Polydopamine modified cerium oxide composite temperature-sensitive hydrogel as well as preparation method and application thereof

Abstract

The invention discloses a polydopamine modified cerium oxide composite temperature-sensitive hydrogel as well as a preparation method and application thereof. The composite hydrogel is composed of a chitosan / sodium beta-glycerophosphate temperature-sensitive hydrogel matrix and polydopamine modified cerium oxide nanoparticles uniformly dispersed in the matrix. The preparation method of the composite hydrogel comprises the following steps: polymerizing on the surfaces of the cerium oxide nanoparticles under a weak alkaline condition to form a polydopamine coating layer; and then mixing with a chitosan solution and beta-sodium glycerophosphate at a low temperature. The material disclosed by the invention is in an injectable liquid state at low temperature, can be quickly converted into solid gel with relatively strong adhesion performance under body temperature and near-infrared light irradiation, and is firmly adhered to wet nervous tissues, so that suture-free fixation is realized, and the clinical operation difficulty can be remarkably simplified. The photothermal effect of polydopamine is utilized to promote the local metabolism and repair process, regeneration of peripheral nerves can be effectively promoted, formation of traumatic neuroma after amputation is remarkably inhibited, and the method has good application prospects in the field of nerve repair.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of polydopamine modified cerium oxide composite temperature-sensitive hydrogel and its preparation method and application, belong to the field of biomedical materials and nerve tissue engineering. BACKGROUND

[0002] Peripheral nerve injury is a common clinical disabling disease, which is often caused by trauma, iatrogenic injury or amputation surgery. After injury, if the broken nerve axons cannot regenerate effectively or grow in a disordered manner, it will lead to nerve conduction dysfunction, which seriously affects the patient's motor and sensory recovery. More seriously, if the nerve stumps cannot be repaired biologically, the abnormal proliferation of Schwann cells and fibroblasts at the stump often forms a painful neuroma, causing chronic and intractable pain, which greatly reduces the patient's quality of life.

[0003] Currently, the main repair strategies for peripheral nerve injury in clinical practice include autologous nerve transplantation, nerve conduit bridging, and degradable material wrapping. However, these methods have obvious limitations: autologous nerve transplantation has limited sources and functional loss of the donor site; nerve conduits often lack biological activity and are difficult to guide directional axon regeneration; traditional hydrogel materials have single functions and cannot actively regulate the immune microenvironment at the injury site, nor do they have dynamic response capabilities. In addition, most existing repair materials ignore the active regulation of oxidative stress and inflammatory response, which is a key microenvironmental factor affecting the quality of nerve regeneration and neuroma formation.

[0004] In recent years, photo-thermal responsive materials have received widespread attention in the field of biomedicine, particularly in tumor treatment and tissue repair, showing good spatiotemporal regulation potential. For example, Chinese patent application CN120053688A discloses a photo-thermal-immune-chemotherapy synergistic anti-tumor system based on mesoporous polydopamine nanoparticles, but its design target and mechanism of action are aimed at the tumor microenvironment, and it does not have the antioxidant and pro-regenerative functions required for nerve repair. Chinese patent application CN114432498B uses polydopamine-coated hydroxyapatite nanoparticles to achieve light-controlled release of osteogenic factors, but its core lies in the delivery and controlled release of growth factors, and it does not involve the immune regulation function of the material itself.

[0005] Other related technologies such as CN111671914B, CN117919403A, and CN118384293B have innovations in photo-thermal response, drug delivery, antibacterial or improvement of tumor hypoxia, but their application scenarios are not for nerve repair, and most of them rely on the loading of exogenous drugs or biological factors, which have potential toxicity, poor stability, short action time, and other issues. More importantly, existing technologies generally lack the ability to actively intervene in the core pathological link of oxidative stress and immune imbalance after nerve injury.

