CN110433316B - Photo-thermal/ionic synergistic antibacterial hydrogel and preparation method and application thereof - Google Patents
Photo-thermal/ionic synergistic antibacterial hydrogel and preparation method and application thereof Download PDFInfo
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/412—Tissue-regenerating or healing or proliferative agents
Abstract
The invention provides a photo-thermal/ionic synergistic antibacterial hydrogel and a preparation method and application thereof, and relates to a polydopamine/copper-doped bioactive ceramic composition, which comprises the following raw materials: modified polyglutamic acid high-molecular water solution grafted and modified by dopamine and adipic dihydrazide and copper-doped bioactive ceramic powder; wherein the mass percentage concentration of the modified polyglutamic acid macromolecule aqueous solution is 2.5-10%, and the adding amount of the copper-doped bioactive ceramic powder is 0.5-5% of the mass of the modified polyglutamic acid macromolecule aqueous solution.
Description
Technical Field
The invention relates to a photo-thermal/ionic synergistic antibacterial hydrogel and a preparation method and application thereof, belonging to the fields of biomedicine, material technology, wound repair and medical appliances.
Background
Wounds caused by fire, mechanical accidents, diseases and the like are easy to infect, and the wounds are suppurative, festered and difficult to heal, thereby causing great pain to patients. How to efficiently eliminate the existing infection, inhibit the breeding of bacteria for a long time, and simultaneously play a role in promoting healing of large-area wound surfaces, has great significance in the treatment of infected wound surfaces, and is worthy of exploration and innovation.
Inorganic metal ions such as copper ions can inhibit breeding of various bacteria for a long time, and have good killing effect on some drug-resistant bacteria, but the copper ions and the bacteria need a long action time to achieve the sterilization effect, and the effect is slow. The photo-thermal antibacterial material can quickly and effectively kill various bacteria on the surface by utilizing the high temperature generated by near infrared light irradiation, and has quick antibacterial effect and high efficiency. However, the photo-thermal antibacterial material has the defect that bacteria are easy to breed repeatedly after the high temperature is removed, and cannot achieve the long-acting and stable antibacterial effect. Meanwhile, the two types of antibacterial materials have the problem of insufficient biocompatibility. Theoretically, the higher the copper ion concentration and the higher the temperature generated by photo-heat, the better the antibacterial effect. However, in practice, when the concentration of copper ions is too high, toxicity is generated to cells and tissues, and excessive high temperature generated by photothermal damage to surrounding tissues. Moreover, the problem of rapid repair of the wound surface after the infection is removed is not solved.
Disclosure of Invention
The present inventors have recognized that dopamine is a neurotransmitter in the human body and that oxidative auto-polymerization occurs under alkaline conditions to produce polydopamine with a photothermal effect. It is recognized, on the other hand, that copper-doped bioactive ceramics (e.g., copper-doped calcium silicate, copper-doped bioglass, copper-doped calcium phosphate, copper-doped hydroxyapatite, etc.) are capable of undergoing degradation in water, creating an alkaline environment and releasing copper ions and silicon ions. The released copper ions can inhibit bacterial proliferation, and simultaneously, the silicon ions and the copper ions jointly promote angiogenesis, thereby being beneficial to the repair and regeneration of wound tissues. And copper ions are complexed with dopamine. Based on the situation, the invention aims to provide a composite hydrogel (existing as a dressing) which is interacted between dopamine and copper-doped calcium silicate, can rapidly eliminate infection and has long-acting antibacterial effect, and a preparation method and application thereof.
In a first aspect, the present invention provides a polydopamine/copper-doped bioactive ceramic composition, wherein the raw material composition of the polydopamine/copper-doped bioactive ceramic composition comprises: modified polyglutamic acid high-molecular water solution grafted and modified by dopamine and adipic dihydrazide and copper-doped bioactive ceramic powder; wherein the mass percentage concentration of the modified polyglutamic acid macromolecule aqueous solution is 2.5-10%, and the adding amount of the copper-doped bioactive ceramic powder is 0.5-5% of the mass of the modified polyglutamic acid macromolecule aqueous solution.
Taking copper-doped calcium silicate as an example, the interaction of copper-doped calcium silicate with dopamine is manifested in two ways: on one hand, the copper-doped calcium silicate is alkaline due to the change of pH microenvironment caused by rapid ion exchange in aqueous solution. Therefore, alkaline signals released by the copper-doped calcium silicate in an aqueous solution can be used for stimulating the oxidation of dopamine, and the generated polydopamine can be used as a photothermal preparation. Meanwhile, copper ions in the aqueous solution are complexed with the generated polydopamine, so that the crosslinking of the system is enhanced.
