Temperature-sensitive injectable anti-adhesion double network hydrogel and preparation method thereof

Abstract

The application discloses a temperature-sensitive injection type anti-adhesion double-network hydrogel and a preparation method thereof, relates to the technical field of gel matrixes, and comprises, according to weight / volume percentage (w / v), poloxamer 407 15%-25%, poloxamer 188 2%-8%, sodium alginate 1.0%-1.5%, water-soluble chitosan derivative 0.5%-1.0%, CaCO3 0.2%-0.5%, GDL 0.1%-0.3%, mannitol 1.5%-2.5%, sodium chloride and phosphate buffer solution with a pH value of 6.8-7.4; the osmotic pressure of the hydrogel is 280-320 mOsm / kg, and the gelation temperature is 30 DEG C-34 DEG C; the double-network structure of the poloxamer temperature-sensitive network and the alginate delayed crosslinking network is arranged, the hydrogel realizes the cooperation of rapid gelation and long-term structural stability, significantly improves the anti-washing capacity of the material, and reduces the loss of the material in a postoperative exudation environment; the modified chitosan component is arranged, dynamic reversible adhesion of a wet tissue surface is realized, and the hydrogel can stably cover irregular and complex wounds.

Description

Technical Field

[0001] This invention relates to the field of gel matrix technology, specifically to a thermosensitive injectable anti-adhesion dual-network hydrogel and its preparation method. Background Technology

[0002] Postoperative adhesions are a common and serious complication of abdominal, gynecological, and orthopedic surgeries. Their mechanisms primarily involve tissue damage, inflammatory responses, fibrin deposition, and fibroblast proliferation. Postoperative adhesions can lead to chronic pain, intestinal obstruction, and infertility, and significantly increase the difficulty and risk of subsequent surgeries.

[0003] Currently, commonly used anti-adhesion methods in clinical practice mainly include hyaluronic acid gels, carboxymethyl cellulose membranes, and absorbable barrier materials such as polylactic acid. These materials primarily achieve tissue isolation by forming physical barriers. In actual clinical applications, postoperative wounds are usually in a moist, exudative, and dynamic environment. Existing materials have the following shortcomings: they are easily washed away and detached in a moist environment, have difficulty adhering stably to complex wounds, lack mechanical strength, do not provide long-lasting coverage, and have poor adaptability to irregular tissue surfaces. In addition, although single thermosensitive gels have good injectability, their structure is weak after gelation and cannot remain stable in a dynamic environment for a long time. Summary of the Invention

[0004] The purpose of this invention is to provide a temperature-sensitive injectable anti-adhesion dual-network hydrogel and its preparation method, so as to solve the problems of poor wet adhesion, easy erosion by exudate, insufficient mechanical strength, and uncontrollable degradation of existing anti-adhesion materials.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] A thermosensitive injectable anti-adhesion dual-network hydrogel, by weight / volume percentage (w / v), comprises poloxamer 407 18%–22%, poloxamer 188 3%–6%, sodium alginate 1.0%–1.5%, modified chitosan 0.5%–1.0%, CaCO3 0.2%–0.5%, GDL 0.1%–0.3%, mannitol 1.5%–2.5%, sodium chloride, and phosphate buffer with a pH of 6.8–7.4; the modified chitosan is carboxymethyl chitosan or quaternized chitosan, with a degree of deacetylation ≥95% and a molecular weight of 80–120 kDa; the hydrogel has an osmotic pressure of 280–320 mOsm / kg and a gelation temperature of 30℃–34℃.

[0007] Furthermore, the hydrogel has a dual-network structure: the first network is a poloxamer thermosensitive physical cross-linking network, and the second network is an alginate-calcium ion delayed-release chemical cross-linking network induced by the CaCO3 / GDL sustained-release system; it is liquid at 20℃-25℃ with a viscosity of 500-2000 cP, allowing it to pass smoothly through conventional injection needles; it cures within 30-60 seconds after contact with an environment of 36℃-37℃, and the wet adhesion strength after 24 hours of curing is ≥0.5 N / cm. 2 It can adhere stably to moist, exudative wounds and completely degrade in vivo in 7-14 days, avoiding the risk of long-term residue.

