Programmed release hydrogel as well as preparation method and application thereof
By loading conductive polymers and anti-inflammatory drugs onto an aldehyde-modified pullulan polysaccharide and an amino-modified hyaluronic acid crosslinking network, and combining pH and temperature stimulation to control drug release, the mechanical weaknesses and drug control problems of traditional hydrogel materials are solved, enabling programmed wound treatment, improving antibacterial and anti-inflammatory effects, and promoting wound healing.
Patent Information
- Application Number
- CN202511409457.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-29
- Publication Date
- 2026-01-09
AI Technical Summary
Traditional hydrogel materials are difficult to withstand mechanical stress in wound dressings, are prone to cracking or deformation, lack antibacterial activity, and cannot effectively prevent or treat wound infections. Furthermore, existing drug delivery systems cannot control the sequential release of multiple drugs, which can easily lead to drug abuse and drug resistance.
A Schiff base cross-linking network was formed by aldehyde-modified pullulan polysaccharide and amino-modified hyaluronic acid, which was loaded with conductive polymers and the anti-inflammatory drug quercetin. The drug release was programmed by pH and temperature stimulation, releasing tobramycin and quercetin respectively. The release was controlled by monitoring changes in wound temperature.
It achieves preferential release of the antibacterial drug tobramycin under acidic conditions and release of the anti-inflammatory drug quercetin upon electrical stimulation when the temperature rises, thereby improving the mechanical strength and antibacterial and anti-inflammatory effects of wound dressings, avoiding drug abuse and drug resistance, and promoting wound healing.
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Figure CN121287992A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical materials technology, and more specifically to a programmed drug release hydrogel, its preparation method, and its application. Background Technology
[0002] Skin injuries are highly susceptible to bacterial infection, and wound infection can severely impact the healing process. Severe infections can even lead to complications such as sepsis, which can be life-threatening. Hydrogels, due to their high water content, good biocompatibility, and biodegradability, are considered an ideal wound dressing material. Their high water content provides a moist environment for the wound, promoting cell migration and proliferation, and accelerating wound healing. However, traditional hydrogel materials still have many limitations in practical applications. For example, they are unable to withstand the mechanical stress of wounds, are prone to cracking or deformation, lack antibacterial activity, and cannot effectively prevent or treat wound infections.
[0003] Currently, the active ingredient in most antibacterial dressings remains antibiotics. While traditional antibiotics can slow the progression of bacterial infections to some extent, overuse leads to widespread bacterial resistance. Therefore, designing a responsive release hydrogel is highly significant for wound healing in bacterial infections. Hydrogels can respond to various external stimuli, such as temperature, pH, light, and electric fields. Acid-base environments are crucial for normal physiological activities, and abnormal pH is an important characteristic of diseased tissues, widely used to trigger drug release. After skin injury, the pH value slightly decreases due to the production of organic acids and an increase in local carbon dioxide partial pressure. Hydrogels based on Schiff base bonds can be effectively stimulated under low pH conditions, thereby achieving pH-responsive delivery of bioactive substances.
[0004] Once a wound forms, inflammatory cells immediately migrate to the wound site, initiating the inflammatory phase of wound repair and causing a rise in local temperature. The resistance of conductive hydrogels changes with temperature; by detecting these changes, the temperature at the wound site can be indirectly measured. Monitoring temperature changes at the wound site allows for timely detection of the inflammatory phase and the implementation of anti-inflammatory measures.
[0005] Currently, there are studies on the treatment of infected wounds with hydrogels from the perspectives of antibacterial and anti-inflammatory effects. However, the drug loading is mostly reflected in the controlled release of a single drug. If two drugs are loaded at the same time, it is impossible to control the sequential release of the two drugs. Summary of the Invention
[0006] To address the above problems, this invention provides a programmed drug-release hydrogel, its preparation method, and its application. The programmed drug-release hydrogel prepared by this invention can simultaneously load anti-inflammatory and antibacterial drugs. During use, bacterial infection of the wound leads to a decrease in pH. Under acidic conditions, the programmed drug-release hydrogel preferentially releases the antibacterial drug tobramycin. When the hydrogel detects that the wound temperature is higher than normal body temperature, it releases the anti-inflammatory drug quercetin through electrical stimulation, achieving programmed drug release and graded wound treatment.
