CN110448722B - Temperature-sensitive composite antibacterial hydrogel material capable of being injected and containing tannic acid, and preparation and application thereof - Google Patents
Temperature-sensitive composite antibacterial hydrogel material capable of being injected and containing tannic acid, and preparation and application thereof Download PDFInfo
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Abstract
The invention provides a temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid, and preparation and application thereof. The material has temperature and pH sensitivity, can be injected in situ and sprayed, and can be used as antibacterial dressing. Firstly, dissolving temperature-sensitive polyhydroxy-containing polymer such as chitin derivative in water at low temperature, adding tannic acid solution and metal ion solution in a liquid state, mixing uniformly, injecting or spraying the mixture to the surface of a wound to form gel rapidly at body temperature, wherein tannic acid is used as a cross-linking agent and has chelation with metal ions to be used as a slow-release antibacterial agent. The antibacterial hydrogel dressing is mainly characterized by simple preparation; the low-temperature fluidity is good, the gel is quickly formed at body temperature, the antibacterial agent can be slowly released, the antibacterial range is wide, and the antibacterial time is long; the dressing has good biocompatibility and biodegradability, and secondary damage caused by dressing replacement is avoided; is beneficial for wound healing, effectively promotes skin regeneration, reduces scar formation, and has antiinflammatory and antioxidant effects.
Description
Technical Field
The invention belongs to the technical field of biomedical materials and preparation thereof, and relates to an injectable temperature-sensitive composite antibacterial hydrogel material containing tannic acid, and preparation and application thereof.
Background
The skin, which is composed of the stratum corneum, epidermis and dermis, is a basic barrier to protect internal tissues, prevent pathogen invasion, and maintain fluid balance. However, wounds such as cuts, contusions, cuts, burns and the like may impair the function of the skin, thereby causing problems such as bacterial infection, excessive loss of protein and water, and imbalance of endocrine and immune systems. Traditional medical dressings such as gauze, bandage, absorbent cotton and the like are made of dry fabrics, can absorb tissues exuded in the initial stage, but cannot provide a moist environment for wounds, are easy to adhere to the wounds, and easily damage newly generated tissues during replacement. The ideal wound dressing should block exogenous pollutants and microorganisms, provide a moist environment for the wound, perform gas exchange, be free of adhesion to the wound, be non-toxic, cause no allergic reaction, have antibacterial properties, promote wound healing, and the like.
The polymer hydrogel has a three-dimensional cross-linked network structure and hydrophilicity, can absorb a large amount of water and has strong water retention capacity. The hydrogel has good permeability to water and oxygen, is soft in property, can keep a certain shape, is similar to extracellular matrix, and has good biocompatibility. The hydrogel dressing can maintain the moist environment of the wound surface, absorb the tissue exudates and relieve the pain of patients. The temperature-sensitive polymer such as chitin-based temperature-sensitive hydrogel can keep liquid at low temperature, can uniformly encapsulate cells/medicines and fill irregular wound parts, and can quickly form gel after the temperature rises after contacting with a wound, thereby providing a bacterial barrier layer for the wound, creating a good environment suitable for tissue growth and promoting tissue growth. Chitin and its derivatives have good biocompatibility, biodegradability and various biological activities, and are suitable for skin tissue regeneration. The preparation of carboxyl chitin with pH sensitivity and temperature sensitivity can be prepared by reacting chitin with a carboxylation reagent in a sodium hydroxide-urea system (Chinese patent application publication No. CN 201310641249.6), the preparation of hydroxypropyl chitin with temperature sensitivity can be prepared by reacting chitin with a hydroxypropylation reagent in a sodium hydroxide-urea system (Chinese patent application publication No. CN 201410170871.8), and the preparation of temperature-sensitive hydroxybutyl chitosan (Chinese patent application publication No. CN 200810033699.6) and temperature-sensitive hydroxypentyl chitosan (Chinese patent application publication No. CN 201210220246.0) are reported by Houchulin and the like.
