CN114344246A - Injectable temperature-sensitive hydrogel and preparation method and application thereof - Google Patents
Injectable temperature-sensitive hydrogel and preparation method and application thereof Download PDFInfo
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- CN114344246A CN114344246A CN202111477847.5A CN202111477847A CN114344246A CN 114344246 A CN114344246 A CN 114344246A CN 202111477847 A CN202111477847 A CN 202111477847A CN 114344246 A CN114344246 A CN 114344246A
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Abstract
An injectable temperature-sensitive hydrogel and a preparation method and application thereof are disclosed, wherein hydroxypropyl methylcellulose, hyaluronic acid and glycerol are used as raw materials, and the aromatic polypeptides are carried to prepare a gel which is flowable at room temperature and can be converted into a non-flowable gel under physiological conditions, namely the medical injectable temperature-sensitive hydrogel containing the aromatic polypeptides; the preparation method of the temperature-sensitive hydrogel comprises the following steps: mixing a hydroxypropyl methyl cellulose solution and a hyaluronic acid solution, uniformly stirring to obtain a solution A, adding a fenugreek polypeptide solution into the solution A to obtain a solution B, finally, dropwise adding glycerol into the solution B, and uniformly stirring to obtain the temperature-sensitive hydrogel system carrying the fenugreek polypeptide. The preparation method is simple, low in cost, free of cytotoxicity, good in bacteriostatic effect and convenient to popularize and use subsequently.
Description
Technical Field
The invention belongs to the technical field of biomedical science, and particularly relates to an injectable temperature-sensitive hydrogel for treating periodontal and peri-implant diseases and wounds, and a preparation method and application thereof.
Background
Periodontitis and peri-implantitis are chronic diseases caused by plaque microorganisms attached to teeth and implant surfaces, resulting in destruction of periodontal and peri-implant tissues. Currently, the main treatment regimen is mechanical treatment assisted by the topical or systemic application of antibiotics or antimicrobials. However, these methods have not shown satisfactory efficacy in treatment due to limited efficacy of mechanical therapy, increased bacterial resistance, adverse effects of drugs, failure to achieve sufficient antimicrobial concentrations, and the like. Therefore, developing new therapeutic regimens to alleviate these problems has significant scientific value.
The hydrogel is composed of a hydrophilic polymer network, has unique water swelling property, a porous structure and good biocompatibility, and the temperature-sensitive hydrogel is one type of physical hydrogel and shows reversible phase change characteristics when the temperature changes: the gel exhibited a sol-like state with good fluidity at room temperature, and gradually changed into a gel-like state with poor fluidity as the temperature increased. Therefore, the systems have wide application prospect in the field of local medicine application around periodontium and implant.
Hyaluronic Acid (HA) HAs unique biocompatibility, viscoelasticity and rheological properties and HAs been used to make hydrogels. In addition, hyaluronic acid has been shown to have anti-inflammatory and anti-edematous effects in the treatment of periodontal disease and in the promotion of the healing process of periodontal mineralized and non-mineralized tissues. Hydroxypropyl methylcellulose (HPMC) is a heat-sensitive hydrophilic polymer, has the excellent characteristics of no toxicity, low cost, high expansibility, surface activity and the like, and an HPMC aqueous solution generally has the thermally reversible gel characteristic, but the gelation temperature is far higher than the body temperature (more than 60 ℃). Glycerol is a small polyhydroxyl molecule with strong hydrophilicity, and can lower the gel temperature of HPMC aqueous solution to body temperature by removing water from the hydrated sheath of polymer chains.
The temperature-sensitive material hydroxypropyl methylcellulose and hyaluronic acid are physically crosslinked, antibacterial yeast polypeptide is carried, and the gel temperature of the system is reduced by using glycerol, so that the injectable temperature-sensitive hydrogel is prepared.
Disclosure of Invention
The technical problem to be solved is as follows: the invention provides an injectable temperature-sensitive hydrogel and a preparation method and application thereof, aiming at the defects of the prior art. The temperature-sensitive hydrogel takes hydroxypropyl methylcellulose, hyaluronic acid and glycerol as raw materials and carries antibacterial yeast polypeptide. On one hand, the temperature-sensitive characteristic of the hydroxypropyl methyl cellulose is utilized, so that the hydrogel is flowable sol at room temperature, is converted into gel under physiological conditions, and is convenient to inject; on the other hand, the good biocompatibility and the effect of promoting tissue healing of hyaluronic acid are utilized, and meanwhile, the antibacterial phenthol polypeptide is carried to prepare the injectable antibacterial temperature-sensitive hydrogel.
