CN114832152B

CN114832152B - Photothermal antibacterial medical injectable hydrogel and preparation method thereof

Info

Publication number: CN114832152B
Application number: CN202210452503.7A
Authority: CN
Inventors: 刘慧玲; 郭瑞
Original assignee: Guangzhou Bioscience Co ltd
Current assignee: Guangzhou Bioscience Co ltd
Priority date: 2022-04-27
Filing date: 2022-04-27
Publication date: 2023-06-30
Anticipated expiration: 2042-04-27
Also published as: CN114832152A

Abstract

The invention relates to a photo-thermal antibacterial medical injectable hydrogel and a preparation method thereof, wherein the photo-thermal antibacterial medical injectable hydrogel comprises hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, methacryloylated gelatin, oxidized dextran, gelatin, a photoinitiator and an aqueous medium, has the advantages of injectability and quick solidification, realizes complete closure of irregular wound surfaces in a crosslinking mode after injection, maintains a moist environment of the wound surfaces, and is beneficial to accelerating wound healing; in addition, the aminolevulinate hydrochloride is loaded in the cavity of the hollow bismuth nanospheres, so that the aminolevulinate hydrochloride is used for realizing an immunoregulation function, and the bismuth nanomaterial has a photo-thermal sterilization effect, so that the wound infection problem can be effectively solved, the aminolevulinate hydrochloride can be used as a slow release carrier material, the long-term release of the aminolevulinate hydrochloride is realized, and the problems that the wound surface needs multiple times of drug administration and the treatment process is complex in the prior art when the nanometer antibacterial solution and the like are used are avoided.

Description

Photothermal antibacterial medical injectable hydrogel and preparation method thereof

Technical Field

The invention relates to the technical field of medical biological materials, in particular to a photo-thermal antibacterial medical injectable hydrogel and a preparation method thereof.

Background

The modern medical nursing means for wounds difficult to heal mainly comprise operation debridement, negative pressure drainage and the like, however, the technical means can only promote the healing of the wounds within a small range, and patients still face a great economic burden and the affliction of skin ulcers, so that the life quality of the patients is seriously influenced. In addition, for some long-term infection ulcers, a wound surface that is not healed for a long time, serious people may face amputation risks. The existing treatment means still have difficulty in achieving satisfactory therapeutic effects for these conditions.

Through years of researches on wound healing mechanisms, researchers find that the reason that the wound is difficult to heal is mainly concentrated at two points, namely, one point is exposed to the external environment for a long time to cause bacterial colonization, and the wound faces serious bacterial infection; secondly, the deficiency of blood supply at the wound surface leads to hypoxia, and macrophages can not finish phenotype switching regulation under the normal state.

Clinically, the treatment means aiming at the infected wound surface are mainly concentrated on antibiotics, and in recent years, some silver-containing dressings are also used as new high-end nursing modes to enter an ordinary treatment scheme. However, long-term use of antibiotics increases the risk of bacterial resistance, while nano silver has a remarkable antibacterial effect, its cytotoxicity is a not inconsiderable problem, and it is still irrelevant whether the metabolism of nano-drugs in the body and the long-term influence on the human body are caused. Various novel antimicrobial treatments have been developed such as photothermal therapy, photodynamic therapy, gas therapy, and the like. The photothermal treatment is means for converting light energy into local hyperthermia under the irradiation of laser with specific wavelength by photosensitizer, and destroying proteins in bacteria by various hyperthermia effects to kill bacteria. The photothermal treatment has the advantages of strong antibacterial effect, less damage to normal tissues, certain penetration depth and the like, and provides a new way for the development of wound antibacterial dressing, but the existing photosensitizer can be rarely used as a drug carrier, and simultaneously delivers therapeutic drugs and only plays a role of photothermal conversion.

In addition, for inflammatory reaction disorder faced in the wound healing process, some researches have been conducted to use antioxidant drugs, such as resveratrol, tea extracts and the like, to clear free radicals at the wound, however, the drugs generally have poor water solubility, and increase the difficulty of clinical application.

Hydrogels are becoming more and more noticed under the guidance of wound moist healing theory due to their good moisture retention, and various hydrogel dressings have been developed for the treatment of wound healing. The injectable hydrogel can fill irregular wound surfaces, can better realize wound surface sealing, and is a popular direction for developing hydrogel wound surface dressing in the future.

