Periodontitis treated with G-SR-HA@TZ injectable hydrogel; (7) Periodontitis treated with G-SR-HA@TZ injectable hydrogel; (8) Periodontitis treated with G-LR-HA injectable hydrogel; (9) Periodontitis treated with G-LR-HA@TZ injectable hydrogel.

[0057] Treatment plan: After removing the ligature wire, the treatment phase begins, with injections every three days. Each injection may consist of approximately 200µL of hydrogel or PBS into the periodontal pocket, and the treatment lasts for 4 weeks.

[0058] Evaluation of efficacy: After 4 weeks, rats were euthanized, and the maxillae were collected and fixed in 4% paraformaldehyde. Micro-CT scans were used to evaluate the alveolar bone repair around the molars in each group of rats.

[0059] Experimental results: Micro-CT scan results are as follows Figure 4 In the Periodontitis group, significant alveolar bone resorption was observed, with a significantly increased cementoenamel-alveolar ridge distance. There was no significant difference between the G group and the Periodontitis group. Compared to the GS-HA, G-SR-HA, and G-LR-HA groups, the GS-HA@TZ, G-SR-HA@TZ, and G-LR-HA@TZ groups showed significantly reduced alveolar bone resorption and a significantly decreased cementoenamel-alveolar ridge distance. This indicates that the GS-HA@TZ, G-SR-HA@TZ, and G-LR-HA@TZ groups have good therapeutic effects on periodontitis in vivo.

[0060] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. An injectable hydrogel, characterized in that, The injectable hydrogel is prepared by mixing chitosan and its derivatives, oxidized natural polysaccharides and modified hydroxyapatite nanoparticles in water. The modified hydroxyapatite nanoparticles comprise hydroxyapatite nanoparticles, and the surface of the hydroxyapatite nanoparticles is modified with a metal polyphenol network.

2. The injectable hydrogel of claim 1, wherein, The oxidized natural polysaccharides comprise at least one of oxidized sodium hyaluronate, oxidized sodium alginate, oxidized sodium carboxymethyl cellulose, oxidized starch or oxidized dextran. The chitosan and its derivatives comprise at least one of chitosan, carboxymethyl chitosan, thiolated chitosan, quaternary ammonium salt chitosan or amphiphilic chitosan.

3. The injectable hydrogel of claim 1, wherein, The natural polyphenol is selected from at least one of tannic acid, tea polyphenol, dopamine or quercetin. The metal ion is selected from at least one of zinc ion, iron ion, copper ion, manganese ion or cobalt ion.

4. The injectable hydrogel of claim 1, wherein, The preparation method of the modified hydroxyapatite nanoparticles comprises the following steps: The hydroxyapatite nanoparticles, the natural polyphenol and the metal ion salt are uniformly mixed in water, the pH of the obtained reaction solution is adjusted to 8-10, and the reaction is carried out to prepare the modified hydroxyapatite nanoparticles.

5. The injectable hydrogel of claim 4, wherein, The reaction time is 8-24 h. The reaction is carried out under stirring.

6. The injectable hydrogel of claim 4, wherein, The mass ratio of the hydroxyapatite nanoparticles to the natural polyphenol is 1:(0.1-0.3). The mass ratio of the hydroxyapatite nanoparticles to the metal ion salt is 1:(0.1-0.5).

7. The injectable hydrogel of claim 1, wherein, The mass ratio of the modified hydroxyapatite nanoparticles to the chitosan and its derivatives is 1:(0.3-2). The mass ratio of the modified hydroxyapatite nanoparticles to the oxidized natural polysaccharides is 1:(0.7-3).

8. A method of preparing the injectable hydrogel according to any one of claims 1 to 7, characterized in that, The preparation method comprises the following steps: mixing chitosan and its derivatives, oxidized natural polysaccharides and modified hydroxyapatite nanoparticles in water to prepare the injectable hydrogel.

9. Use of the injectable hydrogel according to any one of claims 1-7 in the preparation of a medicament for treating chronic inflammation.

10. Use according to claim 9, characterized in that, The chronic inflammation is periodontitis.

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