The preparation method of the injectable temperature-sensitive hydrogel comprises the following preparation steps: (1) heating double distilled water to not less than 80 ℃, mixing hydroxypropyl methyl cellulose powder with the heated double distilled water, fully stirring, and balancing at 4 ℃ overnight to obtain hydroxypropyl methyl cellulose solution; respectively adding hyaluronic acid powder and Fingermine polypeptide powder into double distilled water, continuously stirring at room temperature, and completely dissolving to obtain hyaluronic acid solution and Fingermine polypeptide solution; (2) mixing a hydroxypropyl methyl cellulose solution with a hyaluronic acid solution, and uniformly stirring to obtain a solution A; (3) adding the fenugreek polypeptide solution into the solution A, and uniformly stirring to obtain a solution B; (4) dropwise adding glycerol into the solution B under stirring, and fully and uniformly stirring to finally obtain a hydroxypropylmethylcellulose/hyaluronic acid/glycerol temperature-sensitive hydrogel system carrying the phenthoate polypeptide; according to the percentage content of the total weight of the hydrogel, the content of the hydroxypropyl methylcellulose is 5-10%, the content of the hyaluronic acid is 1-2%, the content of the Fenugen polypeptide is 0.01-0.1%, the content of the glycerol is 10-25%, and the balance is water.
Preferably, the content of the hydroxypropyl methyl cellulose is 7%, the content of the hyaluronic acid is 2%, the content of the phenformin is 0.05%, the content of the glycerol is 20%, and the balance is water.
The injectable temperature-sensitive hydrogel prepared by the preparation method.
The injectable temperature-sensitive hydrogel is in a flowable sol state at room temperature, is in a non-flowable gel state at 37 ℃, and has a phase transition temperature of 35-37 ℃.
The injectable temperature-sensitive hydrogel is applied to preparation of materials for treating periodontal and peri-implant diseases and wounds.
Has the advantages that: 1. the temperature of the hydroxypropyl methylcellulose solution for generating sol-gel transition is over 60 ℃, and glycerin can reduce the phase transition temperature of the polymer by removing water in a hydration sheath of the polymer, and meanwhile, the addition of the glycerin also increases the mechanical strength of the hydrogel. 2. The hyaluronic acid not only endows the hydrogel with good biocompatibility and the effect of promoting tissue healing, but also has the obvious characteristic of shear thinning, can adjust the rheological property of a gel system and promotes the injectability of the hydrogel. 3. The addition of the Fenugen polypeptide which has excellent antibacterial ability and wide antibacterial spectrum effectively enhances the antibacterial function of the product. Compared with similar products, the hydrogel is scientific in preparation method, simple in process, special in temperature-sensitive characteristic, injectable and non-cytotoxic, has the capability of promoting healing of tissues around periodontium and implant while resisting bacteria and inflammation, and therefore has good application feasibility.
Drawings
FIG. 1 is a rheological analysis of hydroxypropyl methylcellulose/hyaluronic acid hydrogels containing different percentages of glycerin; a. HPMC/HA/10% Gyl; b. HPMC/HA/15% Gyl; HPMC/HA/20% Gyl; d. HPMC/HA/25% Gyl;
FIG. 2 is a view showing a state of a hydroxypropylmethylcellulose/hyaluronic acid hydrogel containing 20% glycerin at room temperature and 37 ℃; a. the temperature-sensitive hydrogel is in a flowable sol state at 4 ℃; b, the hydrogel is in a non-flowing gel state at 37 ℃;
FIG. 3 is an in vitro cytotoxicity assay of hydrogels on gingival fibroblasts;
FIG. 4 is an in vitro antimicrobial performance analysis of hydrogels.
Detailed Description
The following examples and experimental examples are given to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention in any way.