[0007] The first objective of this invention is to provide a method for preparing a programmed drug-release hydrogel, comprising the following steps: Aldehyde-modified pullulan and amino-modified hyaluronic acid undergo a Schiff base reaction in water to give the first solution.
[0008] The first solution, acrylamide, cross-linking agent, and tobramycin are mixed to obtain the second solution.
[0009] After mixing the quercetin solution and the conductive polymer, an electrostatic adsorption reaction occurs during stirring, yielding a third solution.
[0010] The third solution and the second solution are mixed, and a free radical polymerization reaction occurs under the action of an initiator to obtain a programmed drug release hydrogel.
[0011] In a preferred embodiment of the present invention, the mass fraction of aldehyde-modified pullulan in the first solution is 1% to 5%.
[0012] The mass fraction of amino-modified hyaluronic acid in the first solution is 1% to 5%.
[0013] In a preferred embodiment of the present invention, the preparation of aldehyde-modified pullulan includes the following steps: Sodium periodate was added to pullulan solution, and an oxidation reaction occurred to obtain aldehyde-modified pullulan. Sodium periodate was chosen as the oxidant in this invention because it exhibits high selectivity and specificity in oxidizing the vicinal diol structure in the polysaccharide chain, and the reaction conditions are mild and easily controlled.
[0014] In a preferred embodiment of the present invention, the mass ratio of pullulan to sodium periodate is 2:1 to 1.5.
[0015] The oxidation reaction was carried out at 25℃~30℃ in the dark for 20h~24h.
[0016] In a preferred embodiment of the present invention, the preparation of amino-modified hyaluronic acid includes the following steps: After activating the hyaluronic acid solution with a carboxyl activator, an amine compound is added, and an amidation reaction occurs at pH 6 to obtain amino-modified hyaluronic acid.
[0017] In a preferred embodiment of the present invention, the mass ratio of hyaluronic acid to carboxyl activator is 3:1~2.
[0018] The ratio of hyaluronic acid to amine compound is 1g:7ml~8ml; the amine compound is ethylenediamine; when the amine compound is ethylenediamine, the ethylenediamine molecule chain is short, the reaction is fast, the water solubility is high, and there are few side reactions.
[0019] The activation reaction is carried out at 25℃~30℃ for 30min~40min.
[0020] The amidation reaction was carried out at 25℃~30℃ in the dark for 1.5h~2h.
[0021] In a preferred embodiment of the present invention, the volume ratio of quercetin solution to conductive polymer is 1:1, the concentration of quercetin solution is 10 mg / ml to 15 mg / ml, and the mass concentration of conductive polymer solution is 5%.
[0022] The electrostatic adsorption reaction takes 48 to 50 hours.
[0023] The conductive polymer is poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate). Poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate) was chosen because it has good biocompatibility, uniform dispersion, and is well-suited for use in wound dressings.
[0024] The mass ratio of acrylamide to tobramycin is 10:0.1~0.2.
[0025] The mass ratio of quercetin to tobramycin is 10-15:1.
[0026] The reaction temperature for free radical polymerization is 60℃~70℃, and the reaction time is 0.5h~1h.
[0027] In a preferred embodiment of the present invention, the amount of crosslinking agent added is 0.1% to 0.2% of the mass of acrylamide; the amount of initiator added is 0.5% to 1% of the mass of acrylamide.
[0028] During the preparation process, changes in parameters can affect the mechanical properties of programmed drug release hydrogels.
[0029] A second objective of this invention is to provide a programmed drug release hydrogel prepared by the above-described preparation method.
[0030] A third objective of this invention is to provide the application of the above-mentioned programmed drug-release hydrogel as a wound dressing, which releases tobramycin when the pH at the wound site is less than 7, and releases the anti-inflammatory drug quercetin via electrical stimulation when the wound temperature is greater than 34°C to 36°C. The voltage during electrical stimulation is 3V to 4V.
