CN116440317A - Photothermal antibacterial hydrogel and preparation method thereof - Google Patents
Photothermal antibacterial hydrogel and preparation method thereof Download PDFInfo
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- CN116440317A CN116440317A CN202310357917.6A CN202310357917A CN116440317A CN 116440317 A CN116440317 A CN 116440317A CN 202310357917 A CN202310357917 A CN 202310357917A CN 116440317 A CN116440317 A CN 116440317A
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a photothermal antibacterial hydrogel and a preparation method thereof. The invention takes bismuth oxide and epsilon-polylysine modified black phosphorus quantum dots, 3-aminophenylboric acid modified oxidized chondroitin sulfate and polyvinyl alcohol as raw materials, and BP/Bi taking dynamic boric acid ester bonds as main components, hydrogen bonds, pi-pi stacking and dynamic imine bond crosslinking as auxiliary components are formed in aqueous solution 2 O 3 E-PL@APBA-g-OCS/PVA hydrogel. The hydrogel has good multiple stimulus response, self-healing property, adhesiveness and bleeding stopping property, can realize synergistic antibacterial effect through the photo-thermal chemical effect, and can improve the wound microenvironment. Not only can provide good healing environment for common wounds, but also can accelerate the healing of diabetic infected wounds.
Description
Technical Field
The invention relates to a photothermal antibacterial hydrogel and a preparation method thereof, belonging to the technical field of medical biological materials.
Background
The skin serves as a first barrier for the human body, not only protects the viscera from the external environment, but also prevents the loss of body fluid without restriction. If the skin is improperly treated, bacteria can cause wound infection, which affects tissue repair and delays healing process. Particularly for Diabetic Feet (DF), the formation of drug-resistant bacterial biofilms and deregulation of the wound microenvironment make the wound difficult to heal, and in severe cases, cause infections, ulcers, and result in amputation. Clinically, debridement, systemic antibiotics, negative pressure therapy and maggot therapy are often utilized to combat diabetic foot wound infection caused by bacterial biofilm, but the effect is not ideal. In contrast, topical application of antimicrobial dressings is more beneficial for wound healing. However, traditional antibacterial dressing is easy to adhere to the wound when the wound is dry, and is easy to be polluted by exudates to infect the wound. The antibacterial hydrogel has the advantages of antibacterial property, ventilation, moisture retention, exudate control and absorption, and the like, so that the wound can be helped to heal rapidly.
The multifunctional antibacterial hydrogel dressing is prepared by polymerizing rigid natural polysaccharide functionalized by antibacterial activity quaternary ammonium salt and a flexible polyacrylamide network to form a double network, wherein two-dimensional nanomaterial phenylboronic acid functionalized graphene is taken as a nanofiller in prepolymerized dopamine. The multifunctional hydrogel has excellent adhesion performance and hemostatic performance, but has poor effect in treating diabetes wound infection.
As in the patent application No. CN115317660a, a near infrared corresponding antibacterial nanocomposite hydrogel dressing is disclosed, which is composed of an acrylamide-alginate hydrogel and bismuth sulfide nanocrystal particle-protein complexes loaded in situ in the hydrogel. The antibacterial nano composite hydrogel dressing has photothermal antibacterial property, but can not accelerate the healing of diabetic infected wounds.
Disclosure of Invention
The invention aims to solve the problems, and provides a photothermal antibacterial hydrogel and a preparation method thereof. The invention uses Bi 2 O 3 And epsilon-PL modified BPQDs, APBA modified OCS and PVA are taken as raw materials, and BP/Bi taking dynamic borate ester bonds as main materials and taking various non-covalent adhesion mechanisms as auxiliary materials is formed in aqueous solution 2 O 3 epsilon-PL@APBA-g-OCS/PVA antibacterial hydrogel. The hydrogel not only promotes common wound healing, but also can improve wound by photo-thermal/chemical synergistic antibacterial effectMicroenvironment to accelerate wound healing in diabetic infections.
The technical scheme for solving the problems is as follows:
a photo-thermal antibacterial hydrogel is prepared from BP/Bi 2 O 3 Mixing epsilon-PL nanoparticle aqueous solution, APBA-g-OCS PBS solution and PVA aqueous solution;
the BP/Bi 2 O 3 The epsilon-PL nanoparticle is BP/Bi formed by surface modification of epsilon-polylysine and occupation of defect sites of BP by bismuth oxide 2 O 3 A nanoparticle;
the APBA-g-OCS is oxidized chondroitin sulfate modified by 3-aminophenylboric acid.