In a second aspect, the present invention provides a polydopamine/copper complex prepared by the process of:
(1) adding an alkaline solution into a modified polyglutamic acid polymer aqueous solution grafted and modified by dopamine and adipic dihydrazide to obtain a mixed solution;
(2) adding equal volume of copper ion solution into the mixed solution to perform a complexing reaction to obtain the polydopamine/copper complex; wherein the mass percentage concentration of the modified polyglutamic acid macromolecule aqueous solution is 2.5-10%; the alkaline solution is 0.5-2M NaOH solution, and the addition amount of the alkaline solution is 5-15% of the mass of the modified polyglutamic acid macromolecule aqueous solution; the copper ion solution is a standard copper ion aqueous solution, and the concentration of the copper ion solution is not more than 1000 ppm; preferably, the concentration of the copper ion solution is 1-1000 ppm, and more preferably 1-50 ppm.
In a third aspect, the present invention provides a polydopamine/bioactive ceramic composite hydrogel, wherein the raw material composition of the polydopamine/bioactive ceramic composite hydrogel includes: modified polyglutamic acid high-molecular water solution grafted and modified by dopamine and adipic dihydrazide, copper-doped bioactive ceramic powder, glutamic acid and oxidized glucan water solution; wherein the mass percentage concentration of the modified polyglutamic acid macromolecule aqueous solution is 2.5-10%, and the adding amount of the copper-doped bioactive ceramic powder is 0.5-5% of the mass of the modified polyglutamic acid macromolecule aqueous solution; the addition amount of the glutamic acid is 40 to 60 percent of the mass of the copper-doped bioactive ceramic powder, preferably 50 percent; the mass percentage concentration of the oxidized dextran aqueous solution is 2.5-10%; the volume ratio of the modified polyglutamic acid macromolecule aqueous solution to the oxidized glucan aqueous solution is 1: (0.5 to 1.5), preferably 1: 1.
preferably, the modified polyglutamic acid polymer is formed by grafting dopamine and adipic dihydrazide on a polyglutamic acid polymer long chain by using an amide reaction, wherein the molar ratio of the dopamine, the adipic dihydrazide and the polyglutamic acid polymer is (0.05-0.2): (0.5-1.5): 1, preferably 0.1: 1: 1.
preferably, the copper-doped bioactive ceramic powder is selected from at least one of copper-doped bioglass, copper-doped calcium phosphate, copper-doped hydroxyapatite and copper-doped calcium silicate; the doping amount of copper in the copper-doped bioactive ceramic powder is 1wt% -20 wt%, and preferably 5 wt%.
Preferably, the particle size of the copper-doped bioactive ceramic powder is below 71 microns.
In the present invention, the presence of copper-doped calcium silicate is exemplified by calcium silicate which stabilizes the pH of the polydopamine/copper-doped bioactive ceramic composition in a strongly basic range, which can be adjusted to be weakly basic or neutral by the acidic amino acid glutamic acid. And (3) chemically bonding a hydrazide group based on the modified polyglutamic acid and an aldehyde group of the oxidized glucan to generate the acylhydrazone bond-based composite hydrogel.
Preferably, the mass ratio of the glucan to the sodium periodate is 0.2:1 or 0.4:1 when the oxidized glucan is prepared. Preferably 0.4: 1.
In a fourth aspect, the invention provides an antibacterial method, wherein the polydopamine/bioactive ceramic composite hydrogel is irradiated by laser, so that the temperature is raised and copper ions are released at the same time, so as to realize synergistic antibacterial; preferably, the laser has a wavelength of 808nm and a power of 0.41W/cm2～1.21W/cm2。
In a fifth aspect, the invention provides an application of the polydopamine/bioactive ceramic composite hydrogel in preparation of an infectious wound repair material.