[0031] Compared with the prior art, the present invention has the following beneficial effects: In preparing a programmed drug-release hydrogel, this invention uses aldehyde-modified pullulan (OPU), amino-modified hyaluronic acid (HA-NH2), and polyacrylamide (PAM) as the main materials, and loads conductive materials, the antibacterial drug tobramycin (TOB), and the anti-inflammatory drug quercetin (Que). The aldehyde groups of aldehyde-modified pullulan and the amino groups of amino-modified hyaluronic acid undergo a Schiff base reaction to crosslink into the first network structure of the hydrogel, imparting self-healing properties. Acrylamide undergoes free radical polymerization through the crosslinking agent N,N-methylenebisacrylamide and the initiator ammonium persulfate to form the second network structure of the hydrogel, enhancing its mechanical strength. The amino groups on tobramycin and the aldehyde groups on aldehyde-modified pullulan form Schiff base bonds, which can break under acidic conditions, achieving pH-responsive drug release. Negatively charged conductive polymers and positively charged quercetin combine through electrostatic adsorption and are embedded in the hydrogel network structure through physical cross-linking, giving the hydrogel conductivity and enabling it to monitor temperature and release drugs via electrical stimulation.
[0032] When skin is wounded, bacteria release acidic substances such as lactic acid and carbonic acid as they grow. The amino group of tobramycin in the programmed drug-release hydrogel and the aldehyde group of aldehyde-modified pullulan form Schiff base bonds, which can break under acidic conditions. Therefore, TOB can be released in response to bacterial proliferation, eliminating bacteria and preventing drug resistance. The addition of a conductive polymer causes the resistance of the programmed drug-release hydrogel to change with temperature; monitoring this resistance change allows for indirect measurement of the wound temperature. Wound temperature typically rises after inflammation and gradually returns to normal as the wound heals. Therefore, by continuously monitoring temperature changes at the wound site, the inflammatory phase can be detected promptly. An electrical stimulator can then be connected to the programmed drug-release hydrogel prepared in this invention, allowing for controlled release of the anti-inflammatory drug quercetin via electrical stimulation, achieving anti-inflammatory effects and accelerating wound healing. This avoids the problems of existing preparation methods that rely solely on microenvironment response, which cannot control the sequential release of two drugs, easily leading to drug abuse, drug resistance, and hindering wound healing.
[0033] The programmed drug-release hydrogel of this invention is prepared from aldehyde-modified pullulan (OPU), amino-modified hyaluronic acid (HA-NH2), polyacrylamide (PAM), poly(3,4-ethyldioxothiabenzene) polystyrene sulfonate (PEDOT:PSS)-quercetin (Que), and tobramycin (TOB). The resulting programmed drug-release hydrogel has good biocompatibility, adhesion, self-healing properties, conductivity, antibacterial properties, anti-inflammatory properties, and wound healing promotion ability, especially showing significant effects on the treatment or improvement of infected wounds. Attached Figure Description
[0034] Figure 1 This is the NMR spectrum of the aldehyde-modified pullulan polysaccharide of the present invention.
[0035] Figure 2 The NMR spectrum of the amino-modified hyaluronic acid of this invention is shown.
[0036] Figure 3 The hydrogel exhibits strong adhesion on different substrates for programmed drug release.
[0037] Figure 4 Self-healing properties of programmed drug release hydrogels.
[0038] Figure 5 This is a conductivity diagram of a programmed drug release hydrogel.
[0039] Figure 6 This is a diagram showing the antibacterial properties of a programmed drug release hydrogel.
[0040] Figure 7 To verify the wound healing status of each group of mice in the infected mice.
[0041] Figure 8 This is a flowchart illustrating the preparation process of the programmed drug release hydrogel of this invention. Detailed Implementation
[0042] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0043] The PEDOT:PSS solution used in this invention was purchased from Aladdin, with a mass fraction of 5% and catalog number P466689.
