Preparation method and application of multifunctional biodegradable medical hydrogel based on polyurethane

Abstract

The invention provides a preparation method and application of multifunctional biodegradable medical hydrogel based on polyurethane. The preparation method comprises the following steps: adding BPU into a phosphate buffer solution to prepare a BPU pre-solution; adding oxidized hyaluronic acid into a phosphate buffer solution to obtain an oxidized hyaluronic acid solution; the preparation method comprises the following steps: mixing mesoporous hydroxyapatite with a VEGF solution to obtain VEGF loaded mesoporous hydroxyapatite microspheres; adding the BPU pre-solution into an oxidized hyaluronic acid solution, then adding chitosan quaternary ammonium salt and nano-silver / chitosan composite microspheres, adding trehalose and EDTA (Ethylene Diamine Tetraacetic Acid) for stirring reaction, and then adding VEGF (Vascular Endothelial Growth Factor) loaded mesoporous hydroxyapatite microspheres to obtain a medical hydrogel precursor; and sub-packaging the medical hydrogel precursor into a sterile syringe, sterilizing, and preserving in a dark place at low temperature to obtain the medical hydrogel. Therefore, the prepared medical hydrogel has better functions of stopping bleeding, resisting bacteria and promoting healing.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of high polymer materials, in particular to a preparation method and application of a multifunctional biodegradable medical hydrogel based on polyurethane. BACKGROUND

[0002] In the field of biomedical materials, medical hydrogels have become one of the core materials in wound repair, drug delivery and other scenarios due to their similar water content, elasticity and good biocompatibility to human soft tissue. However, with the upgrading of clinical needs such as surgical precision and complex chronic wound treatment, traditional medical hydrogels (especially pure polysaccharide gels) gradually expose their performance short board.

[0003] Polysaccharide gels based on oxidized hyaluronic acid and chitosan have low mechanical strength in general due to the intermolecular cross-linking mainly relying on hydrogen bonds and weak electrostatic interactions, which are easily broken in surgical pressing hemostasis, minimally invasive intervention and other scenarios, not only failing to continuously cover the wound, but also possibly causing local inflammatory reactions due to the residual gel fragments. At the same time, the insufficient tensile strength makes it difficult to make the gel into a film-shaped dressing, which cannot be applied to the wounds of active parts such as joints and fingers, limiting its application in skin replacement repair.

[0004] The degradation of pure polysaccharide gels mainly depends on enzymatic hydrolysis or simple hydrolysis, and the degradation rate is significantly affected by environmental pH and enzyme concentration, which is difficult to accurately control: for shallow wounds, traditional gels often cause the wound to lose protection too early due to too fast degradation; while for deep wounds, the slow degradation requires a second surgery to remove the gel, increasing the pain and medical cost of patients, and this contradiction is particularly prominent in the treatment of chronic diabetic foot ulcers. SUMMARY

[0005] The present application aims to solve the problems in the prior art, and provides a preparation method and application of a multifunctional biodegradable medical hydrogel based on polyurethane, which can solve the problem of weak mechanical properties of traditional polysaccharide gels and adapt to complex operations, can realize the regulation of gel degradation rate and multi-dimensional wound treatment, and can improve the flowability and formability of medical hydrogels to adapt to minimally invasive intervention.

[0006] In a first aspect, the present application provides a preparation method of a multifunctional biodegradable medical hydrogel based on polyurethane, which comprises: adding a biodegradable polyurethane BPU into an ethanol-containing phosphate buffer, and preparing a BPU pre-solution under constant temperature water bath conditions.

[0007] Specifically, 3-5 parts by weight of biodegradable polyurethane BPU can be taken, 10-15 parts by weight of sterile phosphate buffer solution (PBS, pH 7.2-7.4) containing 5% ethanol is added, and stirring is carried out in a 40°C constant temperature water bath for 1 hour, during which ultrasonic dispersion is carried out every 15 minutes for 2 minutes at a power of 200W, to prepare a BPU pre-solution with a concentration of 5%-6%, which is cooled to room temperature for standby.

