CN111569088B - Dressing for oral submucosa fibrosis and preparation and application thereof - Google Patents

Dressing for oral submucosa fibrosis and preparation and application thereof Download PDF

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CN111569088B
CN111569088B CN202010345200.6A CN202010345200A CN111569088B CN 111569088 B CN111569088 B CN 111569088B CN 202010345200 A CN202010345200 A CN 202010345200A CN 111569088 B CN111569088 B CN 111569088B
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cesium
water
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oral
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CN111569088A (en
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刘咏
和祥
谭彦妮
王平卫
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China Mineral Resources Group Co.,Ltd.
JIANGXI DONGPENG NEW MATERIALS Co.,Ltd.
Central South University
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Jiangxi Dongpeng New Materials Co ltd
Central South University
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Abstract

The invention belongs to the technical field of external oral cancer treatment materials, and particularly relates to an Oral Submucosal Fibrosis (OSF) hydrogel medical dressing which is one of oral precancerous lesions and is alginate/acrylic acid/montmorillonite composite hydrogel of chemical cross-linked cesium ions. In addition, the invention also provides a preparation method and application of the hydrogel. According to the composite hydrogel disclosed by the invention, cesium ions are innovatively added into the alginate/acrylic acid/montmorillonite composite hydrogel, the cell protection effect of the hydrogel on the damaged arecoline is regulated, the inflammatory reaction of oral epithelial cells can be reduced, the secretion of oral mucosa adhesive protein is increased, so that an epithelial barrier is constructed, the collagen disorder state is regulated, the further damage of the arecoline is prevented, and the OSF is prevented from being deteriorated into oral cancer, so that the purpose of preventing is achieved.

Description

Dressing for oral submucosa fibrosis and preparation and application thereof
Technical Field
The invention belongs to the technical field of oral cancer prevention materials, and particularly relates to a medical hydrogel material for relieving oral mucosa fibrosis.
Background
Oral Submucosa Fibrosis (OSF) is a potential malignant disease, is a special oral mucosal wound mainly caused by mechanical stimulation of long-term chewing of areca catechu and chemical action of arecoline, is mainly commonly seen in Asian regions such as India, China and the like, and has a rapidly-developing tendency of the attack of OSF. OSF is initially expressed as inflammation, followed by hypovascularity and fibrosis, clinically manifested as pale oral mucosa, restricted mouth opening, and then possible formation of erosion, ulcer, and finally possible development of squamous cell carcinoma with a malignant transformation rate of 2.3-7.6%, and thus is considered as a precursor of oral cancer. The current research finds that chewing areca is the main cause of disease. The current mainstream treatment regimens include controlling the habit of chewing betel nuts, using nutritional supplements, antioxidants, using immunomodulators such as steroids, etc. However, chewing betel nut is addictive and difficult to completely withdraw, the improvement effect of using the nutritional supplement on fibrosis is limited, and the immunomodulator has certain side effect.
In the prior art, a main treatment scheme aiming at OSF is mainly hormone treatment, hormone is injected to an affected part, the treatment mechanism is to promote inflammatory cell apoptosis, and the method has the defects of easy medicine stopping relapse, large side effect after long-term use and the like. When OSF is deteriorated into oral cancer for a long time, surgical means such as operation, radiotherapy, single or combined chemotherapy and the like are mainly adopted for treatment; however, the five-year survival rate is only about 50% regardless of the treatment. In conclusion, the above methods cannot safely solve the early hidden danger of oral cancer, OSF.
For this reason, prevention of oral cancer is of particular importance, and thus, alleviation of OSF is currently the most central treatment regimen. However, there is no safe and effective means for treating OSF and preventing further progression to oral cancer in the prior art.
The invention content is as follows:
in order to fill the blank of the hydrogel dressing technology applied to the treatment of OSF and the prevention of further deterioration into oral cancer in the prior art, the invention aims to provide a brand-new composite hydrogel dressing which is high in viscosity, good in biocompatibility, good in anti-inflammatory effect, free of cytotoxicity and capable of repairing cells.
The second purpose of the invention is to provide a preparation method of the dressing for the oral submucosa fibrosis.
A third object of the present invention is to provide the use of said dressing for the treatment of OSF and further to prevent its progression to oral cancer.
A dressing for fibrosis under oral mucosa is a composite hydrogel compounded with cesium ions and inorganic filler.