Example 1
(1) Weighing 1.4g of hydroxypropyl methylcellulose, 2g of hyaluronic acid, 0.1g of Fenugen polypeptide and 2mL of glycerol;
(2) adding hydroxypropyl methyl cellulose into 14mL of ultrapure water with the temperature of not lower than 80 ℃, fully stirring, and balancing overnight at the temperature of 4 ℃ after uniformly stirring to obtain a hydroxypropyl methyl cellulose solution;
(3) preparing hyaluronic acid into a solution with the mass concentration of 10% by using 20mL of ultrapure water for later use;
(4) preparing a 10% solution of the Fenugen polypeptide by using 1mL of ultrapure water for later use;
(5) dropwise adding 4mL of the hyaluronic acid solution obtained in the step (3) into the hydroxypropyl methyl cellulose solution at room temperature, and uniformly stirring to obtain a hydroxypropyl methyl cellulose/hyaluronic acid mixed solution;
(6) dripping 100 mu L of the Fenugen polypeptide solution obtained in the step (4) into the hydroxypropyl methyl cellulose/hyaluronic acid mixed solution at room temperature, and uniformly stirring to obtain a hydroxypropyl methyl cellulose/hyaluronic acid solution carrying the Fenugen polypeptide;
(7) 2mL of glycerol was added dropwise to the jellyfish polypeptide-loaded hydroxypropyl methylcellulose/hyaluronic acid solution, resulting in a hydrogel containing 7wt.% hydroxypropyl methylcellulose, 2 wt.% hyaluronic acid, 0.05 wt.% jellyfish polypeptide, and 10 wt.% glycerol.
Example 2
(1) Weighing 1.4g of hydroxypropyl methylcellulose, 2g of hyaluronic acid, 0.1g of fenugreek polypeptide and 3mL of glycerol;
(2) adding hydroxypropyl methyl cellulose into 13mL of ultrapure water with the temperature of not lower than 80 ℃, fully stirring, uniformly stirring, and balancing overnight at the temperature of 4 ℃ to obtain a hydroxypropyl methyl cellulose solution;
(3) preparing hyaluronic acid into a solution with the mass concentration of 10% by using 20mL of ultrapure water for later use;
(4) preparing a 10% solution of the Fenugen polypeptide by using 1mL of ultrapure water for later use;
(5) dropwise adding 4mL of the hyaluronic acid solution obtained in the step (3) into the hydroxypropyl methyl cellulose solution at room temperature, and uniformly stirring to obtain a hydroxypropyl methyl cellulose/hyaluronic acid mixed solution;
(6) dripping 100 mu L of the Fenugen polypeptide solution obtained in the step (4) into the hydroxypropyl methyl cellulose/hyaluronic acid mixed solution at room temperature, and uniformly stirring to obtain a hydroxypropyl methyl cellulose/hyaluronic acid solution carrying the Fenugen polypeptide;
(7) 3mL of glycerol was added dropwise to the jellyfish polypeptide-loaded hydroxypropyl methylcellulose/hyaluronic acid solution, resulting in a hydrogel containing 7wt.% hydroxypropyl methylcellulose, 2 wt.% hyaluronic acid, 0.05 wt.% jellyfish polypeptide, and 15 wt.% glycerol.
Example 3
(1) Weighing 1.4g of hydroxypropyl methylcellulose, 2g of hyaluronic acid, 0.1g of fenugreek polypeptide and 4mL of glycerol;
(2) adding hydroxypropyl methylcellulose into 12mL of ultrapure water with the temperature of not lower than 80 ℃, fully stirring, uniformly stirring, and balancing overnight at the temperature of 4 ℃ to obtain a hydroxypropyl methylcellulose solution;
(3) preparing hyaluronic acid into a solution with the mass concentration of 10% by using 20mL of ultrapure water for later use;
(4) preparing a 10% solution of the Fenugen polypeptide by using 1mL of ultrapure water for later use;
(5) dropwise adding 4mL of the hyaluronic acid solution obtained in the step (3) into the hydroxypropyl methyl cellulose solution at room temperature, and uniformly stirring to obtain a hydroxypropyl methyl cellulose/hyaluronic acid mixed solution;
(6) dripping 100 mu L of the Fenugen polypeptide solution obtained in the step (4) into the hydroxypropyl methyl cellulose/hyaluronic acid mixed solution at room temperature, and uniformly stirring to obtain a hydroxypropyl methyl cellulose/hyaluronic acid solution carrying the Fenugen polypeptide;
(7) 4mL of glycerol was added dropwise to the jellyfish polypeptide-loaded hydroxypropyl methylcellulose/hyaluronic acid solution, resulting in a hydrogel containing 7wt.% hydroxypropyl methylcellulose, 2 wt.% hyaluronic acid, 0.05 wt.% jellyfish polypeptide, and 20 wt.% glycerol.