Microbial infections pose a serious threat to organ transplantation, prosthesis transplantation and tissue engineering construction. To solve this problem, some researchers load antibacterial substances such as antibiotics and nano silver into the stent. However, the problem of bacterial resistance is now becoming increasingly serious, as antibiotics typically act at very specific sites in cell membranes or on very specific metabolic pathways, which make it relatively easy for bacteria to develop resistance to antibiotics by natural selection, delivery of plasmids encoding resistance, or by other means. The nano silver particles can kill most of bacteria, fungi, mildew, spores and other microorganisms which are contacted with the nano silver particles, have good bactericidal effect on stubborn bacteria, drug-resistant bacteria and deeper tissue infection caused by the fungi, and cannot generate drug resistance. However, recent studies show that the silver nanoparticles have strong cytotoxicity [ tang jing long, king large, liuli, wangchun, lingling, willina, heyngian, the cytotoxic action and mechanism of the silver nanoparticles are first discovered, beijing biomedical engineering, 2013,32,5,485-489], the silver nanoparticles have different degrees of side effects on urinary system, digestive system, respiratory system, nervous system, reproductive system and blood system [ prescription, wangbabong, songxing, phoenix, toxic effect and action mechanism research progress of the silver nanoparticles, chinese pharmacological report, 2016,32,5,593-598], so the long-term biosafety problem of heavy metal accumulation caused by the contact of the silver nanoparticles is widely concerned. Therefore, the design and synthesis of injectable hydrogels with antibacterial activity are expected as scaffold materials for tissue engineering.
Tannic acid is a complex polybasic phenolic acid widely existing in nature, has remarkable antibacterial property, can effectively inhibit the formation of staphylococcus aureus and escherichia coli biofilms, can contract wound surfaces and accelerate the formation of granulation tissues and collagen protein [ Chinese patent application publication No. CN201711348496 ]. Tannic acid is rich in bark and fruit of various trees, can be used as food antioxidant, and is approved by the Food and Drug Administration (FDA) for use as food additive. Although tannic acid has low toxicity, the tannic acid has obvious toxicity even if the concentration is too high, the tannic acid and metal ions are introduced into an injectable temperature-sensitive polyhydroxy-containing polymer such as chitin-based temperature-sensitive hydrogel to obtain the injectable antibacterial hydrogel with temperature sensitivity and pH sensitivity, and the tannic acid is expected to be slowly released to realize relatively long-term antibacterial, anti-inflammatory and anti-oxidation effects and low toxicity and no toxicity.
Disclosure of Invention
In order to solve various problems in the existing wound dressing, the invention aims to provide a temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid, and preparation and application thereof. The dressing has temperature sensitivity and pH sensitivity, has good fluidity at low temperature, can be injected in situ and sprayed, and can fill irregular wound shapes. The dressing is quick in gelling at body temperature, the tannin is not easy to wash away, the tannin antibacterial agent can be slowly released, the toxicity of the tannin antibacterial agent is reduced, and the dressing has long-term antibacterial performance, wide antibacterial range, good biocompatibility and biodegradability and wide application in the field of biomedical materials.
A temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid comprises the following three parts:
(1) the temperature-sensitive polymer solution A matrix containing polyhydroxy is capable of in-situ spontaneous physical crosslinking under physiological conditions, and is liquid at low temperature;
(2) aqueous solution of tannic acid;
(3) a metal ion solution.
The temperature-sensitive polyhydroxy-containing polymer can be a temperature-sensitive starch modified polymer, a temperature-sensitive cellulose modified substance, a temperature-sensitive chitin modified substance and the like; the low temperature here means a body temperature of 37 ℃ or lower.
Preparation method of temperature-sensitive composite antibacterial hydrogel material capable of being injected and containing tannic acid
(1) Preparing a temperature-sensitive polyhydroxy-containing polymer solution A capable of in-situ spontaneous physical crosslinking under physiological conditions, and storing at low temperature;
(2) adding a tannic acid solution into the solution A at a low temperature, and uniformly mixing to obtain a mixed solution B;
(3) and adding the metal ion solution into the mixed solution B at low temperature, uniformly mixing to obtain a mixed solution C, adding acid or alkali to adjust the pH value to obtain an injectable composite antibacterial hydrogel precursor solution with good fluidity at low temperature, and forming the composite antibacterial hydrogel material in situ under physiological conditions.
Preferably, the solution a is temperature-sensitive modified chitin, specifically any one of temperature-sensitive hydroxybutyl chitosan, temperature-sensitive hydroxypentyl chitosan, temperature-sensitive carboxymethyl chitin, temperature-sensitive hydroxyethyl chitin, temperature-sensitive hydroxypropyl chitin, and temperature-sensitive hydroxybutyl chitin or their mixture.