[0008] Its preparation method includes the following steps:

[0009] S1. Low-temperature dissolution of poloxamer: Poloxamer 407 and poloxamer 188 were dispersed in phosphate buffer solution with a pH of 6.8-7.4 at 2℃-8℃ and dissolved at a shear rate of 50-500 s. -1 Stir until completely dissolved;

[0010] S2, Mixing basic components: Add sodium alginate and water-soluble chitosan derivative sequentially, at a shear rate of 50-500 s. -1 Stir until evenly dispersed;

[0011] S3. Adjusting osmotic pressure: Add mannitol and sodium chloride to adjust the osmotic pressure of the system to 280-320 mOsm / kg;

[0012] S4. Constructing a sustained-release crosslinking system: After dispersing CaCO3 particles, add GDL and stir to form a homogeneous sol;

[0013] S5. Post-processing: After multi-stage step-by-step pre-filtration combined with terminal aseptic filtration, the solution is filled into pre-filled syringes and stored in a low-temperature cold chain.

[0014] Furthermore, the stirring time in S1 is 3-5 hours; in S2, stirring is performed for 1-2 hours after each addition of a component, with the system temperature maintained at 2℃-8℃ throughout the process, and the temperature fluctuation range ≤±1℃; the optimal shear rate in the laboratory is 250-350 s. -1 Industrial production can use shear rate / material volume ratio instead of specific laboratory parameters to adapt to the needs of large-scale production.

[0015] Furthermore, the S5 uses a multi-stage pre-filtration process, employing 1μm and 0.45μm microporous membranes to remove large particles and agglomerates, followed by sterile final filtration with a 0.22μm polyethersulfone microporous membrane. The filtration process is maintained at a temperature of 2℃-8℃ to prevent premature gel cross-linking. The final filtration pressure is 0.08-0.12MPa, and the filtration speed is 10-15mL / min. The filling accuracy is ±0.05mL / vial, and the product is stored in a low-temperature cold chain at 2℃-8℃ with a relative humidity of 40%-60% to ensure batch consistency and product stability.

[0016] Furthermore, the hydrogel of this invention meets the biosafety standards: cytotoxicity was tested according to GB / T16886.5 standard, and the relative proliferation rate of L929 cells was ≥90%, with no cytotoxicity; intradermal reaction was tested according to GB / T16886.10 standard, and no erythema, edema, or irritation was observed in rabbits 72 hours after intradermal injection, meeting the biosafety requirements for medical implant materials.

[0017] Compared with existing technologies, this invention provides a thermosensitive injectable anti-adhesion dual-network hydrogel and its preparation method. By setting a dual-network structure of a poloxamer thermosensitive network and an alginate delayed crosslinking network, it achieves synergy between rapid gelation and long-term structural stability, significantly improving the material's resistance to erosion and reducing material loss in the postoperative exudate environment. By setting a water-soluble chitosan derivative component, it achieves dynamic reversible adhesion to moist tissue surfaces, which can stably cover irregular and complex wounds. By setting a sustained-release crosslinking system of CaCO3 and GDL, it avoids pre-gelation before injection, ensuring the injectability of the material. At the same time, the crosslinking process is mild and controllable, without affecting tissue compatibility. Through the synergistic regulation of the dual-network structure, it achieves controllable degradation in 7-14 days, which not only ensures the barrier coverage effect during the high incidence of postoperative adhesions, but also avoids the inflammatory risks caused by long-term material residue. Detailed Implementation

[0018] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below.