The invention fills the technical blank of no application in the field of oral submucosa fibrosis local treatment, and provides hydrogel for treating OSF without hormone so as to prevent oral cancer. Research shows that the composite hydrogel provided by the invention initiatively bonds cesium ions into the hydrogel in an in-situ chemical crosslinking manner, so that the activity of epithelial cells at the OSF damaged part can be improved and inflammatory reaction can be reduced based on the synergistic effect between the chemically bonded cesium ions and the hydrogel, furthermore, the expression of fibronectin can be synergistically promoted, the epithelial repair of the damaged part can be promoted, an epithelial barrier can be successfully constructed, and the collagen disorder symptom can be synergistically regulated, so that the self-mucosal barrier effect can be enhanced to prevent OSF induction factors such as arecoline chemical invasion and mechanical friction damage of areca fiber. The composite hydrogel disclosed by the invention can effectively relieve the symptoms of OSF, inhibit excessive hyperplasia of collagen disorders, remove fibrosis, and effectively prevent OSF from further deteriorating into oral cancer.
In the invention, the cesium ions are compounded in the composite hydrogel in a mode of chemically crosslinking alginate chains.
Preferably, the composite hydrogel is formed by cross-linking, interpenetrating and polymerizing a single-network hydrogel of alginic acid and salts thereof and an olefin acid monomer under an inorganic filler; wherein, the carboxylic acid group of the single-network hydrogel of alginic acid and the salt thereof is based on chemically crosslinked cesium ions.
The olefin acid monomer is at least one monomer with a structure shown in a formula 1;
Figure BDA0002469929850000021
R1、R2is an alkyl group of H, C1 to C4 or-COOR4；
R3Is an alkyl group of H, C1-C4;
R4h, alkali metal or C1-C4 alkyl. The alkali metal is, for example, sodium or potassium.
Preferably, R is4Is H. The research of the invention finds that the-COOH crosslinking monomer is beneficial to further cooperating with the chemically bonded cesium ions and the inorganic filler, further reducing the stimulation of OSF induction factors, facilitating inflammation repair, promoting the growth of adhesive protein, promoting the repair of epithelial mucosa, further improving the treatment effect of OSF and effectively avoiding the cancerous deterioration of OSF.
In the invention, the reduction-site composite inorganic filler in the composite hydrogel is helpful for improving the mechanical strength of the hydrogel and regulating the absorption capacity of the hydrogel such as areca catechu liquid, and can be cooperated with the hydrogel and in-situ bonded cesium ions to further improve the activity of epithelial cells at the damaged part of OSF, promote the formation of adhesive protein of oral mucosa, repair the damaged mucosa and further improve the effect of the composite hydrogel in treating OSF.
The inorganic filler is a two-dimensional layered structure material. Researches show that the inorganic filler with the layered structure in the composite hydrogel system is beneficial to further improving the formation of the fibronectin in the OSF part, promoting the mucous membrane repair and further improving the treatment effect of the OSF.
Preferably, the inorganic filler is at least one of montmorillonite, kaolin, saponite, illite, nano silica and graphene oxide.
Preferably, in the dressing, the weight content of cesium ions is 0.1-2 wt%; the weight content of the inorganic filler is 0.1-4 wt%. With this preferred ratio, not only the liquid-absorbing ability of the hydrogel can be improved, but also the therapeutic effect thereof in the oral cavity can be improved.
The invention also provides a preparation method of the dressing for the fibrosis under the oral mucosa, which comprises the following steps:
step (1): gelling alginic acid and cesium salt to obtain cesium alginate single-network hydrogel solution A;
step (2): adding an inorganic filler suspension into the solution A, and mixing to obtain a solution B;
and (3): adding an olefin acid monomer into the solution B prepared in the step (2) to perform double-layer network gel prepolymerization;
and (4): sequentially adding a cross-linking agent into the pre-polymerized gel in the step (3) and carrying out double-layer polymerization (also called interpenetrating polymerization in the invention) under the condition of compounding an initiator to obtain colloid; the composite initiator comprises a reduction initiator and an oxidation initiator;
and (5): and (4) neutralizing the colloid obtained in the step (4) to be neutral, and washing to obtain the product.