Drawings
FIG. 1 is a gel-forming photograph of a polydopamine/copper-doped calcium silicate composite hydrogel;
FIG. 2 is a graph demonstrating the interaction of dopamine with copper-doped calcium silicate, wherein a) an alkaline environment is created for the copper-doped calcium silicate to oxidize dopamine; b) releasing Cu ions and Si ions for the copper-doped calcium silicate; complexing the generated polydopamine with copper ions, and changing the color d) and the absorbance c) of the obtained solution;
FIG. 3 is a schematic representation of the enhancement of photothermal properties of a polydopamine/copper complex solution after complexing Cu ions, a) the photothermal profile of copper ions, b) the photothermal profile of polydopamine after complexing with copper ions;
fig. 4 is a schematic diagram of antibacterial performance of copper-doped calcium silicate hydrogel (Cu) and complexed polydopamine/copper-doped calcium silicate composite hydrogel (P/Cu), a schematic diagram of biocompatibility to fibroblasts b) and biocompatibility to endothelial cells c), and it can be seen that the antibacterial performance and biocompatibility of the material are improved;
FIG. 5 shows a graph of the in vitro vascularization performance of different hydrogels formed by complexation, which can be seen to further promote in vitro vascularization;
FIG. 6 is a photo-thermal characterization of polydopamine/copper-doped calcium silicate hydrogels (P/Cu or PDA/Cu-CS) and control hydrogels (Ctrl): wherein a) is a real-time infrared thermal image; b) photothermal curves for different hydrogel samples; c) the photo-thermal curve is the poly-dopamine/copper-doped calcium silicate hydrogel photo-thermal curve with different ceramic contents; d) the photo-thermal curve is a poly-dopamine/copper-doped calcium silicate hydrogel photo-thermal curve with different laser power; e) the continuous heating-cooling photothermal curve of the polydopamine/copper-doped calcium silicate hydrogel shows that the polydopamine/copper-doped calcium silicate hydrogel has excellent photothermal performance and photothermal stability, and the photothermal curve can be adjusted through ceramic compounding amount and laser power;
figure 7 is a representation of polydopamine/copper-doped calcium silicate hydrogel active ion release performance: a) comparing laser irradiation with non-irradiation for 8 h; b) the ion release research of the hydrogel in short term (15min) and long term (12h) under 15min laser irradiation is carried out; c) the ion release research is carried out on the composite hydrogel after 7 days of degradation; the result shows that the hydrogel can continuously release copper ions and silicon ions for a long time, and the ion release can be regulated and controlled by laser irradiation;
fig. 8 shows that the polydopamine/copper-doped calcium silicate hydrogel has excellent antibacterial performance, wherein a) is an antibacterial result of a polydopamine/copper-doped calcium silicate composite hydrogel plate counting method, and b) and c) are antibacterial rate statistics, which indicates that the hydrogel can quickly and long-term inhibit bacteria;
FIG. 9 shows the effect of polydopamine/copper-doped calcium silicate hydrogel on the proliferation of fibroblasts a) and endothelial cells b).
FIG. 10 is a graph showing the bacteriostatic effect of polydopamine/copper-doped calcium silicate hydrogel on the infected wound in rats, wherein a) is a comparison of the wound infection in rats on day 8; b) for the statistics of the rat wound surface antibacterial rate at different time periods, it can be seen that the composite hydrogel has the best killing effect on bacteria at the wound surface infected part under the assistance of laser irradiation (wherein Blank represents that no material is used for the infected wound surface as a negative control group, and Blank represents that ciprofloxacin hydrochloride serving as a commercially available antibacterial ointment is used as a positive control);
figure 11 shows the results of polydopamine/copper-doped calcium silicate hydrogel on the repair of infected wounds in rats at different time periods of digital photographs a) of rat wounds and percentage of wound healing b);
FIG. 12 shows the H & E staining results of the wound tissues for healing infected wounds in rats with polydopamine/copper-doped calcium silicate hydrogel at different time periods;
FIG. 13 shows the result of staining of wound tissue CD31 in rat infected wound repair with polydopamine/copper-doped calcium silicate hydrogel at different time periods;
fig. 14 is a statistics of the number of blood vessels of wound tissues of polydopamine/copper-doped calcium silicate hydrogel on infected wound repair in rats at different time periods a) and a statistics of diameter distribution of the size of blood vessels of the wound tissues on the eighth day b);
FIG. 15 shows the COLL-I staining results of the wound tissues in rat infected wound repair with polydopamine/copper-doped calcium silicate hydrogel at different time periods.
Detailed Description
The present invention is further illustrated by the following examples, which are to be understood as merely illustrative and not restrictive.
In the present disclosure, a polydopamine/copper-doped calcium silicate composition comprises: modified polyglutamic acid high molecular water solution grafted with dopamine and adipic dihydrazide and copper-doped calcium silicate powder. Wherein, the content of the modified polyglutamic acid polymer grafted with dopamine and adipoyl hydrazine and the content of the copper-doped calcium silicate powder are respectively (2.5-10 wt%) and (0.5-5 wt%). It will be appreciated that all or part of the above components of the dopamine/copper doped calcium silicate may be present separately or in admixture. In this system, dopamine interacts with the copper-doped calcium silicate. For example, the interaction of copper-doped calcium silicate with dopamine is manifested in that the copper-doped calcium silicate generates an alkaline environment to promote oxidative autopolymerization of dopamine, resulting in polydopamine. Meanwhile, copper ions in the aqueous solution are complexed with the generated polydopamine, so that the crosslinking of the system is enhanced.
FIG. 2 shows that when copper-doped calcium silicate is added into the modified polyglutamic acid polymer solution grafted with dopamine, the pH value of the solution reaches 11-12 within 1min, and strong basicity is shown. And can release a large amount of copper ions and silicon ions within 1 min. As the compounding amount of the copper-doped calcium silicate is increased, the alkalinity of the solution is enhanced, and the release of copper ions and silicon ions is increased. 100 mu L of 1M NaOH was added to the modified polyglutamic acid polymer solution to form a polydopamine solution. After copper ion solutions with different concentrations are added into the polydopamine solution, the color of the mixed solution becomes light, and the absorbance changes, which indicates that the polydopamine and the copper ions are complexed.