Disclosure of Invention

Based on the above, aiming at the problems of bacterial infection, inflammatory reaction disorder and the like in the healing process of wound surfaces difficult to heal, the embodiment of the invention aims to provide the photo-thermal antibacterial medical injectable hydrogel which can have the photo-thermal antibacterial effect and the immunoregulation effect at the same time, realize sterilization at wound surface tissues, reduce inflammatory reaction and accelerate tissue regeneration.

The embodiment of the invention achieves the technical purposes through the following technical scheme:

a photo-thermal antibacterial medical injectable hydrogel, which comprises hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, methacryloylated gelatin, oxidized dextran, gelatin, a photoinitiator and an aqueous medium.

The photo-thermal antibacterial medical injectable hydrogel is prepared by adding methacrylic acylated gelatin, oxidized dextran, gelatin, a photoinitiator and an aqueous medium, condensing amino groups of the gelatin and aldehyde groups of the oxidized dextran to form Schiff base bonds, and initiating free radical polymerization of carbon-carbon double bonds in the methacrylic acylated gelatin under 405nm blue light irradiation by using the photoinitiator to realize crosslinking; the injectable hydrogel has the advantages of injectability and rapid solidification, realizes complete closure of irregular wound surfaces in a crosslinking mode after injection, maintains moist environment of the wound surfaces, and is beneficial to accelerating wound surface healing;

by loading aminolevulinate hydrochloride into a cavity of a hollow bismuth nanosphere, the bismuth nanomaterial has the characteristic of photo-thermal effect, can convert light energy into heat energy under the irradiation of 808nm near infrared light so as to generate local high temperature, and can destroy structures such as proteins in bacteria through the high thermal effect, thereby killing bacteria and effectively solving the problem of wound infection; in addition, through the hollow structure of the bismuth nano material, the bismuth nano material can be used as a carrier material for slowly releasing the medicine while realizing the photo-thermal conversion effect, so that the long-term release of the functional medicine is realized, and the uniform dispersion and stable loading of the nano particles can be realized by further combining the hydrogel matrix;

the aminolevulinate hydrochloride is an FDA approved certification medicament, can generate carbon monoxide gas after being metabolized in vivo, is a gas signal molecule, can reduce inflammatory reaction at wound tissues, regulates the conversion of macrophages to M2 type, and realizes immunoregulation function; in addition, the load of the aminoacetoacrylate hydrochloride can realize a slow release effect, so that the problem that the treatment of the wound surface by using nano antibacterial solution and the like in the prior art requires multiple drug administration and the treatment process is complex is solved.

Further, in the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, the aminolevulinate hydrochloride and the hollow bismuth nanospheres are prepared according to the following steps of 2:1 to 3:1 weight part ratio of the components.

Further, the photoinitiator is phenyl-2, 4, 6-trimethyl benzoyl lithium phosphonate, and the aqueous medium is deionized water, normal saline or phosphoric acid buffer solution.

In addition, the embodiment of the invention also provides a preparation method of the photo-thermal antibacterial medical injectable hydrogel, which comprises the following specific operation steps:

1) Preparation of hollow bismuth nanospheres: bismuth nitrate is dissolved in nitric acid solution, polyvinylpyrrolidone and ethylene glycol are added into the solution, and then the mixed solution is transferred into a hydrothermal kettle and reacts for 12 hours at 180 ℃; centrifuging the reaction solution, collecting the precipitate, washing the precipitate with deionized water for several times, and drying to obtain the hollow bismuth nanospheres;

2) Load of aminolevulinate hydrochloride: dispersing aminolevulinate hydrochloride and the hollow bismuth nanospheres obtained in the step 1) into deionized water according to the weight part ratio, stirring and reacting for 22-26 hours at the temperature of 4 ℃, centrifugally collecting the reaction liquid, washing the precipitate with deionized water for a plurality of times, and drying to obtain the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride;