In the invention, how to successfully prepare the hydrogel dressing, how to reasonably release cesium ions, how to ensure the drug effect of the dressing in OSF, how to realize oral medication (such as the liquid absorption capacity and safety of the material) and the like are difficult problems in the preparation of the material disclosed by the invention. Therefore, the research of the invention finds that alginic acid is innovatively subjected to gelation reaction under cesium ions in advance, the cesium ions are modified into gel by chemical bonds, and the inorganic filler and the composite initiator are further matched for the interpenetrating polymerization of the olefin acid monomer, so that the dressing which is chemically and physically loaded and is compounded with the inorganic filler in situ can be successfully prepared, and the dressing can also improve and regulate the release of the cesium ions and improve the biological performance of the dressing. In addition, in the aspect of drug effect, the dressing prepared by the preparation method can repair cells damaged by the stimulation of OSF induction factors (such as arecoline), and animal experiment results show that the dressing can obviously reduce the epithelial inflammation degree and the atrophy degree of the affected part of OSF diseases, reduce the disordered deposition of collagen, promote the formation of the fibronectin of oral mucosa and promote the repair of mucosa. In addition, the dressing has good elasticity, toughness, viscosity, self-healing property and biocompatibility. The hydrogel medical dressing disclosed by the invention is safe and nontoxic in components, can be well attached to a patient, and has a good application prospect.
The present study surprisingly found that the chemical modification of cesium into a mononetwork structure of alginic acid in advance, contributes to the unexpected achievement of successful preparation of said dressing.
In the step (1), cesium salt and alginic acid solution are mixed and reacted to obtain the solution A.
Preferably, the solution A contains cesium alginate; the preferred method for obtaining solution a is: and mixing cesium salt and alginic acid solution for reaction, and then mixing with cesium alginate solution to obtain solution A.
Preferably, the cesium salt is one or more of cesium chloride, cesium nitrate, and cesium carbonate.
Preferably, the molar ratio of the alginate to the cesium ions in the solution A is 1-3: 1.
In the invention, the olefin acid monomer is one or more of acrylic acid, acrylate, maleic acid and disodium maleate. Acid monomers are preferred.
The inorganic filler is a layered inorganic filler, preferably at least one of montmorillonite, kaolin, saponite, illite, nano silicon dioxide and graphene oxide; more preferably, the inorganic filler has a layered structure such as montmorillonite or kaolin. In the inorganic filler suspension, the mass concentration of the inorganic filler is 0.01 g/ml-5 g/ml.
Preferably, in the step (3), the temperature of the prepolymerization reaction is 20-60 ℃; the time is 0.5-2 h; the stirring speed is 50-1700 r/min.
Preferably, the cross-linking agent is at least one of methylene bisacrylamide and glutaraldehyde.
The research of the invention finds that the interpenetrating polymer has higher requirements on the safety and the drug effect of the interpenetrating polymer in consideration of the particularity of direct contact drug administration at the oral disease part. The existing crosslinking means are difficult to meet the requirements of the invention. Through intensive research, the dressing can be successfully prepared by adopting the combined oxidized and reduced composite initiator, the in-situ loading effect of cesium ions can be improved, and the treatment effect of OSF of the dressing can also be improved.
Preferably, the reduction type initiator is at least one of L-ascorbic acid (vitamin C), vitamin E and nitrite.
The oxidation type initiator is at least one of ammonium persulfate, potassium persulfate and sodium persulfate.
Preferably, the weight ratio of the cross-linking agent to the reduction initiator to the oxidation initiator is 0.001-0.1: 0.001-0.1: 0.001 to 0.1.
Preferably, the bilayer polymerization (interpenetration polymerization) is carried out under uv irradiation.
After the bilayer polymerization is completed, the colloid is neutralized to neutrality, followed by washing (e.g., water washing, organic solvent such as alcohol washing), to obtain the composite hydrogel.
The invention provides a preferable preparation method, which comprises the following steps:
step (1): obtaining alginate single-network hydrogel solution A;
step (2): obtaining a montmorillonite powder suspension, carrying out ultrasonic treatment for 2 hours, and gradually pouring the suspension into the solution A prepared in the step (1) for mixing to obtain a solution B;
and (3): adding acrylic acid into the solution B prepared in the step (2) to perform double-layer network gel prepolymerization.
And (4): and (3) adding a cross-linking agent, a reducing initiator and an oxidizing initiator into the pre-crosslinked gel in the step (3), uniformly stirring, and standing to form gel.
And (5): the pH was neutralized to 7 with an alkaline solution and the organic monomers were rinsed off with ethanol and water.
