A thermosensitive hydrogel wound dressing and its preparation method and application

Abstract

The present invention discloses a thermosensitive hydrogel wound dressing, a preparation method, and an application thereof, belonging to the field of biomedical materials technology. The preparation method comprises the following steps: melting a segmented thermosensitive gel copolymer by heating, adding a carboxyl-containing bioactive molecule, performing a melting reaction after melting, purifying and freeze-drying to obtain a multifunctional polymer; dispersing the multifunctional polymer into a PBS buffer solution, and forming a single-component hydrogel after complete dispersion to obtain a multifunctional single-component thermosensitive hydrogel wound dressing containing a carboxyl-containing bioactive molecule. The wound dressing exhibits good biocompatibility both in vivo and in vitro, and also has good antibacterial and anti-inflammatory properties. Therefore, the hydrogel dressing has a good application prospect in wound healing and tissue regeneration for multidrug-resistant bacterial infections.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials, and in particular relates to a multifunctional single-component carboxyl-containing bioactive molecule-based thermosensitive hydrogel wound dressing, a method and an application thereof. Background Art

[0002] The rapid healing and repair of wounds infected with multidrug-resistant bacteria remains a challenge in the field of wound surgery. The development of multifunctional bioactive materials with anti-infection treatment and tissue regeneration promotion functions is an effective strategy. At present, a variety of multifunctional bioactive materials, such as hydrogels, powders, semi-permeable membranes, etc. have been explored and reported. Among them, hydrogels have become the most competitive candidate materials for wound repair due to their good hydrophilicity, biocompatibility and extracellular matrix (ECM)-like three-dimensional porous structure. However, most reported multifunctional hydrogels for the healing of wounds infected with multidrug-resistant bacteria show complex components and preparation processes, as well as unclear bioactivity mechanisms, which may limit their clinical translation.

[0003] Itaconic acid, salicylic acid, ferulic acid, citric acid, and other carboxyl-containing bioactive molecules have been shown to have significant potential in wound healing and tissue regeneration. Itaconic acid, a key metabolite produced by the mitochondrial tricarboxylic acid cycle, is reportedly safe, nontoxic, and highly permeable. Itaconic acid exhibits excellent bioactivity in immunomodulatory, antioxidant, antibacterial, and antiviral properties. Ferulic acid exhibits anti-radiation and antioxidant activities. These carboxyl-containing bioactive molecules have attracted widespread interest among researchers and are being used in various biomedical applications.

[0004] Existing wound dressings can be used to quickly heal and repair wounds. However, the preparation methods of most multifunctional bioactive materials for anti-infection treatment and tissue regeneration promotion are complex, and they have disadvantages such as organic solvent residues and poor biocompatibility. Summary of the Invention

[0005] The first object of the present invention is to provide a method for preparing a thermosensitive hydrogel wound dressing. The method has a simple process and the prepared hydrogel dressing has good biocompatibility.

[0006] The second object of the present invention is to provide a method for preparing a thermosensitive hydrogel wound dressing.

[0007] The third object of the present invention is that the carboxyl-containing bioactive molecule-based single-component thermosensitive hydrogel wound dressing has important applications in promoting wound healing and tissue regeneration caused by multi-drug resistant bacterial infection.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] A method for preparing a thermosensitive hydrogel wound dressing, comprising:

[0010] The block thermosensitive gel copolymer is heated and melted, a carboxyl-containing bioactive molecule is added, and a melting reaction is performed after melting, and the multifunctional polymer is obtained after purification and freeze-drying;

[0011] The multifunctional polymer is dispersed in PBS buffer, and after being completely dispersed, a single-component hydrogel is formed, thereby obtaining a multifunctional single-component carboxyl-containing bioactive molecule-based thermosensitive hydrogel wound dressing.

[0012] As a further improvement of the present invention, the carboxyl-containing bioactive molecule is itaconic acid, salicylic acid, ferulic acid, citric acid, chlorogenic acid, aspirin, diclofenac, folic acid, ibuprofen, indomethacin, succinic acid, maleic acid, malic acid, γ-linolenic acid or retinoic acid.