[0019] Example 1: Preparation of a thermosensitive injectable anti-adhesion dual-network hydrogel:

[0020] Raw material and equipment preparation:

[0021] Poloxamer 407: Meets USP / NF standards, with a hydroxyl value of 44.0-60.0 mg KOH / g, an average molecular weight of 9840-14600 Da, and bacterial endotoxin <0.03 EU / mg;

[0022] Poloxamer 188: Meets USP / NF standards, with a hydroxyl value of 196.0-224.0 mgKOH / g, an average molecular weight of 7680-9510 Da, and bacterial endotoxin <0.03 EU / mg;

[0023] Sodium alginate: meets the medical grade standards of the 2025 edition of the Chinese Pharmacopoeia, with a viscosity ≥200 mPa・s (1% aqueous solution, 25℃), calcium content ≤0.3%, and heavy metals ≤10ppm;

[0024] Carboxymethyl chitosan: Deacetylation degree ≥95% (determined by potentiometric titration), molecular weight 100kDa (determined by gel permeation chromatography), degree of substitution 0.8-1.0, bacterial endotoxin < 0.05EU / mg;

[0025] CaCO3: Medical-grade nanoparticles, particle size 200-400nm (measured by laser particle size analyzer), purity ≥99.5%, heavy metals ≤5ppm;

[0026] GDL (glucono-δ-lactone): Complies with GB 1886.129-2015 food additive standard, medical grade refined, purity ≥99.5%, loss on drying ≤0.5%;

[0027] Mannitol: Meets the Chinese Pharmacopoeia 2025 edition standards for injection, with a content ≥98.0% and bacterial endotoxin <0.03 EU / mg;

[0028] Sodium chloride: Meets the Chinese Pharmacopoeia 2025 edition standard for injection, with a content ≥99.5% and heavy metals ≤2ppm;

[0029] Phosphate buffer (pH=7.0): Prepared according to GB / T20245.4 standard, with components of sodium dihydrogen phosphate 0.68g / L and disodium hydrogen phosphate 7.2g / L, osmotic pressure 280mOsm / kg, sterile and pyrogen-free.

[0030] Equipment calibration and environmental preparation:

[0031] Cold room: Turn on 24 hours in advance, set the temperature to 4℃, control the temperature fluctuation within ±0.5℃, achieve a cleanliness level of Class 1000 (≤1000 particles ≥0.5μm per cubic meter), and maintain a relative humidity of 45%–55%.

[0032] Magnetic stirrer: Uses IKA RCT basic type magnetic stirrer, with pre-calibrated shear rate error ≤ ±5s -1 The temperature probe calibration error is ≤ ±0.2℃;

[0033] Osmometer: A German Roze freezing point osmometer was used, calibrated in advance with 290mOsm / kg standard solution, with an error ≤±2mOsm / kg;

[0034] Rotational viscometer: Brookfield DV-S viscometer with N63 rotor, pre-calibrated with standard silicone oil, error ≤ ±3%;

[0035] Aseptic filtration system: Employs a Millipore Stericup filtration device, equipped with 1μm, 0.45μm, and 0.22μm polyethersulfone (PES) filter membranes in sequence, with integrity tests performed in advance, and a bubble point ≥0.3MPa;

[0036] Aseptic filling machine: adopts a pre-filled syringe filling machine, and the filling accuracy is calibrated in advance, with an error of ≤±0.03mL / syringe.

[0037] Preparation steps:

[0038] S1: Low-temperature dissolution of poloxamer

[0039] Pour 100 mL of pH 7.0 phosphate buffer into a 150 mL sterile glass beaker and place it on a magnetic stirrer in a cold room. The stir bar is made of polytetrafluoroethylene and is 25 mm in length.

[0040] Set the shear rate to 300s -1 (Laboratory optimal parameters, industrial production is adjusted according to volume ratio) After the buffer solution temperature stabilizes at 4℃, add poloxamer in batches: first slowly add 20.0g of poloxamer 407, and control the feeding speed at 1g / min to avoid clumping;

[0041] After adding poloxamer 407, continue stirring for 1 hour, then slowly add 5.0g of poloxamer 188, with the feeding speed also controlled at 1g / min;

[0042] After all materials have been fed, maintain the temperature at 4°C for 300 seconds. -1 (Continue stirring for 4 hours, take a sample every 30 minutes to observe, until the solution is completely transparent and there are no white particles visible to the naked eye, then the temperature-sensitive basic solution is obtained.)