A more preferred preparation method of the present invention comprises the steps of:
step (a): adding cesium carbonate and alginic acid into deionized water in sequence, carrying out chemical reaction at a set temperature under magnetic stirring, and obtaining a cesium alginate solution after the reaction is finished;
step (b): adding montmorillonite powder into water, stirring to form montmorillonite suspension, performing ultrasonic treatment for 2 hours, adding the treated montmorillonite suspension into the solution obtained in the step a), and completely stirring;
step (c): adding acrylic acid into the solution obtained in the step b), and stirring and mixing uniformly to obtain a pre-crosslinking solution;
step (d): adding a cross-linking agent MBAA into the solution obtained in the step c), uniformly stirring, adding L-ascorbic acid, uniformly stirring, adding ammonium persulfate, uniformly stirring for about 1min, pouring into a mold, rapidly forming gel at room temperature, pouring into a glass container, irradiating by ultraviolet light (with the wavelength of 365nm), exciting to react, and obtaining the product after the reaction is finished.
In the step a), the molar ratio of alginic acid to cesium salt is 1-5: 1; the mass concentration of the alginic acid monomer is 0.04-0.06 g/ml; setting the temperature to be 30-80 ℃, the magnetic stirring speed to be 50-1700 r/min, the reaction time to be 10-40 min, and the molar concentration (0.1-5.96) x 10 of cesium alginate-5mol/ml。
In the step a), the cesium salt is one or more of cesium-containing compounds such as cesium chloride, cesium nitrate, cesium carbonate and the like.
In the step b), the mixing speed is 50-1700 r/min, and the mixing time is 60-120 min.
In the step c), the mass of the montmorillonite is 0.01-5g/ml, the stirring speed is 50-1700 r/min, and the stirring time is 10-60 min.
In the step d), the weight ratios of Methylene Bisacrylamide (MBAA) (cross-linking agent), L-ascorbic acid (reducing initiator) and Ammonium Persulfate (APS) (oxidizing initiator) in the whole solution are (0.001-0.1), (0.01-0.1) and (0.001-0.1), the cross-linking reaction time is 0.1-2 h, the stirring speed is 50-1700 r/min, and the ultraviolet irradiation time is less than 2 h.
The invention also provides application of the dressing for treating the oral mucosal fibrosis, and the dressing is used for preparing an external preparation for treating the oral mucosal fibrosis.
According to the invention, the dressing is directly pasted on the site of the focus of fibrosis under the oral mucosa, and through the combined action of the components in the dressing, the inflammation is prevented, cells damaged by arecoline are repaired at the same time, and the expression level of the adhesive protein at the damaged site of the oral cavity is effectively improved, so that an epithelial barrier is established, the state of collagen disorder is regulated and controlled, the arecoline is prevented from being further damaged, the OSF is prevented from deteriorating into oral cancer, and the purpose of preventing is achieved.
Preferably, it is used for preparing an external preparation for treating arecoline-induced OSF.
Further preferably, it is used for the preparation of an external preparation for preventing oral cancer.
The invention has the beneficial effects that:
1) the invention fills the technical blank of the anhydrous gel dressing in the field of local treatment of OSF, and innovatively provides the hydrogel for treating OSF without hormone so as to prevent oral cancer. The composite hydrogel is innovatively modified with cesium ions through chemical bonding on a polymer network of the hydrogel. The research of the invention finds that based on the mutual cooperation of hydrogel and chemically bonded modified cesium ions, the gel can repair damaged cells, enhance the activity of oral epithelial cells, inhibit inflammation, increase the expression of adhesion protein, regulate and control collagen disorder, construct an epithelial barrier, contribute to effectively improving OSF symptoms and avoid further stimulation and deterioration of OSF.
2) The invention innovatively chemically bonds cesium ions on alginate chains of an interpenetrating network of alginic acid/acrylic acid monomers, and further cooperates with inorganic fillers, particularly lamellar fillers, so that the invention is favorable for further promoting an OSF modification mechanism and further improving the treatment effect of OSF.
3) The hydrogel medical dressing also has good elasticity, toughness, viscosity, self-healing property and biocompatibility.
4) In order to successfully construct the composite hydrogel and improve the treatment effect of the composite hydrogel on OSF, the cesium ions are innovatively bonded to the alginic acid polymeric chain in advance, and the action of the meta-acid crosslinking monomer and the composite initiator of the reducing initiator and the oxidizing initiator is further matched, so that the chemical crosslinking behavior and synchronous in-situ crosslinking of the cesium ions can be regulated and controlled, and the dressing with good OSF treatment effect and properties can be successfully obtained.