[0013] As a further improvement of the present invention, the block temperature-sensitive gel copolymer is a temperature-sensitive gel triblock copolymer, a temperature-sensitive gel diblock copolymer, and a temperature-sensitive gel multiblock copolymer;

[0014] The temperature-sensitive gelling triblock copolymer may be Pluronic, polylactic acid-co-glycolic acid-polyethylene glycol-polylactic acid-co-glycolic acid.

[0015] The temperature-sensitive gelable diblock copolymer may be a polypropylene-poly(n-isopropylacrylamide) block polymer.

[0016] The temperature-sensitive gelling multi-block copolymer may be poly(N-isopropylacrylamide)-Pluronic-poly(N-isopropylacrylamide).

[0017] As a further improvement of the present invention, the molar ratio of the segmented temperature-sensitive gel copolymer to the carboxyl-containing bioactive molecule is 1:(0.25-4).

[0018] As a further improvement of the present invention, the conditions for the melt reaction are a temperature of 80-180° C., a reaction time of 4-16 hours, or a microwave power of 500-1000 W for 30-180 minutes.

[0019] As a further improvement of the present invention, the multifunctional polymer is further subjected to post-processing after being obtained, and the post-processing method is as follows:

[0020] After the reaction is completed, the multifunctional polymer is dissolved in water, dialyzed, freeze-dried and stored at low temperature.

[0021] As a further improvement of the present invention, the solid-to-liquid ratio of the polymer to the PBS buffer solution is (50 mg-450 mg) / 1 mL.

[0022] As a further improvement of the present invention, the gelling temperature for forming the single-component hydrogel is 4-37°C.

[0023] A multifunctional single-component carboxyl-containing bioactive molecule-based thermosensitive hydrogel wound dressing is characterized in that it is prepared by the preparation method.

[0024] The multifunctional single-component carboxyl-containing bioactive molecule-based thermosensitive hydrogel wound dressing prepared by the preparation method is used in the preparation of drugs for promoting wound healing and tissue regeneration caused by multi-drug resistant bacteria.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The method uses carboxyl-containing bioactive molecules and segmented thermosensitive gel copolymers as raw materials, and obtains a multifunctional thermosensitive gel-forming poly (CCBM-BTGP) polymer through a high-temperature melt reaction. Finally, the poly (CCBM-BTGP) polymer obtained by freeze-drying is dissolved in PBS buffer to obtain a multifunctional single-component thermosensitive hydrogel wound dressing containing carboxyl-containing bioactive molecules. The preparation method of the present invention is simple, and there is no organic solvent residue. The raw materials used are green and environmentally friendly, easy to operate, and low in cost. The dressing prepared by the method of the present invention can be used for wound healing and tissue regeneration of multi-drug resistant bacterial infections. Experimental results show that the multifunctional single-component thermosensitive hydrogel wound dressing containing carboxyl-containing bioactive molecules prepared by the method has good biocompatibility and good biological effects both in vivo and in vitro. The prepared multifunctional single-component carboxyl-based bioactive molecule thermosensitive hydrogel wound dressing (poly (itaconic acid-F127), FIA) has a simple preparation process, environmentally friendly raw materials, low cost, can exhibit good antibacterial and anti-inflammatory properties, can accelerate wound healing and promote tissue regeneration. Therefore, this hydrogel wound dressing has a good application prospect in the healing of wounds infected with multidrug-resistant bacteria. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] To more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort.

[0028] Figure 1 The structural formulas of the monomers and polymers in the multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing synthesized by the present invention are as follows;

[0029] Figure 2 is the FT-IR spectrum of each monomer and the prepared poly(itaconic acid-F127) polymer;

[0030] Figure 3 This is a SEM image of the multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel (FIA) prepared in the present invention;

[0031] Figure 4 The cytotoxicity of the multifunctional single-component poly (itaconic acid-F127) polymer prepared in the present invention on fibroblasts (L929) was determined;

[0032] Figure 5 The results of the multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA) prepared in the present invention on the inhibition of Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA);

[0033] Figure 6 The in vitro anti-inflammatory results of the multifunctional single-component poly (itaconic acid-F127) polymer prepared by the present invention are as follows;

[0034] Figure 7 The present invention provides the in vivo MRSA-infected wound healing results of the multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA) prepared by the present invention. DETAILED DESCRIPTION

[0035] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit this application.