[0044] Example 1 In the programmed drug release hydrogel of this invention, the raw materials aldehyde-modified pullulan (OPU) and amino-modified hyaluronic acid (HA-NH2) are prepared using the following method: Step 1, Preparation of aldehyde-modified pullulan (OPU): 1 g pullulan was dissolved in 100 ml of water, and 0.5 g of sodium periodate was added. The mixture was reacted at 25°C in the dark for 24 h. After the reaction was completed, 2 ml of ethylene glycol was added to terminate the reaction for 1 h. The reaction solution was added to a dialysis bag with a molecular weight cutoff of 8000-14000 Daltons, dialyzed with water for 4 days, and then freeze-dried to obtain aldehyde-modified pullulan (OPU).
[0045] The results are as follows Figure 1 As shown, this indicates that pullulan polysaccharide modification was successful.
[0046] Step 2, Preparation of Aminated Hyaluronic Acid (HA-NH2): 1 g of hyaluronic acid was dissolved in 100 ml of water, and 0.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The mixture was activated at 25 °C for 30 min to activate the carboxyl group of the hyaluronic acid. Then, 7 ml of ethylenediamine was added to adjust the pH to 6, and the reaction was carried out at 25 °C in the dark for 2 h. The reaction solution was added to a dialysis bag with a molecular weight cutoff of 8000-14000 Daltons, dialyzed with water for 4 days, and then freeze-dried to obtain amino-modified hyaluronic acid (HA-NH2).
[0047] The results are as follows Figure 2 As shown, this indicates that the modification of hyaluronic acid was successful.
[0048] Step 3, Preparation of PEDOT:PSS: Step 3.1. Dissolve 10 mg of quercetin (Que) in 1 ml of PBS (pH=8) solution and stir at room temperature for 1 h to obtain quercetin solution.
[0049] Step 3.2. Add the quercetin solution prepared in Step 3.1 to the PEDOT:PSS solution, with a volume ratio of quercetin solution to PEDOT:PSS solution of 1:1, and stir at room temperature for 48 h to obtain the PEDOT:PSS-Que solution.
[0050] Step 4: The preparation method of the programmed drug release hydrogel includes the following steps: Step 4.1. Add 0.03 g of aldehyde-modified pullulan and 0.03 g of amino-modified hyaluronic acid to 2 ml of deionized water, heat at 75°C for 30 minutes to obtain a mixed solution.
[0051] Step 4.2. Add 1 g of acrylamide and 0.0015 g of N,N-methylenebisacrylamide to the mixed solution from step 4.1.
[0052] Step 4.3. Add 10 mg tobramycin and 0.2 ml PEDOT:PSS-Que solution to the mixed solution in step 4.1 to obtain the hydrogel precursor solution.
[0053] Step 4.4. Add 0.01g of ammonium persulfate to the hydrogel precursor solution from Step 4.3 and mix well. Place the above precursor solution into a mold and react at 60 °C for 1 h to obtain a programmed drug release hydrogel.
[0054] Example 2 In the programmed drug-release hydrogel of this invention, the raw materials aldehyde-modified pullulan (OPU) and amino-modified hyaluronic acid (HA-NH2) are prepared using the following method: Step 1, Preparation of aldehyde-modified pullulan (OPU): 1 g pullulan was dissolved in 100 ml of water, and 0.75 g of sodium periodate was added. The mixture was reacted at 30 °C in the dark for 20 h. After the reaction was completed, 2 ml of ethylene glycol was added to terminate the reaction for 1 h. The reaction solution was added to a dialysis bag with a molecular weight cutoff of 8000-14000 Daltons, dialyzed with water for 4 days, and then freeze-dried to obtain aldehyde-modified pullulan (OPU).