Wherein the acetyl degree range of the temperature-sensitive hydroxybutyl chitosan is 0.01-0.4; the acetyl degrees of the temperature-sensitive carboxymethyl chitin, the temperature-sensitive hydroxyethyl chitin, the temperature-sensitive hydroxypropyl chitin and the temperature-sensitive hydroxybutyl chitin are in the range of 0.7-0.92; the molecular weight of these temperature sensitive polymers is in the range of 5kDa to 1000 kDa.
Preferably, the kind of the added metal ions is any one of iron ions, copper ions, zinc ions or a mixture thereof.
Preferably, the mass concentration range of the temperature-sensitive polymer in the mixed solution A is 0.5-20 wt%.
Preferably, the mass concentration range of the tannic acid in the mixed solution C is 0.01-0.4 wt%; the mass concentration of the metal ions in the mixed solution C is 0.001-0.5 wt%.
Preferably, in the step (3), acid or alkali is added to adjust the pH, the molar concentration of the added acid or alkali is 0.01-6 mol/L, and the pH range of the mixed solution C is 4-10.
Preferably, the preparation temperature in the steps (1), (2) and (3) is 2-14 ℃, and the components are quickly and uniformly mixed by using a vortex apparatus to form the injectable hydrogel precursor solution with good fluidity. The physiological condition in the step (3) is a body temperature condition, and the product can be directly used in situ without post-treatment.
The application of a temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid is characterized in that the composite antibacterial hydrogel material is used as an antibacterial dressing for wound healing and has anti-inflammatory and anti-oxidation effects.
The material has temperature sensitivity and pH sensitivity, can be injected in situ and sprayed, and can be used as an antibacterial dressing. Firstly, dissolving temperature-sensitive polyhydroxy-containing polymer such as chitin derivative in water at low temperature, adding tannic acid solution and metal ion solution in a liquid state, mixing uniformly, injecting or spraying the mixture to the surface of a wound to form gel rapidly at body temperature, wherein tannic acid is used as a cross-linking agent and has chelation with metal ions to be used as a slow-release antibacterial agent. The antibacterial hydrogel dressing is mainly characterized by simple preparation; the low-temperature fluidity is good, the gel is quickly formed at body temperature, the antibacterial agent can be slowly released, the antibacterial range is wide, and the antibacterial time is long; the dressing has good biocompatibility and biodegradability, and secondary damage caused by dressing replacement is avoided; is beneficial for wound healing, effectively promotes skin regeneration, reduces scar formation, and has antiinflammatory and antioxidant effects.
Compared with the prior art, the technology has the following beneficial effects:
(1) the invention directly mixes the temperature-sensitive polyhydroxy-containing polymer such as the temperature-sensitive chitin base derivative solution, the tannic acid and the metal ion aqueous solution, and the preparation process is simple. The hydrogel is formed through physical crosslinking, a small-molecule crosslinking agent is not required to be introduced, and the chitin derivative has good biodegradability, so that secondary damage to a wound when a dressing is replaced is avoided. The temperature-sensitive injectable jettable characteristic of the composite antibacterial hydrogel is liquid with good fluidity at low temperature, and can completely fill irregular wound shapes and block exogenous pollutants and microorganisms.
(2) The composite antibacterial hydrogel material is used as a wound antibacterial dressing to quickly gel at body temperature, so that tannic acid is not easy to wash away, and the tannic acid antibacterial agent can be continuously and slowly released for one week under normal physiological conditions, and the toxicity of the tannic acid antibacterial agent is reduced; can accelerate the release of tannic acid under the bacteria-containing acidic condition, can effectively exert the broad-spectrum antibacterial performance of tannic acid, reduce the toxic effect of tannic acid and effectively prevent wound infection.
(3) The composite antibacterial hydrogel material prepared by the invention has good biocompatibility as an antibacterial wound dressing, provides a moist healing environment for wounds, has a good treatment effect on wound healing, promotes skin regeneration and reduces scar formation.
Drawings
Figure 1 is a rheological test of 2 wt% hydroxypropyl chitin HPCH hydrogel and hydroxypropyl chitin/tannic acid/iron HPCH/TA/Fe composite hydrogel in example 2 (a) temperature sweep and (b) time sweep at 37 degrees.