5) In the invention, acidic crosslinking monomers such as acrylic acid and the like are preferably introduced into the crosslinking system in the step (3), and polymerization is carried out under the condition of a crosslinking agent and a composite initiator after prepolymerization is finished, so that the system has weak acidity, can prevent arecoline from invading epithelium, is high in viscosity and elasticity, is suitable for being pasted in the oral cavity of animals, and further improves the treatment effect for OSF.
6) The raw materials of the hydrogel dressing are nontoxic and good in biocompatibility, and the components in the dressing interact with each other, so that the hydrogel dressing is beneficial to synergistically promoting the removal of scars, the removal of fibrosis, the inflammation diminishing and the improvement of treatment effects.
Drawings
Figure 1 digital photographs of different cesium-containing samples: as can be seen from the figure (samples A, B, C and D from left to right), the gel can be firmly adhered to the bottom of the glass bottle and has the properties of transparency, high elasticity and high viscosity
FIG. 2 micro-topography test and elemental analysis plots: SEM and EDS images of the hydrogel dressings in comparative example 1, examples 1-3; wherein (a, B, C, D) is the micro-topography of A, B, C, D gel, (e), (f), (g) are the energy spectra of A.C.D gel respectively, and the scale bar is 20 μm; (h) the distribution diagram of the main elements D is shown in (i), (j) and (k), which shows that the cesium is uniformly distributed in the matrix, and the uniform porous property of the hydrogel is not changed along with the addition of the cesium.
FIG. 3 is a graph of A, B, C, D gel Simulated Body Fluid (SBF) swell test: the gel of each component is found to have strong liquid absorption performance, the gel still has a higher level after 72-hour test, interestingly, the swelling capacity is improved along with the increase of the cesium content, and the addition of the cesium can reduce the crosslinking compactness of the copolymer, so that the swelling absorption capacity is improved, the liquid absorption capacity is improved, the arecoline liquid absorbed by oral mucosa of a person after chewing arecoline can be absorbed, and further invasion of the arecoline is blocked.
FIG. 4 is a diagram of in vitro cell activity assay evaluation: hydrogel cell test patterns in comparative example 1, examples 1-3: the left panel shows that different arecolines (Arc for short) stimulate oral epithelial cells, and the optimal concentration of 40 μ g/ml Arc for killing half of the cells was screened by a 2-day CCK8 experiment. The right panel shows the activity of co-culture of oral epithelial cells and hydrogel injured by Arc for 2 days, and the cells treated with Arc for two days at 40 μ g/ml were seeded into 24-well plates of different cesium-containing hydrogels (a, B, C, D), and the cells were found to have stronger and stronger activity as cesium content increased by two-day cck8 test.
FIG. 5 is a graph of in vivo experimental evaluation (oral mucosa Masson staining after gel treatment in OSF animals): screening comparative example 1 and examples 2-3 by in vitro cell experiments to carry out in vivo animal experiments, wherein the in vivo experiment process comprises the following steps: firstly, normal 8-week SD rats are mechanically rubbed with the epithelium by betel nut fibers every day, 40ug/ml arecoline is smeared to chemically stimulate the rats, double stimulation is carried out to carry out OSF molding, the frequency is reduced after two weeks of molding, mechanical stimulation and chemical stimulation are continued every 3 days, 15 minutes are carried out each time, the rats are anesthetized after 6 hours after stimulation, the oral cavities of the rats are pasted with the hydrogel patches containing the components of the invention until 8 and 16 weeks of experiments are finished, and tissues are taken for observation.
The effect of the hydrogels of each group on OSF mice 8, 16 weeks later immunohistochemistry (masson staining) is illustrated in figure 5: OSF group compared to normal group: the atrophy of oral epithelium is obvious, the barrier function of epithelium is damaged, collagen is densely deposited under the mucous membrane, and the number of blood vessels is reduced. The cesium-free hydrogel group acted on OSF: epithelial atrophy, degree of inflammation and degree of submucosal collagen fiber deposition were all reduced, and the number of blood vessels was greater than that of OSF group. With the increase of the cesium content, the epithelial atrophy degree and the collagen fiber density are sequentially reduced, which shows that the cesium and the material cooperate to regulate and control the symptoms of collagen disorder and reduce inflammatory reaction.