[0036] In this application, the term "and / or" describes the relationship between associated objects, indicating that three possible relationships exist. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. A and B can be singular or plural. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0037] In this application, "at least one" means one or more, and "more than one" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b, or c", or "at least one of a, b, and c" can all mean: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, and c can be single or multiple.

[0038] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0039] The terms used in the embodiments of the present application are for the purpose of describing specific embodiments only and are not intended to limit the present application. The singular forms "a", "an", "the" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms unless the context clearly indicates otherwise.

[0040] The weights of the relevant components mentioned in the examples of this application may not only refer to the specific content of each component, but also represent the weight ratio between the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the examples of this application, it is within the scope disclosed in the examples of this application. Specifically, the mass described in the examples of this application may be a mass unit known in the chemical industry, such as μg, mg, g, kg, etc.

[0041] Temperature-sensitive hydrogel (abbreviated as thermosensitive hydrogel) is a temperature-responsive in-situ gel whose state is closely related to temperature. It is in a liquid state with good fluidity under low temperature conditions and becomes a semi-solid state at human body temperature. It has good adhesion and can be well applied to tissue damage sites. These advantages make thermosensitive hydrogel one of the research hotspots in the field of biotechnology. The development of single-component multifunctional thermosensitive hydrogels based on carboxyl-containing bioactive molecules to promote the healing of wounds infected with multidrug-resistant bacteria is very promising. So far, research on the use of single-component multifunctional thermosensitive hydrogel dressings based on carboxyl-containing bioactive molecules for wound healing and tissue regeneration of multidrug-resistant bacterial infections has not been reported.

[0042] The present invention provides a method for preparing a multifunctional single-component temperature-sensitive hydrogel wound dressing, comprising:

[0043] The block thermosensitive gel copolymer (BTGP) is melted at high temperature, and a carboxyl-containing bioactive molecule (CCBM) is added and melted under inert gas protection, and a melt reaction is carried out under vacuum conditions to obtain a multifunctional poly (CCBM-BTGP) polymer.

[0044] The poly(CCBM-BTGP) polymer was purified and lyophilized to collect;

[0045] The multifunctional poly (CCBM-BTGP) polymer is dispersed in PBS buffer, and after being completely dispersed, the temperature is adjusted to form a single-component hydrogel, thereby obtaining a multifunctional single-component carboxyl-containing bioactive molecule-based thermosensitive hydrogel wound dressing.

[0046] Bioactive molecules containing carboxyl groups have attracted widespread interest due to their safety, nontoxicity, high permeability, and anti-inflammatory and antioxidant properties. They are being used in various biomedical applications. Block thermoresponsive gelling copolymers exhibit temperature-responsive gelling behavior, good biocompatibility, environmental friendliness, and low cost.

[0047] Therefore, in the present invention, carboxyl-containing bioactive molecules are grafted onto segmented temperature-sensitive gel copolymers to obtain a multifunctional single-component carboxyl-containing bioactive molecule-based temperature-sensitive hydrogel wound dressing. The wound dressing exhibits good biocompatibility as well as good antibacterial and anti-inflammatory properties. It is a multifunctional single-component hydrogel wound dressing used to accelerate the healing of wounds infected with multidrug-resistant bacteria and promote tissue repair.

[0048] The present invention is described in further detail below with reference to the accompanying drawings:

[0049] The present invention provides a method for preparing a multifunctional single-component thermosensitive hydrogel wound dressing, comprising the following steps:

[0050] 1) First, a melt esterification reaction is performed to prepare a multifunctional polymer. A 1 mM block thermosensitive gel copolymer (e.g., F127) is first melted at high temperature. Then, 0.25-4 mM of a carboxyl-containing bioactive molecule is added and dissolved at 80-180°C under an inert gas atmosphere. The multifunctional polymer is then reacted under vacuum at 80-180°C for 4-16 hours to obtain the multifunctional polymer. Alternatively, a microwave heating reaction is performed at a power of 500-1000 W for 30-180 minutes.