As a two-dimensional semiconductor nanomaterial, black Phosphorus (BP) has the advantages of high photo-thermal conversion efficiency, good biocompatibility and no toxicity of metabolites. However, the surface defects of 2D BP make it prone to decomposition under water-oxygen conditions. Bismuth oxide (Bi) 2 O 3 ) Can occupy the defect site of BP to form heterostructure nano-particles to improve BP stability. Simultaneously, epsilon-polylysine (epsilon-PL) with excellent chemical antibacterial effect is modified on the surfaces of the nano particles to prepare the photo-thermal conversion agent BP/Bi 2 O 3 epsilon-PL, and loaded into the hydrogel, is resistant to bacterial biofilm in chronic wounds.
The production of excess reactive oxygen species and the over-expression of inflammatory chemokines in diabetic foot wounds results in a deregulation of the wound microenvironment. Negatively charged sulfate groups on extracellular matrix glycosaminoglycans (e.g., chondroitin sulfate CS) can bind to positively charged amino acid residues on inflammatory chemokines through electrostatic interactions, regulating extracellular matrix chemokine transport to improve wound microenvironment and promote DF wound healing.
PVA is a natural polymer material, has good biocompatibility and good stability in aqueous solution, and can be used as a cross-linking agent and a supporting material in hydrogel.
The preparation method of the photothermal antibacterial hydrogel comprises the following steps:
s1, dispersing the ground black phosphorus crystals in methyl pyrrolidone (NMP), carrying out ice bath and ultrasonic centrifugation to obtain supernatant containing Black Phosphorus Quantum Dots (BPQDs) with uniform particle size;
s2, adding epsilon-PL alcohol solution and Bi (NO) into the BPQDs solution 3 ) 3 ·5H 2 O alcohol solution, stirring, standing, centrifuging, dispersing precipitate in water, and preparing BP/Bi 2 O 3 An epsilon-PL nanoparticle solution;
s3, adding NaIO into the Chondroitin Sulfate (CS) solution 4 Uniformly mixing, stirring in a dark place, adding reducing alcohol, dialyzing the obtained solution, and freeze-drying the dialysate to obtain Oxidized Chondroitin Sulfate (OCS);
s4, preparing the OCS into an aqueous solution, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS), performing a first pH value adjustment and light-proof reaction, adding 3-aminophenylboric acid (APBA) solution, performing a second pH value adjustment and light-proof reaction, dialyzing the obtained reaction solution, and performing freeze drying on the dialyzate to obtain 3-aminophenylboric acid modified oxidized chondroitin sulfate (APBA-g-OCS);
s5, the BP/Bi is processed 2 O 3 Mixing the epsilon-PL nanoparticle solution, the APBA-g-OCS solution and the PVA aqueous solution to obtain the BP/Bi in a wet state 2 O 3 An epsilon-PL@APBA-g-OCS/PVA antibacterial hydrogel;
the APBA-g-OCS solution is prepared by dissolving the APBA-g-OCS in PBS.
Preferably, in step S1, the grinding of the black phosphorus crystals is performed in a state of N 2 Is performed in the middle (a).
Preferably, the supernatant liquid containing BPQDs is further diluted to 0.1-0.3 mg/mL.
Preferably, the supernatant containing the BPQDs with the concentration of 0.1-0.3 mg/mL is further refrigerated at the temperature of 3-5 ℃ for standby.
Preferably, in step S2, the ε -PL alcohol solution and Bi (NO 3 ) 3 ·5H 2 The solvents of the O alcohol solution are ethylene glycol; the concentration of the epsilon-PL alcohol solution is 2-6 mg/mL; the Bi (NO) 3 ) 3 ·5H 2 The concentration of the O alcohol solution is 30-34 mg/mL; and standing for 4-6 hours.
Preferably, in step S2, the ε -PL and Bi (NO 3 ) 3 ·5H 2 The mass ratio of O to BPQDs is as follows: (0.8-1.2) to (16-24) to (0.8-1.2); the BP/Bi 2 O 3 The concentration of the epsilon-PL nanoparticle solution is 0.01-0.45 mg/mL.
Preferably, in the step S3, the concentration of the CS solution is 8-12 mg/mL; the light-shielding stirring time is 5-7 hours; the reducing alcohol is ethylene glycol; the dialysis time is 2-4 d; the dialysis process comprises the steps of changing water every 6-8 hours; the freeze drying temperature of the dialysate is-70 to-90 ℃; the freeze drying time of the dialysate is 2-4 d; the CS and NaIO 4 The molar ratio of (2.4-3.6) to (0.8-1.2).
Preferably, in step S4, the concentration of the OCS solution is 3-5 mg/mL; the pH value is adjusted to be 4-5 for the first time, and the light-shielding reaction time is 0.5-1.5 h; the pH value is adjusted to 4-5 for the second time, and the light-shielding reaction time is 10-12 hours; the dialysis condition is that the dialysis is carried out for 1.5-3 d in an aqueous solution with the pH value of 4-5 and for 1.5-3 d in ultrapure water; the freeze drying temperature of the dialysate is-70 to-90 ℃; and the freeze drying time of the dialysate is 2-4 d.