In an alternative embodiment, in the polydopamine/copper-doped calcium silicate composition, the mass ratio of the dopamine-containing polymer (modified polyglutamic acid polymer grafted with dopamine and adipimide) to the copper-doped calcium silicate may be (2.5% to 10%): (0.5% -5%). The term "0.5 to 5%" as used herein means 0.5% or more and 5% or less, including 0.5% and 5%. The copper doping amount in the copper-doped calcium silicate is 1 to 20 weight percent, and the preferred amount is 5 percent. The copper-doped calcium silicate particles are sieved by a 200-mesh sieve, and the size is below 71 mu m. Preferably, the copper-doped calcium silicate is incorporated in the composition in an amount of up to 5% by weight.
In an alternative embodiment, when modifying polyglutamic acid, the molar ratio of dopamine to polyglutamic acid is 0.1:1, and the molar ratio of adipic dihydrazide to polyglutamic acid is 1:1, so as to prepare modified polyglutamic acid polymer grafted with dopamine and adipic dihydrazide.
It is to be understood that the copper-doped calcium silicate in the polydopamine/copper-doped calcium silicate composition may further be optionally copper-doped bioactive ceramic to prepare a polydopamine/copper-doped bioactive ceramic composition. For example, the copper-doped bioactive ceramic can also be copper-doped bioglass, copper-doped calcium phosphate, copper-doped hydroxyapatite and the like.
On the other hand, the invention also provides a polydopamine/copper complex which is obtained by at least carrying out complexation reaction on a modified polyglutamic acid macromolecule aqueous solution (with the concentration of 5 percent for example) grafted with dopamine and adipic dihydrazide, an alkaline solution and a copper ion solution. Wherein the copper ion solution is 1000ppm (1.000g/L) of a copper ion standard solution (e.g., purchased from national institute of metrological testing and technology, Shanghai, model number GBW (E) 08027). The copper ion solutions of different concentrations are standard solutions of copper ions diluted with ultrapure water, for example, 0, 1, 20, 50, 500, 1000ppm, etc. The addition amount of the copper ion solution is the same as the total volume of the mixed solution of the modified polyglutamic acid macromolecule aqueous solution grafted with dopamine and adipic dihydrazide and the alkaline solution. The alkaline solution is 0.5-2M NaOH solution, and the addition amount of the alkaline solution is 5-15% of the mass of the modified polyglutamic acid macromolecule aqueous solution. In this system, the polydopamine/copper complex promotes enhancement of the photothermal properties of the polydopamine solution. Specifically, polydopamine and copper ions are complexed, so that the photothermal performance of the compound is enhanced, and meanwhile, the antibacterial performance of hydrogel, the proliferation performance of fibroblasts and endothelial cells and the in vitro angiogenesis performance are enhanced.
Fig. 3 shows that after the polydopamine solution is mixed with the copper ion solution, the photothermal performance of the mixed solution is improved due to complexation of the polydopamine and the copper ions, and the temperature change of the mixed solution is larger than that of the mixed solution of the polydopamine solution and the aqueous solution. When the concentration of copper ions is more than 1000ppm, the active sites of polydopamine are occupied by the copper ions due to the excessive copper ions, and the photo-thermal performance of the mixed solution is reduced. And the single copper ion solution has weak photo-thermal property, and when the concentration is more than 1000ppm, the temperature is only increased by 4-5 ℃ in 5 min.
Fig. 4 to 5 show that, due to the complexation of polydopamine and copper ions, the polydopamine/copper-doped calcium silicate composite hydrogel (P/Cu) has improved bacteriostatic properties compared with copper-doped calcium silicate hydrogel (Cu) with the action of copper ions alone, has improved biocompatibility to fibroblasts and endothelial cells, and can promote the in vitro culture of endothelial cells into blood vessels.
In the disclosure, a preparation method and application are explained in detail by taking polydopamine/copper-doped calcium silicate composite hydrogel as an example. The composite hydrogel is prepared on the basis of interaction of dopamine and copper-doped calcium silicate and crosslinking of modified polyglutamic acid and oxidized glucan. The polydopamine/copper-doped calcium silicate composite hydrogel has obviously enhanced antibacterial performance, fibroblast and endothelial cell proliferation performance and in vitro angiogenesis performance compared with copper ions under the action of polydopamine/copper complex.