[0008] Further, the BPU is a polycaprolactone PCL-based or polylactic acid PLA-based polyurethane with a molecular weight of 10000-15000 and a segment containing amino groups (-NH2) and hydroxyl groups (-OH).

[0009] Then, oxidized hyaluronic acid is added to the phosphate buffer solution and stirred until completely dissolved to obtain an oxidized hyaluronic acid solution. For example, 6-10 parts by weight of oxidized hyaluronic acid can be added to 20-30 parts by weight of sterile PBS, and stirred at 4°C for 2 hours until completely dissolved to prepare an oxidized hyaluronic acid solution with a mass concentration of 2%-3%, the oxidized degree of the oxidized hyaluronic acid being 20%-30%, and the weight average molecular weight being 50-80 kDa.

[0010] The mesoporous hydroxyapatite is then mixed with a vascular endothelial growth factor VEGF solution to obtain VEGF-loaded mesoporous hydroxyapatite microspheres, and further, the mass ratio of the mesoporous hydroxyapatite to the vascular endothelial growth factor VEGF solution is 0.05-1.5:0.02-0.1.

[0011] For example, 3-5 parts by weight of mesoporous hydroxyapatite can be mixed with a vascular endothelial growth factor VEGF solution at a mass ratio of 1:0.05, and after incubation at 37°C for 1 hour, freeze-drying is carried out to obtain VEGF-loaded mesoporous hydroxyapatite microspheres, the mesoporous hydroxyapatite having a pore size of 2-50nm and a specific surface area of 50-100m 2 / g, and the VEGF solution having a concentration of 100-200μg / mL and being prepared using sterile PBS.

[0012] Then, the BPU pre-solution is added to the oxidized hyaluronic acid solution for reaction, and chitosan quaternary ammonium salt and nano-silver / chitosan composite microspheres are further added, and stirring is continued to obtain a first mixed solution.

[0013] Specifically, the BPU pre-solution can be first added to the oxidized hyaluronic acid solution, and the aldehyde group (-CHO) of the oxidized hyaluronic acid and the amino group of the BPU can be subjected to a Schiff base reaction at room temperature under stirring at a speed of 400 rpm for 20 minutes. Then, 4-6 parts by weight of the quaternary ammonium salt of chitosan, 1-2 parts by weight of the nano-silver / chitosan composite microspheres, and the stirring at room temperature is continued for 30 minutes. The quaternary ammonium salt of chitosan has a deacetylation degree of greater than or equal to 85%, and the nano-silver / chitosan composite microspheres have a nano-silver particle diameter of 10-50 nm.

[0014] The physical cross-linking points formed by the BPU hard segment and the Schiff base chemical cross-linking of O-HA / BPU are synergistic, so that the tensile strength reaches 15-20 kPa, the gel is not easy to break in the scene of surgical operation pressing hemostasis, minimally invasive intervention push injection (such as a 25G needle), and the like, and the push injection force is less than or equal to 12N, so that the doctor is more convenient to operate, and secondary damage to the wound caused by the broken gel is avoided. By adjusting the molecular weight of the BPU soft segment (the molecular weight of the PCL-based BPU is 10000-15000) and the oxidation degree of O-HA (20%-30%), the degradation period of the gel can be flexibly adjusted within 45-90 days: for a shallow wound (such as a skin abrasion), a low molecular weight BPU (10000) is selected, and the degradation rate is greater than or equal to 98% in 45 days to avoid gel residue; for a deep wound (such as muscle defect), a high molecular weight BPU (15000) is selected, and the degradation rate is greater than or equal to 95% in 90 days.

[0015] Further, the nano-silver / chitosan composite microspheres have a diameter of 10-50 nm, and the weight ratio of trehalose to EDTA is (2-4):(0.1-0.3).

[0016] Then, trehalose and EDTA are added to the first mixed solution for stirring reaction, and the VEGF-loaded mesoporous hydroxyapatite microspheres are added to obtain a medical hydrogel precursor.

