A physically cross-linked hyaluronic acid hydrogel and its application in the treatment of radiation-induced skin damage

Abstract

The present invention relates to a physically cross-linked hyaluronic acid hydrogel and its application in the treatment of radiation skin damage. The physically cross-linked hyaluronic acid hydrogel is obtained by dispersing deferoxamine and retinoic acid in a physically cross-linked hyaluronic acid hydrogel. The hydrogel material for promoting the repair of radiation skin damage wounds prepared by the present invention has good biocompatibility and excellent anti-inflammatory properties, can maintain the pharmacological activity of the drug, and has a good promoting effect on wound healing.

Description

Technical Field

[0001] The invention relates to the technical field of biomedical materials, and in particular to a physically cross-linked hyaluronic acid hydrogel and application thereof in the treatment of radiation skin damage. Background Art

[0002] Wound and wound healing is an important issue in the field of surgery. Special types of wounds require targeted treatment to achieve healing of wounds that were originally unhealable, or to accelerate the healing of wounds that originally required a long time to heal. With the progress of production and life, radiation has gradually become an indispensable part of medicine, industry and other fields. The damage caused by ionizing radiation to the human body has also become an urgent problem to be solved. Among them, radiation skin damage is one of the most common physical injuries after radiation exposure. Among patients with malignant tumors receiving radiotherapy, more than half will suffer from radiation skin damage at some point, especially in cancers of the breast, perineum, head and neck. Because the skin is also included in the target range of radiation treatment, the acute and chronic skin damage caused after treatment is more significant. The soft tissue in the irradiated area will undergo fibrosis, the skin will gradually lose its normal elasticity, the original sebaceous gland secretion function and skin protection function will be destroyed, the skin will become dry and thin, and the walls of blood vessels and lymphatic vessels will thicken or even occlude, resulting in a decrease in the skin's healing ability. The large amount of reactive oxygen free radicals and inflammatory mediators produced by radiation make it difficult for normal cell physiological activities and protein and lipid metabolism to proceed normally, such as increased apoptosis of endothelial cells and fibroblasts, neovascularization disorders, cell division and differentiation, and cell cycle arrest. Therefore, skin damage caused by radiation exposure is often very difficult to heal.

[0003] Different from the general wound healing process, radiation injury caused by radiation exposure has severe oxidative stress and inflammatory response. In the acute phase after radiation, a large amount of reactive oxygen species (ROS) is generated in cells. The accumulated ROS in cells destroy the cell structure, directly leading to cell damage and inducing the aggregation of inflammatory cells, which then enters a long-term inflammatory phase. The activation of fibroblasts through transforming factor β1 (TGF-β1) is the core. The long-term chronic inflammatory response and fibrosis process make the radiation wounds unhealed for a long time. In addition, due to the irreversible DNA breakage, excessive deposition of extracellular matrix and abnormal cell cycle caused by radiation, the radiation wounds are less sensitive to treatment than general wounds. At present, there is a lack of standardized guidelines for the treatment of radiation injury at home and abroad. Most of the treatments for radiation skin injury are ineffective, and some even have significant side effects. Common treatments are mainly based on anti-inflammatory, anti-oxidant, anti-infective, promoting angiogenesis, supplementing growth factors, and providing a moist healing environment, but the treatment effect is limited. For example, although growth factor products are widely used in wounds, growth factors that can accelerate healing in general wounds cannot play a significant role in radiation ulcers. The tissues in radiation ulcer wounds are inert, insensitive to treatment, and the course of the disease is repeated. Another example is that drugs with anti-inflammatory effects such as retinoic acid have been used to treat skin diseases in the past. Although they have therapeutic effects on common skin injuries such as vitiligo and acne vulgaris, they often cause additional damage to the skin surface due to their own skin irritation when treating radiation skin injuries. The treatment of radiation skin injuries is a long process. The damage after irradiation is divided into acute and chronic stages. In the acute stage within six months, the skin pathological reaction may range from grade I erythema and hair follicle damage to pigmentation, blisters and even grade IV necrotic ulcers, while the long-term damage of more than six months is manifested as atrophic dermatitis, fibrosis, and ulcers that do not heal for a long time. Acute radiation dermatitis resembles a burn injury and may subside after a few weeks in mild cases. However, if the underlying injury is not taken seriously and treated, the reaction may persist and cause complications, which can have a significant negative impact on the patient's quality of life.