The polydopamine/copper-doped calcium silicate composite hydrogel is prepared by mixing copper-doped calcium silicate, modified polyglutamic acid (short for modified polyglutamic acid) containing dopamine and hydrazide groups, oxidized glucan containing aldehyde groups and glutamic acid for adjusting pH value to form glue. The composite hydrogel comprises a polydopamine/copper-doped calcium silicate composition, an aqueous solution of oxidized glucan (the concentration is 2.5-10 wt%), glutamic acid is used for adjusting the pH range, and the modified polyglutamic acid and the oxidized glucan form acylhydrazone hydrogel. The total mass content fraction of the modified polyglutamic acid and the oxidized dextran can be 2.5-10%, and is preferably 5%. As an example of detailed preparation of polydopamine/copper-doped calcium silicate composite hydrogel, include; preparing a modified polyglutamic acid aqueous solution, and adding copper-doped calcium silicate powder to mix to obtain a mixed solution. Wherein the mass concentration of the modified polyglutamic acid in the mixed solution is 2.5-10%, and the mass concentration of the copper-doped calcium silicate is 0.5-5%, preferably 0.5-2%, and more preferably 2%. And (3) adding glutamic acid to adjust the pH value of the solution to be neutral or weakly alkaline (pH is 7-8), mixing with an oxidized dextran solution with the mass fraction of 2.5% -10%, and forming gel in situ within a certain time to obtain the composite hydrogel. Wherein the volume ratio of the mixed solution to the oxidized dextran solution is 1: (0.5 to 1.5).
The invention provides a rapid and long-acting antibacterial method by utilizing photo-thermal/ionic synergistic action of the polydopamine/copper-doped calcium silicate composite hydrogel. Firstly irradiating the hydrogel for 15min by using a 808nm laser to generate over-high temperature (more than 45 ℃) to kill bacteria, and then utilizing the hydrogel to release copper ions for a long time to further inhibit bacteria and proliferate so as to prevent the bacteria from breeding repeatedly. The power of the laser is 0.41W/cm2～1.21W/cm2Preferably 0.8W/cm2. The concentration range of copper ion release is 1-5 mug/mL, preferably 1-3 mug/mL.
In the invention, the polydopamine/copper-doped calcium silicate composite hydrogel is applied to healing of in-vivo infected skin wounds.
In the invention, the performance of the polydopamine/copper-doped calcium silicate composite hydrogel is detected.
And (3) detecting the photo-thermal property: the hydrogel is irradiated by near infrared light of 808nm, and the temperature change is monitored in real time by a thermal imager to obtain a temperature rise image and a curve.
And (3) ion release detection: and (3) soaking the freshly prepared composite hydrogel in ultrapure water, respectively carrying out continuous laser irradiation and laser-free irradiation, and respectively sampling and supplementing a new solution every other hour within 8 hours. And (3) soaking the freshly prepared composite hydrogel in ultrapure water, respectively carrying out laser irradiation and laser-free irradiation for 15min, and respectively sampling and supplementing new liquid at 15min and 12 h. The freshly prepared composite hydrogel was soaked in ultrapure water, and samples were taken on days 1, 3, 5 and 7 and replenished with fresh solution. The extract was tested for Cu and Si ion concentration using inductively coupled plasma emission spectrometer (ICP-AES).
In-vitro antibacterial detection: 500. mu.L of freshly prepared composite hydrogel was placed in a 5mL centrifuge tube, to which 1mL of 10 was added6CFU·mL-1Irradiating the hydrogel with 808nm laser for 15min, culturing in a shaker at 37 deg.C and 120rpm for 12h, diluting ten thousand times, coating, culturing in a biochemical incubator at 37 deg.C for 15h, and counting. 500. mu.L of freshly prepared composite hydrogel was placed in a 5mL centrifuge tube, to which 1mL of 10 was added6CFU·mL-1Irradiating the hydrogel with 808nm laser for 30min, culturing in a shaker at 37 deg.C and 120rpm for 1.5h, continuously performing laser irradiation for 30min and normal culture for 1.5h within 8h, diluting the bacterial culture solution for ten thousand times, plating, culturing in a biochemical incubator at 37 deg.C for 15h, and counting.
In vitro cell proliferation assay: placing 1mL of freshly prepared composite hydrogel into a 15mL centrifuge tube, and adding 10mL of MEM high-sugar culture medium or ECM culture medium to prepare a composite hydrogel leaching solution. Sterilizing the leaching solution with 0.22 μm mycoderm, adding 10% serum and 1% double antibody, respectively, and diluting with 1/2 as gradient. 1000 cells per well of a 96-well cell culture plate were cultured for 24 hours, then the leaching solution diluted in a gradient was used to replace the previous cell culture medium, and after 1 day, 3 days and 5 days, the cck-8 test solution was added to measure the OD at 450 nm.
In vivo antibacterial effect: round wounds 15mm in diameter were made on the backs of SD rats and infected with 100. mu.L of 3X 109CFU·mL-1The Escherichia coli solution of (1). After infection for 24h, polydopamine/copper-doped calcium silicate composite hydrogel is applied, and the laser beam with the wavelength of 808nm is used for irradiating for 15min every other day. On day 4, day 8, day 14, exudate from the wound was collected with sterile swabs, and after 4h of amplification in bacterial culture medium, the wound was diluted by ten thousand-fold plating and counted.