[0017] Specifically, 2-4 parts by weight of trehalose and 0.1-0.3 parts by weight of EDTA can be added, the pH of the system is adjusted to 7.3 by using a 0.1 mol / L hydrochloric acid solution or a 0.1 mol / L sodium hydroxide solution, and stirring is performed at a speed of 300-500 rpm for 15 minutes. The VEGF-loaded mesoporous hydroxyapatite microspheres are added, ultrasonic dispersion is performed at a power of 350W for 6 minutes, and then vacuum degassing is performed at a vacuum degree of-0.08~-0.1MPa and a temperature of 25°C for 10-15 minutes to obtain the medical hydrogel precursor.

[0018] Finally, the medical hydrogel precursor is divided into sterile syringes, sterilized, and stored in a dark place at low temperature after sterilization to obtain the medical hydrogel.

[0019] Further, the sterilization treatment includes 60Co-γ irradiation sterilization at a dose of 25 kGy, the dose deviation of the 60Co-γ irradiation sterilization is not more than 1 kGy, and the gel temperature is controlled at 20-25°C during irradiation. The 60Co-γ fractionation irradiation sterilization ensures the uniformity of sterilization (sterilization rate ≥ 99.99%), and the cell survival rate of the gel after irradiation is still ≥ 95%, without obvious cytotoxicity (LD50 > 500 mg / kg), which meets the biological safety standard of ISO 10993-5:2009, and reduces the risk of adverse reactions such as allergy and inflammation of patients.

[0020] Specifically, the medical hydrogel precursor can be divided into sterile syringes, gradient solidified at 30°C for 2 hours, then sterilized by 60Co-γ irradiation at a dose of 25 kGy ± 1 kGy, the gel temperature is controlled at 20-25°C during irradiation, and the gel is stored in a dark environment at 4°C after sterilization, to obtain a multifunctional biodegradable medical hydrogel based on polyurethane.

[0021] In this embodiment, the quaternary ammonium salt of chitosan (degree of deacetylation ≥ 85%) cooperates with the nano-silver / chitosan composite microspheres, and the hydrophobic segment of polyurethane can assist in the uniform dispersion of nano-silver, avoiding the cytotoxicity caused by the excessive local concentration of silver ions; at the same time, the gel network formed by oxidized hyaluronic acid (O-HA) and BPU has a more uniform pore size (20-50 μm), which can quickly adsorb platelets, combined with the physical plugging effect of mesoporous hydroxyapatite (pore size 2-50 nm), the rabbit liver wound hemostasis time is stable ≤ 3 minutes, which is 15%-20% shorter than the traditional pure polysaccharide gel.

[0022] The VEGF-loaded microspheres are released more gently in the polyurethane network, and the cumulative release rate of VEGF within 14 days is 85%, the wound closure rate of diabetic rat ulcer model is ≥ 98% in 4 weeks, and the neovascular density is increased by 20% compared with the original scheme, effectively solving the problem of slow healing and easy recurrence of chronic wounds.

[0023] With the help of the hydrophobic segment (such as PCL soft segment) of BPU, the gel can load fat-soluble antibiotics (such as clindamycin, metronidazole) with a loading capacity of 0.5%-1% (based on the total mass of the gel), and through the slow hydrolysis of the polyurethane segment, it realizes 7-14 days of long-acting release, and the blood drug concentration is maintained within the effective therapeutic window (1-5 μg / mL), which can specifically solve the problem of bacterial infection of deep wounds (such as postoperative lacuna of liver abscess).

[0024] The prepared hydrogel has better flowability, can be precisely injected into deep wounds (such as brain surgery cavities and post-liver tumor resection wounds) through a fine caliber syringe (25-27G), and can be quickly shaped (10-15 minutes) after 30℃ gradient solidification (humidity 40%-60%) to avoid treatment area deviation caused by gel flow.

[0025] Further, the polycaprolactone PCL-based biodegradable polyurethane is prepared by mixing polycaprolactone diol (molecular weight 5000-20000) with isophorone diisocyanate (IPDI) at a molar ratio of 1:2, reacting at 80℃ for 2 hours, adding ethylenediamine as a chain extender (molar ratio of polycaprolactone diol: ethylenediamine = 1:1), and continuing to react for 1 hour, to obtain a PCL-based polyurethane containing amino-terminated groups after cooling.