[0004] Since the late 20th century, with the rapid development of tissue engineering, many biomaterials have been widely used in the medical field, especially in wound healing. Biomaterials have the advantages of good cell biocompatibility, degradability, low toxicity and side effects, and certain biological activity that promotes repair. As a macromolecular polysaccharide widely present in organisms, hyaluronic acid is used in the biomedical field because of its good biocompatibility, easy large-scale production, and functions such as regulating osmotic pressure, maintaining tissue morphology, lubrication, and buffering stress. In order to meet practical applications, hyaluronic acid often needs to be constructed into a three-dimensional mesh gel structure during the preparation process, and during the construction, hyaluronic acid is often modified by a chemical crosslinker to gel it and obtain a gel with diverse mechanical properties and controllable degradation time. The chemical crosslinking method improves the performance of hyaluronic acid gel, but the use of crosslinkers has potential cytotoxicity and causes local side effects. Such adverse reactions reduce the application in difficult-to-heal wounds, inflammation, etc. Therefore, it is extremely urgent to develop a green synthetic and non-cytotoxic hydrogel that can treat radiation skin damage. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a physically cross-linked hyaluronic acid hydrogel of a composite small molecule drug deferoxamine and retinoic acid, which is used as a tissue repair material for treating radiation-induced skin damage, thereby minimizing the effect of chemical cross-linking agents on the biocompatibility of the material.

[0006] The first object of the present invention is to provide a physically cross-linked hyaluronic acid hydrogel, wherein the physically cross-linked hyaluronic acid hydrogel is obtained by dispersing deferoxamine and retinoic acid in a hyaluronic acid hydrogel cross-linked by a physical method, wherein the physical method is a freeze-thaw method.

[0007] Furthermore, the freeze-thaw method is to freeze at -25 to -15°C and then thaw at 1 to 10°C.

[0008] The second object of the present invention is to provide a method for preparing the above-mentioned physically cross-linked hyaluronic acid hydrogel, comprising the following steps:

[0009] S1. preparing a hyaluronic acid aqueous solution into a gel by a freeze-thaw method under acidic conditions;

[0010] S2. The gel obtained in step S1 is placed in a buffer system with a pH of 7-8, and then placed in water until the pH of the aqueous solution rises to 6.8-7.2 to prepare a neutral gel. Deferoxamine and retinoic acid are added to the neutral gel, and the physically cross-linked hyaluronic acid hydrogel is obtained by a freeze-thaw method.

[0011] Furthermore, the molecular weight of the hyaluronic acid is 890,000-1.5 million.

[0012] Furthermore, in step S1, the acidic condition is to adjust the pH to 1-3 with hydrochloric acid.

[0013] Furthermore, the concentration of hydrochloric acid is 0.5-1.5 mol / L.

[0014] Furthermore, in step S2, the concentration of deferoxamine is 50-70 umol / L.

[0015] Furthermore, in step S2, the concentration of retinoic acid is 40-60 umol / L.

[0016] The third object of the present invention is to provide the use of the above-mentioned physically cross-linked hyaluronic acid hydrogel in the preparation of drugs for treating radiation skin damage.

[0017] In the present invention, hyaluronic acid is used to prepare a hydrogel that promotes the repair of radiation skin damage by freeze-thawing method without an external cross-linking agent. The applicant found in preliminary experiments that the performance of the drug-loaded hyaluronic acid hydrogel prepared by combining retinoic acid and deferoxamine alone, preparing silk fibroin hydrogel by a physical method of temperature concentration regulation, and preparing drug-loaded hyaluronic acid hydrogel by other physical methods in the treatment of radiation skin damage is not ideal, while the drug-loaded hyaluronic acid hydrogel prepared by freeze-thawing method alone can effectively treat radiation skin damage, maintain the pharmacological activity of the drug, do not affect cell activity, and have a good promoting effect on wound healing.