Preferably, in the step S4, the concentration of the APBA solution is 11-13 mg/mL; the solvent of the APBA solution is dimethyl sulfoxide (DMSO); the molar ratio of OCS, EDC, NHS, APBA is (0.8-1.2) to (0.8-1.2).
Preferably, in step S5, the pH of the PBS is 7.2 to 7.4; the concentration of the APBA-g-OCS solution is 6-12 wt%; the concentration of the PVA solution is 2-4wt%; the reaction time is 25-35 s.
Preferably, in step S5, the BP/Bi 2 O 3 The mass ratio of epsilon-PL to APBA-g-OCS to PVA is as follows: (0.01-0.45): (6-12): (2-4).
The invention has the following beneficial effects:
1. the photo-thermal antibacterial hydrogel prepared by the invention has multiple stimulus responsiveness, self-healing property, adhesiveness and hemostatic property, and can effectively close wounds;
2. the photo-thermal antibacterial hydrogel prepared by the invention can realize photo-thermal/chemical synergistic antibacterial effect, and is beneficial to resisting wound infection;
3. the photo-thermal antibacterial hydrogel prepared by the invention has the capabilities of removing active oxygen and adsorbing inflammatory chemokines, and can improve the microenvironment of wounds;
4. the photothermal antibacterial hydrogel prepared by the invention not only can provide a good healing environment for common wounds, but also can accelerate healing of diabetic infected wounds;
5. the raw materials used in the invention are cheap and easy to obtain, the preparation process is simple and pure, the preparation of the hydrogel does not need an organic solvent, the preparation period is extremely short, and the hydrogel can be formed into gel in situ within 30 s without expensive instruments.
Drawings
FIG. 1 is a flow chart of the preparation of a photothermal antimicrobial hydrogel;
FIG. 2 shows BP/Bi 2 O 3 SEM images of hydrogels with mass ratios of ε -PL, APBA-g-OCS and PVA of 0:9:3 (Blank gel) and 0.25:9:3 (NPs@gel-2);
FIG. 3 shows BP/Bi 2 O 3 A temperature rise profile of hydrogels with mass ratios of ∈ -PL, APBA-g-OCS and PVA of 0:9:3 (Blank gel) and 0.25:9:3 (NPs@gel-2) by NIR irradiation of 808 nm for 15 min;
FIG. 4 shows BP/Bi 2 O 3 Self-healing plot of hydrogels with mass ratio of ∈ -PL, APBA-g-OCS and PVA of 0.25:9:3 (NPs@gel-2);
FIG. 5 shows BP/Bi 2 O 3 Adhesion of hydrogel (a) to pig skin with a mass ratio of ∈ -PL, APBA-g-OCS and PVA of 0.25:9:3 (NPs@gel-2); (b, d) adhesion to various tissues and different materials; (c) adhesion to human joints;
FIG. 6 shows BP/Bi 2 O 3 Hydrogels with mass ratio of epsilon-PL, APBA-g-OCS and PVA of 0.25:9:3 (NPs@gel-2) were immersed in different solutions (PBS, 1 mM H) 2 O 2 16.6 mM Glucose) degradation rate at different time intervals;
FIG. 7 shows BP/Bi 2 O 3 Hydraulic set of mass ratio of ∈ -PL, APBA-g-OCS and PVA of 0:9:3 (Blank gel) and 0.25:9:3 (NPs@gel-2)The gel scavenges ROS inside the cell;
FIG. 8 shows BP/Bi 2 O 3 The adsorption capacities of hydrogels with respect to inflammatory chemokines IL-8 and MCP-1 with a mass ratio of ∈ -PL, APBA-g-OCS and PVA of 0:9:3 (Blank gel) and 0.25:9:3 (NPs@gel-2);
FIG. 9 shows BP/Bi 2 O 3 epsilon-PL antibacterial Activity of hydrogels with APBA-g-OCS and PVA in mass ratio of 0:9:3 (Blank gel) and 0.25:9:3 (NPs@gel-2);
FIG. 10 shows BP/Bi 2 O 3 Hemostatic Properties of hydrogels with a mass ratio of ∈ -PL, APBA-g-OCS and PVA of 0.25:9:3 (NPs@gel-2).
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings.
Example 1
FIG. 1 is a flow chart showing the preparation of a photothermal antimicrobial hydrogel; sequentially comprises BP/Bi 2 O 3 Preparation of epsilon-PL nanoparticle, preparation of APBA-g-OCS and BP/Bi 2 O 3 Preparation of epsilon-PL@APBA-g-OCS/PVA hydrogel.