[0026] Further, the oxidized hyaluronic acid is prepared by a sodium periodate oxidation method, specifically: mixing hyaluronic acid with a sodium periodate solution, reacting at room temperature under light-proof conditions for 2-3 hours, adding ethylene glycol to terminate the reaction after the reaction is completed, and freeze-drying after dialysis to obtain oxidized hyaluronic acid.

[0027] For example, hyaluronic acid is mixed with 0.1mol / L sodium periodate solution at a mass-volume ratio of 1:10, reacted at 25℃ under light-proof conditions for 2-3 hours, ethylene glycol is added to terminate the reaction (molar ratio of ethylene glycol to sodium periodate is 1:1), and freeze-drying is performed after dialysis for 72 hours to obtain oxidized hyaluronic acid.

[0028] Further, the preparation method of the nano-silver / chitosan composite microspheres comprises: dissolving chitosan in an acetic acid solution, adding a silver nitrate solution, stirring and reacting, then adding a sodium borohydride solution dropwise until the system is colorless, and continuing to stir to obtain nano-silver / chitosan composite microspheres.

[0029] Specifically, chitosan is dissolved in a 1% acetic acid solution (mass concentration 2%), 0.01mol / L silver nitrate solution is added (mass ratio of chitosan to silver nitrate is 5:1), stirring at 60℃ for 1 hour, 0.1mol / L sodium borohydride solution is added dropwise until the system is colorless (molar ratio of sodium borohydride to silver nitrate is 2:1), and stirring is continued for 30 minutes, then centrifugal separation is performed, and the obtained product is washed with deionized water until it is neutral, and then freeze-drying is performed to obtain nano-silver / chitosan composite microspheres.

[0030] Further, the trehalose is anhydrous trehalose, and the weight ratio of the anhydrous trehalose to the biodegradable polyurethane BPU is (2-4):(3-5).

[0031] Further, in the gradient solidification process, the humidity of the 30℃ static environment is controlled at 40%-60% to avoid rapid water loss on the surface of the gel.

[0032] The medical hydrogel prepared by each embodiment of the present application can load a fat-soluble antibiotic, the loading amount is 0.5%-1% (based on the total mass of the gel), and the antibiotic release period is 7-14 days.

[0033] In a second aspect of the present application, a multifunctional biodegradable medical hydrogel based on polyurethane is provided, which is obtained according to the preparation method of the multifunctional biodegradable medical hydrogel based on polyurethane described in each embodiment of the present application.

[0034] In a third aspect of the present application, the application of a multifunctional biodegradable medical hydrogel based on polyurethane in the preparation of a deep wound repair material for minimally invasive interventional therapy or a film-shaped wound care material for skin replacement repair is provided.

[0035] Advantages The BPU pre-solution in the embodiments of the present application reacts with the oxidized hyaluronic acid solution, and a double crosslinking network is constructed by means of physical crosslinking of the BPU hard segment and chemical crosslinking of the BPU amino group and the oxidized hyaluronic acid aldehyde group, which greatly improves the mechanical strength of the gel, so that the compressive strength is significantly better than that of traditional polysaccharide gels, and the gel can withstand external force during surgical compression hemostasis without being easily broken, and at the same time has good toughness, can be precisely injected through a thin-gauge needle, and solves the problem of easy breakage of traditional gels during operation; and the BPU is made of biodegradable material, and the degradation rate thereof can be flexibly controlled by the molecular weight of the soft segment, and the auxiliary adjustment effect of the oxidized hyaluronic acid, so that the gel degradation period can be accurately matched with the healing period of different types of wounds such as superficial wounds and deep wounds, avoiding the situation of premature failure or the need for secondary surgery removal, and significantly improving the convenience of clinical use.