The in vivo tissue repair effect is as follows: wound tissue was photographed on day 4, day 8, and day 14, and wound healing rate was counted. Fixing wound tissues with paraformaldehyde, performing H & E, CD31 and COLL-I staining treatment, and observing the growth condition of the tissues in the wound area.
The present invention will be described in detail by way of examples. It is also to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art may be made in light of the above teachings. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.
Example 1 Polydopamine/copper-doped calcium silicate composition
(1) Utilizing an amide reaction to graft dopamine and adipic dihydrazide on a polyglutamic acid high-molecular long chain, and preparing a 5% modified polyglutamic acid solution;
(2) and adding the copper-doped calcium silicate powder into the modified polyglutamic acid solution, and uniformly mixing to obtain the polydopamine/copper-doped calcium silicate composition. The mass fractions of the copper-doped calcium silicate powder in the polydopamine/copper-doped calcium silicate composition are respectively 0.5%, 1%, 2% and 5%.
Dopamine interacts with the copper-doped calcium silicate in this system: the copper-doped calcium silicate generates an alkaline environment to promote the oxidation of dopamine, and simultaneously, copper ions in the aqueous solution are complexed with the generated polydopamine.
The results (a) and (b) in fig. 2 show that copper-doped calcium silicate is able to create an alkaline environment and release ions, oxidizing dopamine; the generated polydopamine is complexed with the released copper ions.
EXAMPLE 2 preparation of Polydopamine/copper complexes
(1) Utilizing an amide reaction to graft dopamine and adipic dihydrazide on a polyglutamic acid high-molecular long chain, and preparing a 5% modified polyglutamic acid solution;
(2) to a 5% modified polyglutamic acid solution (0.5mL) was added a 10 wt% 1M NaOH solution (100. mu.L) to form a polydopamine solution;
(3) to the polydopamine solution (0.5mL) was added 0.5mL of 0, 1, 20, 50, 500, 1000ppm copper ion solution (GBW (E)08027, Hokkiso, Mediterranean, technology) to form polydopamine/copper complexes.
The results (c) and (d) in fig. 2 show that the color and absorbance of the solution are changed after the generated polydopamine is complexed with copper ions. The results in fig. 3 illustrate the enhancement of photothermal properties of the solution after complexation.
EXAMPLE 3 Polydopamine/copper-doped calcium silicate composite hydrogel (P/Cu)
(1) Utilizing an amide reaction to graft dopamine and adipic dihydrazide on a polyglutamic acid high-molecular long chain, and preparing a 5% modified polyglutamic acid solution;
(2) oxidizing glucan macromolecules by sodium periodate to prepare oxidized glucan with aldehyde groups and preparing a 5% solution by using an o-diol structure of the glucan macromolecules;
(3) respectively adding 0.5%, 1%, 2% and 5% copper-doped calcium silicate into the modified polyglutamic acid solution, and mixing uniformly. Then, 1/2 glutamic acid with the mass fraction being the mass fraction of the copper-doped calcium silicate is added into the modified polyglutamic acid solution, and the pH is adjusted to be neutral or alkalescent;
(4) and adding the prepared oxidized dextran solution with the same volume into the mixed solution, and forming gel within a certain time to obtain the polydopamine/copper-doped calcium silicate composite hydrogel.
As can be seen from FIG. 1, after 2% copper-doped calcium silicate was added, the modified polyglutamic acid solution changed from pale yellow to black, and dopamine was oxidized. After the glutamic acid and oxidized dextran were added, the solution became colloidal and did not flow when inverted in the test tube.
Fig. 4 and 5 show that due to the complexation of polydopamine and copper ions, the antibacterial performance of the complexed hydrogel (the hydrogel P/Cu in fig. 4 and 5 is generally a hydrogel added with 2% copper-doped calcium silicate) is enhanced, the biocompatibility of fibroblasts and endothelial cells is improved, and the in vitro vascularization is further enhanced.
Example 4 hydrogel for control group (Ctrl)
(1) Grafting adipic hydrazide on a polyglutamic acid high-molecular long chain by using an amide reaction, and preparing a 5% hydrazide modified polyglutamic acid solution;
(2) oxidizing glucan macromolecules by sodium periodate to prepare oxidized glucan with aldehyde groups and preparing a 5% solution by using an o-diol structure of the glucan macromolecules;
(3) and mixing the hydrazide modified polyglutamic acid solution and the oxidized glucan solution in equal volume, and forming the gel within a certain time.