[0043] S2: Mixed basic components

[0044] Maintain shear rate for 300 s -1 Keeping the temperature constant at 4℃, add 1.2g of sodium alginate to the temperature-sensitive basic solution. When adding the material, slowly sprinkle it along the wall of the beaker to avoid it sticking to the stir bar.

[0045] After sodium alginate is added, stir continuously for 1.5 hours. Take a sample and observe the solution. If there are no filamentous gel clusters, then mixed solution A is obtained.

[0046] 0.8 g of carboxymethyl chitosan was dissolved in 8 mL of phosphate buffer and stirred at 4 °C for 2 hours to prepare a 10% stock solution. The solution was then pre-filtered through a 0.45 μm filter membrane to remove insoluble matter.

[0047] The carboxymethyl chitosan stock solution was slowly added dropwise to mixed solution A at a rate of 1 mL / min, while maintaining a shear rate of 300 s during the addition process. -1 ;

[0048] After the addition is complete, continue stirring for 1.5 hours until the solution is uniform and clear, without any layering, thus obtaining mixed solution B.

[0049] S3: Adjust osmotic pressure

[0050] Add 2.0 g of mannitol to mixed solution B, stir for 30 minutes until completely dissolved, and take a sample to observe that no crystal particles are found;

[0051] Take 1 mL of solution sample and measure the initial osmotic pressure using an osmometer. Record the value as 265 mOsm / kg.

[0052] Prepare a 10% sterile sodium chloride solution and slowly add it dropwise to mixed solution B at a rate of 0.1 mL / min. Stir for 5 minutes after each 0.1 mL drop is added, and then take a sample to measure the osmotic pressure.

[0053] Repeat the above steps until the osmotic pressure stabilizes at 300 mOsm / kg. Stop adding sodium chloride and continue stirring for 30 minutes to obtain mixed solution C.

[0054] S4: Constructing a sustained-release crosslinking system

[0055] Increase the shear rate to 500 s -1 Add 0.3g of CaCO3 nanoparticles to the mixed solution C. When adding the material, use a small amount and multiple times, adding 0.1g in 3 times to avoid particle agglomeration.

[0056] After CaCO3 is fed in, 500 seconds -1 After continuous shearing for 1 hour, a drop of the solution was observed under an optical microscope. The particles were uniformly dispersed and there were no aggregates ≥1μm.

[0057] Reduce the shear rate to 200 s -1 Add 0.2g GDL, stir for 30 minutes after adding the material until the GDL is completely dissolved, and the system forms a uniform light milky white sol with no obvious sedimentation.

[0058] S5: Aseptic filtration and filling

[0059] The prepared sol was transferred to the storage bottle of the aseptic filtration system and pre-filtered sequentially through 1μm and 0.45μm PES membranes to remove trace aggregates, and then connected to a 0.22μm PES membrane for final aseptic filtration. The temperature was controlled at 4℃ throughout the process, the nitrogen pressure was adjusted to 0.1MPa, and the filtration rate was controlled at 12mL / min.

[0060] During the filtration process, a sample was taken for observation every 20 mL of filtrate. The filtrate was clear and free of particles, and the filter membrane was undamaged. After filtration, the filter membrane was rinsed with 10 mL of sterile buffer, and the filtrates were combined.

[0061] The filtrate is transferred to the hopper of the aseptic filling machine, and the filling volume is set to 2.8 mL / vial. A 3 mL medical-grade pre-filled syringe is used, and the syringe is sterilized by gamma rays in advance.

[0062] During the filling process, sample and weigh every 10 vials to calculate the filling volume, ensuring the error is within ±0.05mL; immediately after filling, install the rubber piston and cap, and affix the label;

[0063] Immediately transfer the filled products to a 2-8℃ medical refrigerator for cold chain storage. Set the refrigerator temperature to 4℃ and the relative humidity to 50% to avoid temperature fluctuations and ensure batch consistency.