FIG. 2 shows the release of tannic acid in different pH buffers of the hydroxypropylchitin/tannic acid/iron composite hydrogel HPCH/TA/Fe (b) in example 2 and the hydroxypropylchitin/tannic acid composite hydrogel HPCH/TA (a) in example 5.
FIG. 3 is a graph showing the results of the cytotoxicity and in vitro cell migration ability studies of the hydrogel in example 9 of the present invention. Cytotoxicity data (a), photographs of dead and live cell staining (b) and cell migration (c) of the extracts of HPCH hydrogel, HPCH/TA hydrogel, HPCH/Fe hydrogel and HPCH/TA/Fe hydrogel, respectively, on NIH 3T3 cells.
FIG. 4 is a graph showing the long-term antibacterial effects of the HPCH/TA/Fe hydrogel of the present invention on E.coli (E.coli) and S.aureus (S.aureus) in example 2, using a PBS solution containing no hydrogel and the hydrogels HPCH and HPCH/Fe without TA as control groups, respectively.
FIG. 5 is a photograph of wound (a), a photograph of wound area analysis (b) and a photograph of H & E-stained, masson's pine trichrome-stained and sirius red-stained sections (c) of wounds after 12 days of treatment in different time periods in a BALB/c mouse dorsal full-thickness excision wound model of a Staphylococcus aureus infection with a HPCH/TA/Fe hydrogel dressing in example 2 of the present invention
Detailed Description
In order that the invention may be more readily understood, specific embodiments thereof will be described further below.
The invention will be further described with reference to examples and figures, which are intended to facilitate a better understanding of the contents of the invention, but these specific examples do not in any way limit the scope of the invention.
Example 1 preparation of temperature-sensitive chitin derivative A
According to our previous research work [ Chinese patent application publication No. CN201410170871.8]The hydroxypropyl chitin with low deacetylation degree is prepared in a sodium hydroxide-urea system by a homogeneous phase method. Weighing 2 g of purified chitin, stirring and dispersing in 100 g of pre-frozen aqueous solution containing 11 wt% of sodium hydroxide and 4wt% of urea, freezing for 24h at-30 ℃, taking out, mechanically stirring at room temperature and thawing to obtain dissolved chitin aqueous solution. To the obtained chitin solution (100 g, 2 wt%) was added 11.4 g of propylene oxide, and the system was stirred at 2 ℃ to mix the reactants uniformly, then heated to 5 ℃ for reaction for 24h, and subsequently heated to 15 ℃ for reaction for 6 h. Finally, cooling the system to 2 ℃, adjusting the pH value of the system to 7 by using 3M hydrochloric acid, dialyzing by using deionized water, and freeze-drying to obtain white spongy hydroxypropyl chitin (HPCH) with the yield of 87%.1The degree of acetylation of the product is 0.89 and the degree of substitution is 0.8 by calculation of H NMR spectrum4. Viscosity average molecular weight M measured by Ubbelohde viscometerη410 kDa. The homogeneously synthesized HPCH solution is temperature sensitive and the rheological results show reversible sol-gel transition behavior, wherein the gel transition temperature of a 2 wt% HPCH solution is 18 ℃ (fig. 1 a).
According to our previous research work [ Chinese patent application publication No. CN201310641249.6]The carboxymethyl chitin with low deacetylation degree is prepared in a sodium hydroxide-urea system by a homogeneous phase method,1the HNMR spectrogram calculates that the acetyl degree of the product is 0.87, and the carboxymethyl substitution degree is 0.19. Similarly, hydroxyethyl chitin and hydroxybutyl chitin with low deacetylation degree are prepared in a sodium hydroxide-urea system by a homogeneous phase method, wherein the acetylation degree range of the chitin derivatives is 0.7-0.92, and the molecular weight range of the chitin derivatives is 5 kDa-1000 kDa.