[0018] Among them, (1) hyaluronic acid is selected as the gel matrix, not only because it is a naturally occurring substance in the body, does not produce harmful products, can minimize the inflammatory response caused by the material and the potential cytotoxicity caused by chemical residues, but also hyaluronic acid has a full water retention effect. The negative ion repulsion effect formed by the carboxyl group in its disaccharide unit allows it to bind more than 100 times its own water, providing a good environment for the healing of radiation wounds. (2) Compared with other physical methods, the freeze-thaw method has a simple preparation process, low cost, safety and stability, and little effect on the characteristics of the material itself. It can give full play to the auxiliary therapeutic effect of the matrix material. Through the freeze-thaw process, the solvent in the homogeneous solution is frozen, and the hydrogen bonds between the molecular chains in the solute region form discrete physical cross-linking points, forming a three-dimensional mesh gel under the action of non-covalent bonds. It not only has good water retention performance, but also has injectability and spreadability. (3) Retinoic acid is a derivative of vitamin A. Retinoic acid can promote skin regeneration and repair through anti-inflammatory, promoting fibroblast proliferation, and promoting the regeneration of skin appendages such as hair follicles. However, retinoic acid was found to be irritating in wounds, causing local redness and swelling, epidermal loss, and the specific mechanism is not yet clear; there is no report mentioning the effect of deferoxamine on the repair of radiation skin damage. The applicant tested the physical hyaluronic acid hydrogel of composite RA and DFO using the rabbit back skin drug stimulation experiment in a preliminary experiment, and scored the degree of rabbit skin lesions. The results showed no obvious stimulation. The present invention prepares a hyaluronic acid hydrogel loaded with small molecule drugs deferoxamine and retinoic acid by a safe and gentle physical cross-linking method. The hydrogel three-dimensional network structure can protect the medium, reduce the oxidation of conjugated double bonds in retinoic acid, evenly disperse the medium, reduce the toxicity of local high-concentration drugs and the irritation of simple drugs, and has a significant effect on the treatment of special wounds.

[0019] The fourth object of the present invention is to provide a drug for treating radiation-induced skin damage, which comprises the above-mentioned physically cross-linked hyaluronic acid hydrogel.

[0020] Furthermore, the physically cross-linked hyaluronic acid hydrogel is an injectable dosage form.

[0021] By means of the above scheme, the present invention has at least the following advantages:

[0022] The present invention aims at the key problem of poor treatment effect on radiation skin damage at present, and provides a physical cross-linked hyaluronic acid hydrogel of composite small molecule drugs deferoxamine and retinoic acid, which is used for tissue repair materials for treating radiation skin damage. Physical cross-linked hyaluronic acid hydrogel has good biocompatibility and is suitable as a carrier of small molecule drugs deferoxamine and retinoic acid. It can promote the healing of radiation skin ulcers while maintaining the pharmacological activity of the drugs, and has a good promoting effect on wound vascularization and inflammation control. The present invention also expands the biomedical application of hyaluronic acid materials in the field of special types of wounds, and also provides a new method for preparing hyaluronic acid materials with better biocompatibility.

[0023] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a description of the preferred embodiments of the present invention in conjunction with detailed drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to make the contents of the present invention more clearly understood, the present invention is further described in detail below based on specific embodiments of the present invention in conjunction with the accompanying drawings.

[0025] Figure 1 Schematic diagram of physically cross-linked hyaluronic acid hydrogel composited with deferoxamine and retinoic acid;

[0026] Figure 2 Schematic diagram of push injection of physically cross-linked hyaluronic acid hydrogel;

[0027] Figure 3 This is the microscopic morphology of physically cross-linked hyaluronic acid hydrogel;

[0028] Figure 4 This is the Raman spectrum of physically cross-linked hyaluronic acid hydrogel;

[0029] Figure 5 To test the effects of deferoxamine and retinoic acid on cell growth after irradiation injury;

[0030] Figure 6 Fluorescence images of cell proliferation;

[0031] Figure 7 Results of cell clone formation experiments;

[0032] Figure 8 For wound healing images;

[0033] Fig. 9 The evaluation of the effect of hyaluronic acid hydrogel loaded with deferoxamine and retinoic acid on promoting the angiogenesis of endothelial cells and the evaluation of the silk fibroin hydrogel in improving the angiogenesis of cells under the same conditions in the comparative example;

[0034] Fig.10 The purpose is to evaluate the function of freeze-thaw hyaluronic acid hydrogel in enhancing the migration of cells after irradiation and to evaluate the ability of photo-crosslinked hyaluronic acid hydrogel in promoting the migration of cells after irradiation in a comparative example;

[0035] Among them, p<0.05, * indicates compared with photo-cross-linked hydrogel; # indicates compared with blank control group. DETAILED DESCRIPTION

[0036] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0037] In the following embodiments, unless otherwise specified, irradiation refers to X-rays, a single irradiation is adopted, the irradiation intensity unit is Gy, the irradiated area is placed on the irradiation plate, and the 4Mev electron beam generated by the linear accelerator is used for local irradiation, the non-irradiated area is shielded by lead plates, and the absorbed dose rate is 598MU / min.