[0064] Detailed product performance testing:

[0065] Three prepared samples were randomly selected and subjected to full testing according to the following standards:

[0066] Appearance inspection: Under 4000 lux illumination, the sol is a light milky white semi-transparent color, without turbidity, sediment or foreign matter. The CaCO3 particles are uniformly suspended and there is no sedimentation after standing for 24 hours.

[0067] pH value test: The pH value was measured using a precision pH meter at 25℃ and was 7.0±0.1, which is within the range of 6.8-7.4.

[0068] Gelation temperature detection: Differential scanning calorimetry (DSC) was used with a heating rate of 2℃ / min. The onset temperature of the endothermic peak was determined to be 32.5℃, which meets the requirement of 30-34℃.

[0069] Viscosity testing: At 23℃, a Brookfield DV-S viscometer with an N63 rotor and a rotation speed of 30 r / min was used to measure a viscosity of 1100 cP, which is within the range of 500-2000 cP.

[0070] Injection performance test: Connect a 22G injection needle, manually inject, injection force ≤15N, no jamming or leakage;

[0071] Curing time test: Take 1 mL of sol and place it in a petri dish in a 37℃ constant temperature water bath. Record the time from contact with the water bath to the time when it stops flowing when inverted. The time is 45 seconds, which is within the range of 30-60 seconds.

[0072] Wet adhesion strength test: Using a universal testing machine, a fresh porcine peritoneum (1-2 mm thick) was fixed in a fixture, and 0.5 mL of gel was applied to a 1 cm layer. 2 The peritoneal surface was cured at 37°C for 24 hours, and then stretched at a speed of 1 mm / min. The maximum adhesion force was measured to be 0.72 N / cm. 2 ≥0.5N / cm 2 standard;

[0073] Degradation performance test: Take 1g of the cured gel and place it in simulated body fluid (SBF) at 37℃. Change the simulated body fluid every day. On the 7th day, weigh and calculate the degradation rate as 42% and on the 14th day, the degradation rate is 96%, which meets the requirement of complete degradation in 7-14 days.

[0074] Sterility test: The membrane filtration method was used for sterility test according to GB / T16886.7-2015 standard. After 14 days of incubation, no microbial growth was observed in any of the three samples.

[0075] Endotoxin detection: The Limulus amebocyte lysate (LAL) gel electrophoresis was used to determine the bacterial endotoxin level. The result was <0.5 EU / mL, which meets the requirements for medical injectables.

[0076] Cytotoxicity test: According to GB / T16886.5 standard, the relative proliferation rate of L929 cells was 95% and no cytotoxicity was detected by MTT assay;

[0077] Intradermal reaction test: According to GB / T16886.10 standard, the gel extract was injected intradermally into the back of rabbits. After 72 hours, no erythema, edema, or irritation reaction was observed.

[0078] Example 2: Preparation and Testing of High-Adhesion Formulation

[0079] Formula adjustment: The formula was adjusted by weight-volume percentage as follows: Poloxamer 407 18%, Poloxamer 188 6%, Sodium alginate 1.5%, Quaternized chitosan 1.0%, CaCO3 0.5%, GDL 0.3%, Mannitol 2.5%, Sodium dihydrogen phosphate 0.6 g / L and disodium hydrogen phosphate 9.0 g / L in the phosphate buffer, and the osmotic pressure was adjusted to 285 mOsm / kg.

[0080] Preparation process adjustment:

[0081] The stirring time in S1 is extended to 4.5 hours, and the shear rate is 320 s. -1 Ensure that the high concentration of poloxamer is completely dissolved;

[0082] In S2, the concentration of the quaternized chitosan mother liquor was adjusted to 8%, the dropping rate was slowed to 0.8 mL / min, and the shear rate was 280 s. -1 To avoid excessively high local concentrations that could lead to flocculation;

[0083] The stirring time for CaCO3 in S4 was extended to 1.5 hours, and the shear rate was 550 s⁻¹. -1 This ensures that high-concentration particles are evenly dispersed.