[0055] Step 2, Preparation of Aminated Hyaluronic Acid (HA-NH2): 1 g of hyaluronic acid was dissolved in 100 ml of water, and 0.67 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The mixture was activated at 30 °C for 40 min to activate the carboxyl group of the hyaluronic acid. Then, 8 ml of ethylenediamine was added to adjust the pH to 6, and the mixture was reacted at 30 °C in the dark for 1.5 h. The reaction solution was added to a dialysis bag with a molecular weight cutoff of 8000-14000 Daltons, dialyzed with water for 4 days, and then freeze-dried to obtain amino-modified hyaluronic acid (HA-NH2).
[0056] Step 3, Preparation of PEDOT:PSS: Step 3.1. Dissolve 13 mg of quercetin (Que) in 1 ml of PBS (pH=8) solution and stir at room temperature for 1 h to obtain quercetin solution.
[0057] Step 3.2. Add the quercetin solution prepared in Step 3.1 to the PEDOT:PSS solution, with a volume ratio of quercetin solution to PEDOT:PSS solution of 1:1, and stir at room temperature for 49 h to obtain the PEDOT:PSS-Que solution.
[0058] Step 4: The preparation method of the programmed drug release hydrogel includes the following steps: Step 4.1. Add 0.02 g of aldehyde-modified pullulan and 0.1 g of amino-modified hyaluronic acid to 2 ml of deionized water, heat at 75°C for 30 minutes to obtain a mixed solution.
[0059] Step 4.2. Add 1 g of acrylamide and 0.002 g of N,N-methylenebisacrylamide to the mixed solution from step 4.1.
[0060] Step 4.3. Add 20 mg tobramycin and 0.2 ml PEDOT:PSS-Que solution to the mixed solution in step 4.1 to obtain the hydrogel precursor solution.
[0061] Step 4.4. Add 0.008g of ammonium persulfate to the hydrogel precursor solution from step 4.3 and mix well. Place the above precursor solution into a mold and react at 70 °C for 30 min to obtain a programmed drug release hydrogel.
[0062] Example 3 In the programmed drug-release hydrogel of this invention, the raw materials aldehyde-modified pullulan (OPU) and amino-modified hyaluronic acid (HA-NH2) are prepared using the following method: Step 1, Preparation of aldehyde-modified pullulan (OPU): 1 g pullulan was dissolved in 100 ml of water, and 0.6 g of sodium periodate was added. The mixture was reacted at 28°C in the dark for 22 h. After the reaction was completed, 2 ml of ethylene glycol was added to terminate the reaction for 1 h. The reaction solution was added to a dialysis bag with a molecular weight cutoff of 8000-14000 Daltons, dialyzed with water for 4 days, and then freeze-dried to obtain aldehyde-modified pullulan (OPU).
[0063] Step 2, Preparation of Aminated Hyaluronic Acid (HA-NH2): Dissolve 1 g of hyaluronic acid in 100 ml of water, add 0.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and activate at 28°C for 35 min to activate the carboxyl group of hyaluronic acid; then add 7.5 ml of ethylenediamine, adjust the pH to 6, and react at 28°C in the dark for 100 min; add the reaction solution to a dialysis bag with a molecular weight cutoff of 8000-14000 Daltons, dialyze with water for 4 days, and freeze-dry to obtain amino-modified hyaluronic acid (HA-NH2).
[0064] Step 3, Preparation of PEDOT:PSS: Step 3.1. Dissolve 15 mg of quercetin (Que) in 1 ml of PBS (pH=8) solution and stir at room temperature for 1 h to obtain quercetin solution.
[0065] Step 3.2. Add the quercetin solution prepared in Step 3.1 to the PEDOT:PSS solution, with a volume ratio of quercetin solution to PEDOT:PSS solution of 1:1, and stir at room temperature for 50 h to obtain the PEDOT:PSS-Que solution.
[0066] Step 4: The preparation method of the programmed drug release hydrogel includes the following steps: Step 4.1. Add 0.1 g of aldehyde-modified pullulan and 0.02 g of amino-modified hyaluronic acid to 2 ml of deionized water, heat at 75°C for 30 minutes to obtain a mixed solution.
[0067] Step 4.2. Add 1 g of acrylamide and 0.001 g of N,N-methylenebisacrylamide to the mixed solution from step 4.1.