[0038] Example 1

[0039] (1) Preparation of hyaluronic acid hydrogel under acidic conditions

[0040] Macklin's sodium hyaluronate powder has a molecular weight of about 1 million. Dissolve the hyaluronic acid powder in pure water at room temperature to a concentration of 10 mg / ml, stir magnetically at 300 rpm until completely dissolved, adjust the pH to 2 with 1 mol / L hydrochloric acid, centrifuge at 4000 r / min for 20 minutes twice to remove bubbles. Freeze the solution at -20°C for 7 days and thaw at 4°C for 12 hours.

[0041] (2) Physically cross-linked hyaluronic acid hydrogel loaded with deferoxamine and retinoic acid

[0042] The gel was placed in a phosphate buffer at pH 7 for 4 hours, and then replaced with deionized water until the pH of the aqueous solution increased to 7, thereby obtaining a hyaluronic acid hydrogel. After adding 60umol / L deferoxamine and 50umol / L retinoic acid to the hyaluronic acid hydrogel, the mixture was physically mixed, frozen at -20°C for 7 days, and thawed at 4°C for 12 hours to obtain a sample, i.e., a physically cross-linked hyaluronic acid hydrogel of composite small molecule drugs deferoxamine and retinoic acid.

[0043] Example 2

[0044] (1) Preparation of hyaluronic acid hydrogel under acidic conditions

[0045] Macklin's sodium hyaluronate powder has a molecular weight of about 1.5 million. Dissolve the hyaluronic acid powder in pure water at room temperature to a concentration of 10 mg / ml, stir magnetically at 300 rpm until completely dissolved, adjust the pH to 2 with 0.5 mol / L hydrochloric acid, centrifuge at 4000 r / min for 20 minutes twice to remove bubbles. Freeze the solution at -15°C for 5 days and thaw at 10°C for 10 hours.

[0046] (2) Physically cross-linked hyaluronic acid hydrogel loaded with deferoxamine and retinoic acid

[0047] The gel was placed in a phosphate buffer at pH 8 for 3 hours, and then replaced with deionized water until the pH of the aqueous solution increased to 7, thereby obtaining a hyaluronic acid hydrogel. After adding 50umol / L deferoxamine and 60umol / L retinoic acid to the hyaluronic acid hydrogel, the mixture was physically mixed, frozen at -15°C for 6 days, and thawed at 7°C for 12 hours to obtain a sample, i.e., a physically cross-linked hyaluronic acid hydrogel of composite small molecule drugs deferoxamine and retinoic acid.

[0048] Example 3

[0049] (1) Preparation of hyaluronic acid hydrogel under acidic conditions

[0050] Macklin's sodium hyaluronate powder has a molecular weight of about 890,000. Dissolve the hyaluronic acid powder in pure water at room temperature to a concentration of 10 mg / ml, stir magnetically at 300 rpm until completely dissolved, adjust the pH to 1 with 1.5 mol / L hydrochloric acid, centrifuge at 4000 r / min for 20 minutes twice to remove bubbles. Freeze the solution at -25°C for 4 days and thaw at 1°C for 12 hours.

[0051] (2) Physically cross-linked hyaluronic acid hydrogel loaded with deferoxamine and retinoic acid

[0052] The gel was placed in a phosphate buffer at pH 7 for 4 hours, and then replaced with deionized water until the pH of the aqueous solution increased to 7, thereby obtaining a hyaluronic acid hydrogel. After adding 40umol / L deferoxamine and 70umol / L retinoic acid to the hyaluronic acid hydrogel, the mixture was physically mixed, frozen at -25°C for 7 days, and thawed at 3°C ​​for 12 hours to obtain a sample, i.e., a physically cross-linked hyaluronic acid hydrogel of composite small molecule drugs deferoxamine and retinoic acid.

[0053] Example 4

[0054] (1) Performance test of physically cross-linked hyaluronic acid hydrogels composited with deferoxamine and retinoic acid (the gel prepared in Example 1 was used for the test in this example)

[0055] The injectability of the hydrogel before and after drug loading was tested by injecting with a 1 ml syringe with and without a needle (23G). Figure 2 .