[0006] Therefore, developing an intelligent nerve repair material with active immune regulation, antioxidant stress, photothermal response and good biocompatibility to realize dynamic remodeling of the nerve regeneration microenvironment and effectively inhibit traumatic neuroma formation has become a key technical problem to be solved in the cross field of nerve regeneration medicine and material science. The present application is proposed in this background. SUMMARY

[0007] The purpose of the present application is to provide a polydopamine modified cerium oxide composite temperature-sensitive hydrogel, by constructing a polydopamine modified cerium oxide nanoparticle / chitosan temperature-sensitive hydrogel composite system, the triple synergistic effect of photothermal response, oxidative stress regulation and immune remodeling is realized for the first time, which has significant innovation and clinical transformation potential in the field of nerve tissue engineering and postoperative neuroma prevention and treatment.

[0008] The polydopamine modified cerium oxide composite temperature-sensitive hydrogel provided by the present application comprises polydopamine modified cerium oxide nanoparticles and a chitosan / β-glycerophosphate sodium temperature-sensitive hydrogel matrix, wherein the polydopamine modified cerium oxide nanoparticles are uniformly dispersed in the hydrogel matrix. The polydopamine modified cerium oxide composite temperature-sensitive hydrogel has near-infrared light responsiveness, temperature sensitivity, tissue adhesion and antioxidant immune regulation functions.

[0009] Preferably, the particle size of the cerium oxide nanoparticles in the polydopamine modified cerium oxide nanoparticles is 50-400 nm. Preferably, the mass concentration of chitosan in the hydrogel matrix is 2%-6%, and the addition amount of β-glycerophosphate sodium makes the pH value of the system 7.2-7.4. Preferably, the mass fraction of the polydopamine modified cerium oxide nanoparticles in the polydopamine modified cerium oxide composite temperature-sensitive hydrogel is 0.1%-5%.

[0010] Preferably, the composite temperature-sensitive hydrogel is an injectable liquid at 4-15°C, and can be converted into a solid adhesive gel under 808 nm near-infrared light irradiation for 5-10 minutes at 37°C.

[0011] The present application also provides a preparation method of the polydopamine modified cerium oxide composite temperature-sensitive hydrogel, comprising the following steps: S1, preparing polydopamine modified cerium oxide nanoparticles: dissolving polydopamine in Tris-HCl buffer solution, adding cerium oxide nanoparticles, reacting for 8-24 hours, and centrifuging and washing to obtain the polydopamine modified cerium oxide nanoparticles; S2, preparing a chitosan / β-glycerophosphate sodium temperature-sensitive hydrogel precursor solution: dissolving chitosan in acetic acid solution, slowly adding β-glycerophosphate sodium under ice bath condition, and adjusting the pH to 7.2-7.4; S3. Add the polydopamine-modified cerium oxide nanoparticles obtained in step S1 to the hydrogel precursor solution obtained in step S2, and mix them evenly under ice bath to obtain a composite thermosensitive hydrogel.

[0012] In the preparation method of the present invention, in step S1, the concentration of polydopamine is 1-5 mg / mL, and the amount of cerium oxide nanoparticles added is 0.5-5 mg / mL; In the preparation method of the present invention, in step S2, the concentration of the chitosan solution is 2%-6%.

[0013] The polydopamine-modified cerium oxide composite thermosensitive hydrogel of this invention can be used to prepare medical materials for promoting peripheral nerve regeneration. The peripheral nerve regeneration includes at least one of the following: repair of complete nerve transection, axonal extension, Schwann cell migration, and myelin regeneration.

[0014] The polydopamine-modified cerium oxide composite thermosensitive hydrogel of this invention can also be used to prepare medical materials for inhibiting the formation of traumatic neuromas. The traumatic neuroma is a painful neuroma formed from the nerve stump after amputation.

[0015] The polydopamine-modified cerium oxide composite thermosensitive hydrogel of this invention can further be used to prepare materials for regulating the local immune microenvironment of nerve injury. The composite thermosensitive hydrogel can promote macrophage polarization towards the M2 phenotype and inhibit M1 phenotype polarization.

[0016] The polydopamine-modified cerium oxide composite thermosensitive hydrogel of the present invention can also be used to prepare medical materials for local photothermal therapy. The photothermal therapy uses 808 nm near-infrared light irradiation to raise the local temperature by 2-5°C. The polydopamine-modified cerium oxide composite thermosensitive hydrogel of the present invention can also be used to prepare injectable in-situ gel-forming nerve repair materials; the nerve repair materials are implanted into the nerve injury site by injection and form an adhesive gel in situ under body temperature and / or near-infrared light irradiation.