BP/Bi 2 O 3 Preparation of epsilon-PL nanoparticles
BP/Bi 2 O 3 The preparation method of the epsilon-PL nanoparticle comprises the following steps:
will be at N 2 Dispersing the black phosphorus crystal ground in NMP, ice-bathing, centrifuging after ultrasonic treatment, quantitatively diluting the supernatant containing BPQDs with uniform particle size to 0.2 mg/mL, and storing in a refrigerator;
adding 4 mg/mL epsilon-PL alcohol solution with ethylene glycol as solvent and 32 mg/mL Bi (NO) into the BPQDs solution 3 ) 3 ·5H 2 O alcohol solution, stirring the obtained mixed solution uniformly, standing at room temperature for 5h, and centrifuging. Dispersing 0 mg precipitate in water to prepare 0 mg/mL BP/Bi 2 O 3 epsilon-PL nanoparticle solution.
In the method, the mass and the dosage of each substance are respectively epsilon-PL and Bi (NO 3 ) 3 ·5H 2 O∶BPQDs=1：20：1。
Preparation of APBA-g-OCS
The preparation method of the APBA-g-OCS comprises the following steps:
NaIO was added to 10 mg/mL CS solution 4 Stirring for 6 h in dark, adding 1 mL glycol to terminate reaction, placing the obtained solution in a dialysis bag, dialyzing at room temperature for 3 d, and freeze-drying the obtained dialysate at-80deg.C for 3 d to obtain OCS;
EDC and NHS are added into the prepared OCS solution with the concentration of 4 mg/mL, the pH value of the solution is regulated to 4-5, and the solution reacts at room temperature in a dark place for 1 h; adding APBA solution with a solvent of DMSO and a concentration of 12 mg/mL into the solution, adjusting the pH to 4-5, and carrying out light-shielding reaction at room temperature overnight; the reaction solution is placed in a dialysis bag, dialyzed for 2 days in aqueous solution with pH value of 4-5, dialyzed for 2 days in ultrapure water, and the obtained dialysate is freeze-dried at-80 ℃ for 3 d, thus obtaining APBA-g-OCS.
In the method, the molar ratio of each substance is CS to NaIO 4 =1∶3；OCS：EDC∶NHS∶APBA=1∶1∶1∶1。
BP/Bi 2 O 3 Preparation of epsilon-PL@APBA-g-OCS/PVA hydrogel
At room temperature: APBA-g-OCS was dissolved in PBS at ph=7.4 to prepare a 9wt% APBA-g-OCS solution; PVA is dissolved in distilled water to prepare a PVA solution with the weight percent of 3; the mass ratio is as follows: BP/Bi 2 O 3 Mixing the above solutions with the ratio of epsilon-PL to APBA-g-OCS to PVA=0:9:3, and reacting the mixed solution with 30 s to obtain BP/Bi in wet state 2 O 3 An epsilon-PL@APBA-g-OCS/PVA antibacterial hydrogel; freeze drying the obtained wet hydrogel to obtain BP/Bi in dry state 2 O 3 E-PL@APBA-g-OCS/PVA hydrogel.
Example 2
BP/Bi 2 O 3 Preparation of epsilon-PL nanoparticles
BP/Bi 2 O 3 The preparation method of the epsilon-PL nanoparticle comprises the following steps:
will be at N 2 Dispersing the black phosphorus crystal ground in NMP, ice-bathing, centrifuging after ultrasonic treatment, quantitatively diluting the supernatant containing BPQDs with uniform particle size to 0.2 mg/mL, and storing in a refrigerator;
adding 4 mg/mL epsilon-PL alcohol with ethylene glycol as solvent into the BPQDs solutionSolution and 32 mg/mL Bi (NO 3 ) 3 ·5H 2 O alcohol solution, stirring the obtained mixed solution uniformly, standing at room temperature for 5h, and centrifuging. Dispersing the precipitate in water to prepare BP/Bi of 0.25 mg/mL 2 O 3 epsilon-PL nanoparticle solution.
In the method, the mass and the dosage of each substance are respectively epsilon-PL and Bi (NO 3 ) 3 ·5H 2 O∶BPQDs=1∶20∶1。
Preparation of APBA-g-OCS
The preparation method of the APBA-g-OCS comprises the following steps:
NaIO was added to the 10 mg/mLCS solution 4 Stirring for 6 h in dark, adding 1 mL glycol to terminate reaction, placing the obtained solution in a dialysis bag, dialyzing at room temperature for 3 d, and freeze-drying the obtained dialysate at-80deg.C for 3 d to obtain OCS;
EDC and NHS are added into the prepared OCS solution with the concentration of 4 mg/mL, the pH value of the solution is regulated to 4-5, and the reaction is carried out at room temperature and in a dark place for 1 h; adding APBA solution with a solvent of DMSO and a concentration of 12 mg/mL into the solution, adjusting the pH to 4-5, and carrying out light-shielding reaction at room temperature overnight; the reaction solution is placed in a dialysis bag, dialyzed for 2 days in aqueous solution with pH value of 4-5, dialyzed for 2 days in ultrapure water, and the obtained dialysate is freeze-dried at-80 ℃ for 3 d, thus obtaining APBA-g-OCS.