FIG. 6 is a graph of in vivo fluorescent staining (immunofluorescent staining of the oral mucosal protein occludin in OSF animals after gel treatment): the effect of each group of hydrogels on OSF mice 8, 16 weeks later as an important indicator of oral mucin, occludin immunofluorescence (green for occludin protein and blue for cells) is shown in FIG. 6: OSF group compared to normal group: the oral epithelium atrophy is obvious, the expression of OSF histone is less, the epithelium of the cesium-free hydrogel group is complete, the expression of the fibronectin is increased, which shows that the material has a repairing effect, the expression amount of the fibronectin (green above the substrate becomes heavier and the amount is increased) is obviously enhanced along with the increase of the cesium content, which shows that the epithelial barrier is effectively established, and further shows that the cesium has a synergistic repairing effect.
The specific implementation mode is as follows:
COMPARATIVE EXAMPLE-cesium-free (nomenclature A)
1. Pouring 0.47g of alginic acid into 8ml of water, and uniformly stirring to prepare a alginic acid solution;
2. adding 0.15g of montmorillonite into 2ml of water, uniformly dispersing, and carrying out ultrasonic treatment for 2 hours; uniformly dispersing montmorillonite in water;
3. slowly dripping the suspension liquid obtained in the step (2) into the solution obtained in the step (1), and uniformly stirring;
4. 2.378g of acrylic acid is poured into the solution in the step 3, stirred to be uniform and pre-crosslinked (pre-polymerized);
5. continuously adding 0.01g of MBAA into the solution obtained in the step 4, and uniformly stirring;
6. continuously adding 0.0129g of ascorbic acid and 0.0167g of ammonium persulfate into the solution in the step 5 respectively, uniformly stirring, pouring into a mold, and quickly forming gel under the conditions of room temperature and ultraviolet irradiation;
7. standing overnight after gelling to allow complete polymerization (aging);
8. before use, the surface is washed by ammonia water (or ammonium bicarbonate solution) to neutralize the pH value to 7, and then washed by alcohol and water to remove the organic monomer.
Example 1-with a small amount of Cesium (name B)
1. Pouring 0.47g of alginic acid and 0.1938g of cesium carbonate into 8ml of water, and uniformly stirring to prepare a cesium alginate solution;
2. adding 0.2g of montmorillonite into 2ml of water, uniformly dispersing, and carrying out ultrasonic treatment for 2 hours to uniformly disperse the montmorillonite in the water;
3. taking 4ml of the solution in the step 1, adding 4ml of water for dilution, slowly dripping the suspension in the step 2 into the diluted solution, and uniformly stirring;
4. slowly dripping 2.378g of acrylic acid into the solution in the step 3, uniformly stirring, and in the process, inserting an organic monomer between montmorillonite layers and simultaneously carrying out double-layer network pre-crosslinking;
5. continuously adding 0.01g of MBAA into the solution obtained in the step 4, and uniformly stirring;
6. continuously adding 0.0129g of ascorbic acid and 0.0167g of ammonium persulfate into the solution in the step 5 respectively, uniformly stirring, pouring into a mold, and quickly forming gel at room temperature under the irradiation of an ultraviolet lamp;
7. standing overnight after gelling to allow complete polymerization (aging);
8. before use, the surface is washed by ammonia water (or ammonium bicarbonate solution) to neutralize the pH value to 7, and then washed by alcohol and water to remove the organic monomer.
Example 2 Medium concentration of Cesium (name C)
1, pouring 0.47g of alginic acid and 0.1938g of cesium carbonate into 8ml of water, and uniformly stirring to prepare a cesium alginate solution;
2. adding 0.1g of montmorillonite into 2ml of water, uniformly dispersing, and carrying out ultrasonic treatment for 2 hours to uniformly disperse the montmorillonite in the water;
3. taking 5.6ml of the solution in the step 1, adding 2.4ml of water for dilution, slowly dripping the suspension in the step 2 into the diluted solution, and uniformly stirring;
4. slowly dripping 2.378g of acrylic acid into the solution in the step 3, uniformly stirring, and in the process, inserting an organic monomer between montmorillonite layers and simultaneously carrying out double-layer network pre-crosslinking;
5. continuously adding 0.01g of MBAA into the solution obtained in the step 4, and uniformly stirring;
6. continuously adding 0.0129g of ascorbic acid and 0.0167g of ammonium persulfate into the solution in the step 5 respectively, uniformly stirring, pouring into a mold, and quickly forming gel at room temperature under the irradiation of an ultraviolet lamp;
7. standing overnight after gelling to allow complete polymerization (aging);
8. before use, the surface is washed by ammonia water (or ammonium bicarbonate solution) to neutralize the pH value to 7, and then washed by alcohol and water to remove the organic monomer.