[0017] The present invention has the following beneficial technical effects: (1) Significantly improved the antioxidant level of peripheral nerve repair-related cells. The cerium oxide nanoparticles (CeO2) in this invention have unique CeO2 content. 3+ / Ce 4+The reversible redox pair can dynamically scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the damaged microenvironment, effectively maintaining local redox homeostasis, reducing oxidative stress damage, and inhibiting the occurrence and persistence of chronic inflammatory responses from the source. By regulating the immune and oxidative states in the early stages of nerve repair, the material of this invention can significantly promote the survival and functional maintenance of Schwann cells, accelerate the axonal regeneration process, thereby promoting peripheral nerve regeneration and effectively inhibiting the formation of post-amputation traumatic neuroma.

[0018] (2) Sutureless repair of peripheral nerve transection injuries was achieved. Inspired by the excellent wet adhesion properties of mussel adhesive proteins, this invention introduces a polydopamine (PDA) coating onto the surface of cerium oxide nanoparticles. Utilizing the abundant catechol groups on PDA, covalent or non-covalent interactions are formed with the amino and hydroxyl groups on the nerve tissue surface, thereby endowing the hydrogel with excellent tissue adhesion properties. This characteristic enables the material to achieve natural apposition and sealing of the severed ends during nerve transection repair, avoiding the mechanical damage and scar formation problems caused by traditional microsurgical suturing, thus simplifying surgical procedures, improving nerve anastomosis accuracy, and promoting rapid recovery of nerve function.

[0019] (3) It possesses near-infrared light response (808 nm) thermoregulation function. The polydopamine layer endows the material of this invention with excellent near-infrared light absorption and photothermal conversion capabilities. Under irradiation with an 808 nm wavelength laser, the surface temperature of the material can rise by about 3 °C in a short time, forming a mild thermoregulatory effect, promoting local microcirculation and blood perfusion, and enhancing nutrient supply and metabolic activity. At the same time, this thermoregulatory stimulation can activate the proliferation and differentiation process of Schwann cells, promote myelin regeneration and nerve axon extension, thereby accelerating the nerve repair process. Attached Figure Description

[0020] Figure 1 Scanning electron microscope images of cerium oxide (CeO2) and polydopamine-modified cerium oxide (PDA@CeO2) prepared in Example 1 of this invention.

[0021] Figure 2 This refers to the state of the PDA@CeO2 / CS / β-GP prepared according to the present invention.

[0022] Figure 3 This invention demonstrates the adhesion properties of the composite hydrogel to peripheral nerve stumps.

[0023] Figure 4 The results show the in vitro cytotoxicity assessment of the hydrogel of this invention using an extraction method.

[0024] Figure 5 This invention demonstrates the promoting effect of the composite hydrogel on Schwann cell proliferation and differentiation.

[0025] Figure 6To investigate the regulatory effect of the composite hydrogel of this invention on the immunophenotypic polarization of macrophages.

[0026] Figure 7 This invention demonstrates the promoting effect of the composite hydrogel on the repair of peripheral nerve transection injuries.

[0027] Figure 8 This is the result of covering amputation-type peripheral nerve injury with the composite hydrogel of the present invention. Detailed Implementation

[0028] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0029] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0030] This invention belongs to the field of neural tissue engineering and biomedical materials technology, specifically relating to an intelligent composite hydrogel for peripheral nerve repair and neuroma prevention and treatment, and its preparation method.

[0031] To address the limitations of existing neural repair materials, such as limited functionality, lack of dynamic responsiveness, and insufficient active immune regulation, this invention provides a polydopamine-modified cerium oxide composite thermosensitive hydrogel. This material uses a chitosan / β-glycerophosphate sodium thermosensitive hydrogel as a matrix, with uniformly dispersed polydopamine-modified cerium oxide nanoparticles (PDA@CeO2NPs) within it. This system is an injectable liquid at low temperatures and rapidly transforms into a solid adhesive gel upon triggering with body temperature and 808 nm near-infrared light. The cerium oxide nanoparticles, through their CeO2... 3+ / Ce 4+ Reversible redox reactions continuously scavenge reactive oxygen species / nitrogen, reduce oxidative stress, and guide macrophages to polarize towards the pro-repair M2 phenotype; the polydopamine layer endows the material with excellent wet tissue adhesion and photothermal conversion properties, enabling sutureless reattachment of nerve ends and localized gentle thermotherapy.