3) Preparation of methacryloylated gelatin: dissolving gelatin in deionized water, and heating in water bath at 50deg.C until gelatin solution is completely dissolved; then dropwise adding methacrylic anhydride into the gelatin solution, and stirring the obtained mixed solution for reaction for 1-4 h under the water bath heating condition of 50 ℃; placing the reaction solution in a dialysis bag, and dialyzing in deionized water for 3 days to remove unreacted anhydride; finally, centrifuging the dialyzed reaction solution to collect supernatant, freezing at-80 ℃, then placing the supernatant in a freeze dryer, freeze-drying to obtain the methacryloylated gelatin, and placing the methacryloylated gelatin at-20 ℃ for later use;

4) Preparation of oxidized dextran: dissolving glucan in deionized water and stirring until glucan is completely dissolved to obtain glucan solution; adding sodium periodate into the dextran solution under the condition of light shielding, stirring the mixture for reaction for 3 to 4 hours under the condition of room temperature and light shielding, finally adding glycol solution into the reaction solution, and continuously stirring the mixture for 1 to 2 hours to neutralize unreacted sodium periodate so as to stop the reaction; collecting the reaction solution, filling the reaction solution into a dialysis bag, and dialyzing the reaction solution with deionized water for 3 days; freezing the dialyzed reaction solution at-80 ℃, then placing the frozen reaction solution in a freeze dryer, freeze-drying to obtain oxidized dextran, and placing the oxidized dextran at-20 ℃ for standby;

5) Preparation of injectable hydrogels: and respectively dispersing and dissolving the methacryloylated gelatin, oxidized dextran and gelatin in an aqueous medium according to the mass percentages of 5%, 5% and 5% to obtain a mixed solution, dispersing hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in the mixed solution, adding a photoinitiator into the mixed solution, and initiating a crosslinking reaction under irradiation of blue light with the wavelength of 405nm to obtain the photo-thermal antibacterial medical injectable hydrogel.

The preparation method of the photo-thermal antibacterial medical injectable hydrogel comprises the steps of firstly taking bismuth nitrate as a bismuth source, taking polyvinylpyrrolidone as an inducer, preparing hollow bismuth nanospheres in a mixed solution of water and glycol by adopting a hydrothermal method, further loading aminolevulinate hydrochloride, and reacting with methacryloylated gelatin, oxidized dextran and a photoinitiator to prepare the photo-thermal antibacterial medical injectable hydrogel.

Further, in the step 1), the average molecular weight of polyvinylpyrrolidone is 9000-11000, the particle size of the hollow bismuth nanospheres obtained by the method of dynamic light scattering is 500-600 nm, and the average molecular weight of polyvinylpyrrolidone influences the size and the cavity volume of the hollow bismuth nanospheres obtained by the method of dynamic light scattering.

Further, the concentration of the gelatin solution in the step 3) is 0.1g/mL, and 0.5 to 0.8mL of methacrylic anhydride is used for every 1g of gelatin.

Further, the mass part ratio of the sodium periodate to the dextran used in the step 4) is 0.6-1.2; sodium periodate and glycol solution.

Further, the dialysis bags used in step 3) and step 4) were cellulose dialysis bags having a molecular weight cut-off of 3500Da.

Further, in the step 5), the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride are dispersed in the mixed solution according to the concentration of 100-300 mug/mL.

Further, 0.05mL of a 2% (w/v) solution of lithium phenyl-2, 4, 6-trimethylbenzoyl phosphonate was used for each 1mL of the mixed solution in step 5).

For a better understanding and implementation, the present invention is described in detail below with reference to the drawings.

Drawings

FIG. 1 is a transmission electron microscope image of the hollow bismuth nanospheres prepared in example 3 of the present invention;

FIG. 2 is an X-ray diffraction pattern of bismuth nanospheres and hollow bismuth nanospheres prepared in example 3 of the present invention;

fig. 3 is a schematic diagram of a photo-thermal temperature rise curve of the photo-thermal antibacterial medical injectable hydrogel prepared in examples 3 and 6-7 of the invention.

Detailed Description

The foregoing objects, features and advantages of the invention will be more readily apparent from the following detailed description of the invention.

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the embodiments disclosed below.

Example 1

The embodiment 1 of the invention provides a photo-thermal antibacterial medical injectable hydrogel, which comprises hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, methacryloylated gelatin, oxidized dextran, gelatin, a photoinitiator and an aqueous medium, wherein the aminolevulinate hydrochloride and the hollow bismuth nanospheres in the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride are prepared according to the following steps of 2:1 weight portion of the photo initiator is phenyl-2, 4, 6-trimethyl benzoyl lithium phosphonate, and the aqueous medium is deionized water.