[0084] Performance test results:

[0085] Gelation temperature: 30.8℃, viscosity at 23℃: 1850 cP, curing time: 55 seconds;

[0086] Wet adhesion strength: 0.81 N / cm 2 It is suitable for abdominal surgical wounds with significant exudation;

[0087] Degradation performance: 38% degradation rate on day 7 and 94% degradation rate on day 14, providing a longer-lasting barrier effect;

[0088] Cytotoxicity: L929 cells showed a relative proliferation rate of 92% and no cytotoxicity.

[0089] Intradermal reaction: No erythema, edema, or irritation was observed after 72 hours.

[0090] Example 3: Preparation and Testing of Rapid-Curing Formulation

[0091] Formula adjustment: The formula was adjusted by weight-volume percentage as follows: Poloxamer 407 22%, Poloxamer 188 3%, Sodium alginate 1.0%, Carboxymethyl chitosan 0.5%, CaCO3 0.2%, GDL 0.1%, Mannitol 1.5%, Sodium dihydrogen phosphate 0.9 g / L and disodium hydrogen phosphate 6.0 g / L in the phosphate buffer, and the osmotic pressure was adjusted to 315 mOsm / kg.

[0092] Preparation process adjustment:

[0093] The shear rate in S1 is increased to 350 s. -1 The mixing time is reduced to 3 hours;

[0094] After the osmotic pressure in S3 is adjusted, the stirring time is shortened to 20 minutes; the filtration speed is increased to 15 mL / min, improving production efficiency.

[0095] Performance test results:

[0096] Gelation temperature: 33.7℃, viscosity at 23℃: 620 cP, curing time: 32 seconds;

[0097] Wet adhesion strength: 0.58 N / cm 2 Suitable for rapid coverage of superficial orthopedic wounds;

[0098] Degradation performance: 51% degradation rate on day 7 and 97% degradation rate on day 12, indicating faster degradation speed;

[0099] Cytotoxicity: L929 cells showed a relative proliferation rate of 94% and no cytotoxicity.

[0100] Intradermal reaction: No erythema, edema, or irritation was observed after 72 hours.

[0101] Example 4: Clinical simulation application verification

[0102] The sample prepared in Example 1 was used for a simulated laparoscopic application:

[0103] The sample was removed from the 4°C refrigerator and left at room temperature for 5 minutes. When the temperature was raised to 22°C, it remained liquid.

[0104] Connect the laparoscopic-specific injection catheter (1mm inner diameter) and insert it into the simulated abdominal cavity through a 10mm puncture sheath;

[0105] Gel was injected onto the surface of the simulated wound (a porcine peritoneal defect model). The gel solidified 40 seconds after contacting the 37°C tissue, and evenly covered the irregular wound surface of 2cm×3cm.

[0106] The wound was rinsed with saline at a rate of 100 mL / min for 1 minute. The gel did not fall off or shift and remained completely covered the wound.

[0107] Seven days later, the simulated wound was observed. The gel was partially degraded, and there was no fibrin deposition or signs of tissue adhesion on the wound surface.

[0108] The foregoing has only described certain exemplary embodiments of the present invention by way of illustration. Undoubtedly, those skilled in the art can modify the described embodiments in various ways without departing from the spirit and scope of the present invention. Therefore, the above description is illustrative in nature and should not be construed as limiting the scope of protection of the claims of the present invention.

Claims

1. A temperature-sensitive injectable anti-adhesion dual-network hydrogel, characterized in that, By weight-volume percentage (w / v), it includes poloxamer 407 15%–25%, poloxamer 188 2%–8%, sodium alginate 1.0%–1.5%, water-soluble chitosan derivative 0.5%–1.0%, CaCO3 0.2%–0.5%, GDL 0.1%–0.3%, mannitol 1.5%–2.5%, sodium chloride, and phosphate buffer at pH 6.8–7.4; The water-soluble chitosan derivative has a degree of deacetylation ≥95% and a molecular weight of 80-120 kDa; The phosphate buffer solution contains 0.5-1 g / L sodium dihydrogen phosphate and 5-10 g / L disodium hydrogen phosphate; the hydrogel has an osmotic pressure of 280-320 mOsm / kg and a gelation temperature of 30℃-34℃.