Example 2 preparation of hydroxypropyl chitin/tannin/ferric chloride HPCH/TA/Fe hydrogel
The temperature-sensitive hydroxypropyl chitin HPCH prepared in the example 1, tannic acid TA and ferric chloride FeCl hexahydrate3·6H2Dissolving O in ultrapure water at low temperature of 2-14 deg.C, respectively, and preparing HPCH solution with mass concentration of 3 wt%, TA solution with mass concentration of 0.75 wt% and FeCl solution with mass concentration of 0.8 wt%3·6H2And (4) O solution. Adding 0.4g of TA solution into 1g of HPCH solution, quickly and uniformly mixing by vortex at the low temperature of 2-14 ℃, and quickly adding 0.1g of FeCl3The solution is evenly mixed by vortex at the low temperature of 2-14 ℃, the pH value is adjusted to 7.4 by using 1MNaOH solution, the neutral solution containing the tannic acid has good fluidity at the low temperature of 2-14 ℃, can be injected and sprayed, and is placed in a water bath with the temperature of 37 ℃ for standing for 1min to form hydrogel (figure 1).
Example 3: preparation of hydroxypropyl chitin/tannic acid/ferric chloride HPCH/TA/Fe hydrogel
The temperature-sensitive hydroxypropyl chitin HPCH prepared in the example 1, tannic acid TA and ferric chloride FeCl hexahydrate3·6H2Dissolving O in ultrapure water at low temperature of 4 ℃ respectively, and preparing HPCH solution with mass concentration of 3 wt%, TA solution with mass concentration of 0.75 wt% and FeCl solution with mass concentration of 9.6 wt%3·6H2And (4) O solution. Adding 0 g of HPCH solution into 1g of HPCH solutionQuickly mixing 4g of TA solution at the low temperature of 2-15 ℃ by vortex uniformly, and then quickly adding 0.1g of FeCl3The solution is mixed evenly by vortex at a low temperature of 2-10 ℃. Adjusting pH to 7.4 with 1M NaOH solution, wherein the neutral solution containing tannic acid has good fluidity at low temperature of 2-10 deg.C, can be injected and sprayed, and can be placed in water bath at 37 deg.C for 1min to form hydrogel rapidly. Similar results were obtained using a HPCH solution with a mass concentration of 0.75 wt% instead of a HPCH solution with a mass concentration of 3 wt%. Using a lower molecular weight HPCH solution (M)η40kDa) similar injectable tannic acid-containing temperature-sensitive complex antimicrobial hydrogel materials can be prepared using HPCH solutions at a mass concentration of 30 wt%.
Example 4 preparation of hydroxypropyl chitin/tannin/ferric chloride HPCH/TA/Fe hydrogel
The temperature-sensitive hydroxypropyl chitin HPCH prepared in the example 1, tannic acid TA and ferric chloride FeCl hexahydrate3·6H2Dissolving O in ultrapure water at low temperature of 4 ℃ respectively, and preparing HPCH solution with mass concentration of 3 wt%, TA solution with mass concentration of 1.125 wt% and FeCl with mass concentration of 14.4 wt%3·6H2And (4) O solution. Adding 0.4g of TA solution into 1g of HPCH solution, quickly and uniformly mixing by vortex at the low temperature of 2-15 ℃, and quickly adding 0.1g of FeCl3The solution is mixed evenly by vortex at a low temperature of 2-10 ℃. Adjusting pH to 7.4 with 1M NaOH solution, wherein the neutral solution containing tannic acid has good fluidity at low temperature of 2-10 deg.C, can be injected and sprayed, and can be placed in water bath at 37 deg.C for 1min to form hydrogel rapidly. When the mass concentration range of the tannic acid in the C solution before pH adjustment is 0.01-0.4 wt%, and the mass concentration range of the metal ion iron is 0.001-0.5 wt%, similar temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid can be prepared.
Example 5 preparation of hydroxypropyl chitin/tannic acid HPCH/TA hydrogel
The temperature-sensitive hydroxypropyl chitin HPCH and the tannic acid TA prepared in the example 1 are respectively dissolved in ultrapure water at a low temperature of 4 ℃, and an HPCH solution with the mass concentration of 3 wt% and a TA solution with the mass concentration of 0.75 wt% are prepared. And adding 0.4g of TA solution into 1g of HPCH solution, quickly and uniformly mixing by vortex at the low temperature of 2-15 ℃, and quickly adding 0.1g of pure water, and uniformly mixing by vortex at the low temperature of 2-15 ℃. Adjusting pH to 7.4 with 1M NaOH solution, standing in water bath at 37 deg.C for 1min to form hydrogel rapidly, but the neutral hydrogel containing tannic acid without metal ions has no good fluidity at low temperature of 2-10 deg.C and loses reversible temperature sensitivity and injectability.
