CN115887746B - Composite hydrogel dressing with photo-thermal photodynamic synergistic antibacterial capability - Google Patents
Composite hydrogel dressing with photo-thermal photodynamic synergistic antibacterial capability Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a composite hydrogel dressing with photo-thermal and photo-dynamic synergistic antibacterial capability. Belongs to the technical field of wound dressing loaded with functional active ingredients. The wound dressing loaded by the functional active ingredient has stronger biocompatibility, tissue affinity and adhesiveness, can realize the functions of protecting an infected area, absorbing tissue seepage and the like while carrying out photo-thermal photodynamic therapy, and further enhances the application capability of photo-thermal photodynamic cooperative therapy in the field of wound therapy.
Description
Technical Field
The invention relates to the technical field of wound dressing loaded with functional active ingredients, in particular to a composite hydrogel dressing with photo-thermal-photodynamic synergistic antibacterial capability.
Background
The skin serves as the largest organ of the human body and is also the first line of defense for the human body. Skin injury can lead to impaired skin barrier function, is susceptible to internal and external environments, and can even cause lesions in the body. Wound repair of skin lesions is the best way to solve this problem. Skin wound repair refers to a series of pathophysiological processes of repairing local tissues through regeneration, repair and reconstruction after skin tissue is lost due to injury factors. Infection and complications caused by bad wound repair can bring serious consequences and influence to the patient, the family and the society.
Skin wound repair is firstly required to avoid wound infection, the wound infection is often caused by bacterial infection, the infection can cause cell degeneration of different degrees, tissue necrosis and infection spread can also be caused, chronic wound is caused, the wound healing speed is influenced, even sepsis and septicemia are formed, and life is endangered. The local use of antibiotics or the delivery of other anti-inflammatory drugs is a common clinical treatment mode, but most antibacterial agents and antibiotics often have stimulation and toxic and side effects, and even chronic wounds can generate drug resistance, so that the treatment effect is affected. Unlike acute skin injury, which can heal rapidly, chronic wound surface is released by relevant enzymes, active oxygen free radicals and inflammatory transmitters caused by repeated infection, growth factor activity is reduced, and healing speed is greatly reduced. Therefore, wound repair healing for chronic wounds becomes a challenging problem.
At present, the treatment and the treatment of the wound surface are mainly carried out by using a dry dressing, and the dry dressing excessively absorbs the growth factors secreted by the human body, so that the wound environment is excessively dried, the healing time is prolonged, and even secondary injury and infection are caused. The theory of wound wet healing by Winter promotes the development of wet dressings. Natural polymer (such as chitosan, sodium alginate, gelatin, etc.) based hydrogel becomes the main raw material of the wet dressing. The hydrogel is a high molecular compound with a three-dimensional network structure, and has excellent water absorption and retention properties, biocompatibility and similar cell growth environments. In addition, the active ingredients such as the antibacterial agent, the medicine, the cytokine and the like are loaded to endow the hydrogel with corresponding functional activity. The dressing for chronic wound surface has good antibacterial performance, prevents wound infection, and also needs to inhibit excessive inflammatory reaction of wound to cooperatively promote wound surface repair.
Photo-thermal antibiosis is favored because of the limitation of bacterial drug dependence and biotoxicity of the antibacterial agent. Near infrared light (780-2526 nm) can penetrate deep tissues to reach focus compared with other wavelengths, and damage to skin and tissues is minimal. The material for utilizing near infrared light to thermally inhibit bacteria is designed, so that not only can sterilization and disinfection be realized, but also the problems of narrow antibacterial spectrum, drug resistance and drug toxic and side effects existing in the traditional antibiotics can be solved. In addition, near infrared light is beneficial to tissue regeneration and promotes wound healing. Gold nanoparticles are classical photothermal reagents in photothermal therapy, and have excellent photothermal properties due to conversion of excited photon energy into heat by surface plasmon resonance. The gold nanoparticles are subjected to antibacterial functionalization, so that the light stability and biocompatibility of the gold nanoparticles can be improved, and bacteria can be killed by generating a local thermal effect under the irradiation of near infrared light through the light thermal property of the gold nanoparticles. The carbon nanomaterial is also an excellent photo-thermal reagent and has excellent photo-thermal conversion performance. In addition, the carbon dots have photodynamic therapeutic activity, active oxygen free radicals are generated through a photoinduced oxidation-reduction process to act on wounds, scar tissue generation is inhibited, and healing is promoted.