[0032] This invention integrates multiple mechanisms, including anti-oxidation, immunomodulation, photothermal response, and thermosensitive adhesion, through the functional design of the material itself. It can effectively promote nerve axon regeneration, Schwann cell migration, and myelin formation, and significantly inhibit the occurrence of traumatic neuroma, providing a novel integrated intelligent solution for the repair of peripheral nerve injury.

[0033] Example 1: Preparation of polydopamine-modified cerium oxide composite thermosensitive hydrogel (1) Preparation of polydopamine-modified cerium oxide nanoparticles (PD@CeO2) First, polydopamine was dissolved in Tris-HCl (10 Mm Tris-HCl, pH=8.5) to prepare a 2 mg / ml solution for later use. A certain amount of cerium oxide nanoparticles were placed in the above polydopamine Tris-HCl solution and reacted at 4°C for 12 hours. After the reaction was completed, PD@CeO2 was collected at 8000 rpm for 20 min and washed three times repeatedly with deionized water and anhydrous ethanol.

[0034] (2) Preparation of chitosan hydrogel A certain amount of chitosan solution was dissolved in a 1% acetic acid solution to prepare a chitosan solution (4%). β-GP was slowly added dropwise under an ice bath until the pH value was approximately 7.2-7.4.

[0035] (3) PD@CeO2 is mixed into CS / β-GP solution under ice bath and mixed thoroughly to obtain the final product.

[0036] Figure 1 Scanning electron microscope (SEM) images of cerium oxide (CeO2) and polydopamine-modified cerium oxide (PDA@CeO2) prepared in this embodiment. The size of the cerium oxide nanoparticles is approximately 200 nm.

[0037] Figure 2 The PDA@CeO2 / CS / β-GP near-infrared light-responsive thermosensitive bone wax prepared in this embodiment is liquid at 4℃~15℃. In a 37℃ water environment, it rapidly forms a solid adhesive hydrogel in 5~10 minutes under near-infrared light (808 nm) response. Specifically, as shown in Figure A, the hydrogel of this invention is in a liquid flow state at 4~15℃, exhibiting good injectability and moldability; as shown in Figure B, after irradiation with 808 nm near-infrared light in a 37℃ water environment for 5-10 minutes, it rapidly transforms into a solid adhesive hydrogel, achieving stable in-situ gelation and tissue adhesion; as shown in Figure C, the scanning electron microscope (SEM) observation results show that the hydrogel of this invention has a uniform porous network structure, which is beneficial to cell adhesion, growth, and nutrient exchange.

[0038] Example 2: Tissue Adhesion Performance Test To verify the adhesion performance of the composite hydrogel of this invention to peripheral nerve stumps, the samples were divided into three groups: a conventional chitosan / sodium β-glycerophosphate (CS / β-GP) group, a CeO2 / CS / β-GP group without polydopamine modification, and a PDA@CeO2 / CS / β-GP composite hydrogel group with polydopamine modification (PDA@CeO2 / CS / β-GP) (prepared in Example 1). Fresh rat sciatic nerve tissue (approximately 10 mm in length) was taken, and an equal volume of hydrogel precursor solution was added in a 37 ℃ water bath to allow it to gel in situ and cover the nerve surface. After gel formation, a tensile peel test was performed using an electronic universal testing machine (peeling speed 5 mm / min, initial preload 0.1 N), and the maximum peel force and adhesion work were recorded.

[0039] The results are as follows Figure 3 As shown, it can be seen that the adhesion properties of composite hydrogels can be enhanced by incorporating polydopamine-modified cerium oxide.