Example 2

The embodiment 2 of the invention provides a photo-thermal antibacterial medical injectable hydrogel, which comprises hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, methacryloylated gelatin, oxidized dextran, gelatin, a photoinitiator and an aqueous medium, wherein the aminolevulinate hydrochloride and the hollow bismuth nanospheres in the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride are prepared according to the following steps of 3:1 weight portion of the photo initiator is phenyl-2, 4, 6-trimethyl benzoyl lithium phosphonate, and the aqueous medium is Phosphate Buffer Solution (PBS).

Example 3

The embodiment 3 of the invention provides a preparation method of a photo-thermal antibacterial medical injectable hydrogel, which comprises the following specific operation steps:

1) Preparation of hollow bismuth nanospheres: weighing 0.148g of bismuth nitrate, dissolving in 5mL of nitric acid solution, and adding 0.15g of polyvinylpyrrolidone and 25mL of ethylene glycol into the solution, wherein the average molecular weight of the polyvinylpyrrolidone is 10000; subsequently transferring the mixture to a hydrothermal kettle and reacting for 12 hours at 180 ℃; centrifuging the reaction solution, collecting the precipitate, washing the precipitate with deionized water for several times, and drying to obtain the hollow bismuth nanospheres, wherein the particle size of the hollow bismuth nanospheres is 500-600 nm as measured by a Dynamic Light Scattering (DLS) method;

2) Load of aminolevulinate hydrochloride: weighing 6mg of aminolevulinate hydrochloride and 2mg of hollow bismuth nanospheres obtained in the step 1) to disperse in 1mL of deionized water, stirring and reacting for 24 hours at the temperature of 4 ℃, centrifuging the reaction liquid, collecting the precipitate, washing the precipitate with deionized water for a plurality of times, and drying to obtain the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, wherein the load weight ratio is 3:1, a step of;

3) Preparation of methacryloylated gelatin: dissolving 1g gelatin in 10mL deionized water, heating in water bath at 50deg.C until completely dissolved to obtain gelatin solution with concentration of 0.1 g/mL; then 0.6mL methacrylic anhydride is dropwise added into the gelatin solution, and the obtained mixed solution reacts for 1-4 hours under the water bath heating condition of 50 ℃ and the stirring speed of 600 rpm; placing the reaction solution in a dialysis bag, and dialyzing in deionized water for 3 days to remove unreacted anhydride, wherein the dialysis bag is a cellulose dialysis bag with molecular weight cut-off of 3500Da; finally, centrifuging the dialyzed reaction solution to collect supernatant, freezing at-80 ℃, then placing the supernatant in a freeze dryer, freeze-drying to obtain the methacryloylated gelatin, and placing the methacryloylated gelatin at-20 ℃ for later use;

4) Preparation of oxidized dextran: dissolving 5.0g of glucan in 250mL of deionized water and stirring until the glucan is completely dissolved to obtain a glucan solution; adding 5.0g of sodium periodate into the glucan solution under the light-shielding condition, namely in the embodiment, the mass fraction ratio of the sodium periodate to the glucan usage amount is 1, then stirring the mixture for reaction for 3.5 hours under the room temperature condition under the light shielding condition, finally adding 3mL of glycol solution into the reaction solution, and continuing stirring the mixture for 1 hour to neutralize unreacted sodium periodate so as to stop the reaction; collecting the reaction solution, putting the reaction solution into a dialysis bag, and dialyzing the reaction solution for 3 days by using deionized water, wherein the dialysis bag is a cellulose dialysis bag with the molecular weight cutoff of 3500Da; freezing the dialyzed reaction solution at-80 ℃, then placing the frozen reaction solution in a freeze dryer, freeze-drying to obtain oxidized dextran, and placing the oxidized dextran at-20 ℃ for standby;

5) Preparation of injectable hydrogels: the preparation method comprises the steps of dispersing and dissolving methacryloylated gelatin, oxidized dextran and gelatin in deionized water according to the mass percentages of 5%, 5% and 5% respectively to obtain a mixed solution, dispersing 200 mug hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in 1mL of the mixed solution, namely the dispersion concentration of the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in the mixed solution is 200 mug/mL in the embodiment, adding 0.05mL of 2% (w/v) phenyl-2, 4, 6-trimethylbenzoyl lithium phosphonate aqueous solution into the mixed solution, and then initiating a crosslinking reaction under blue light irradiation with the wavelength of 405nm to obtain the photo-thermal antibacterial medical injectable hydrogel.