Overuse of antibiotics greatly impair the therapeutic effect due to the emergence of drug-resistant bacteria and even superbacteria. At present, for the purpose of achieving a bacteriostatic effect, a single photothermal therapy or photodynamic therapy is mostly adopted. Whereas a single photothermal therapy requires a treatment temperature of over 70 ℃ for the affected area, it may lead to normal tissue damage. Single photodynamic therapy requires large amounts of Reactive Oxygen Species (ROS) to kill bacteria, however, excess reactive oxygen species can necrose normal tissues by inducing inflammation. Meanwhile, since the active oxygen has a short life span, the effectiveness of PDT is limited, so that the active oxygen does not cause significant killing of enough bacteria. In addition, the generation of active oxygen requires the participation of oxygen, oxygen use during the active oxygen generation process can lead to hypoxia of wound tissues, and the active oxygen concentration can be reduced due to hypoxia, so that the effectiveness of PDT is further limited.
If the photothermal therapy and the photodynamic therapy are combined to play a synergistic effect, the treatment temperature can be reduced, the requirement on active oxygen is reduced, sterilization and inflammation diminishing can be realized under the irradiation of near infrared light, and the repair and healing of the wound surface can be promoted. The method not only can solve the defects of two monotherapy methods, but also can integrate the advantages of the two methods, thereby realizing the effect of 1+1> 2.
However, the application of photothermal photodynamic synergistic therapy to wound dressing has been recently reported, and most of the existing products are injectable liquids, and have great limitation in practical wound treatment application.
In summary, how to provide a composite hydrogel dressing with excellent photo-thermal effect and photo-dynamic effect, good biocompatibility and photo-thermal and photo-dynamic synergistic therapeutic capability is a problem to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the invention provides a composite hydrogel dressing with photo-thermal and photo-dynamic synergistic antibacterial capability. According to the invention, carbon point CuCCDs with Photodynamic (PDT) treatment capability and gold nanoparticle AuNPs with photothermal treatment capability are used as photosensitizers, and are combined with hydrogel to prepare the composite hydrogel with photothermal photodynamic synergistic antibacterial capability, so that the composite hydrogel is used as a medical dressing for antibacterial treatment and repair promotion of chronic wound surface wounds.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the preparation method of the photosensitizer carbon-point CuCCDs comprises the following steps:
mixing chitosan, ethylenediamine and copper chloride dihydrate, stirring, dripping a proper amount of concentrated sulfuric acid after uniformly mixing, cooling to room temperature, adding water, stirring, then performing alcohol precipitation, centrifuging, filtering, rotary steaming, dialyzing, and freeze-drying to obtain CuCCDs.
Further, the mass-volume ratio of chitosan, copper chloride dihydrate, ethylenediamine and concentrated sulfuric acid is 0.4g:0.2g:6mL:4mL.
Further, the dialysis is carried out for 12 hours by using a cellulose dialysis bag with the speed of 500-1000 Da.
The application of the photosensitizer carbon-point CuCCDs in preparing hydrogel dressing.
A hydrogel dressing comprising gold nanoparticles AuNPs and the photosensitizer carbon dots CuCCDs described above.
The beneficial effects are that: the use of chitosan as a starting material has developed a novel near infrared excitation to generate PDT-capable photosensitizer carbon dots (CuCCDs) that can produce ROS through photodynamic redox reactions to achieve anti-inflammatory properties. Meanwhile, chitosan is used as a reducing agent to synthesize gold nanoparticles (AuNPs) with good dispersibility and stability, and the gold nanoparticles can provide good photo-thermal capability under the irradiation of near infrared laser to realize the thermal killing of bacteria. The invention combines the two, utilizes the photo-thermal property of the gold nano particles and the photo-dynamic activity of the carbon dots, plays a synergistic effect by the double light therapy under the irradiation of near infrared light, sterilizes and eliminates inflammation, repairs wound injury, improves the performance of antibiosis and wound healing, and has great potential in the field of chronic wound repair.
On the basis, cuCCDs and AuNPs are further compounded with natural polymer-based hydrogel to form photosensitive antibacterial, anti-inflammatory and repair-promoting multifunctional composite hydrogel, the hydrogel improves the light absorption capacity of the two photosensitizers, and the material is endowed with stronger photo-thermal-photodynamic conversion effect under the excitation of near infrared light, and meanwhile, the material has good biocompatibility, tissue affinity and adhesiveness.
Further, the preparation method comprises the following steps:
(1) Preparing photosensitizer carbon dots CuCCDs;
(2) Adding chitosan into acetic acid solution, stirring to dissolve, and adding HAuCl 4 Carrying out heating reflux reaction on the solution after uniformly mixing, and cooling to room temperature to obtain gold nanoparticle AuNPs solution;
(3) Mixing AuNPs solution with chitosan solution to obtain AuNPs/CS mixed solution;
(4) Mixing the CuCCDs solution with the gelatin solution to obtain a CuCCDs/G mixed solution;
(5) And (3) fully and uniformly mixing the AuNPs/CS mixed solution and the CuCCDs/G mixed solution, adding the genipin solution, uniformly mixing, and incubating at 37 ℃ for 24 hours.