In the method, the molar ratio of each substance is CS to NaIO 4 =1∶3；OCS∶EDC∶NHS∶APBA=1∶1∶1∶1。
BP/Bi 2 O 3 Preparation of epsilon-PL@APBA-g-OCS/PVA hydrogel
At room temperature: APBA-g-OCS was dissolved in PBS at ph=7.4 to prepare a 9wt% APBA-g-OCS solution; PVA is dissolved in distilled water to prepare a PVA solution with the weight percent of 3; the mass ratio is as follows: BP/Bi 2 O 3 Mixing the above solution with the ratio of epsilon-PL to APBA-g-OCS to PVA=0.25:9:3, and reacting the mixed solution with 30 s to obtain BP/Bi in wet state 2 O 3 epsilon-PL@APBA-g-OCS/PVA antibacterial hydrogel; freeze drying the obtained wet hydrogel to obtain BP/Bi in dry state 2 O 3 E-PL@APBA-g-OCS/PVA hydrogel.
Example 3
BP/Bi 2 O 3 Preparation of epsilon-PL nanoparticles
BP/Bi 2 O 3 The preparation method of the epsilon-PL nanoparticle comprises the following steps:
will be at N 2 Dispersing the black phosphorus crystal ground in NMP, ice-bathing, centrifuging after ultrasonic treatment, quantitatively diluting the supernatant containing BPQDs with uniform particle size to 0.2 mg/mL, and storing in a refrigerator;
adding 4 mg/mL epsilon-PL alcohol solution with ethylene glycol as solvent and 32 mg/mL Bi (NO) into the BPQDs solution 3 ) 3 ·5H 2 O alcohol solution, stirring the obtained mixed solution uniformly, standing at room temperature for 5h, and centrifuging. Dispersing the precipitate in water to prepare BP/Bi of 0.15 mg/mL 2 O 3 epsilon-PL nanoparticle solution.
In the method, the mass and the dosage of each substance are respectively epsilon-PL and Bi (NO 3 ) 3 ·5H 2 O∶BPQDs=1∶20∶1。
Preparation of APBA-g-OCS
The preparation method of the APBA-g-OCS comprises the following steps:
NaIO was added to the 10 mg/mLCS solution 4 Stirring for 6 h in dark, adding 1 mL glycol to terminate reaction, placing the obtained solution in a dialysis bag, dialyzing at room temperature for 3 d, and freeze-drying the obtained dialysate at-80deg.C for 3 d to obtain OCS;
EDC and NHS are added into the prepared OCS solution with the concentration of 4 mg/mL, the pH value of the solution is regulated to 4-5, and the solution reacts at room temperature in a dark place for 1 h; adding APBA solution with a solvent of DMSO and a concentration of 12 mg/mL into the solution, adjusting the pH to 4-5, and carrying out light-shielding reaction at room temperature overnight; the reaction solution is placed in a dialysis bag, dialyzed for 2 days in aqueous solution with pH value of 4-5, dialyzed for 2 days in ultrapure water, and the obtained dialysate is freeze-dried at-80 ℃ for 3 d, thus obtaining APBA-g-OCS.
In the method, the molar ratio of each substance is CS to NaIO 4 =1∶3；OCS∶EDC∶NHS∶APBA=1∶1∶1∶1。
BP/Bi 2 O 3 Preparation of epsilon-PL@APBA-g-OCS/PVA hydrogel
At room temperature: APBA-g-OCS was dissolved in PBS ph=7.4 to make 7.5wt%APBA-g-OCS solution; PVA is dissolved in distilled water to prepare a PVA solution with the weight percent of 3; the mass ratio is as follows: BP/Bi 2 O 3 Mixing the above solution with/ε -PL: APBA-g-OCS: PVA=0.15:7.5:3, and reacting the mixed solution with 30 s to obtain BP/Bi in wet state 2 O 3 epsilon-PL@APBA-g-OCS/PVA antibacterial hydrogel; freeze drying the obtained wet hydrogel to obtain BP/Bi in dry state 2 O 3 E-PL@APBA-g-OCS/PVA hydrogel.