Example 6 preparation of hydroxypropyl chitin/tannic acid/zinc chloride HPCH/TA/Zn hydrogel
The temperature-sensitive hydroxypropyl chitin HPCH prepared in the example 1, tannic acid TA and zinc chloride ZnCl2Respectively dissolving in ultrapure water at low temperature of 4 ℃, and preparing HPCH solution with mass concentration of 3 wt%, TA solution with mass concentration of 0.75 wt% and ZnCl solution with mass concentration of 0.8 wt%2And (3) solution. Adding 0.4g of TA solution into 1g of HPCH solution, quickly and uniformly mixing by vortex at the low temperature of 2-15 ℃, and quickly adding 0.1g of ZnCl2The solution is mixed evenly by vortex at a low temperature of 2-15 ℃. Adjusting pH to 7.4 with 1M NaOH solution, wherein the neutral solution containing tannic acid has good fluidity at low temperature of 2-15 deg.C, can be injected and sprayed, and can be placed in water bath at 37 deg.C for 1min to form hydrogel.
Example 7 hydroxypropyl chitin/tannic acid/copper chloride HPCH/TA/CuCl2Preparation of hydrogels
The temperature-sensitive hydroxypropyl chitin HPCH, tannic acid TA and copper chloride CuCl prepared in example 1 are mixed2Respectively dissolving in ultrapure water at low temperature of 4 ℃, and preparing HPCH solution with mass concentration of 3 wt%, TA solution with mass concentration of 0.75 wt% and CuCl with mass concentration of 0.8 wt%2And (3) solution. Adding 0.4g of TA solution into 1g of HPCH solution, quickly and uniformly mixing by vortex at the low temperature of 2-15 ℃, and quickly adding 0.1g of CuCl2The solution is mixed evenly by vortex at a low temperature of 2-15 ℃. Adjusting pH to 7.4 with 1M NaOH solution, wherein the neutral solution containing tannic acid has good fluidity at low temperature of 2-15 deg.C, can be injected and sprayed, and can be placed in water bath at 37 deg.C for 1min to form hydrogel.
Example 8 preparation of hydrogel containing tannic acid and iron ions Using temperature-sensitive polyhydroxyl-containing Polymer instead of temperature-sensitive hydroxypropyl chitin
The temperature prepared in example 2 was adjustedDissolving sensitive carboxymethyl chitin CMCH in 0.5M NaOH at low temperature of 4 deg.C, adjusting pH to 7.4 with 3M HCl solution, and mixing tannic acid TA and ferric chloride FeCl hexahydrate3·6H2Dissolving O in ultrapure water at low temperature of 4 ℃ respectively, and preparing a CMCH solution with the mass concentration of 3 wt%, a TA solution with the mass concentration of 0.75 wt% and FeCl with the mass concentration of 0.8 wt%3·6H2And (4) O solution. Adding 0.4g of TA solution into 1g of CMCH solution, quickly and uniformly mixing by vortex at the low temperature of 2-10 ℃, and quickly adding 0.1g of FeCl3The solution is mixed evenly by vortex at a low temperature of 2-10 ℃. Placing in water bath at 37 deg.C, standing for 1min to quickly form hydrogel.
Other temperature-sensitive polyhydroxy-containing polymers such as temperature-sensitive collagen, modified xyloglucan temperature-sensitive hydrogel, temperature-sensitive hydroxypropyl cellulose, temperature-sensitive hydroxypropyl methylcellulose, temperature-sensitive hydroxybutyl cellulose, temperature-sensitive hydroxybutyl chitosan, temperature-sensitive hydroxypentyl chitosan, temperature-sensitive hydroxyethyl chitin or temperature-sensitive hydroxybutyl chitin are used for replacing the temperature-sensitive hydroxypropyl chitin, and a tannic acid aqueous solution and a metal ion aqueous solution are added at a low temperature to prepare the temperature-sensitive composite hydrogel antibacterial dressing capable of being injected with tannic acid.