2. A thermosensitive injectable anti-adhesion dual-network hydrogel according to claim 1, characterized in that, The water-soluble chitosan derivative is selected from one or more of carboxymethyl chitosan, quaternized chitosan, hydroxypropyl chitosan, and hydroxyethyl chitosan.

3. A thermosensitive injectable anti-adhesion dual-network hydrogel according to claim 1, characterized in that, The hydrogel has an osmotic pressure of 280-320 mOsm / kg and a gelation temperature of 30℃-34℃; it is liquid at 20℃-25℃ and has a viscosity of 500-2000 cP.

4. A thermosensitive injectable anti-adhesion dual-network hydrogel according to claim 1, characterized in that, The hydrogel has a dual-network structure: the first network is a poloxamer thermosensitive physical cross-linking network, and the second network is an alginate-calcium ion delayed-release chemical cross-linking network induced by the CaCO3 / GDL sustained-release system; the hydrogel cures within 30-60 seconds after contact with an environment of 36℃-37℃, and the wet adhesion strength after 24 hours of curing is ≥0.5N / cm. 2 The complete degradation time in the body is 7-14 days.

5. A method for preparing a thermosensitive injectable anti-adhesion dual-network hydrogel, used in conjunction with any one of the thermosensitive injectable anti-adhesion dual-network hydrogels according to claims 1-4, characterized in that, Includes the following steps: S1. Low-temperature dissolution of poloxamer: At 2℃-8℃, poloxamer 407 and poloxamer 188 are dispersed in phosphate buffer solution with pH 6.8-7.4 and stirred at the set shear rate until completely dissolved; S2. Mixing basic components: Add sodium alginate and water-soluble chitosan derivative in sequence, and stir until uniformly dispersed at the set shear rate; S3. Adjusting osmotic pressure: Add mannitol and sodium chloride to adjust the osmotic pressure of the system to 280-320 mOsm / kg; S4. Constructing a sustained-release crosslinking system: After dispersing CaCO3 particles, add GDL and stir to form a homogeneous sol; S5. Post-processing: After multi-stage step-by-step pre-filtration combined with terminal aseptic filtration, the solution is filled into pre-filled syringes and stored in a low-temperature cold chain.

6. A method for preparing a thermosensitive injectable anti-adhesion dual-network hydrogel according to claim 5, characterized in that, The shear rate in S1 is 50-500 s. -1 The stirring time is 3-5 hours; Each addition of a component to S2 results in a shear rate of 50-500 s. -1 Stir for 1-2 hours, maintaining the system temperature between 2℃ and 8℃ throughout the process, with a temperature fluctuation range of ≤±1℃.

7. A method for preparing a thermosensitive injectable anti-adhesion dual-network hydrogel according to claim 5, characterized in that, The S5 uses a multi-stage pre-filtration process, employing 1μm and 0.45μm microporous membranes for pre-filtration, followed by aseptic filtration with a 0.22μm polyethersulfone microporous membrane. The filtration process is maintained at a temperature of 2℃-8℃, with a final filtration pressure of 0.08-0.12MPa and a filtration rate of 10-15mL / min. The filling accuracy is ±0.05mL / vial. The product is stored in a low-temperature cold chain at 2℃-8℃ with a relative humidity of 40%-60%.

8. The application of a thermosensitive injectable anti-adhesion dual-network hydrogel in postoperative wound anti-adhesion, used in conjunction with any one of the thermosensitive injectable anti-adhesion dual-network hydrogels of claims 1-4, characterized in that, Postoperative wounds include abdominal surgical wounds, gynecological surgical wounds, and orthopedic surgical wounds.