The beneficial effects are that: the photo-thermal photodynamic synergistic therapeutic agent is combined with natural polymer hydrogel with good biocompatibility, and chitosan and gelatin are used as raw materials of the hydrogel. Chitosan can destroy the nucleic acid synthesis process in bacteria through polycation interaction and has certain antibacterial capability. Both chitosan and hydrogel have been shown to be beneficial for wound healing. The combination of the hydrogel dressing and the photosensitizer further improves the light utilization rate of the photosensitizer, reduces the dosage of the photosensitizer required by the same effect, and is beneficial to reducing the cost. The composite dressing prepared by combining the photosensitive therapeutic agent and the hydrogel can fill the gap of the existing dressing types, and is also beneficial to promoting the practical application capability of the photo-thermal photodynamic synergistic therapy on wound anti-inflammatory and healing promotion.
Further, in the step (2), chitosan, acetic acid solution and HAuCl 4 The mass-volume ratio of the solution is 0.4g to 20mL to 1mL;
the volume concentration of the acetic acid solution is 1%.
Further, in the step (3), the volume ratio of the AuNPs solution to the chitosan solution is 1:3-1:60.
Further, in the step (4), the volume ratio of the CuCCDs solution to the gelatin solution is 1:3-1:30.
Further, in the step (5), the volume ratio of the AuNPs/CS mixed solution to the CuCCDs/G mixed solution is 1:2-2:1.
The beneficial effects are that: the parameters defined in the steps (3) - (5) can uniformly disperse the two types of photosensitizers, so that the effects of uniform structure, uniform temperature rise and uniform ROS concentration of the whole dressing are achieved, and the damage to normal tissues caused by local high temperature and excessive local ROS concentration is prevented. It can also prevent the interaction of two photosensitizers, agglomeration and structural change, and reduce photosensitizing activity.
Term interpretation:
(1) Carbon Dots (CDs): is a novel carbon nanomaterial, and is widely focused on the characteristics of low cost, high water solubility, good light stability, good biocompatibility, high-efficiency catalytic capability and surface modification flexibility. Thus, a large number of CDs were synthesized by designing various precursors, and a wide range of applications were realized. In particular in the field of nanomedicine, a few CDs have been demonstrated to be useful as nanosensors for photodynamic therapy (PDT).
(2) Gold nanoparticles (AuNPs): gold nanoparticles are a nanomaterial that was earlier studied and are commonly referred to as colloidal gold in biological studies. The particle size of the fluorescent powder is generally between 1 and 100nm, and the fluorescent powder presents different colors along with the change of the particle size, so that the fluorescent powder has various applications. Currently, the method is widely applied to photo-thermal treatment (PTT) under near infrared excitation in the nano medical field.
(3) Photothermal therapy (PTT): the photothermal agent is stimulated by light to selectively locally heat the target abnormal cells and tissue. PTT efficiency depends on the NIR absorption wavelength and coefficient of the photothermal agent and the power of the excitation light.
(4) Photodynamic therapy (PDT): photoactivated photosensitizers produce a series of photochemical reactions that produce Reactive Oxygen Species (ROS), leading to cell death.
(5) Hydrogel (Hydrogel): hydrogels are a class of hydrophilic gels having a three-dimensional network structure that rapidly swell in water, and in this swollen state hold a large amount of water without dissolution.
(6) Chitosan (CS): chitosan is a copolymer composed of N-glucosamine and N-acetylglucosamine comonomers and is prepared from chitin through deacetylation reaction. Its excellent properties such as non-toxicity, biocompatibility, biodegradability, gel forming ability, blood, cell and tissue compatibility, thermal and chemical stability, antifungal and antibacterial activity, and low cost make it a candidate for use in a variety of medical applications, including drug delivery and wound dressings.
(7) Gelatin (G): gelatin is a partially hydrolyzed product of collagen, has good biocompatibility and low immunogenicity, has a water absorption capacity 5 to 10 times of its own weight, and is one of the most attractive biological materials. In addition, due to its abundant functional groups (such as amino and carboxyl groups), modification can be easily performed.
(8) Genipin (GP): genipin (Genipin) is a product of geniposide hydrolyzed by beta-glucosidase, is an excellent natural biological cross-linking agent, can be cross-linked with protein, collagen, gelatin, chitosan and the like to prepare biological materials, and has toxicity far lower than glutaraldehyde and other common chemical cross-linking agents. Can also be used for treating liver diseases, lowering blood pressure, and relieving constipation.