[0040] Example 3: In vitro cell compatibility and functional evaluation 1. Cytotoxicity The biocompatibility of the thermosensitive hydrogel was evaluated using an extraction method. The sterilized hydrogel was cut into 6 cm sections. 2 The extract was placed in sterile complete culture medium at a ratio of / mL and extracted at 37℃ for 24h and 72h, respectively, and filtered through a 0.22μm filter membrane for later use. RSC96 cells were seeded at 8000 cells / well in 96-well plates. After 24h of adhesion, the extract was replaced with 200μL / well of the extract at different time points. The control group used complete culture medium. After another 24h of culture, 10μL of CCK-8 was added, and the cells were incubated for 1h. The optical density was measured at 450 nm using a microplate reader. The relative cell proliferation rate was calculated and compared with the negative control.

[0041] The results are as follows Figure 4 As shown in the figure, the composite hydrogel of the present invention has good biocompatibility.

[0042] 2. Promotes Schwann cell proliferation and myelination gene expression The proliferation of RSC96 cells at 7 days was assessed using the CCK-8 assay. RSC96 cells were seeded at 20,000 cells / well in different samples. After incubation at the predetermined time point, the original culture medium was discarded, and 500 ml of basal medium containing 10 μL CCK-8 was added to each well. The cells were incubated at 37°C for 1 h. The OD value of the samples was measured at 450 nm using a microplate reader to obtain absorbance readings.

[0043] To investigate the regulatory effect of this thermosensitive hydrogel on NGF mRNA, a gene related to myelination in RSC96 cells, RSC96 cells were cultured for 7 days according to experimental groups. Cells were collected and washed twice with PBS, followed by extraction of total RNA using the AG RNAex Pro kit according to the manufacturer's instructions. The purity and concentration of the extracted RNA were determined by spectrophotometry. 1 μg of RNA was reverse transcribed into cDNA using PrimeScript RT Master Mix in a 20 μL reaction system. qRT-PCR was performed using SYBR GreenReal-time PCR Master Mix. The PCR reaction conditions were: 95°C pre-denaturation for 60 s; followed by 40 cycles, including 95°C for 15 s denaturation, 60°C for 15 s annealing, and 72°C for 45 s extension. The gene detected was NGF, and the internal reference gene was GAPDH. After amplification, Ct values ​​were automatically generated by the instrument and analyzed using a 2-... ΔΔCt The relative expression levels of NGF mRNA in each group were calculated to evaluate the ability of this hydrogel to promote the expression of Schwann cells myelination-related genes.

[0044] Figure 5 The figures show the promoting effect of the composite hydrogel of the present invention on the proliferation and differentiation of Schwann cells. Figure A shows the results of the CCK-8 assay on the proliferation of Schwann cells, indicating that the composite hydrogel of the present invention can significantly promote the proliferation of Schwann cells. Figure B shows the effect of different matrix samples on the relative expression level of myelination-related gene mRNA (NGF) in RSC96 cells using qRT-PCR technology, indicating that the composite hydrogel of the present invention can significantly promote the myelination of Schwann cells.

[0045] 3. Regulating macrophage polarization First, RAW 264.7 cells were cultured at a rate of 2 × 10⁻⁶. 4 Cells were seeded at a density per well onto the surface of samples in 24-well plates. Control group cells were cultured in DMEM medium, while experimental group cells were cultured in DMEM containing 1 μg / mL lipopolysaccharide (LPS) to simulate an inflammatory microenvironment. All samples were cultured for 3 days at 37°C in a 5% CO2 cell culture incubator. After culture, RAW 264.7 cells from each group were collected, washed twice with PBS, and resuspended in 200 μL of flow cytometry buffer. Anti-CD86 (M1 phenotype) antibody and anti-CD206 (M2 phenotype) antibody were added to the cell suspension, and the cells were incubated at room temperature in the dark for 30 min. Subsequently, the cells were washed twice more with PBS and resuspended in flow cytometry buffer. Flow cytometry was used for detection, and data analysis was performed using FlowJo software to calculate CD86. + and CD206 +The proportion of cells was used to assess the impact of this invention on macrophage polarization.