[0068] Step 4.3. Add 15 mg tobramycin and 0.2 ml PEDOT:PSS-Que solution to the mixed solution in step 4.1 to obtain the hydrogel precursor solution.
[0069] Step 4.4. Add 0.005g of ammonium persulfate to the hydrogel precursor solution from step 4.3 and mix well. Place the above precursor solution into a mold and react at 65 °C for 40 min to obtain a programmed drug release hydrogel.
[0070] The programmed drug release hydrogels prepared in Examples 1 to 3 all exhibit good biocompatibility, excellent adhesion, self-healing properties, conductivity, antibacterial properties, anti-inflammatory properties, and wound healing promotion capabilities. Example 1 will be used as an example for illustration below.
[0071] The adhesiveness of the programmed drug-release hydrogel prepared in Example 1 was tested using various substrates, such as... Figure 3 As shown, hydrogels can adhere firmly to various substrates, including plastics, metals, glass, rubber, skin, leaves, wood, and paper.
[0072] To evaluate the ability of the programmed drug release hydrogel prepared in Example 1 to monitor temperature changes, the thermal sensitivity of the programmed drug release hydrogel was quantified using the temperature resistivity (TCR). Figure 4 As shown, the conductivity of the hydrogel decreases in the temperature range of 35 ℃ to 44 ℃. The programmed drug release hydrogel prepared in Example 1 exhibits negative thermosensitivity (R / R0 is between 0 and 100%) and good linear correlation.
[0073] like Figure 5 It can be seen that when the circular programmed drug release hydrogel prepared in Example 1 is cut in half and then the two halves are spliced together to form a new circle, the two halves can heal into a complete hydrogel within 30 seconds. When lifted with tweezers and stretched, there is no breakage at the interface.
[0074] The in vitro antibacterial properties of the programmed drug release hydrogel prepared in Example 1 were investigated using Staphylococcus aureus and Escherichia coli. 1 mL of bacterial suspension (10... 8 CFU mL -1 After incubating with 0.1 g of hydrogel at 37°C for 12 h, the bacteria were spread onto agar plates. After 12 h, the colonies on the agar plates were photographed and recorded. A bacterial suspension in physiological saline served as a negative control. Staphylococcus aureus and Escherichia coli were purchased from Shanghai Sangon Biotech Co., Ltd. The catalog numbers for Staphylococcus aureus and Escherichia coli were ATCC25923 and ATCC25922, respectively.
[0075] See the experimental results. Figure 6 The number of bacterial colonies on the agar plates after treatment with the control group and the blank hydrogel group was still very high, while the number of bacterial colonies on the agar plates after treatment with the drug-loaded hydrogel was significantly reduced, indicating that the hydrogel has good antibacterial properties.
[0076] The wound healing effect of hydrogels was evaluated using full-thickness wounds infected with S. aureus. Mice were randomly divided into four groups: Control (control group), Hydrosorb hydrogel (positive control), HPAP / TOB-Que, and HPAP / TOB-Que+ES.
[0077] The control group consisted of samples without any added hydrogel.
[0078] Hydrosorb hydrogel was purchased from Boehman.
[0079] HPAP / TOB-Que is the hydrogel prepared in Example 1.
[0080] HPAP / TOB-Que+ES is a solution obtained by applying a 3V current to the hydrogel prepared in Example 1 for 30 minutes.
[0081] Mice were anesthetized with isoflurane and their back hair was removed. A circular wound with a diameter of 8 mm was then created on the back of each mouse, and a suspension of *S. aureus* was injected into the wound. Different treatments were administered 24 hours after infection. The wound status was recorded at predetermined times.
[0082] See the experimental results. Figure 7 . Figure 7 The images show macroscopic images of wound healing in different treatment groups. It can be seen that the wounds in the control group and the Hydrosorb hydrogel group healed relatively slowly, failing to fully heal and leaving noticeable scars after 10 days. In contrast, the wound in the HPAP / TOB-Que+ES hydrogel treatment group healed the fastest, completing healing completely after 10 days without significant scarring.