Compared with the prior art, the invention has the beneficial effects that: (1) According to the invention, natural biomacromolecule chitosan is used as a raw material, and copper chloride is added to realize copper element doping so as to enhance the absorption of the copper element in a near infrared region. The novel carbon dot with good photodynamic property which can be excited by near infrared laser is simply prepared by a direct oxidation method, and the defects of low yield, high purification cost and the like caused by a solvothermal method are avoided (the yield of the method for preparing the carbon dot is 20-25 percent). Compared with the existing photosensitizer carbon dot, the novel carbon dot has the advantages of low cost, easy obtainment, high yield, high stability, good biocompatibility and the like, and is favorable for popularization and application in the biomedical field. (2) According to the invention, chitosan is used as a reducing agent to synthesize gold nanoparticles (AuNPs), the raw materials are environment-friendly, the operation is simple, and the prepared gold nanoparticles have good dispersibility and stability. (3) The photo-thermal therapy and the photodynamic therapy are combined to realize the synergistic effect of the two under low-power near-infrared illumination, so that the advantages of the two can be effectively combined, the treatment temperature of the infected area at about 50 ℃ can be realized, and the generation of the required active oxygen can be reduced. Reduces the damage to normal tissues, also overcomes the problem of insufficient killing power of single PDT treatment to bacteria, and realizes good broad-spectrum bacteria killing capacity. (4) According to the invention, chitosan and gelatin are used as raw materials, and safe and nontoxic genipin is used as a cross-linking agent to prepare the novel hydrogel dressing with good biocompatibility. The hydrogel dressing can enhance the light absorption capacity of gold nanoparticles and carbon dots, and the porous structure of the hydrogel dressing remarkably improves the photo-thermal performance of AuNPs and the photodynamic performance of CuCCDs. (5) AuNPs and CuCCDs photosensitizers in the invention are protected by hydrogel, so that the loss of the photosensitizers is reduced, and the recycling capability is improved. And binding of AuNPs to hydrogels further reduced their cytotoxicity. (6) The photo-thermal photodynamic synergistic treatment composite hydrogel dressing can quickly obtain higher temperature through near infrared laser irradiation, has stable photo-thermal conversion capability and high photo-thermal conversion efficiency, can stably generate singlet oxygen, and further has a good photo-thermal photodynamic synergistic sterilization effect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a drawing showing TEM and HRTEM images of CuCCDs and AuNPs prepared in example 1 and example 2, and showing a histogram of particle size distribution; wherein A is a TEM image of CuCCDs, B is an HRTEM image of CuCCDs, C is a TEM image of AuNPs, and D is an HRTEM image of AuNPs;
FIG. 2 is a graph showing the ultraviolet absorption spectrum of CuCCDs and fluorescence spectra at different excitation wavelengths; wherein A is the ultraviolet absorption spectrum of CuCCDs under the optimal condition (the mass ratio of chitosan to copper chloride dihydrate is 0.4g:0.2 g), and B is the fluorescence spectrum of CuCCDs under different excitation wavelengths;
FIG. 3 is a graph showing the photo-thermal properties of AuNPs and AuNPs-CuCCDs@gel in experiment 1 of the present inventionStudy results; wherein A is AuNPs at 808nm (1W/cm 2 ) The photo-thermal temperature rise curve under irradiation, B is that the hydrogel with different gold nanometer and carbon point adding proportion is at 808nm (0.45W/cm) 2 ) A photothermal temperature rise curve under irradiation;
FIG. 4 is a graph showing the results of the photodynamic performance studies of CuCCDs and AuNPs-CuCCDs@gel in experiment 2 of the present invention; wherein A is the mixture of CuCCDs and DPBF at 660nm (1W/cm 2 ) Absorption spectra at different times under irradiation, B being the ratio of AuNPs-CuCCDs@gel (200:100) to DPBF blend at 660nm (1W/cm) 2 ) Absorption spectra at different times under irradiation;
FIG. 5 is a graph showing the photo-thermal photodynamic synergistic antibacterial effect of AuNPs-CuCCDs@gel on Escherichia coli in experiment 3 of the present invention;
FIG. 6 is a graph showing the photo-thermal photodynamic synergistic antibacterial effect of AuNPs-CuCCDs@gel on Staphylococcus aureus in experiment 3 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The required medicament is a conventional experimental medicament and is purchased from a commercial channel; the test methods not mentioned are conventional test methods and will not be described in detail herein.
EXAMPLE 1 Synthesis of CuCCDs
0.4g of chitosan and 0.4g of copper chloride dihydrate were weighed into a 100mL beaker, and 6mL of ethylenediamine was added and mixed and stirred for 15min. 4mL of concentrated sulfuric acid was added dropwise to the mixed solution, the concentration of the concentrated sulfuric acid being 98wt%. After the system cooled to room temperature, 20mL deionized water was added and stirred for 8h. Adding 200mL of absolute ethyl alcohol for alcohol precipitation, centrifuging for 20min at 8000rpm, filtering by a filter head with the aperture of 0.45 mu m, rotary evaporating at the temperature of 45 ℃ and the vacuum degree of 100mbar, concentrating the solution, dialyzing for 12h by using a cellulose dialysis bag with the vacuum degree of 500-1000 Da, and freeze-drying until the solution is completely dried to obtain CuCCDs, and preparing 1mg/mL solution for later use at the temperature of 4 ℃.