[0046] Figure 6 The diagram illustrates the regulatory effect of the composite hydrogel of this invention on macrophage immunophenotype polarization. As shown in Figure A, flow cytometry was used to investigate macrophage immunophenotypes. The results showed that, under lipopolysaccharide (LPS) stimulation, the composite hydrogel of this invention significantly inhibited macrophage polarization towards the M1 immunophenotype (Figure B) and promoted macrophage differentiation towards the M2 immunophenotype (Figure C).

[0047] Example 4: In vivo animal experiment—Repair of sciatic nerve transection injury 1. Model Establishment and Processing: In vivo experiments were conducted using SPF-grade male SD rats, housed at 22 ± 2 ℃, 55 ± 5% humidity, and a 12-hour light-dark cycle, with free access to food and water. Preoperative anesthesia was induced with 5% isoflurane and maintained with 1.5-2% isoflurane, with the rats fixed in a supine or lateral decubitus position on the operating table. The surgical area of ​​the right thigh was shaved, disinfected with povidone-iodine, and draped sterilely. A 1.5-2 cm incision was made along the posterolateral aspect of the thigh, and the subcutaneous and muscle layers were bluntly dissected to expose the main trunk of the sciatic nerve. The sciatic nerve was severed at the lower border of the piriformis muscle, creating a standard transverse transection model. The proximal and distal ends of the nerve were then gently aligned, and the thermosensitive hydrogel of this invention was placed between the severed ends. Under body temperature and near-infrared (808 nm) irradiation, the hydrogel gelled in situ and fixed the two severed ends, achieving sutureless adhesive nerve reconnection. After confirming a tension-free state, the muscle layer was sutured with 6-0 sutures, and the skin incision was closed with 4-0 sutures.

[0048] 2. Results Evaluation Eight weeks post-surgery, samples were taken for histological and functional analysis.

[0049] Figure 7 The image shows the promoting effect of the composite hydrogel of this invention on the repair of peripheral nerve transection injuries. Representative immunofluorescence images (Figure A) of regenerated nerve axons (NF200, green) and remyelinated nerves (S100β, red) repaired by the composite hydrogel of this invention are shown. Quantitative analysis results of regenerated nerve axons (Figure B) and remyelinated nerves (Figure C) are also presented. The results indicate that this invention can significantly promote peripheral nerve regeneration.

[0050] Example 5: In vivo animal experiment—suppression of neuroma after amputation 1. Model Establishment and Processing Eight to ten-week-old SD rats were selected and acclimatized in an SPF animal facility under constant temperature and humidity, with a 12-hour light-dark cycle and free access to food and water. After anesthesia, a posterolateral incision was made in the thigh to expose the sciatic nerve. Under a microscope, the sciatic nerve was transversely severed at the level of the lesser trochanter of the femur. The distal residual nerve tissue and its branches were then thoroughly removed to completely eliminate the distal nerve segment, simulating amputation-type peripheral nerve injury. After confirming hemostasis, the pre-prepared hydrogel of this invention was applied to the proximal nerve stump under near-infrared (808nm) irradiation, forming an in-situ gel. The incision was then sutured layer by layer. Postoperatively, wound healing and animal activity were observed daily. Tissue samples were collected at predetermined time points for neuroma formation and immune microenvironment analysis.

[0051] 2. Results Evaluation Eight weeks post-surgery, the nerve stump was dissected and examined, and samples were taken.

[0052] Figure 8 The image shows the composite hydrogel of the present invention covering amputation-type peripheral nerve injuries. The composite hydrogel of the present invention is applied to the stump of the amputation-type peripheral nerve injury. After 8 weeks, the composite hydrogel of the present invention significantly reduced the incidence of traumatic neuroma (Figure A) and decreased the occurrence of autophagy (Figure B), indicating that the composite hydrogel of the present invention can significantly reduce the formation of traumatic neuroma in amputation-type peripheral nerve injuries.

[0053] The PDA@CeO2 / CS / β-GP composite thermosensitive hydrogel provided by this invention successfully integrates multiple biological functions through the synergistic effect of polydopamine and cerium oxide, as well as the support of the thermosensitive hydrogel matrix. It can not only be safely and conveniently applied to nerve injury sites, but also actively create a favorable regenerative microenvironment through mechanisms such as anti-oxidation, immunomodulation, photothermal stimulation and strong adhesion. While promoting high-quality regeneration of peripheral nerves, it effectively inhibits the formation of traumatic neuromas, showing significant innovation and clinical application potential.