Example 4

The embodiment 4 of the invention provides a preparation method of a photo-thermal antibacterial medical injectable hydrogel, which comprises the following specific operation steps:

1) Preparation of hollow bismuth nanospheres: 0.148g of bismuth nitrate is weighed and dissolved in 5mL of nitric acid solution, and 0.15g of polyvinylpyrrolidone and 25mL of ethylene glycol are added into the solution, wherein the average molecular weight of the polyvinylpyrrolidone is 9000; subsequently transferring the mixture to a hydrothermal kettle and reacting for 12 hours at 180 ℃; centrifuging the reaction solution, collecting the precipitate, washing the precipitate with deionized water for several times, and drying to obtain the hollow bismuth nanospheres, wherein the particle size of the hollow bismuth nanospheres is 500-600 nm as measured by a dynamic light scattering method;

2) Load of aminolevulinate hydrochloride: weighing 4mg of aminolevulinate hydrochloride and 2mg of hollow bismuth nanospheres obtained in the step 1) to disperse in 1mL of deionized water, stirring and reacting for 22h at the temperature of 4 ℃, centrifuging the reaction liquid, collecting precipitate, washing the precipitate with deionized water for a plurality of times, and drying to obtain the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, wherein the load weight ratio is 2:1, a step of;

3) Preparation of methacryloylated gelatin: dissolving 1g gelatin in 10mL deionized water, heating in water bath at 50deg.C until completely dissolved to obtain gelatin solution with concentration of 0.1 g/mL; subsequently, 0.6mL of methacrylic anhydride is dropwise added into the gelatin solution, and the obtained mixed solution is reacted for 2 hours under the water bath heating condition of 50 ℃ and the stirring speed of 500 rpm; placing the reaction solution in a dialysis bag, and dialyzing in deionized water for 3 days to remove unreacted anhydride, wherein the dialysis bag is a cellulose dialysis bag with molecular weight cut-off of 3500Da; finally, centrifuging the dialyzed reaction solution to collect supernatant, freezing at-80 ℃, then placing the supernatant in a freeze dryer, freeze-drying to obtain the methacryloylated gelatin, and placing the methacryloylated gelatin at-20 ℃ for later use;

4) Preparation of oxidized dextran: dissolving 5.0g of glucan in 250mL of deionized water and stirring until the glucan is completely dissolved to obtain a glucan solution; adding 3.0g of sodium periodate into the glucan solution under the light-shielding condition, namely in the embodiment, the mass fraction ratio of the sodium periodate to the glucan usage amount is 0.6, then stirring the mixture for reaction for 3 hours under the room temperature condition under the light shielding condition, finally adding 3mL of glycol solution into the reaction solution, and continuing stirring the mixture for 1 hour to neutralize unreacted sodium periodate, so that the reaction is stopped; collecting the reaction solution, putting the reaction solution into a dialysis bag, and dialyzing the reaction solution for 3 days by using deionized water, wherein the dialysis bag is a cellulose dialysis bag with the molecular weight cutoff of 3500Da; freezing the dialyzed reaction solution at-80 ℃, then placing the frozen reaction solution in a freeze dryer, freeze-drying to obtain oxidized dextran, and placing the oxidized dextran at-20 ℃ for standby;

5) Preparation of injectable hydrogels: the preparation method comprises the steps of dispersing and dissolving methacryloylated gelatin, oxidized dextran and gelatin in a PBS buffer solution according to the mass percentages of 5%, 5% and 5% respectively to obtain a mixed solution, dispersing 100 mug hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in 1mL of the mixed solution, namely the dispersion concentration of the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in the mixed solution is 100 mug/mL in the embodiment, adding 0.05mL of 2% (w/v) phenyl-2, 4, 6-trimethylbenzoyl lithium phosphonate solution into the mixed solution, and then initiating a crosslinking reaction under blue light irradiation with the wavelength of 405nm to obtain the photo-thermal antibacterial medical injectable hydrogel.