Fig. 1A is a TEM image of CuCCDs, and fig. 1B is an HRTEM image of CuCCDs.
EXAMPLE 2 Synthesis of AuNPs
0.4g of chitosan was weighed, 20mL of 1% (V/V) acetic acid solution was added, and stirred until it was sufficiently dissolved. 1mL of 1% HAuCl was added 4 Stirring at room temperature for 10min to completely disperse. The solution was refluxed at 95℃for about ten minutes to give a reddish-white AuNPs solution, which was cooled and stored at room temperature for further use.
Fig. 1C is a TEM image of AuNPs, and fig. 1D is an HRTEM image of AuNPs.
EXAMPLE 3 preparation of CuCCDs/G Mixed solution
1g of gelatin was weighed, 20mL of deionized water was added, and magnetically stirred at 50℃until complete dissolution gave a 5% (W/V) gelatin solution. The volume ratio of the added amount of 1mg/mLCuCCDs to the gelatin solution was (1:30, 1:6, 1:3). Mixing the two solutions, and stirring for 20min to obtain CuCCDs/G mixed solution.
TABLE 1 CuCCDs/G Mixed solution batching Table with different proportions
EXAMPLE 4 preparation of AuNPs/CS Mixed solution
0.4g of chitosan is weighed, 20mL of 1% (V/V) acetic acid solution is added, the solution is mechanically stirred until the solution is completely dissolved to obtain 2% (W/V) chitosan solution, ultrasonic defoaming is carried out for 15min, and then the solution is refrigerated at 4 ℃ for standby. The volume ratio of the addition amount of the AuNPs solution to the chitosan solution is (1:60-1:3). Mixing the two solutions, and stirring for 20min to obtain AuNPs/CS mixed solution.
TABLE 2 AuNPs/CS mixed solution batching Table with different proportions
Example 5 preparation of AuNPs-CuCCDs@gel
Mixing the CuCCDs/G mixed solution and the AuNPs/CS mixed solution according to different volume ratios, magnetically stirring for 20min, adding 150mg/mL genipin solution, and magnetically stirring for 15min to fully disperse the crosslinking agent. Pouring the mixed solution into a mould, carrying out ultrasonic degassing for 10min, putting into a shaking table at 37 ℃, and incubating for 24h to enable the mixed solution to be crosslinked completely. The resulting sample was refrigerated at 4℃for further use.
TABLE 3 composition ratios of AuNPs-CuCCDs@gel samples in different proportions
Example 6
The preparation method of the photo-thermal photodynamic synergistic composite hydrogel dressing comprises the following steps:
(1) 0.4g of chitosan and 0.4g of copper chloride dihydrate were weighed, mixed with 6mL of ethylenediamine at 200rpm, and stirred for 15min. 4mL of concentrated sulfuric acid was added dropwise to the mixed solution, the concentration of the concentrated sulfuric acid being 98wt%. After the system cooled to room temperature, 20mL deionized water was added and stirred for 8h. Adding 200mL of absolute ethyl alcohol for alcohol precipitation, centrifuging for 20min at 8000rpm, filtering by a filter head with the aperture of 0.45 mu m, rotary evaporating at the temperature of 45 ℃ and the vacuum degree of 100mbar, concentrating the solution, dialyzing for 12h by using a cellulose dialysis bag with the vacuum degree of 500-1000 Da, and freeze-drying until the solution is completely dried to obtain CuCCDs, and preparing 1mg/mL solution for later use at the temperature of 4 ℃.
(2) 0.4g of chitosan was weighed, 20mL of 1% (V/V) acetic acid solution was added, and stirred until it was sufficiently dissolved. 1mL of 1% HAuCl was added 4 Stirring at room temperature for 10min to completely disperse. The solution was refluxed at 95℃for about ten minutes to give an AuNPs solution, which was cooled and stored at room temperature for further use.
(3) 1g of gelatin was weighed, 20mL of deionized water was added, and magnetically stirred at 50℃until complete dissolution gave a 5% (W/V) gelatin solution. The volume ratio of the added amount of 1mg/mL CuCCDs to the gelatin solution was 1:30. Mixing the two solutions, and stirring for 20min to obtain CuCCDs/G mixed solution.
(4) 0.4g of chitosan is weighed, 20mL of 1% (V/V) acetic acid solution is added, the solution is mechanically stirred until the solution is completely dissolved to obtain 2% (W/V) chitosan solution, ultrasonic defoaming is carried out for 15min, and then the solution is refrigerated at 4 ℃ for standby. The volume ratio of AuNPs solution to chitosan solution was 1:60. Mixing the two solutions, and stirring for 20min to obtain AuNPs/CS mixed solution.