Claims

1. A polydopamine-modified cerium oxide composite thermosensitive hydrogel, comprising polydopamine-modified cerium oxide nanoparticles and a chitosan / β-glycerophosphate sodium thermosensitive hydrogel matrix, wherein the polydopamine-modified cerium oxide nanoparticles are uniformly dispersed in the hydrogel matrix; The polydopamine-modified cerium oxide composite thermosensitive hydrogel has near-infrared light responsiveness, thermosensitivity, tissue adhesion, and antioxidant and immunomodulatory functions.

2. The composite thermosensitive hydrogel according to claim 1, characterized in that: The cerium oxide nanoparticles modified with polydopamine have a particle size of 50-400 nm. The chitosan in the hydrogel matrix has a mass concentration of 2% to 6%, and the amount of sodium β-glycerophosphate added makes the pH of the system 7.2-7.4; The mass fraction of the polydopamine-modified cerium oxide nanoparticles in the polydopamine-modified cerium oxide composite thermosensitive hydrogel is 0.1%-5%.

3. The composite thermosensitive hydrogel according to claim 1 or 2, characterized in that: The composite thermosensitive hydrogel is an injectable liquid at 4-15℃, and can be transformed into a solid adhesive gel after being irradiated with 808 nm near-infrared light at 37℃ for 5-10 minutes.

4. A method for preparing the polydopamine-modified cerium oxide composite thermosensitive hydrogel according to any one of claims 1-3, comprising the following steps: S1. Preparation of polydopamine-modified cerium oxide nanoparticles: Polydopamine was dissolved in Tris-HCl buffer, cerium oxide nanoparticles were added, and the reaction was carried out for 8 to 24 hours. After centrifugation and washing, the polydopamine-modified cerium oxide nanoparticles were obtained. S2. Preparation of chitosan / β-glycerophosphate sodium thermosensitive hydrogel precursor solution: Chitosan was dissolved in acetic acid solution, and β-glycerophosphate sodium was slowly added under ice bath conditions to adjust the pH to 7.2-7.4; S3. Add the polydopamine-modified cerium oxide nanoparticles obtained in step S1 to the hydrogel precursor solution obtained in step S2, and mix them evenly under ice bath to obtain a composite thermosensitive hydrogel.

5. The preparation method according to claim 4, characterized in that: In step S1, the concentration of polydopamine is 1-5 mg / mL, and the amount of cerium oxide nanoparticles added is 0.5-5 mg / mL. In step S2, the concentration of the chitosan solution is 2%-6%.

6. The use of the polydopamine-modified cerium oxide composite thermosensitive hydrogel according to any one of claims 1-3 in the preparation of medical materials for promoting peripheral nerve regeneration.

7. The application according to claim 6, characterized in that: The peripheral nerve regeneration includes at least one of complete nerve transection injury repair, axonal extension, Schwann cell migration, and myelin regeneration.

8. The use of the polydopamine-modified cerium oxide composite thermosensitive hydrogel according to any one of claims 1-3 in the preparation of medical materials for inhibiting the formation of traumatic neuromas; The traumatic neuroma is a painful neuroma formed from the nerve stump after amputation.

9. The use of the polydopamine-modified cerium oxide composite thermosensitive hydrogel according to any one of claims 1-3 in the preparation of materials for regulating the local immune microenvironment of nerve injury; The composite thermosensitive hydrogel can promote macrophage polarization towards the M2 phenotype and inhibit M1 phenotype polarization.

10. The use of the polydopamine-modified cerium oxide composite thermosensitive hydrogel according to any one of claims 1-3 in the preparation of medical materials for local photothermal therapy, or in injectable in-situ gel-forming nerve repair materials; The photothermal therapy uses 808 nm near-infrared light irradiation to raise the local temperature by 2-5°C. The nerve repair material is implanted into the nerve injury site by injection, and forms an adhesive gel in situ under body temperature and / or near-infrared light irradiation.

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