[0051] The molar ratio of the segmented thermosensitive gel copolymer to the carboxyl group-containing bioactive molecule is 1:(0.25-4). Other molar ratios may include 1:(0.25-2), 1:(0.4-3), 1:(2-4), 1:0.25, 1:0.3, 1:0.5, 1:1, 1:2, 1:4, 1:4, etc.

[0052] Microwave heating reaction conditions are 500-1000W for 30-180 minutes. You can also choose 500-800W for 50-100 minutes, 600-900W for 80-150 minutes, 500W for 180 minutes, 1000W for 30 minutes, 560W for 150 minutes, 700W for 120 minutes, 900W for 170 minutes, etc. Microwave heating is more efficient, resulting in a faster and more complete reaction. Microwaves can promote the rapid linking of melted molecular chains to form multifunctional polymers.

[0053] Among them, maintaining the temperature at 80-180°C for reaction for 4-16 hours can also be: maintaining the temperature at 80°C for reaction for 16 hours, maintaining the temperature at 100°C for reaction for 10 hours, maintaining the temperature at 120°C for reaction for 12 hours, maintaining the temperature at 120°C for reaction for 5 hours, maintaining the temperature at 150°C for reaction for 6 hours, maintaining the temperature at 80°C for reaction for 4 hours, maintaining the temperature at 80-130°C for reaction for 4-10 hours, maintaining the temperature at 120-180°C for reaction for 8-16 hours, maintaining the temperature at 150-170°C for reaction for 5-10 hours, etc.

[0054] 2) The multifunctional polymer was dissolved in water at 4° C., and then purified using a dialysis tube (10 kDa) for 2 to 3 days. After freeze-drying, the resulting multifunctional polymer was collected and stored for further use.

[0055] The number of days of dialysis is determined according to the final purification effect, such as 2 days, 3 days, 2.5 days, etc.

[0056] 3) Add 50 mg to 450 mg of the multifunctional polymer to 1 mL of PBS buffer solution and stir on ice to dissolve. After the multifunctional polymer is completely dissolved, adjust the temperature to 4-37°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel wound dressing.

[0057] Among them, the addition of 50mg-450mg of multifunctional polymer can be 50mg-150mg, 150mg-350mg, 250mg-450mg, 50mg, 150mg, 250mg, 350mg, 100mg, 200mg, 300mg, 400mg, etc.

[0058] The itaconic acid used in the above example can also be replaced by other raw materials, such as salicylic acid, ferulic acid, citric acid, chlorogenic acid, aspirin, diclofenac, folic acid, ibuprofen, indomethacin, succinic acid, maleic acid, malic acid, γ-linolenic acid, or retinoic acid. The carboxyl group-containing bioactive molecule can also be itaconic acid, salicylic acid, ferulic acid, citric acid, chlorogenic acid, aspirin, diclofenac, folic acid, ibuprofen, indomethacin, succinic acid, maleic acid, malic acid, γ-linolenic acid, or retinoic acid.

[0059] The temperature-sensitive gelling triblock copolymer may be Pluronic, polylactic acid-co-glycolic acid-polyethylene glycol-polylactic acid-co-glycolic acid.

[0060] The temperature-sensitive gelable diblock copolymer may be a polypropylene-poly(n-isopropylacrylamide) block polymer.

[0061] The temperature-sensitive gelling multi-block copolymer may be poly(N-isopropylacrylamide)-Pluronic-poly(N-isopropylacrylamide).

[0062] The present invention is devoted to preparing a multifunctional single-component thermosensitive hydrogel wound dressing with good biocompatibility, which can accelerate the healing of wounds infected by multi-drug resistant bacteria and promote tissue repair.

[0063] The present invention also provides a multifunctional single-component carboxyl-containing bioactive molecule-based thermosensitive hydrogel wound dressing, which is characterized in that it is prepared by the above-mentioned preparation method.