(5) Mixing the CuCCDs/G mixed solution and the AuNPs/CS mixed solution in a volume ratio of 1:1, magnetically stirring for 20min, adding 150mg/mL genipin solution, and magnetically stirring for 15min to fully disperse the crosslinking agent. Pouring the mixed solution into a mould, carrying out ultrasonic degassing for 10min, putting into a shaking table at 37 ℃, and incubating for 24h to enable the mixed solution to be crosslinked completely. The resulting sample was refrigerated at 4℃for further use.
Example 7
The preparation method of the photo-thermal photodynamic synergistic composite hydrogel dressing comprises the following steps:
(1) 0.4g of chitosan and 0.2g of copper chloride dihydrate were weighed, mixed with 6mL of ethylenediamine at 200rpm, and stirred for 15min. 4mL of concentrated sulfuric acid was added dropwise to the mixed solution, the concentration of the concentrated sulfuric acid being 98wt%. After the system cooled to room temperature, 20mL deionized water was added and stirred for 8h. Adding 200mL of absolute ethyl alcohol for alcohol precipitation, centrifuging for 20min at 8000rpm, filtering by a filter head with the aperture of 0.45 mu m, rotary evaporating at the temperature of 45 ℃ and the vacuum degree of 100mbar, concentrating the solution, dialyzing for 12h by using a cellulose dialysis bag with the vacuum degree of 500-1000 Da, and freeze-drying until the solution is completely dried to obtain CuCCDs, and preparing 1mg/mL solution for later use at the temperature of 4 ℃.
(2) 0.4g of chitosan was taken, 20mL of 1% (V/V) acetic acid solution was added, and stirred until it was sufficiently dissolved. 1mL of 1% HAuCl was added 4 Stirring at room temperature for 10min to completely disperse. The solution was refluxed at 95℃for about ten minutes to give an AuNPs solution, which was cooled and stored at room temperature for further use.
(3) 1g of gelatin was weighed, 20mL of deionized water was added, and magnetically stirred at 50℃until complete dissolution gave a 5% (W/V) gelatin solution. The volume ratio of the added amount of 1mg/mL CuCCDs to the gelatin solution was 1:6. Mixing the two solutions, and stirring for 20min to obtain CuCCDs/G mixed solution.
(4) 0.4g of chitosan is weighed, 20mL of 1% (V/V) acetic acid solution is added, the solution is mechanically stirred until the solution is completely dissolved to obtain 2% (W/V) chitosan solution, ultrasonic defoaming is carried out for 15min, and then the solution is refrigerated at 4 ℃ for standby. The volume ratio of AuNPs solution to chitosan solution is 1:15. Mixing the two solutions, and stirring for 20min to obtain AuNPs/CS mixed solution.
(5) Mixing the CuCCDs/G mixed solution and the AuNPs/CS mixed solution in a volume ratio of 1:1, magnetically stirring for 20min, adding 150mg/mL genipin solution, and magnetically stirring for 15min to fully disperse the crosslinking agent. Pouring the mixed solution into a mould, carrying out ultrasonic degassing for 10min, putting into a shaking table at 37 ℃, and incubating for 24h to enable the mixed solution to be crosslinked completely. The resulting sample was refrigerated at 4℃for further use.
Example 8
The preparation method of the photo-thermal photodynamic synergistic composite hydrogel dressing comprises the following steps:
(1) 0.4g of chitosan and 0.1g of copper chloride dihydrate were weighed, mixed with 6mL of ethylenediamine at 200rpm, and stirred for 15min. 4mL of concentrated sulfuric acid was added dropwise to the mixed solution, the concentration of the concentrated sulfuric acid being 98wt%. After the system cooled to room temperature, 20mL deionized water was added and stirred for 8h. Adding 200mL of absolute ethyl alcohol for alcohol precipitation, centrifuging for 20min at 8000rpm, filtering by a filter head with the aperture of 0.45 mu m, rotary evaporating at the temperature of 45 ℃ and the vacuum degree of 100mbar, concentrating the solution, dialyzing for 12h by using a cellulose dialysis bag with the vacuum degree of 500-1000 Da, and freeze-drying until the solution is completely dried to obtain CuCCDs, and preparing 1mg/mL solution for later use at the temperature of 4 ℃.
(2) 0.4g of chitosan was taken, 20mL of 1% (V/V) acetic acid solution was added, and stirred until it was sufficiently dissolved. 1mL of 1% HAuCl was added 4 Stirring at room temperature for 10min to completely disperse. The solution was refluxed at 95℃for about ten minutes to give an AuNPs solution, which was cooled and stored at room temperature for further use.