[0056] (2) Scanning electron microscopy test of physically cross-linked hyaluronic acid hydrogels with deferoxamine and retinoic acid

[0057] The hydrogel prepared in Example 1 was freeze-dried and then a cube with a side length of about 10 mm was obtained. The cube was attached to the round table of an electron microscope through a conductive adhesive and sprayed with platinum (10 mA, 90 s). The S-4800 scanning electron microscope was used for testing at a test voltage of 3 kV to collect the nanostructure micromorphology of the physically cross-linked hyaluronic acid gel. Figure 3 It can be seen that the microscopic morphology of the hyaluronic acid hydrogel prepared by the present invention presents a bundle-like long fiber network structure that is cross-linked with each other.

[0058] (3) Raman spectroscopy of physically cross-linked hyaluronic acid hydrogels containing deferoxamine and retinoic acid

[0059] Calibrate the Raman spectrometer to 520.7 cm -1 The peak of the single crystal silicon wafer was used as the benchmark, and the uniform parameters were set to test HA and DFO-RA-HA. The spectra of different substances were collected, and the obtained spectra were statistically processed using Matlab software. The NGSLabSpec software was used to smooth and correct the baseline for further observation and statistics. The results are shown in Figure 4 In the Raman spectrum of the composite drug-loaded hydrogel system, DFO is observed at 1050cm -1 Characteristic peak, RA at 1580cm -1 The characteristic peaks at 667 and 945 cm -1 It is the typical absorption peak of HA.

[0060] (4) Detection of the effects of deferoxamine and retinoic acid on the growth of radiation-damaged endothelial cells

[0061] Cell proliferation experiments were performed on cells 24h, 48h, and 72h after intervention, and the optical density of each well was measured at a wavelength of 450nm using an enzyme marker to calculate cell survival. The concentrations of deferoxamine and retinoic acid suitable for cell growth after radiation damage were detected.

[0062] Results Figure 5 and Figure 6 In the CCK-8 experiment, free DFO had obvious cytotoxicity to irradiated cells, and the toxicity increased with the increase of DFO concentration. When compounded with hyaluronic acid hydrogel, the drug cytotoxicity was alleviated under the same conditions. At a concentration of 60uM, endothelial cells had strong angiogenesis ability and strong ability to promote wound healing. Therefore, the preferred DFO concentration was 60uM. RA had no obvious cytotoxicity to HUVECs. In order to screen the concentration of RA drugs, HA-RA was used to intervene in irradiated cells for EdU cell proliferation experiment. Figure 6The blank control is the PBS group, the HA group is the pure HA gel group, and the other three groups are HA hydrogels compounded with retinoic acid, in which the RA concentrations are different. It can be observed that the number of EdU-positive cells under the microscope increases with the increase of RA concentration, the proliferation ability is enhanced, and the cell proliferation increases, but when the concentration is 100uM, the proliferation is lower than 50uM, so 50uM is the preferred RA concentration. The following experiments are all conducted at this preferred concentration.

[0063] (5) Effects of physically cross-linked hyaluronic acid hydrogels with deferoxamine and retinoic acid on the growth of radiation-damaged HUVECs

[0064] The cell clone formation experiment and fluorescence staining were used to test the effect of the composite material on the biological behavior of cells. Figure 7 . Figure 7 The control group was a pure HA gel group, and the drug-loaded group was a HA hydrogel containing composite deferoxamine and retinoic acid prepared in Example 1.

[0065] visible, Figure 7 In the cloning experiment, there was no significant difference in the number of cell clones formed in the low-dose irradiation group (2-4Gy) between the simple HA control group and the drug-loaded group, but in the high-dose irradiation group (6-10Gy), the cloning rate in the drug-loaded group was higher than that in the control group.

[0066] (6) Experiment on promoting the healing of radiation-induced skin ulcers

[0067] A rat radiation skin injury model was constructed as a test object to test the therapeutic effect of physically cross-linked hyaluronic acid hydrogel with composite deferoxamine and retinoic acid on actual radiation skin injury. The control group was a normal saline group and a drug group using each drug alone. After anesthesia, the shaved area on the back of the rat was irradiated with 45Gy of electron beam, and the irradiated area was about 45mm×50mm. In the blank control group, 60uM DFO-HA group, 50uM RA-HA group and DFO-RA-HA group, it can be observed that the skin after irradiation showed hair loss and erythema at 2 weeks, and different degrees of skin tissue erosion and necrosis appeared around 30 days, forming radiation ulcer wounds. At 45 days, the healing of the wounds in each group was observed to varying degrees.