[0036] Through the synergy of multiple components, the addition of chitosan quaternary ammonium salt and nano-silver / chitosan composite microspheres, and the antibacterial properties of the two, efficient inhibition of common pathogenic bacteria such as Escherichia coli and Staphylococcus aureus is formed, and the risk of wound infection is effectively reduced; the mesoporous hydroxyapatite loaded with VEGF utilizes the slow-release characteristics of the mesoporous structure, so that VEGF is continuously released to induce angiogenesis and accelerate the healing process of chronic wounds; at the same time, the hydrophobic segment of BPU can simultaneously load fat-soluble antibiotics, and the slow hydrolysis characteristics of BPU realize long-acting drug release, breaking the limitation of traditional gels that can only load water-soluble drugs, realizing integrated treatment of hemostasis-antibacterial-promoting healing-targeted drug delivery, and meeting the multidimensional treatment needs of complex wounds.

[0037] BPU pre-solution is prepared by adding phosphate buffer containing ethanol. The ethanol can reduce the interfacial tension of the system, control the gel viscosity in an appropriate range, meet the flowability requirements of fine needle injection in minimally invasive interventional therapy, and quickly shape after injection by the cross-linking reaction of BPU and oxidized hyaluronic acid, avoiding gel flow deviation, adapting to emerging minimally invasive scenarios such as deep surgical gap repair; the gel precursor is divided into sterile syringes and stored at low temperature and away from light, which is convenient for clinical storage and use, and can ensure the stability of the gel performance within the effective period, and improve the efficiency of medical services.

[0038] Trehalose can enhance the stability of the gel through hydrogen bonding, avoiding adverse reactions such as allergy and inflammation caused by residual small molecule cross-linking agents; the addition of EDTA can chelate trace metal ions in the system, preventing ion-induced gel degradation and cytotoxicity; subsequent sterilization and low-temperature light-protected storage further ensure the sterility and activity of the gel components, maintaining a high level of cell survival rate and meeting the biological safety requirements of medical materials, providing reliable and safe protection for clinical application. DETAILED DESCRIPTION

[0039] I. Experimental Description 1. Basic raw materials and equipment Biodegradable polyurethane (BPU): Type A (polycaprolactone-based, molecular weight 10000), Type B (polylactic acid-based, molecular weight 15000); Raw materials: oxidized hyaluronic acid (oxidation degree 25%, molecular weight 60kDa), chitosan quaternary ammonium salt (deacetylation degree 90%), mesoporous hydroxyapatite (pore size 10-30nm), VEGF (concentration 150μg / mL), nano-silver / chitosan composite microspheres (silver particle diameter 20-30nm); Performance testing equipment: universal material testing machine (for measuring compressive strength), ultraviolet spectrophotometer (for measuring antibacterial rate), degradation instrument (for measuring 60-day degradation rate), cell counter (for measuring cell survival rate).

[0040] II. Specific Steps 1. Example 1: Step (1): Take 4.0g Type A BPU and place it in a 50mL beaker, add 12.0g PBS containing 5% ethanol, place it in a 40°C constant temperature water bath, stir at a speed of 300rpm with a magnetic stirrer for 1 hour; pause the stirring every 15 minutes during this period, transfer the beaker to an ultrasonic disperser, and ultrasonic at a power of 200W for 2 minutes (avoid local aggregation), cool to 25°C after stirring is completed, obtain a transparent BPU pre-solution, and reserve for use.

[0041] Step (2): Take 8.0 g of hyaluronic acid into a 100 mL beaker, add 25.0 g of sterile PBS, seal and place in a 4°C refrigerator, stir at a speed of 200 rpm with a magnetic stirrer for 2 hours (prevent temperature rise and cause degradation), until the solution is free of visible particles, and a uniform O-HA solution is obtained, ready for use.

[0042] Step (3): Take 4.0 g of mesoporous hydroxyapatite into a 20 mL centrifuge tube, add 1.33 g of VEGF solution (containing 0.2 g of VEGF), shake for 30 seconds with a vortex oscillator, and then incubate in a 37°C constant temperature incubator for 1 hour (shake every 20 minutes to ensure uniform loading); after incubation, transfer to a freeze dryer (-50°C, 0.01 mbar) and freeze dry for 12 hours to obtain white powder VEGF-loaded microspheres, ready for use.