Example 9 Performance testing
1. Release behavior of antimicrobial TA in buffers of different pH
mu.L of the hydrogel precursor solutions prepared in examples 2 and 5 above were allowed to gel at 37 ℃ for 30 minutes and then soaked in centrifuge tubes containing 15mL of buffer solutions of different pH, pH3.0, 5.0, 5.5,7.4 and 9.0, respectively. The centrifuge tube was placed in a shaker at 37 ℃ with an oscillation rate of 60 rpm. At regular intervals 1.0mL of solution was removed and the same volume of fresh buffer solution was added. The release of TA from the solution was determined by absorbance at 278nm using an ultraviolet spectrophotometer. As shown in FIG. 2, the HPCH/TA hydrogel had similar sustained release TA of over 40% at various pH values over 48 hours, with no apparent pH sensitivity; while the release speed of TA in the HPCH/TA/Fe hydrogel changes along with the change of pH value, the lower the acidity, the faster the release, and the obvious pH sensitivity. At pH3.0, the HPCH/TA/Fe hydrogel release profile was similar to the TA profile of the HPCH/TA hydrogel release, and about 50% of the TA was released from the HPCH/TA/Fe hydrogel after 48 hours. When the pH value is increased to 5.5,7.4 and 9.0, only 10 percent of TA is released in 7 days, which shows that the TA in the hydrogel can be slowly released for a long time in weak acidic, neutral and alkaline environments, the growth of bacteria is inhibited, the long-term antibacterial, anti-inflammatory and antioxidant effects are exerted, and the tannin can be quickly released under the bacteria-containing acidic condition, so that the broad-spectrum antibacterial performance of the tannin can be effectively exerted.
2. The cytotoxicity and in vitro cell migration ability of the hydrogels were studied.
The in vitro cytotoxicity of the hydrogels was assessed by cell counting kit CCK-8 assay using NIH 3T3 fibroblasts. NIH 3T3 cells were stained for dead and live, green for live cells and red for dead cells, and visualized by confocal laser. As shown in FIG. 3, the results showed that the cell numbers of the HPCH, HPCH/Fe, and HPCH/TA/Fe groups all showed a sustained increase, and the red dead cell number of these three groups was very small, indicating that the growth of 3T3 NIH cells was not affected by the HPCH/TA/Fe hydrogel, whereas the HPCH/TA hydrogel without metal ions was significantly toxic to the cells. In addition, cell migration assays were performed to assess the wound repair ability of the hydrogels. 2D scratch wound assays were performed on NIH 3T3 fibroblast monolayers to simulate monitoring of the effect of different hydrogel conditioned media on wound closure within 48 hours in vitro. Cells cultured in HPCH/TA/Fe hydrogel medium moved to the scratched area faster than the other groups and reached almost 100% confluence after 24 hours. It is demonstrated that HPCH/TA/Fe hydrogels can accelerate the wound healing process.
3. Long term antibacterial property test
The antibacterial activity of the HPCH/TA/Fe hydrogel was evaluated by plate counting using E.coli and S.aureus, 200. mu.L of PBS without hydrogel, HPCH without TA and HPCH/Fe with no TA as controls, respectively. The hydrogel precursor solution (200. mu.L) was added to a 48-well cell culture plate and then placed at 37 ℃ until the hydrogel was formed. The HPCH/TA/Fe hydrogel was soaked in 1mL sterile PBS at 37 ℃ for 24 hours, and then the soaked PBS was replaced with 1mL fresh PBS, and the process was repeated. 10 μ L of the extract containing 106CFU mL-1Escherichia coli or goldPBS suspension of Staphylococcus aureus was spread on the hydrogels soaked with the PBS solution for different days (original hydrogel not soaked, hydrogel soaked for 3 changes and hydrogel soaked for 6 changes were recorded as D1, D4 and D7, respectively). These bacterially inoculated hydrogels were incubated in a humid atmosphere at 37 ℃ for 24 hours. Subsequently, 1mL of PBS was added to each well to resuspend the retained bacteria, and 10. mu.L of the bacterial suspension was spread on a Luria-Bertani agar plate, and after incubation at 37 ℃ for 24 hours, colonies formed on the Luria-Bertani agar plate were counted, as shown in FIG. 4, indicating that the HPCH/TA/Fe gel had a good antibacterial effect for a long period of time. The bacteria were stained for dead and live, green for live bacteria and red for dead bacteria, and the results of confocal laser observation indicated that the HPCH/TA/Fe gel killed E.coli and Staphylococcus aureus (red), whereas the bacteria in the control group were essentially green and viable.