[0068] Results Figure 8At 15 days after irradiation, each group gradually developed early dermatitis symptoms, with local hair loss, erythema and desquamation. At 30 days, the control group had obvious ulcer wounds, while the DFO-HA group and RA-HA group had smaller ulcer wounds, showing a healing trend. Although there was no hair follicle regeneration in the combined drug-loaded gel group, only a small wound was formed. At 45 days, the combined treatment group had completely epithelialized and new hair follicles appeared. The blank group still had a large ulcer wound, showing a slow healing trend. The ulcers in the other two groups healed to varying degrees. The wound healing effect of the combined drug-loaded group was better than that of the single drug-loaded group, indicating that DFO-RA-HA gel can effectively protect against radiation-induced skin damage, accelerate wound healing and protect skin appendages.

[0069] Comparative Example 1

[0070] Silk protein nanofiber hydrogel (SF) was prepared by physical method, specifically cooling-heating-concentrating method. The obtained silk protein hydrogel concentration was 1%. The same dose of DFO and RA was compounded to test the effect of the composite gel on the endothelial cell tube formation ability. The blank control group was PBS test solution. The results are as follows Fig. 9 shown.

[0071] from Fig. 9 It can be seen that compared with the blank control group, the silk protein nanofiber hydrogel composite of DFO and RA has a significant promoting effect on the angiogenesis ability of endothelial cells. Multiple nodes are formed between endothelial cells, and incomplete lumen formation can be seen. The HA hydrogel composite of DFO and RA forms a complete lumen structure within 8 hours, with a longer tube length and significantly better cell proliferation than the silk protein nanofiber hydrogel.

[0072] Comparative Example 2

[0073] Hyaluronic acid was treated by a physical method of photocrosslinking, specifically methacrylated hyaluronic acid was crosslinked under ultraviolet light to prepare a hydrogel (HAMA). The effect of contrast materials on the migration ability of HDF-α cells was detected by cell scratch test.

[0074] The results showed that for irradiated HDF-α, physically cross-linked hyaluronic acid hydrogels can both promote cell movement. However, compared with HAMA, the percentage of scratched areas healing within 8 hours after use of freeze-thaw gel was higher, and the ability to promote migration was better. This indicates that freeze-thaw physical gels may have a stronger ability to promote fibroblast migration and wound coverage during wound healing and granulation tissue formation.

[0075] In summary, the hyaluronic acid hydrogel prepared by the physical cross-linking method minimizes the impact of chemical cross-linkers on the biocompatibility of the material. At the same time, based on the moisturizing and water-retaining properties of hyaluronic acid, it is proposed to be applied to radiation-induced skin damage, and combined with small molecule drugs that have the effects of promoting angiogenesis and anti-inflammatory, to prepare composite materials in multiple dimensions, which is expected to solve the clinical problem that radiation-induced skin damage is difficult to effectively treat.

[0076] Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. Use of a physically cross-linked hyaluronic acid hydrogel in the preparation of a drug for treating radiation skin damage, characterized in that: The physically cross-linked hyaluronic acid hydrogel is obtained by dispersing deferoxamine and retinoic acid in a hyaluronic acid hydrogel cross-linked by a physical method, wherein the physical method is a freeze-thaw method; The preparation method of the physically cross-linked hyaluronic acid hydrogel comprises the following steps: S1. preparing a hyaluronic acid aqueous solution into a gel by a freeze-thaw method under acidic conditions; S2, placing the gel obtained in step S1 in a buffer system of pH 7-8, and then placing it in water until the pH of the aqueous solution rises to 6.8-7.2 to prepare a neutral gel, adding deferoxamine and retinoic acid to the neutral gel, and obtaining the physically cross-linked hyaluronic acid hydrogel by a freeze-thaw method; The molecular weight of the hyaluronic acid is 890,000-1.5 million; The freeze-thaw method is to freeze at -25 to -15°C and then thaw at 1 to 10°C.

2. The use according to claim 1, characterized in that: In step S1, the acidic condition is to adjust the pH to 1-3 with hydrochloric acid.

3. The use according to claim 1, characterized in that: In step S2, the concentration of deferoxamine is 50-70 umol / L.

4. The use according to claim 1, characterized in that: In step S2, the concentration of retinoic acid is 40-60 umol / L.

5. The use according to claim 1, characterized in that: The physically cross-linked hyaluronic acid hydrogel is an injectable dosage form.

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