(3) 1g of gelatin was weighed, 20mL of deionized water was added, and magnetically stirred at 50℃until complete dissolution gave a 5% (W/V) gelatin solution. The volume ratio of the added amount of 1mg/mL CuCCDs to the gelatin solution was 1:3. Mixing the two solutions, and stirring for 20min to obtain CuCCDs/G mixed solution.
(4) 0.4g of chitosan is weighed, 20mL of 1% (V/V) acetic acid solution is added, the solution is mechanically stirred until the solution is completely dissolved to obtain 2% (W/V) chitosan solution, ultrasonic defoaming is carried out for 15min, and then the solution is refrigerated at 4 ℃ for standby. The volume ratio of AuNPs solution to chitosan solution is 1:3. Mixing the two solutions, and stirring for 20min to obtain AuNPs/CS mixed solution.
(5) Mixing the CuCCDs/G mixed solution and the AuNPs/CS mixed solution in a volume ratio of 1:1, magnetically stirring for 20min, adding 150mg/mL genipin solution, and magnetically stirring for 15min to fully disperse the crosslinking agent. Pouring the mixed solution into a mould, carrying out ultrasonic degassing for 10min, putting into a shaking table at 37 ℃, and incubating for 24h to enable the mixed solution to be crosslinked completely. The resulting sample was refrigerated at 4℃for further use.
Experiment 1 photo-thermal Properties of AuNPs and AuNPs-CuCCDs@gel
To investigate the photothermal heating capacity of AuNPs at 808nm near infrared irradiation at low power, 1mL of AuNPs solution was placed in a centrifuge tube. The laser power was set to 1W. The near-red light 808nm was used for irradiation for 10min, followed by turning off the near-infrared light. The temperature was recorded every 30s using an infrared imager and a temperature-time curve was made as shown in fig. 3A.
To investigate the photothermal heating capacity of AuNPs-CuCCDs@gel under 808nm near infrared irradiation at low power, blocks of about 2X 2cm volume AuNPs-CuCCDs@gel were taken in varying proportions (as shown in Table 3) and placed in a plastic plane. The laser power was set to 0.45W. The near-red light 808nm was used for irradiation for 10min, followed by turning off the near-infrared light. The temperature was recorded every 30s using an infrared imager and a temperature-time curve was made as shown in fig. 3B.
As can be seen from FIG. 3, under the irradiation of 808nm laser, the AuNPS and the AuNPs-CuCCDs@gel have good photo-thermal properties, and the AuNPs-CuCCDs@gel (200:100) can be 0.45W/cm 2 Realizing the AuNPs at 1W/cm under the irradiation of power laser 2 The similar heating rate and highest temperature under the irradiation of the power laser show that the hydrogel enhances the light utilization rate of the photosensitizer and enhances the photo-thermal property of the photosensitizer.
In addition, as shown in FIG. 3, under the irradiation of laser with the wavelength of 808nm, the temperature of AuNPs-CuCCDs@gel (200:100) can play a role in effectively killing drug-resistant bacteria.
Experiment 2 photodynamic Properties of CuCCDs and AuNPs-CuCCDs@gel
To investigate the photodynamic properties of CuCCDs under low power of near infrared radiation at 660nm, 1.5mL of 1mg/mL of CuCCDs solution was mixed with 30. Mu.L of 1mg/mL of DPBF solution and placed in a quartz cuvette. The laser power was set to 1W, irradiated with near-red 660nm for 10min, followed by turning off the near-infrared light. The ultraviolet absorption spectrum of the mixture in the range of 350 to 500nm was recorded every 1min using an ultraviolet spectrophotometer, and the graph was made as shown in fig. 4A.
In order to study the photodynamic performance of AuNPs-CuCCDs@gel under 660nm near infrared irradiation low power, V is taken AuNPs ：V CuCCDs About a 2 x 2cm volume of AuNPs-cuccds@gel block =200:100 (ACG-1 in table 3) was placed in a quartz cuvette, 1.5mL of deionized water and 30. Mu.L of a 1mg/mL DPBF solution were added. The laser power was set to 1W, irradiated with near-red 660nm for 10min, followed by turning off the near-infrared light. The ultraviolet absorption spectrum of the mixture in the range of 350 to 550nm was recorded every 1min using an ultraviolet spectrophotometer, and the graph was made as shown in fig. 4B.
As can be seen from FIG. 4B, under the irradiation of laser with the wavelength of 660nm, auNPs-CuCCDs@gel (200:100) can remarkably generate active oxygen and has the capability of killing bacteria. Comparing the results of FIG. 4A with that of FIG. 4B, it can be seen that AuNPs-CuCCDs@gel (200:100) can achieve a degradation effect on DPBF under 660nm laser irradiation similar to that of a 1mg/mL CuCCDs solution at a lower carbon point addition amount. The hydrogel is shown to enhance the light utilization rate of the photosensitizer and enhance the photodynamic performance thereof.