Example 4
BP/Bi 2 O 3 Preparation of epsilon-PL nanoparticles
BP/Bi 2 O 3 The preparation method of the epsilon-PL nanoparticle comprises the following steps:
will be at N 2 Dispersing the black phosphorus crystal ground in NMP, ice-bathing, centrifuging after ultrasonic treatment, quantitatively diluting the supernatant containing BPQDs with uniform particle size to 0.2 mg/mL, and storing in a refrigerator;
adding 4 mg/mL epsilon-PL alcohol solution with ethylene glycol as solvent and 32 mg/mL Bi (NO) into the BPQDs solution 3 ) 3 ·5H 2 O alcohol solution, stirring the obtained mixed solution uniformly, standing at room temperature for 5h, and centrifuging. Dispersing the precipitate in water to prepare BP/Bi of 0.35 mg/mL 2 O 3 epsilon-PL nanoparticle solution.
In the method, the mass and the dosage of each substance are respectively epsilon-PL and Bi (NO 3 ) 3 ·5H 2 O∶BPQDs=1∶20∶1。
Preparation of APBA-g-OCS
The preparation method of the APBA-g-OCS comprises the following steps:
NaIO was added to the 10 mg/mLCS solution 4 Stirring for 6 h in dark, adding 1 mL glycol to terminate reaction, placing the obtained solution in a dialysis bag, dialyzing at room temperature for 3 d, and freeze-drying the obtained dialysate at-80deg.C for 3 d to obtain OCS;
EDC and NHS are added into the prepared OCS solution with the concentration of 4 mg/mL, the pH value of the solution is regulated to 4-5, and the solution reacts at room temperature in a dark place for 1 h; adding APBA solution with a solvent of DMSO and a concentration of 12 mg/mL into the solution, adjusting the pH to 4-5, and carrying out light-shielding reaction at room temperature overnight; the reaction solution is placed in a dialysis bag, dialyzed for 2 days in aqueous solution with pH value of 4-5, dialyzed for 2 days in ultrapure water, and the obtained dialysate is freeze-dried at-80 ℃ for 3 d, thus obtaining APBA-g-OCS.
In the method, the molar ratio of each substance is CS to NaIO 4 =1∶3；OCS∶EDC∶NHS∶APBA=1∶1∶1∶1。
BP/Bi 2 O 3 Preparation of epsilon-PL@APBA-g-OCS/PVA hydrogel
At room temperature: APBA-g-OCS was dissolved in PBS at ph=7.4 to prepare a 10.5wt% APBA-g-OCS solution; PVA is dissolved in distilled water to prepare a PVA solution with the weight percent of 3; the mass ratio is as follows: BP/Bi 2 O 3 Mixing the above solution with/ε -PL: APBA-g-OCS: PVA=0.15:10.5:3, and reacting the mixed solution with 30 s to obtain BP/Bi in wet state 2 O 3 epsilon-PL@APBA-g-OCS/PVA antibacterial hydrogel; freeze drying the obtained wet hydrogel to obtain BP/Bi in dry state 2 O 3 E-PL@APBA-g-OCS/PVA hydrogel.
Hydrogel performance detection:
the hydrogels obtained in examples 1 and 2 were designated as Blank gel and NPs@gel-2, respectively.
As can be seen from FIG. 2, both the Blank gel and the NPs@gel-2 hydrogels exhibit a highly porous and interconnected network structure with relatively uniform pores that facilitates the absorption of the tissue excess exudates by the hydrogels as wound dressings.
As can be seen from FIG. 3, the two hydrogels, blank gel and NPs@gel-2, are gelled 808 nm, 1W/cm 2 After 15 min of NIR irradiation of Blank gel temperature to 32.5℃and NPs@gel-2 temperature to 63.8 ℃; the NPs@gel-2 hydrogel has good photo-thermal property, and the photo-thermal property of the hydrogel is BP/Bi 2 O 3 epsilon-PL nanoparticle.
As can be seen from fig. 4, the broken hydrogel had no external intervention, and after 300s, the crack disappeared and healed completely, indicating that the nps@gel-2 hydrogel had a rapid, stable, efficient self-healing capacity, which was beneficial to providing a closed, moist environment to the wound.
As can be seen from fig. 5a, in the absence of any external force, two pigskin pieces adhered by the hydrogel can hang the weight of 75 g for 10 min and still cannot fall off; as can be seen from fig. 5b and 5d, nps@gel-2 hydrogel can adhere to different visceral surfaces (e.g. kidney, lung, heart, liver) and different material surfaces (e.g. iron, rubber, plastic, glass, paper) of rats and shows good adhesion; as can be seen in FIG. 5c, the NPs@gel-2 hydrogel adheres strongly to the skin surface and accommodates severe frequent and large amounts of finger articulation. These results demonstrate that nps@gel-2 hydrogels are beneficial for wound closure and are not easily destroyed when used as wound dressings, prolonging dressing life.