Example 5

The embodiment 5 of the invention provides a preparation method of a photo-thermal antibacterial medical injectable hydrogel, which comprises the following specific operation steps:

1) Preparation of hollow bismuth nanospheres: weighing 0.148g of bismuth nitrate, dissolving in 5mL of nitric acid solution, and adding 0.15g of polyvinylpyrrolidone and 25mL of ethylene glycol into the solution, wherein the average molecular weight of polyvinylpyrrolidone is 11000, and the limitation of the average molecular weight of polyvinylpyrrolidone is used for limiting the size and the cavity volume of the hollow bismuth nanospheres; subsequently transferring the mixture to a hydrothermal kettle and reacting for 12 hours at 180 ℃; centrifuging the reaction solution, collecting the precipitate, washing the precipitate with deionized water for several times, and drying to obtain the hollow bismuth nanospheres, wherein the particle size of the hollow bismuth nanospheres is 500-600 nm as measured by a dynamic light scattering method;

2) Load of aminolevulinate hydrochloride: weighing 4mg of aminolevulinate hydrochloride and 2mg of hollow bismuth nanospheres obtained in the step 1) to disperse in 1mL of deionized water, stirring and reacting for 26 hours at the temperature of 4 ℃, centrifuging the reaction liquid, collecting precipitate, washing the precipitate with deionized water for a plurality of times, and drying to obtain the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, wherein the load weight ratio is 2:1, a step of;

3) Preparation of methacryloylated gelatin: dissolving 1g gelatin in 10mL deionized water, heating in water bath at 50deg.C until completely dissolved to obtain gelatin solution with concentration of 0.1 g/mL; subsequently, 0.6mL of methacrylic anhydride is dropwise added into the gelatin solution, and the obtained mixed solution is reacted for 4 hours under the water bath heating condition of 50 ℃ and the stirring speed of 600 rpm; placing the reaction solution in a dialysis bag, and dialyzing in deionized water for 3 days to remove unreacted anhydride, wherein the dialysis bag is a cellulose dialysis bag with molecular weight cut-off of 3500Da; finally, centrifuging the dialyzed reaction solution to collect supernatant, freezing at-80 ℃, then placing the supernatant in a freeze dryer, freeze-drying to obtain the methacryloylated gelatin, and placing the methacryloylated gelatin at-20 ℃ for later use;

4) Preparation of oxidized dextran: dissolving 5.0g of glucan in 250mL of deionized water and stirring until the glucan is completely dissolved to obtain a glucan solution; adding 6.0g of sodium periodate into the glucan solution under the light-shielding condition, namely in the embodiment, the mass fraction ratio of the sodium periodate to the glucan usage amount is 1.2, then stirring the mixture for reaction for 3 hours under the room temperature condition under the light shielding condition, finally adding 3mL of glycol solution into the reaction solution, and continuing stirring the mixture for 1 hour to neutralize unreacted sodium periodate so as to stop the reaction; collecting the reaction solution, putting the reaction solution into a dialysis bag, and dialyzing the reaction solution for 3 days by using deionized water, wherein the dialysis bag is a cellulose dialysis bag with the molecular weight cutoff of 3500Da; freezing the dialyzed reaction solution at-80 ℃, then placing the frozen reaction solution in a freeze dryer, freeze-drying to obtain oxidized dextran, and placing the oxidized dextran at-20 ℃ for standby;

5) Preparation of injectable hydrogels: the preparation method comprises the steps of dispersing and dissolving methacryloylated gelatin, oxidized dextran and gelatin in deionized water according to the mass percentages of 5%, 5% and 5% respectively to obtain a mixed solution, dispersing 300 mug hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in 1mL of the mixed solution, namely the dispersion concentration of the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in the mixed solution is 300 mug/mL in the embodiment, adding 0.05mL of 2% (w/v) phenyl-2, 4, 6-trimethylbenzoyl lithium phosphonate solution into the mixed solution, and then initiating a crosslinking reaction under blue light irradiation with the wavelength of 405nm to obtain the photo-thermal antibacterial medical injectable hydrogel.

Example 6

The embodiment 6 of the present invention provides a preparation method of a photo-thermal antibacterial medical injectable hydrogel, which is different from the embodiment 3 only in that: the dispersion concentration of the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in the mixed solution is 100 mug/mL.