4. In vivo bacterial infection wound healing experiments
Female BALB/c mice, 8 weeks old, were anesthetized by intraperitoneal injection of chloral hydrate and the mice were shaved of their back hair using a razor. Full thickness circular wounds (5 mm diameter) were prepared on the dorsal skin of rats by biopsy punch. 20 μ L of Staphylococcus aureus suspension (2X 10)8CFUmL-1) The wound site was added for 5 minutes and then covered with PBS, TA solution (0.2 wt%) or HPCH (2 wt%), HPCH/TA/Fe (composite hydrogel prepared in example 2, HPCH 2 wt%, TA 0.2 wt%, Fe ion 0.01 wt%) hydrogel. Fixing with a transparent film. The dressing was changed and the wound size was measured every 2 days. Mice were euthanized 12 days after wound healing, and skin tissue from the wound area was collected and then fixed in 4% paraformaldehyde. The harvested skin sections were then cut with hematoxylin and eosin (H)&E) Staining to study tissue appearance, Masson trichrome and sirius red were used for histological analysis. FIG. 5 illustrates that the HPCH/TA/Fe group showed a significant reduction in wound size after 6 days of treatment, indicating that the HPCH/TA/Fe hydrogel had better debridement and antimicrobial effects than the other groups. The tissue slice result also shows that the HPCH/TA/Fe hydrogel is more beneficial to wound healing, effectively promotes skin regeneration and reduces scar formation.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. A preparation method of a temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid is characterized by comprising the following steps:
(1) preparing a temperature-sensitive polyhydroxy-containing polymer solution A capable of in-situ spontaneous physical crosslinking under physiological conditions, and storing at low temperature;
(2) adding a tannic acid solution into the solution A at a low temperature, and uniformly mixing to obtain a mixed solution B;
(3) adding a metal ion solution into the mixed solution B at low temperature, uniformly mixing to obtain a mixed solution C, adding acid or alkali to adjust the pH value to obtain an injectable antibacterial composite hydrogel precursor solution with good fluidity at low temperature, and forming a composite antibacterial hydrogel material in situ under physiological conditions;
the added metal ions are any one of iron ions, copper ions and zinc ions or a mixture of the iron ions, the copper ions and the zinc ions; the physiological condition in the step (3) is a body temperature condition.
2. The preparation method of the temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid according to claim 1, wherein the temperature-sensitive polyhydroxy-containing polymer in the solution A is temperature-sensitive modified chitin.
3. The preparation method of the temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid according to claim 2, wherein the temperature-sensitive modified chitin is any one of temperature-sensitive hydroxybutyl chitosan, temperature-sensitive hydroxypentyl chitosan, temperature-sensitive carboxymethyl chitin, temperature-sensitive hydroxyethyl chitin, temperature-sensitive hydroxypropyl chitin and temperature-sensitive hydroxybutyl chitin or a mixture thereof.
4. The preparation method of the temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid according to claim 1, wherein the mass concentration of the polymer in the solution A is 0.5-20 wt%.
5. The preparation method of the injectable tannin-containing temperature-sensitive composite antibacterial hydrogel material as claimed in claim 1, wherein the mass concentration of tannin in the mixed solution C is in the range of 0.01-0.4 wt%; the mass concentration of the metal ions in the mixed solution C is 0.001-0.5 wt%.
6. The preparation method of the temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid according to claim 1, wherein in the step (3), acid or alkali is added to adjust the pH, and the pH range of the final mixed solution is 4-10.
7. The preparation method of the temperature-sensitive composite antibacterial hydrogel material capable of being injected with tannic acid according to claim 1, wherein the preparation temperature in the steps (1), (2) and (3) is 2-14 ℃, and the components are rapidly and uniformly mixed to form an injectable composite antibacterial hydrogel precursor solution with good fluidity.
8. An injectable tannin-containing temperature-sensitive composite antibacterial hydrogel material prepared by the preparation method according to any one of claims 1 to 7, wherein the composite antibacterial hydrogel material comprises:
(1) the temperature-sensitive polymer solution A matrix containing polyhydroxy is capable of in-situ spontaneous physical crosslinking under physiological conditions, and is liquid at low temperature;
(2) aqueous solution of tannic acid;
(3) a metal ion solution;
the low temperature here means a body temperature of 37 ℃ or lower.
9. The use of the injectable tannin-containing temperature-sensitive composite antibacterial hydrogel material as claimed in claim 8, wherein the composite antibacterial hydrogel material is used for preparing a dressing for promoting skin regeneration and reducing scar formation.
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