As can be seen from fig. 6, the degradation rate ratio of nps@gel-2 at ph=7.4 was higher than that at ph=5.2, 1 mM H 2 O 2 And degradation rates at 16 mM Glucose were slow. After incubation 6H, at ph=7.4, ph=5.2, 1 mM H 2 O 2 And 16 mM Glucose, the remaining weight ratios of NPs@gel-2 were 51%, 36%, 25% and 19%, respectively; these results indicate that hydrogels have pH, hydrogen peroxide and glucose dependent degradation behavior; this facilitates the accelerated degradation of nps@gel-2 hydrogels at DF wounds with high sugar and high active oxygen concentration, releasing more active substances to combat wound infection and regulate wound microenvironment.
As can be seen from FIG. 7, NIH3T3 cells treated with the Blank gel and NPs@gel-2 hydrogels showed significant fluorescence quenching, while control cells remained strongly fluorescent, indicating that Blank gel and NPs@gel-2 hydrogels can effectively scavenge active oxygen in the cells; this is beneficial to the NPs@gel-2 hydrogel to protect wound tissues from active oxygen, improve the microenvironment of the wound and avoid the excessive oxidative stress reaction of the wound.
As can be seen from fig. 8, the control group had almost no adsorption to the inflammatory chemokines MCP-1 and IL-8; the adsorption rates of the Blank gel and the NPs@gel-2 to the MCP-1 are respectively up to 87% and 82%; the adsorption rates of IL-8 by Blank gel and NPs@gel-2 are 81% and 73%, respectively; the NPs@gel-2 of 1 mL is calculated to adsorb the MCP-1 of 4.2 ng and the IL-8 of 775, 775 ng, which shows that the hydrogel can effectively remove inflammatory chemokines, is beneficial to the hydrogel to regulate the transportation of the inflammatory chemokines, improves the microenvironment of wounds and accelerates the healing of DF infected wounds.
As can be seen from FIG. 9, the growth conditions of bacteria treated by different groups on an agar plate are observed, and the antibacterial rate of the Blank gel group on three bacteria is 15-18%, because boric acid molecules can be combined with glycol molecules of glycoprotein on the surface of bacterial cells, and a certain antibacterial effect is generated; the antibacterial rate of the NPs@gel-2 group to three bacteria is 84-89%, and the obvious antibacterial capacity mainly derives from the physicochemical effect between the amino group of epsilon-PL and the bacterial membrane, so that the bacterial membrane is broken to kill the bacteria; NPs@gel-2+NIR group shows the strongest antibacterial activity, and the inhibition rate of the NPs@gel-2+NIR group on three bacteria is 100%, which indicates that the combination of photo-thermal and chemical antibacterial is more beneficial to thoroughly killing the bacteria; this is beneficial to the nps@gel-2 hydrogel to resist bacterial infection at DF wounds through photo-thermal-chemical combination antibacterial, reduce inflammatory reaction and promote wound healing.
As can be seen from FIG. 10, the blood loss amounts after 5 min of treatment with Control (+), medical gauze [ Control (-) ] and NPs@gel-2 were 253.3mg, 175.3mg and 24.3 mg, respectively; the time required for hemostasis of the Control (+) and Control (-) groups is 4 min, while the NPs@gel-2 treatment group can immediately stop bleeding; this is mainly due to the good adhesion of nps@gel-2, which can effectively close the liver bleeding site and prevent bleeding.
By combining the comparison data and the pictures, the photo-thermal antibacterial hydrogel prepared by the invention has rapid self-healing property, adhesiveness and hemostatic property, is beneficial to closing wounds and provides a good healing environment for the wounds; has photo-thermal/chemical synergistic sterilization effect, and is beneficial to resisting wound infection; has pH, H 2 O 2 And glucose and other multiple stimulus responsivity, which is beneficial to the hydrogel to regulate and control the wound microenvironment; the ROS can be effectively removed, inflammatory chemokines are adsorbed, and the wound microenvironment can be regulated and controlled; the photothermal antibacterial hydrogel prepared by the invention not only can be beneficial to common wound healing, but also can effectively promote the repair of diabetic infected wounds.
Claims (10)
1. A photothermal antibacterial hydrogel is characterized in that the hydrogel consists of BP/Bi 2 O 3 Aqueous solution of epsilon-PL nanoparticles, APBA-g-OCSIs mixed with the aqueous solution of PVA;
the BP/Bi 2 O 3 The epsilon-PL nanoparticle is BP/Bi formed by surface modification of epsilon-polylysine and occupation of defect sites of BP by bismuth oxide 2 O 3 A nanoparticle;
the APBA-g-OCS is oxidized chondroitin sulfate modified by 3-aminophenylboric acid.