[0064] In order to better understand the present invention, the present invention is described in detail below in conjunction with specific embodiments, but the content of the present invention is not limited to the following embodiments.

[0065] Example 1

[0066] 1) Preparation of poly(itaconic acid-F127) polymer: 1 mM F127 was first dissolved at high temperature, and then 2 mM itaconic acid was added. The itaconic acid was dissolved at 130°C under an inert gas atmosphere, and then the reaction was maintained at 130°C for 10 hours under vacuum conditions.

[0067] 2) Poly(itaconate-F127) polymer collection method: The poly(itaconate-F127) polymer was dissolved in water at 4°C and then purified using dialysis tubing (10 kDa) for 3 days. After freeze-drying, the poly(itaconate-F127) polymer was collected and stored for further use.

[0068] 3) Preparation of a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel: 300 mg of poly(itaconic acid-F127) polymer was added to 1 mL of PBS buffer and stirred in an ice bath to dissolve. After the poly(itaconic acid-F127) polymer was completely dissolved, the temperature was adjusted to 37°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel wound dressing.

[0069] The multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing prepared by the method of the present invention exhibits good biocompatibility and good anti-inflammatory properties. It is a hydrogel wound dressing used to accelerate the healing of wounds infected with multidrug-resistant bacteria and promote tissue repair. The following is a detailed analysis based on experimental data.

[0070] Figure 1The present invention provides the structural formulas of monomers and polymers in the multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing synthesized by the present invention, wherein A is the structural formula of itaconic acid (IA), B is the structural formula of F127, and C is the structural formula of the poly (itaconic acid-F127) polymer.

[0071] Figure 2 The FT-IR spectra of each monomer and the obtained poly (itaconic acid-F127) polymer are shown in Figure 1730 cm -1 The peak at is attributed to -C=O in the poly(itaconic acid-F127) polymer, indicating that the poly(itaconic acid-F127) polymer is formed.

[0072] Figure 3 This is a SEM image of the multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel (FIA) prepared in the present invention. It can be seen from the figure that the FIA ​​hydrogel has a three-dimensional porous structure.

[0073] Figure 4 The cytotoxicity of the multifunctional single-component poly (itaconic acid-F127) polymer prepared in the present invention on fibroblasts (L929) was determined. As can be seen from the figure, different concentrations of FIA have no cytotoxicity and all show good biocompatibility.

[0074] Figure 5 The results of the inhibition of the multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA) prepared in the present invention on Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA) can be seen from the figure. The FIA ​​hydrogel exhibits good broad-spectrum antibacterial ability.

[0075] Figure 6 The in vitro anti-inflammatory results of the multifunctional single-component poly (itaconic acid-F127) polymer prepared in the present invention are shown. It can be seen from the figure that when the concentration of the poly (itaconic acid-F127) polymer is 25 μg / mL, it exhibits good anti-inflammatory ability.

[0076] Figure 7 The results of in vivo wound healing of MRSA-infected wounds using the multifunctional, single-component poly(itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA) prepared in this invention are shown. As can be seen from the figure, on the third day after surgery, the wound area in each group was smaller than on day 0. After seven days of treatment, the FIA ​​group exhibited the greatest wound contraction area (59.16%), while the 3M group (commercial dressing) had a smaller wound contraction area (29.61%). This demonstrates that the multifunctional, single-component poly(itaconic acid-F127) thermosensitive hydrogel significantly promotes the healing of wounds infected with drug-resistant bacteria.

[0077] Example 2

[0078] 1) Preparation of poly(itaconic acid-F127) polymer: 1 mM F127 was first dissolved at high temperature, and then 2 mM itaconic acid was added. The itaconic acid was dissolved at 140°C under an inert gas atmosphere, and then the reaction was maintained at 140°C under vacuum for 8 hours.

[0079] 2) Poly(itaconate-F127) polymer collection method: The poly(itaconate-F127) polymer was dissolved in water at 4°C and then purified using dialysis tubing (10 kDa) for 3 days. After freeze-drying, the poly(itaconate-F127) polymer was collected and stored for further use.