Experiment 3 sterilizing action of AuNPs-CuCCDs@gel
According to the preparation scheme discussed above, V is selected here because it is necessary to reach 50℃in order to have a better antibacterial activity, and because of the mechanical strength of the material AuNPs ：V CuCCDs =200:100 (ACG-1 in table 3) as AuNPs-cuccds@gel represents the sample.
And preparing Gel by taking a 24-pore plate as a template, preparing four samples of AuNPs@Gel, cuCCDs@Gel, auNPs-CuCCDs@gel, and respectively setting an escherichia coli control group, an escherichia coli laser irradiation group, a staphylococcus aureus control group and a staphylococcus aureus laser irradiation group.
Each sample was incubated with bacteria for 12 hours and then placed in a six-well plate for 10min at 806 nm (0.45W/cm) 2 ) Laser irradiation and 10min 660nm (1W/cm) 2 ) Laser irradiation, during which a thermal imaging camera was used to take pictures. Then, 5mL of fresh liquid medium was added to each well to maintain the material in suspension, and the culture was continued at 37℃for 12 hours.
Finally take 10 -5 The bacterial liquid with dilution multiple is coated on a flat plate. The coated culture plate was incubated at 37℃for 12 hours, photographed and counted for colonies, and the antibacterial ratio was calculated, and the results are shown in FIGS. 5 and 6.
As shown in fig. 5 and 6, compared with Gel group, the hydrogel loaded with AuNPs or CuCCDs can obviously reduce escherichia coli and staphylococcus aureus, wherein the sterilization effect of single photo-thermal is more obvious than that of single photo-dynamic, and the hydrogel loaded with AuNPs and CuCCDs can realize more obvious sterilization effect, the antibacterial rate of escherichia coli can reach 91.65%, and the antibacterial rate of staphylococcus aureus can reach 90.46%. The result fully shows that the photo-thermal-photodynamic synergistic treatment of AuNPs-CuCCDs@gel under low power has obvious sterilization effect.
In the present specification, each embodiment is described in a progressive manner, and each embodiment is mainly described in a different point from other embodiments, and identical and similar parts between the embodiments are all enough to refer to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (4)
1. A hydrogel dressing, comprising gold nanoparticles AuNPs and photosensitizer carbon dots CuCCDs;
the preparation method comprises the following steps:
(1) Preparing photosensitizer carbon dots CuCCDs;
mixing chitosan, ethylenediamine and copper chloride dihydrate, stirring, dripping a proper amount of concentrated sulfuric acid after uniformly mixing, cooling to room temperature, adding water, stirring, then performing alcohol precipitation, centrifuging, filtering, rotary steaming, dialyzing, and freeze-drying to obtain CuCCDs;
the mass volume ratio of chitosan, copper chloride dihydrate, ethylenediamine and concentrated sulfuric acid is 0.4g:0.2g:6mL:4mL;
the dialysis is carried out for 12 hours by using a cellulose dialysis bag with the speed of 500-1000 Da;
(2) Adding chitosan into acetic acid solution, stirring to dissolve, and adding HAuCl 4 Carrying out heating reflux reaction on the solution after uniformly mixing, and cooling to room temperature to obtain gold nanoparticle AuNPs solution;
(3) Mixing AuNPs solution with chitosan solution to obtain AuNPs/CS mixed solution;
(4) Mixing the CuCCDs solution with the gelatin solution to obtain a CuCCDs/G mixed solution;
(5) Fully and uniformly mixing the AuNPs/CS mixed solution and the CuCCDs/G mixed solution, adding the genipin solution, uniformly mixing, and incubating at 37 ℃ for 24 hours;
the volume ratio of AuNPs/CS mixed solution to CuCCDs/G mixed solution is 2:1.
2. The hydrogel dressing of claim 1, wherein in step (2), chitosan, acetic acid solution and HAuCl are combined 4 The mass-volume ratio of the solution is 0.4g to 20mL to 1mL;
the volume concentration of the acetic acid solution is 1%.
3. The hydrogel dressing of claim 1, wherein in step (3), the volume ratio of AuNPs solution to chitosan solution is 1:3 to 1:60.
4. The hydrogel dressing of claim 1, wherein in step (4), the volumetric ratio of CuCCDs solution to gelatin solution is from 1:3 to 1:30.
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| 低聚壳聚糖及其稀土(LaCl_3.nH_2O)配合物的抗氧化活性研究;尹学琼, 张岐, 林强, 田国才;食品科学;20020228(第02期);全文 * |
| 可注射的壳聚糖/纳米金温敏性水凝胶的构筑及其光热性能研究;曾金凤;高分子学报;20180620(第10期);摘要、第1.2-1.4节 * |
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