[0043] Step (4): Transfer the O-HA solution to a 250 mL three-necked flask, add the BPU pre-solution, and stir at a speed of 400 rpm with a mechanical stirrer at room temperature (25°C) for 20 minutes (ensure that the aldehyde groups of O-HA and the amino groups of BPU react fully); then add 5.0 g of chitosan quaternary ammonium salt and 1.5 g of nano-silver composite microspheres, continue stirring at 400 rpm for 30 minutes to obtain a light yellow transparent first mixture.

[0044] Step (5): Add 3.0 g of trehalose and 0.2 g of EDTA to the first mixture, adjust the pH to 7.3 with 0.1 mol / L NaOH solution (monitor in real time with a pH meter), and stir at 300 rpm for 15 minutes; then add the VEGF-loaded microspheres, transfer to an ultrasonic disperser and ultrasonic at a power of 350 W for 6 minutes (to ensure uniform dispersion of the microspheres); finally, transfer the mixture to a vacuum degassing machine and degas at -0.09 MPa and 25°C for 12 minutes to obtain a bubble-free gel precursor.

[0045] Step (6): Divide the gel precursor into 5 g per sterile syringe (10 mL, 25G needle) using a sterile syringe (10 mL, 25G needle); place the divided syringes in a 30°C constant temperature oven for 2 hours (gradient curing to enhance mechanical properties); then use 60Co-γ irradiation for sterilization (dose 25 kGy, dose deviation ±0.5 kGy, irradiation temperature 22°C); after sterilization, store in a 4°C refrigerator away from light to obtain the finished medical hydrogel product.

[0046] 2. Example 2: Replace the A-type BPU 4.0 g in the BPU pre-solution preparation in step (1) with B-type BPU 5.0 g, and the rest of the steps (stirring rate, ultrasonic time, temperature, etc.) are exactly the same as in Example 1. The final medical hydrogel product is obtained.

[0047] 3. Comparative Example 1 (no BPU, traditional polysaccharide gel) Delete step (1) BPU pre-solution preparation, and directly combine step (2) O-HA solution with step (4) first mixed solution preparation: transfer the O-HA solution to a 250 mL three-necked flask, directly add 5.0 g of chitosan quaternary ammonium salt and 1.5 g of nano-silver composite microspheres, stir at 400 rpm for 30 minutes to obtain the first mixed solution; the rest of the steps (VEGF-loaded microsphere preparation, gel precursor preparation, post-processing) are exactly the same as in Example 1. The final traditional pure polysaccharide gel is obtained.

[0048] 4. Comparative Example 2 Only omit the operation of adding 0.2 g of EDTA in step (5) gel precursor preparation, directly add 3.0 g of trehalose to the first mixed solution, and fine-tune the pH to 7.3 with 0.1 mol / L NaOH solution. The subsequent ultrasonic dispersion, vacuum degassing and post-processing steps are exactly the same as in Example 1. The final hydrogel without EDTA is obtained.

[0049] III. Performance Test Result Comparison Table

[0050] Performance advantages of Examples 1-2: The compressive strength, degradation rate, antibacterial rate, and cell survival rate of both examples meet or even exceed industry standards, the viscosity is suitable for minimally invasive injection, the performance is stable after 18 months of storage, proving the effectiveness and universality of the technical solution; Example 2 has slightly higher compressive strength than Example 1 due to the increased amount of BPU (5 g), further verifying the enhancing effect of BPU on mechanical properties.

[0051] Defects of Comparative Example 1: No BPU results in a compressive strength of only 42 kPa (lower than the standard), which cannot withstand surgical compression; the viscosity is 4000 cP (exceeding the minimally invasive adaptation range), and there is slight delamination after storage, proving that BPU is the key to improving the mechanical properties and flowability of the gel.

[0052] Defects of Comparative Example 2: No EDTA results in a cell survival rate of only 88% (toxicity increases), a 60-day degradation rate of 82% (too slow, requiring a second surgery), and local gelation, proving that EDTA is crucial for regulating degradation rate and ensuring biological safety.