[0080] 3) Preparation of a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel: 300 mg of poly(itaconic acid-F127) polymer was added to 1 mL of PBS buffer and stirred in an ice bath to dissolve. After the poly(itaconic acid-F127) polymer was completely dissolved, the temperature was adjusted to 37°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel wound dressing.

[0081] Example 3

[0082] 1) Preparation of poly(itaconic acid-F127) polymer: 1 mM F127 was first dissolved at high temperature, and then 2 mM itaconic acid was added. The itaconic acid was dissolved at 120°C under an inert gas atmosphere, and then the reaction was maintained at 120°C for 12 hours under vacuum conditions.

[0083] 2) Poly(itaconate-F127) polymer collection method: The poly(itaconate-F127) polymer was dissolved in water at 4°C and then purified using dialysis tubing (10 kDa) for 3 days. After freeze-drying, the poly(itaconate-F127) polymer was collected and stored for further use.

[0084] 3) Preparation of a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel: 300 mg of poly(itaconic acid-F127) polymer was added to 1 mL of PBS buffer and stirred in an ice bath to dissolve. After the poly(itaconic acid-F127) polymer was completely dissolved, the temperature was adjusted to 37°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel wound dressing.

[0085] Example 4

[0086] 1) Preparation of poly(itaconate-F127) polymer: 1 mM F127 was first dissolved at high temperature, and then 1 mM itaconic acid was added. The itaconic acid was dissolved at 150°C under an inert gas atmosphere, and then the reaction was maintained at 150°C for 10 hours under vacuum conditions.

[0087] 2) Poly(itaconate-F127) polymer collection method: The poly(itaconate-F127) polymer was dissolved in water at 4°C and then purified using dialysis tubing (10 kDa) for 3 days. After freeze-drying, the poly(itaconate-F127) polymer was collected and stored for further use.

[0088] 3) Preparation of a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel: 300 mg of poly(itaconic acid-F127) polymer was added to 1 mL of PBS buffer and stirred in an ice bath to dissolve. After the poly(itaconic acid-F127) polymer was completely dissolved, the temperature was adjusted to 37°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel wound dressing.

[0089] Example 5

[0090] 1) Preparation of poly(itaconate-F127) polymer: 1 mM F127 was first dissolved at high temperature, and then 1 mM itaconic acid was added. The itaconic acid was dissolved at 150°C under an inert gas atmosphere, and then the reaction was maintained at 150°C under vacuum for 8 hours.

[0091] 2) Poly(itaconate-F127) polymer collection method: The poly(itaconate-F127) polymer was dissolved in water at 4°C and then purified using dialysis tubing (10 kDa) for 3 days. After freeze-drying, the poly(itaconate-F127) polymer was collected and stored for further use.

[0092] 3) Preparation of a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel: 300 mg of poly(itaconic acid-F127) polymer was added to 1 mL of PBS buffer and stirred in an ice bath to dissolve. After the poly(itaconic acid-F127) polymer was completely dissolved, the temperature was adjusted to 37°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel wound dressing.

[0093] Example 6

[0094] 1) Preparation of poly(salicylic acid-F127) polymer: 1 mM F127 was first dissolved at high temperature, followed by the addition of 2 mM salicylic acid. The salicylic acid was dissolved at 160°C under an inert gas atmosphere, and then the reaction was maintained at 160°C for 10 hours under vacuum.

[0095] 2) Poly(salicylic acid-F127) polymer collection method: The poly(salicylic acid-F127) polymer was dissolved in water at 4°C and then purified using dialysis tubing (10 kDa) for 3 days. After freeze-drying, the poly(salicylic acid-F127) polymer was collected and stored for further use.

[0096] 3) Preparation of a multifunctional single-component poly(salicylic acid-F127) thermosensitive hydrogel: 300 mg of poly(salicylic acid-F127) polymer was added to 1 mL of PBS buffer and stirred in an ice bath to dissolve. After the poly(salicylic acid-F127) polymer was completely dissolved, the temperature was adjusted to 37°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(salicylic acid-F127) thermosensitive hydrogel wound dressing.