Example 3 high concentration of Cesium (name D)
1. Pouring 0.47g of alginic acid and 0.1938g of cesium carbonate into 8ml of water, and uniformly stirring to prepare a cesium alginate solution;
2. adding 0.15g of montmorillonite into 2ml of water, uniformly dispersing, and carrying out ultrasonic treatment for 2 hours to uniformly disperse the montmorillonite in the water;
3. taking 8ml of the solution in the step 1, slowly dripping the suspension in the step 2 into the diluted solution without diluting, and uniformly stirring;
4. slowly dripping 2.378g of acrylic acid into the solution in the step 3, uniformly stirring, and in the process, inserting an organic monomer between montmorillonite layers and simultaneously carrying out double-layer network pre-crosslinking;
5. continuously adding 0.01g of MBAA into the solution obtained in the step 4, and uniformly stirring;
6. continuously adding 0.0129g of ascorbic acid and 0.0167g of ammonium persulfate into the solution in the step 5 respectively, uniformly stirring, pouring into a mold, and quickly forming gel at room temperature under the irradiation of an ultraviolet lamp;
7. standing overnight after gelling to allow complete polymerization (aging);
8. before use, ammonia water (or ammonium bicarbonate) is used to wash the surface to neutralize the pH value to 7, and then alcohol and water are used to wash the surface to remove the organic monomer.
Comparative example 1
The only difference compared to example 1 is that the montmorillonite described was not added. The preparation fails, the gelling is slow, and the physical properties are poor, so that the requirement of the oral cavity dressing can not be met.
Comparative example 2:
compared with the example 1, the difference is that no acrylic acid monomer is added, interpenetrating polymerization is not carried out, and the cesium alginate polymer is prepared by adopting a double-ion crosslinking mode. The obtained material has strong brittleness, and the required dressing for oral use cannot be obtained.
Comparative example 3:
compared with example 1, the difference is that cesium ions are not pre-modified on the alginate chain, but are added by means of cesium acrylate and interpenetrating polymerization is tried, and the result shows that the biocompatibility is poor and the hydrogel cannot be obtained by successful crosslinking.
Comparative example 4
And a single ammonium persulfate initiator is adopted, and the hydrogel can be crosslinked after being heated in an oven for at least two hours at the temperature of 60-80 ℃, but the obtained hydrogel finished product has dehydration and deformation conditions, and the material toxicity is strong, so that the required oral composite hydrogel cannot be successfully obtained.

Claims (5)

1. A dressing for fibrosis under oral mucosa is characterized in that the dressing is a composite hydrogel compounded with cesium ions and inorganic filler;
the cesium ions are compounded in the composite hydrogel in a mode of chemically crosslinking alginate chains;
the composite hydrogel is formed by cross-linking, interpenetrating and polymerizing single-network hydrogel of alginic acid and salt thereof and an olefin acid monomer under an inorganic filler; wherein, the carboxylic group of the single-network hydrogel of alginic acid and the salt thereof is modified with cesium ions based on a chemical ion exchange mode;
the preparation process of the dressing comprises the following steps:
step (1): gelling alginic acid and cesium salt to obtain cesium alginate single-network hydrogel solution A; the cesium salt is cesium carbonate; in the solution A, the molar ratio of alginic acid to cesium is 1-3: 1;
step (2): adding an inorganic filler suspension into the solution A, and mixing to obtain a solution B; the inorganic filler is montmorillonite; in the inorganic filler suspension, the mass concentration of the inorganic filler is 0.01-5 g/ml;
and (3): adding an olefin acid monomer into the solution B prepared in the step (2) to perform double-layer network gel prepolymerization; the olefin acid monomer is acrylic acid;
and (4): sequentially adding a cross-linking agent into the pre-polymerized gel obtained in the step (3) and carrying out double-layer polymerization under the condition of a composite initiator to obtain a colloid; the composite initiator comprises a reduction initiator and an oxidation initiator; double-layer polymerization is carried out under the irradiation of ultraviolet light;
the cross-linking agent is methylene bisacrylamide; the reduced initiator is vitamin C; the oxidation type initiator is ammonium persulfate; the weight ratio of the cross-linking agent to the reduction initiator to the oxidation initiator is 0.001-0.1: 0.001-0.1: 0.001 to 0.1;
and (5): neutralizing the colloid obtained in the step (4) to be neutral, and washing to obtain the product;
in the dressing, the weight content of cesium ions is 0.1-2 wt%; the weight content of the inorganic filler is 0.1-4 wt%.