[0053] Although the present application is disclosed with reference to the preferred embodiments, it is to be understood that the application is intended to cover all possible modifications and alterations in light of the above teachings. Therefore, the intended scope of the application is to be defined by the following claims.

Claims

1. A process for the preparation of a multifunctional biodegradable medical hydrogel based on polyurethane, characterized in that, The preparation method comprises the following steps: The biodegradable polyurethane BPU is added into the phosphate buffer solution containing ethanol, and a BPU pre-solution is prepared by reaction under constant temperature water bath condition; Oxidized hyaluronic acid is added into the phosphate buffer solution and stirred until completely dissolved to obtain an oxidized hyaluronic acid solution; Mesoporous hydroxyapatite and a vascular endothelial growth factor (VEGF) solution are mixed to obtain VEGF-loaded mesoporous hydroxyapatite microspheres; The BPU pre-solution is added into the oxidized hyaluronic acid solution for reaction, and then chitosan quaternary ammonium salt and nano-silver / chitosan composite microspheres are added for continuous stirring reaction to obtain a first mixed solution; Trehalose and EDTA are added into the first mixed solution for stirring reaction, and then the VEGF-loaded mesoporous hydroxyapatite microspheres are added to obtain a medical hydrogel precursor; The medical hydrogel precursor is divided into sterile syringes, sterilized and stored in a low-temperature and dark place after sterilization, and the medical hydrogel is obtained.

2. The production method according to claim 1, characterized by, The BPU is polycaprolactone (PCL) or polylactic acid (PLA) based polyurethane, the molecular weight is 10,000-15,000, and the chain segment contains amino and hydroxyl groups; The mass concentration of the oxidized hyaluronic acid solution is 2%-3%, the oxidation degree of the oxidized hyaluronic acid is 20%-30%, and the weight-average molecular weight is 50-80 kDa; The mass ratio of the mesoporous hydroxyapatite to the VEGF solution is 0.05-1.5:0.02-0.

1.

3. The method of claim 1, wherein, The diameter of the nano-silver / chitosan composite microspheres is 10-50 nm, and the weight ratio of trehalose to EDTA is (2-4):(0.1-0.3).

4. The method of claim 1, wherein, The sterilization treatment comprises 60Co-γ ray irradiation sterilization at a dose of 25 kGy, the dose deviation of the 60Co-γ ray irradiation sterilization does not exceed 1 kGy, and the gel temperature is controlled at 20-25°C during the irradiation process.

5. The preparation method according to claim 1, characterized in that, The oxidized hyaluronic acid is prepared by a sodium periodate oxidation method, specifically, hyaluronic acid and a sodium periodate solution are mixed, and the reaction is carried out at room temperature for 2-3 hours under light-proof condition, ethylene glycol is added to terminate the reaction after the reaction is completed, and the oxidized hyaluronic acid is obtained by dialysis and freeze-drying.

6. The method of claim 1, wherein, The preparation method of the nano-silver / chitosan composite microspheres comprises the following steps: chitosan is dissolved in an acetic acid solution, silver nitrate solution is added, sodium borohydride solution is added dropwise until the system is colorless after stirring reaction, and the nano-silver / chitosan composite microspheres are obtained by continuous stirring.

7. The preparation method according to claim 1, characterized in that, The trehalose is anhydrous trehalose, and the weight ratio of the anhydrous trehalose to the biodegradable polyurethane BPU is (2-4):(3-5).

8. The method of claim 1, wherein, The compressive strength of the medical hydrogel is ≥80 kPa, the degradation rate within 60 days is ≥95%, the antibacterial rate on Escherichia coli and Staphylococcus aureus is ≥99%, and the cell survival rate is ≥95%.

9. A multifunctional biodegradable medical hydrogel based on polyurethane, characterized in that, The preparation method of the polyurethane-based multifunctional biodegradable medical hydrogel is obtained according to any one of claims 1-8. 10.A polyurethane-based multifunctional biodegradable medical hydrogel in the preparation of a deep wound repair material for minimally invasive interventional treatment or a film-shaped wound care material for skin replacement repair.

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