Example 5 Polydopamine hydrogel (PDA)
(1) Utilizing an amide reaction to graft dopamine and adipic dihydrazide on a polyglutamic acid high-molecular long chain, and preparing a 5% modified polyglutamic acid solution;
(2) oxidizing glucan macromolecules by sodium periodate to prepare oxidized glucan with aldehyde groups and preparing a 5% solution by using an o-diol structure of the glucan macromolecules;
(3) adding 10% of 1M NaOH solution into 5% modified polyglutamic acid solution, and adding 1% glutamic acid to adjust the pH value to form polydopamine solution;
(4) and mixing the hydrazide modified polyglutamic acid solution and the oxidized glucan solution in equal volume, and forming the gel within a certain time.
EXAMPLE 6 copper-doped calcium silicate hydrogel (Cu)
(1) Grafting adipamide on a polyglutamic acid high-molecular long chain by using an amide reaction, and preparing 5% hydrazide polyglutamic acid solution;
(2) oxidizing glucan macromolecules by sodium periodate to prepare oxidized glucan with aldehyde groups and preparing a 5% solution by using an o-diol structure of the glucan macromolecules;
(3) adding 2% copper-doped calcium silicate powder into a 5% hydrazide polyglutamic acid solution, and adding 1% glutamic acid to adjust the pH of the solution;
(4) adding polyglutamic acid solution doped with copper calcium silicate and oxidized dextran solution in an isovolumetric mixing manner, and forming gel within a certain time.
The polydopamine/copper-doped calcium silicate composite hydrogel has a photo-thermal/ionic synergistic antibacterial effect, and can realize a rapid and lasting antibacterial effect in vivo and in vitro. The polydopamine/copper-doped calcium silicate hydrogel disclosed herein has good photo-thermal properties, can generate high temperature under 808nm laser irradiation, and can rapidly kill bacteria. And the composite hydrogel disclosed herein can continuously release bioactive ions, and can utilize the released copper ions to inhibit bacteria for a long time. The repairing effect of polydopamine/copper-doped calcium silicate on infected wound surfaces in combination with laser irradiation (P + I) is researched, and the in-vitro antibacterial effect of polydopamine/copper-doped calcium silicate composite hydrogel (I) and control hydrogel (Ctrl) is achieved by combining polydopamine hydrogel with laser irradiation (P). Fig. 3-5 verify the improvement of material performance after polydopamine is complexed with copper ions.
The results in fig. 6 show that the composite hydrogel has a significant temperature rise in a very short time, and has good photothermal properties. The photo-thermal performance of the composite hydrogel can be regulated and controlled by changing the compounding amount of the copper-doped calcium silicate, the laser power and the like. The hydrogel is subjected to the cyclic operation of laser irradiation heating-laser natural cooling closing, and the hydrogel still keeps good photo-thermal performance, which shows that the hydrogel has photo-thermal stability.
The results of fig. 7 show that the polydopamine/copper-doped calcium silicate composite hydrogel (2% copper-doped calcium silicate) can rapidly release active copper ions and silicon ions for a long time, and laser irradiation has a promoting effect on the release of the copper ions and the silicon ions. While short-term (15min) laser irradiation has less effect on long-term (> 12h) ion release.
The results of fig. 8 show that the polydopamine/copper-doped calcium silicate composite hydrogel (2% copper-doped calcium silicate) has the characteristics of rapid and lasting inhibition on escherichia coli and highest bacteriostasis rate. Compared with pure copper ions (I) and pure photo-thermal ions (P), the photo-thermal ions and the ions act together (P + I), the bacteriostatic effect can be quickly achieved, and the bacteriostatic rate is kept above 98%.
The results in fig. 9 show that after the polydopamine/copper-doped calcium silicate composite hydrogel (2% copper-doped calcium silicate) is diluted in a gradient manner, the polydopamine/copper-doped calcium silicate composite hydrogel has the function of promoting the proliferation of fibroblasts and endothelial cells in a large concentration range.
The in vivo antibacterial and repairing effects of the hydrogel are evaluated by using a rat back infection wound model. The repairing effect of polydopamine/copper-doped calcium silicate on infected wound surfaces in combination with laser irradiation (P + I) is researched, polydopamine hydrogel in combination with laser irradiation (P), polydopamine/copper-doped calcium silicate composite hydrogel (I) alone and control group hydrogel (Ctrl) alone are used, and the antibacterial and repairing effects of a material (-Blank) and a clinical antibacterial drug ciprofloxacin hydrochloride (+ Blank) on infected wound surfaces on the backs of rats are achieved.
The results in fig. 10 show that the polydopamine/copper-doped calcium silicate composite hydrogel (2% copper-doped calcium silicate) is combined with laser irradiation (photo-thermal and ionic synergy, P + I), so that the bacteriostatic effect is best. The results in FIGS. 11-12 show that the P + I group healed the fastest wound. The results in FIGS. 13-14 show that the P + I group has the highest number of new vessels, which are generally larger in diameter than the other components. The results in FIG. 15 show that in the P + I group, the collagen staining is deepest in the neogenetic region and the collagen distribution is highest. The results of fig. 11-15 show that the polydopamine/copper-doped calcium silicate composite hydrogel (2% copper-doped calcium silicate) can obviously promote the repair of the infected wound surface by combining with laser irradiation (P + I), the wound surface is the smallest, the number of new blood vessels is the largest, and the number of collagen arrangements is the largest.