[0097] Example 7

[0098] 1) Preparation of poly(ferulic acid-F127) polymer: 1 mM F127 was first dissolved at high temperature, followed by the addition of 2 mM ferulic acid. The ferulic acid was dissolved at 160°C under an inert gas atmosphere, and then the reaction was continued under vacuum at a microwave power of 1000 W for 30 minutes.

[0099] 2) Poly(ferulic acid-F127) polymer collection method: The poly(ferulic acid-F127) polymer was dissolved in water at 4°C and then purified using dialysis tubing (10 kDa) for 3 days. After freeze-drying, the poly(ferulic acid-F127) polymer was collected and stored for further use.

[0100] 3) Preparation of a multifunctional single-component poly(ferulic acid-F127) thermosensitive hydrogel: 300 mg of poly(ferulic acid-F127) polymer was added to 1 mL of PBS buffer and stirred on ice to dissolve. After the poly(ferulic acid-F127) polymer was completely dissolved, the temperature was adjusted to 37°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(ferulic acid-F127) thermosensitive hydrogel wound dressing.

[0101] Example 8

[0102] The multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA) prepared in the present invention has a simple preparation process, environmentally friendly raw materials, low cost, can exhibit good antibacterial and anti-inflammatory properties, can accelerate the healing of wounds infected with multidrug-resistant bacteria and promote tissue regeneration. Therefore, this hydrogel wound dressing has a good application prospect in the healing of wounds infected with multidrug-resistant bacteria.

[0103] Example 9

[0104] 1) Preparation of poly(succinic acid-F127) polymer: 1 mM F127 was first dissolved at high temperature, followed by the addition of 4 mM succinic acid. The succinic acid was dissolved at 180°C under an inert gas atmosphere, and then reacted under vacuum at a microwave power of 500 W for 180 minutes.

[0105] 2) Poly(succinic acid-F127) polymer collection method: The poly(succinic acid-F127) polymer was dissolved in water at 3°C ​​and then purified using dialysis tubing (10 kDa) for 2 days. After freeze-drying, the poly(succinic acid-F127) polymer was collected and stored for further use.

[0106] 3) Preparation of a multifunctional single-component poly(succinic acid-F127) thermosensitive hydrogel: 50 mg of poly(succinic acid-F127) polymer was added to 1 mL of PBS buffer and stirred in an ice bath to dissolve. After the poly(succinic acid-F127) polymer was completely dissolved, the temperature was adjusted to 25°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(succinic acid-F127) thermosensitive hydrogel wound dressing.

[0107] Example 10

[0108] 1) Preparation of poly(aspirin-F108) polymer: 1 mM F108 was first dissolved at high temperature, and then 2 mM aspirin was added. The aspirin was dissolved at 80°C under an inert gas atmosphere, and then the reaction was maintained at a microwave power of 800 W for 140 minutes under vacuum conditions.

[0109] 2) Poly(aspirin-F108) polymer collection method: The poly(aspirin-F108) polymer was dissolved in water at 4°C and then purified using dialysis tubing (10 kDa) for 3 days. After freeze-drying, the poly(aspirin-F108) polymer was collected and stored for further use.

[0110] 3) Preparation of a multifunctional single-component poly(aspirin-F108) thermosensitive hydrogel: 450 mg of poly(aspirin-F108) polymer was added to 1 mL of PBS buffer and stirred in an ice bath to dissolve. After the poly(aspirin-F108) polymer was completely dissolved, the temperature was adjusted to 30°C to form a stable hydrogel, thereby obtaining a multifunctional single-component poly(aspirin-F108) thermosensitive hydrogel wound dressing.

[0111] The multifunctional single-component carboxyl-containing bioactive molecule-based thermosensitive hydrogel wound dressing prepared by the preparation method of the present invention is used in the preparation of drugs for promoting wound healing and tissue regeneration caused by multi-drug resistant bacteria infection.

[0112] The present invention also has the following advantages:

[0113] (1) The F127 and the like used in the present invention have body temperature-responsive gel behavior, good biocompatibility, are environmentally friendly, and are inexpensive and readily available.