2. The dressing of claim 1, wherein the preparation process comprises:
(1) pouring 0.47g of alginic acid and 0.1938g of cesium carbonate into 8ml of water, and uniformly stirring to prepare a cesium alginate solution;
(2) adding 0.2g of montmorillonite into 2ml of water for uniform dispersion, and carrying out ultrasonic treatment for 2 hours to ensure that the montmorillonite is uniformly dispersed in the water;
(3) taking 4ml of the solution in the step 1, adding 4ml of water for dilution, slowly dripping the suspension in the step 2 into the diluted solution, and uniformly stirring;
(4) slowly dripping 2.378g of acrylic acid into the solution in the step 3, uniformly stirring, and in the process, inserting an organic monomer between montmorillonite layers and simultaneously carrying out double-layer network pre-crosslinking;
(5) continuously adding 0.01g of methylene bisacrylamide into the solution obtained in the step 4, and uniformly stirring;
(6) continuously adding 0.0129g of ascorbic acid and 0.0167g of ammonium persulfate into the solution in the step 5 respectively, uniformly stirring, pouring into a mold, and quickly gelling at room temperature under the irradiation of an ultraviolet lamp;
(7) standing overnight after gelling to allow complete polymerization;
(8) before use, the surface is washed by ammonia water to neutralize the pH value to 7, and then the organic monomer is removed by washing by alcohol and water; obtaining;
or the preparation process comprises the following steps:
(1) pouring 0.47g of alginic acid and 0.1938g of cesium carbonate into 8ml of water, and uniformly stirring to prepare a cesium alginate solution;
(2) adding 0.1g of montmorillonite into 2ml of water for uniform dispersion, and carrying out ultrasonic treatment for 2 hours to ensure that the montmorillonite is uniformly dispersed in the water;
(3) taking 5.6ml of the solution in the step 1, adding 2.4ml of water for dilution, slowly dripping the suspension in the step 2 into the diluted solution, and uniformly stirring;
(4) slowly dripping 2.378g of acrylic acid into the solution in the step 3, uniformly stirring, and in the process, inserting an organic monomer between montmorillonite layers and simultaneously carrying out double-layer network pre-crosslinking;
(5) continuously adding 0.01g of methylene bisacrylamide into the solution obtained in the step 4, and uniformly stirring;
(6) Continuously adding 0.0129g of ascorbic acid and 0.0167g of ammonium persulfate into the solution in the step 5 respectively, uniformly stirring, pouring into a mold, and quickly gelling at room temperature under the irradiation of an ultraviolet lamp;
(7) standing overnight after gelling to allow complete polymerization;
(8) before use, the surface is washed by ammonia water to neutralize the solution until the pH value is about 7, and then the solution is washed by alcohol and water to remove the organic monomer; obtaining;
or the preparation method comprises the following steps:
(1) pouring 0.47g of alginic acid and 0.1938g of cesium carbonate into 8ml of water, and uniformly stirring to prepare a cesium alginate solution;
(2) adding 0.15g of montmorillonite into 2ml of water for uniform dispersion, and carrying out ultrasonic treatment for 2 hours to ensure that the montmorillonite is uniformly dispersed in the water;
(3) taking 8ml of the solution in the step 1, slowly dripping the suspension in the step 2 into the diluted solution without diluting, and uniformly stirring;
(4) slowly dripping 2.378g of acrylic acid into the solution in the step 3, uniformly stirring, and in the process, inserting an organic monomer between montmorillonite layers and simultaneously carrying out double-layer network pre-crosslinking;
(5) continuously adding 0.01g of methylene bisacrylamide into the solution obtained in the step 4, and uniformly stirring;
(6) continuously adding 0.0129g of ascorbic acid and 0.0167g of ammonium persulfate into the solution in the step 5 respectively, uniformly stirring, pouring into a mold, and quickly gelling at room temperature under the irradiation of an ultraviolet lamp;
(7) standing overnight after gelling to allow complete polymerization;
(8) washing the surface with ammonia water to neutralize to pH 7, and washing with alcohol and water to eliminate organic monomer.
3. Use of the dressing for oral submucosa fibrosis according to any one of claims 1 to 2 in the preparation of a topical formulation for the treatment of oral submucosa fibrosis.
4. Use of a dressing for oral submucosa fibrosis according to claim 3 in the preparation of a topical formulation for oral submucosa fibrosis due to arecoline.
5. The use of the dressing for oral submucosa fibrosis according to claim 4, in the preparation of an external preparation for oral submucosa fibrosis caused by arecoline to prevent oral cancer.
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