Example 7

The embodiment 7 of the present invention provides a preparation method of a photo-thermal antibacterial medical injectable hydrogel, which is different from the embodiment 3 only in that: the dispersion concentration of the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in the mixed solution is 300 mug/mL.

Carrying out Transmission Electron Microscope (TEM) analysis and X-ray diffraction analysis (XRD) on the hollow bismuth nanospheres prepared in the embodiment 3, wherein the transmission electron microscope analysis image is shown in fig. 1, the X-ray diffraction patterns of the bismuth nanospheres in the prior art and the hollow bismuth nanospheres prepared in the embodiment 3 of the invention are shown in fig. 2, and the hollow bismuth nanospheres subjected to polyvinylpyrrolidone induction treatment are hollow structures with a plurality of cavities, so that the drug loading can be effectively realized, and the crystal phase structures of the treated hollow bismuth nanospheres are not obviously changed;

the photo-thermal antibacterial medical injectable hydrogel prepared according to the methods described in examples 3 and 6-7 is subjected to photo-thermal heating test, the sample is heated in the same heating mode, the temperature of the sample is measured at regular intervals, data are recorded, and a photo-thermal heating curve of the corresponding sample is drawn, please refer to fig. 3, the higher the concentration of the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in the injectable hydrogel is, the higher the highest temperature which can be reached by photo-thermal heating is, and the stronger the killing effect on bacteria is.

The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.

Claims

1. A photothermal antibacterial medical injectable hydrogel, characterized in that: is formed by carrying out UV cross-linking on hollow bismuth nanospheres loaded with aminolevulinate hydrochloride, methacryloylated gelatin, oxidized dextran, gelatin, a photoinitiator and an aqueous medium;

the amino levulinate hydrochloride and the hollow bismuth nanospheres in the hollow bismuth nanospheres loaded with the amino levulinate hydrochloride are prepared according to the following steps of 2:1 to 3:1 weight part ratio for loading;

the preparation method of the photothermal antibacterial medical injectable hydrogel comprises the following specific operation steps:

1) Preparation of hollow bismuth nanospheres: bismuth nitrate is dissolved in a nitric acid solution with the concentration of 1mol/L, polyvinylpyrrolidone and ethylene glycol are added into the solution, and then the mixed solution is transferred into a hydrothermal kettle and reacts for 12 hours at 180 ℃; centrifuging the reaction solution, collecting the precipitate, washing the precipitate with deionized water for several times, and drying to obtain the hollow bismuth nanospheres;

2. The photothermal antibacterial medical injectable hydrogel according to claim 1, wherein: the photoinitiator is phenyl-2, 4, 6-trimethyl benzoyl lithium phosphonate, and the aqueous medium is deionized water, normal saline or phosphoric acid buffer solution.

3. The photothermal antibacterial medical injectable hydrogel according to claim 1, wherein: the average molecular weight of the polyvinylpyrrolidone in the step 1) is 9000-11000, and the particle size of the hollow bismuth nanospheres obtained by the dynamic light scattering method is 500-600 nm.

4. The photothermal antibacterial medical injectable hydrogel according to claim 1, wherein: the concentration of the gelatin solution in the step 3) is 0.1g/mL, and 0.5-0.8 mL of methacrylic anhydride is correspondingly used for each 1g of gelatin.

5. The photothermal antibacterial medical injectable hydrogel according to claim 1, wherein: the mass part ratio of the sodium periodate to the dextran used in the step 4) is 0.6-1.2.

6. The photothermal antibacterial medical injectable hydrogel according to claim 1, wherein: the dialysis bags used in step 3) and step 4) were cellulose dialysis bags with a molecular weight cut-off of 3500Da.

7. The photothermal antibacterial medical injectable hydrogel according to claim 2, wherein: the hollow bismuth nanospheres loaded with aminolevulinate hydrochloride in the step 5) are dispersed in the mixed solution according to the concentration of 100-300 mug/mL.

8. The photothermal antibacterial medical injectable hydrogel according to claim 7, wherein: for each 1mL of the mixed solution in step 5), 0.05mL of a 2% (w/v) solution of lithium phenyl-2, 4, 6-trimethylbenzoyl phosphonate was used.