[0114] (2) Itaconic acid used in the present invention is an important metabolite produced by the mitochondrial tricarboxylic acid cycle. It is safe, non-toxic, and highly permeable. Itaconic acid exhibits excellent biological activities in immunomodulation, antioxidant, antibacterial, and antiviral properties.

[0115] (3) The poly (itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA) prepared in the present invention has a simple preparation process, can be obtained in one step, and has simple ingredients.

[0116] (4) The multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA) prepared in the present invention has anti-inflammatory and antibacterial capabilities.

[0117] (5) The solvent used in the present invention is deionized water, and the multifunctional single-component poly (itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA) prepared by the method does not contain any organic solvent.

[0118] In summary, the present invention provides a method for preparing a thermosensitive hydrogel wound dressing, which comprises preparing a poly(itaconic acid-F127) polymer by a melt reaction, dispersing the poly(itaconic acid-F127) polymer in a PBS buffer solution, and adjusting the temperature to form a multifunctional single-component hydrogel after the poly(itaconic acid-F127) polymer is completely dispersed, thereby obtaining a multifunctional single-component poly(itaconic acid-F127) thermosensitive hydrogel wound dressing (FIA).

[0119] FIA also exhibits good biocompatibility in vivo and in vitro, and also has good anti-inflammatory and antibacterial properties. Therefore, this hydrogel dressing has good application prospects in wound healing and tissue regeneration caused by multidrug-resistant bacterial infections.

[0120] The above content is only for explaining the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. Any changes made on the basis of the technical solution in accordance with the technical idea proposed by the present invention shall fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a thermosensitive hydrogel wound dressing, characterized in that: include: The block thermosensitive gel copolymer is heated and melted, a carboxyl-containing bioactive molecule is added, and a melting reaction is performed after melting, and the multifunctional polymer is obtained after purification and freeze-drying; The bioactive molecule containing a carboxyl group is itaconic acid; The multifunctional polymer was dispersed in PBS buffer, and after complete dispersion, a single-component hydrogel was formed to obtain a multifunctional single-component carboxyl-containing bioactive molecule-based thermosensitive hydrogel wound dressing poly (itaconic acid-F127); the structural formula is as follows: The block temperature-sensitive gel copolymer is a temperature-sensitive gel triblock copolymer, a temperature-sensitive gel diblock copolymer, and a temperature-sensitive gel multiblock copolymer; The thermosensitive gel triblock copolymer is Pluronic, polylactic-co-glycolic acid-polyethylene glycol-polylactic-co-glycolic acid; The temperature-sensitive gelling diblock copolymer is a polypropylene-poly(n-isopropylacrylamide) block polymer; The temperature-sensitive gel multi-block copolymer is poly(N-isopropylacrylamide)-Pluronic-poly(N-isopropylacrylamide); The conditions of the melt reaction are a temperature of 130-180°C, a reaction time of 4-16 hours or a microwave power of 500-1000W for 30-180 minutes; The molar ratio of the segmented thermosensitive gel copolymer to the carboxyl-containing bioactive molecule is 1:(0.25~4).

2. The method for preparing the thermosensitive hydrogel wound dressing according to claim 1, wherein: After obtaining the multifunctional polymer, post-processing is performed, and the post-processing method is as follows: After the reaction is completed, the multifunctional polymer is dissolved in water, dialyzed, freeze-dried and stored at low temperature.

3. The method for preparing the thermosensitive hydrogel wound dressing according to claim 1, wherein: The solid-to-liquid ratio of the polymer to the PBS buffer solution is (50 mg-450 mg) / 1 mL.

4. The method for preparing the thermosensitive hydrogel wound dressing according to claim 1, wherein: The gelling temperature for forming the single-component hydrogel is 4-37°C.

5. A multifunctional single-component thermosensitive hydrogel wound dressing containing carboxyl-based bioactive molecules, characterized in that: Prepared by the preparation method according to any one of claims 1 to 4.

6. Use of the multifunctional single-component thermosensitive hydrogel wound dressing containing carboxyl-based bioactive molecules prepared by the preparation method according to any one of claims 1 to 4 in the preparation of drugs for promoting wound healing and tissue regeneration caused by multidrug-resistant bacterial infections.

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