[0083] In summary, the programmed drug release hydrogel of this invention utilizes aldehyde-modified pullulan (OPU), amino-modified hyaluronic acid (HA-NH2), polyacrylamide (PAM), tobramycin (TOB), and poly(3,4-ethyldioxothiabenzene) polystyrene sulfonate (PEDOT:PSS)-quercetin (Que) according to... Figure 8 Prepared using the following steps, this programmed drug-release hydrogel material exhibits good biocompatibility, excellent adhesion, self-healing properties, conductivity, antibacterial properties, anti-inflammatory properties, and wound-healing capabilities.
[0084] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.
[0085] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.
Claims
1. A method for preparing a programmed drug release hydrogel, characterized in that, Includes the following steps: Aldehyde-modified pullulan and amino-modified hyaluronic acid undergo a Schiff base reaction in water to obtain a first solution; the first solution, acrylamide, a crosslinking agent, and tobramycin are mixed to obtain a second solution; After mixing the quercetin solution and the conductive polymer, an electrostatic adsorption reaction occurs during stirring, yielding a third solution. The third solution and the second solution are mixed, and a free radical polymerization reaction occurs under the action of an initiator to obtain a programmed drug release hydrogel.
2. The method for preparing a programmed drug release hydrogel according to claim 1, characterized in that, The mass fraction of aldehyde-modified pullulan in the first solution is 1% to 5%; The mass fraction of amino-modified hyaluronic acid in the first solution is 1% to 5%.
3. The method for preparing a programmed drug release hydrogel according to claim 1, characterized in that, The preparation of aldehyde-modified pullulan includes the following steps: Sodium periodate was added to pullulan solution, and an oxidation reaction was carried out to obtain aldehyde-modified pullulan.
4. The method for preparing a programmed drug release hydrogel according to claim 3, characterized in that, The mass ratio of pullulan to sodium periodate is 2:1~1.5; The oxidation reaction was carried out at 25℃~30℃ in the dark for 20h~24h.
5. The method for preparing a programmed drug release hydrogel according to claim 1, characterized in that, The preparation of aminolated hyaluronic acid includes the following steps: After activating the hyaluronic acid solution with a carboxyl activator, an amine compound is added, and an amidation reaction occurs at pH 6 to obtain amino-modified hyaluronic acid.
6. The method for preparing a programmed drug release hydrogel according to claim 5, characterized in that, The mass ratio of hyaluronic acid to carboxyl activator is 3:1~2; The ratio of hyaluronic acid to amine compounds is 1g:7ml~8ml; the amine compound is ethylenediamine. The activation reaction is carried out at 25℃~30℃ for 30min~40min; The amidation reaction was carried out at 25℃~30℃ in the dark for 1.5h~2h.
7. The method for preparing a programmed drug release hydrogel according to claim 1, characterized in that, The volume ratio of quercetin solution to conductive polymer is 1:1, the concentration of quercetin solution is 10 mg / ml~15 mg / ml, and the mass concentration of conductive polymer solution is 5%. The electrostatic adsorption reaction takes 48 to 50 hours. The conductive polymer is poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate); The mass ratio of acrylamide to tobramycin is 10:0.1~0.2; The mass ratio of quercetin to tobramycin is 10-15:1; The reaction temperature for free radical polymerization is 60℃~70℃, and the reaction time is 0.5h~1h.
8. The method for preparing a programmed drug release hydrogel according to claim 1, characterized in that, The amount of crosslinking agent added is 0.1% to 0.2% of the mass of acrylamide; the amount of initiator added is 0.5% to 1% of the mass of acrylamide.
9. A programmed drug-release hydrogel prepared by the preparation method according to any one of claims 1 to 8.
10. The application of the programmed drug-release hydrogel of claim 9 as a wound dressing, characterized in that, When the pH at the wound site is less than 7, tobramycin is released; when the wound temperature is greater than 34℃~36℃, the anti-inflammatory drug quercetin is released through electrical stimulation.