2. The preparation method of the photothermal antibacterial hydrogel comprises the following steps:
s1, dispersing the ground black phosphorus crystals in NMP, carrying out ice bath and ultrasonic treatment, and centrifuging to obtain BPQDs supernatant containing uniform particle size;
s2, adding epsilon-PL alcohol solution and Bi (NO) into the BPQDs solution 3 ) 3 ·5H 2 O alcohol solution, stirring, standing, centrifuging, dispersing precipitate in water, and preparing BP/Bi 2 O 3 An epsilon-PL nanoparticle solution;
s3, adding NaIO into the CS solution 4 After being uniformly mixed, the mixture is stirred in a dark place, reducing alcohol is added, the obtained solution is dialyzed, and the dialysate is freeze-dried to obtain OCS;
s4, preparing the OCS into an aqueous solution, adding EDC and NHS, performing a first pH value adjustment and light-proof reaction, adding an APBA solution, performing a second pH value adjustment and light-proof reaction, dialyzing the obtained reaction solution, and performing freeze drying on the dialyzate to obtain APBA-g-OCS;
s5 the BP/Bi is treated with 2 O 3 Mixing the epsilon-PL nanoparticle solution, the APBA-g-OCS solution and the PVA aqueous solution to obtain the BP/Bi in a wet state 2 O 3 An epsilon-PL@APBA-g-OCS/PVA antibacterial hydrogel; the APBA-g-OCS solution is prepared by dissolving the APBA-g-OCS in PBS.
3. The method of preparing a photothermal antibacterial hydrogel according to claim 2, wherein in step S1, the grinding of the black phosphorus crystals is performed under N 2 Is carried out in the middle; the concentration of the supernatant is 0.1-0.3 mg/mL.
4. The method for producing a photothermal antibacterial hydrogel according to claim 2, wherein in step S2, the epsilon-PL alcohol solution and Bi (NO 3 ) 3 ·5H 2 The solvents of the O alcohol solution are ethylene glycol; the concentration of the epsilon-PL alcohol solution is 2-6 mg/mL; the Bi (NO) 3 ) 3 ·5H 2 The concentration of the O alcohol solution is 30-34 mg/mL; and standing for 4-6 hours.
5. The method for producing a photothermal antibacterial hydrogel according to claim 2, wherein in step S2, the epsilon-PL and Bi (NO 3 ) 3 ·5H 2 The mass ratio of O to BPQDs is as follows: (0.8-1.2): (16-24): (0.8-1.2), said BP/Bi 2 O 3 The concentration of the epsilon-PL nanoparticle solution is 0.01-0.45 mg/mL.
6. The method for preparing a photothermal antibacterial hydrogel according to claim 2, wherein in step S3, the concentration of the CS solution is 8-12 mg/mL; the light-shielding stirring time is 5-7 hours; the reducing alcohol is ethylene glycol; the dialysis time is 2-4 d; the dialysis process comprises the steps of changing water every 6-8 hours; the freeze drying temperature of the dialysate is-70 to-90 ℃; the freeze drying time of the dialysate is 2-4 d; the CS and NaIO 4 The molar ratio of (2.4-3.6) to (0.8-1.2).
7. The method for preparing a photothermal antibacterial hydrogel according to claim 2, wherein in step S4, the OCS solution concentration is 3-5 mg/mL; the pH value is adjusted to be 4-5 for the first time, and the light-shielding reaction time is 0.5-1.5 h; the pH value is adjusted to 4-5 for the second time, and the light-shielding reaction time is 10-12 hours; the dialysis condition is that the dialysis is carried out for 1.5-3 d in an aqueous solution with the pH value of 4-5 and for 1.5-3 d in ultrapure water; the freeze drying temperature of the dialysate is-70 to-90 ℃; and the freeze drying time of the dialysate is 2-4 d.
8. The method for preparing a photothermal antibacterial hydrogel according to claim 2, wherein in step S4, the APBA solution concentration is 11-13 mg/mL; the solvent of the APBA solution is DMSO; the molar ratio of OCS, EDC, NHS, APBA is (0.8-1.2) to (0.8-1.2).
9. The method for preparing a photothermal antibacterial hydrogel according to claim 2, wherein in step S5, the pH of the PBS is 7.2 to 7.4; the concentration of the APBA-g-OCS solution is 6-12 wt%; the concentration of the PVA solution is 2-4wt%; the reaction time is 25-35 s.
10. The method for preparing a photothermal antibacterial hydrogel according to claim 2, wherein in step S5, the BP/Bi 2 O 3 The mass ratio of epsilon-PL to APBA-g-OCS to PVA is as follows: (0.01-0.45): (6-12): (2-4).
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