Claims (15)
1. The polydopamine/copper-doped bioactive ceramic composition is characterized by comprising the following raw materials: modified polyglutamic acid high-molecular water solution grafted and modified by dopamine and adipic dihydrazide and copper-doped bioactive ceramic powder; wherein the mass percentage concentration of the modified polyglutamic acid macromolecule aqueous solution is 2.5-10%, and the adding amount of the copper-doped bioactive ceramic powder is 0.5-5% of the mass of the modified polyglutamic acid macromolecule aqueous solution.
2. The polydopamine/copper-doped bioactive ceramic composition according to claim 1, wherein the modified polyglutamic acid macromolecule is formed by grafting dopamine and adipamide on a long polyglutamic acid macromolecule by an amide reaction, wherein the molar ratio of the dopamine, adipamide and polyglutamic acid macromolecule is (0.05-0.2): (0.5-1.5): 1.
3. the polydopamine/copper doped bioactive ceramic composition of claim 2 wherein the molar ratio of dopamine, adipamide and polyglutamic acid macromolecules is 0.1: 1: 1.
4. the polydopamine/copper-doped bioactive ceramic composition of claim 1, wherein the copper-doped bioactive ceramic powder is selected from at least one of copper-doped bioglass, copper-doped calcium phosphate, copper-doped hydroxyapatite and copper-doped calcium silicate; the doping amount of copper in the copper-doped bioactive ceramic powder is 1wt% -20 wt%.
5. The polydopamine/copper-doped bioactive ceramic composition according to claim 4, wherein the doping amount of copper in the copper-doped bioactive ceramic powder is 5 wt%.
6. The polydopamine/copper-doped bioactive ceramic composition according to any one of claims 1-5, wherein the particle size of the copper-doped bioactive ceramic powder is 71 μm or less.
7. The polydopamine/bioactive ceramic composite hydrogel is characterized in that the raw material composition of the polydopamine/bioactive ceramic composite hydrogel comprises: modified polyglutamic acid high-molecular water solution grafted and modified by dopamine and adipic dihydrazide, copper-doped bioactive ceramic powder, glutamic acid and oxidized glucan water solution; wherein the mass percentage concentration of the modified polyglutamic acid macromolecule aqueous solution is 2.5-10%, and the adding amount of the copper-doped bioactive ceramic powder is 0.5-5% of the mass of the modified polyglutamic acid macromolecule aqueous solution; the addition amount of the glutamic acid is 40 to 60 percent of the mass of the copper-doped bioactive ceramic powder; the mass percentage concentration of the oxidized dextran aqueous solution is 2.5-10%; the volume ratio of the modified polyglutamic acid macromolecule aqueous solution to the oxidized glucan aqueous solution is 1: (0.5 to 1.5).
8. The polydopamine/bioactive ceramic composite hydrogel according to claim 7, wherein the addition amount of the glutamic acid is 50% of the mass of the copper-doped bioactive ceramic powder.
9. The polydopamine/bioactive ceramic composite hydrogel according to claim 7, wherein the volume ratio of the modified polyglutamic acid macromolecule aqueous solution to the oxidized dextran aqueous solution is 1: 1.
10. the polydopamine/bioactive ceramic composite hydrogel according to claim 7, wherein the modified polyglutamic acid macromolecule is formed by grafting dopamine and adipamide on a long polyglutamic acid macromolecule chain by using an amide reaction, wherein the molar ratio of the dopamine, adipamide and polyglutamic acid macromolecule is (0.05-0.2): (0.5-1.5): 1.
11. the polydopamine/bioactive ceramic composite hydrogel according to claim 10, wherein the molar ratio of dopamine, adipamide and polyglutamic acid macromolecules is 0.1: 1: 1.
12. the polydopamine/bioactive ceramic composite hydrogel according to claim 7, wherein the copper-doped bioactive ceramic powder is selected from at least one of copper-doped bioglass, copper-doped calcium phosphate, copper-doped hydroxyapatite and copper-doped calcium silicate; the doping amount of copper in the copper-doped bioactive ceramic powder is 1wt% -20 wt%.
13. The polydopamine/bioactive ceramic composite hydrogel according to claim 12, wherein the copper doping amount in the copper-doped bioactive ceramic powder is 5 wt%.
14. The polydopamine/bioactive ceramic composite hydrogel according to any one of claims 7 to 13, wherein the particle size of the copper-doped bioactive ceramic powder is 71 μm or less.
15. Use of a polydopamine/bioactive ceramic composite hydrogel according to any one of claims 7 to 13 in the preparation of an infectious wound repair material.
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