Example 4
(1) Weighing 1.4g of hydroxypropyl methylcellulose, 2g of hyaluronic acid, 0.1g of fenugreek polypeptide and 5 mL of glycerol;
(2) adding hydroxypropyl methylcellulose into 11mL of ultrapure water with the temperature of not lower than 80 ℃, fully stirring, uniformly stirring, and balancing overnight at the temperature of 4 ℃ to obtain a hydroxypropyl methylcellulose solution;
(3) preparing hyaluronic acid into a solution with the mass concentration of 10% by using 20mL of ultrapure water for later use;
(4) preparing a 10% solution of the Fenugen polypeptide by using 1mL of ultrapure water for later use;
(5) dropwise adding 4mL of the hyaluronic acid solution obtained in the step (3) into the hydroxypropyl methyl cellulose solution at room temperature, and uniformly stirring to obtain a hydroxypropyl methyl cellulose/hyaluronic acid mixed solution;
(6) dripping 100 mu L of the Fenugen polypeptide solution obtained in the step (4) into the hydroxypropyl methyl cellulose/hyaluronic acid mixed solution at room temperature, and uniformly stirring to obtain a hydroxypropyl methyl cellulose/hyaluronic acid solution carrying the Fenugen polypeptide;
(7) 4mL of glycerol was added dropwise to the jellyfish polypeptide-loaded hydroxypropyl methylcellulose/hyaluronic acid solution, resulting in a hydrogel containing 7wt.% hydroxypropyl methylcellulose, 2 wt.% hyaluronic acid, 0.05 wt.% jellyfish polypeptide, and 25 wt.% glycerol.
Experimental example 1 rheological property test of the hydroxypropyl methyl cellulose/hyaluronic acid/glycerin thermo-sensitive hydrogel prepared in examples 1-4 specifically includes:
the experimental method comprises the following steps: the HPMC/HA/Gyl system was rheology tested using a HAAKE MARS4 (Thermo Fisher Scientific, USA) rheometer. The gelation temperature of the sample solution was investigated by measuring the change in elastic modulus (G ') and viscous modulus (G ' ') with temperature. Briefly, a hydrogel precursor solution was placed on a parallel plate with a diameter of 40 mm and a gap of 0.5 mm, the temperature sweep ranged from 20 ℃ to 80 ℃, the heating rate was 1 ℃/min, a layer of dimethicone was coated around the sample to prevent evaporation of water during the test, the set procedure was started to perform the test, and the gel temperature was defined as the intersection of G' and G ″.
And (4) analyzing results: as shown in fig. 1, the gel temperature of the HPMC/HA group to which 10% of glycerin is added is about 43%, the gel temperature of the HPMC/HA group to which 15 wt.% of glycerin is added is 39%, the gel temperature of the HPMC/HA group to which 20 wt.% of glycerin is added is 33%, the gel temperature of the HPMC/HA group to which 25 wt.% of glycerin is added is 24%, and the optimal gel temperature of the group to which 20 wt.% of glycerin is added is 20 wt.% in the HPMC/HA/Gyl temperature-sensitive hydrogel, considering that the temperature in the oral cavity is about 35 to 37 ℃.
Experimental example 2 cytotoxicity test was performed on the hydrogel having the optimal gel temperature obtained in experimental example 1, which specifically includes:
the experimental method comprises the following steps: evaluation of temperature sensitive hydrogels on gingival fibroblasts (HG) using cell proliferation-toxicity assay (CCK-8)Fs) of the cell. The hydrogel was extracted with Dulbecco's Modified Eagle's Medium (DMEM) containing 10% Fetal Bovine Serum (FBS) and 1% penicillin/streptomycin at 37 ℃ for 24h to obtain a leaching solution. Mixing HGFs at 1X 104 The cells were seeded in a 96-well plate at a density of one cell/mL, and cultured in HPMC/Gyl hydrogel leaching solution, HPMC/HA/Gyl-FP hydrogel leaching solution, and DMEM medium, respectively. The medium was changed every 2 days. On days 1, 3, 5 and 7 of the culture, CCK-8 reagent (100 μ L, CCK-8: broth volume ratio =1: 10) was added to each well, and cultured at 37 ℃ for 2 hours under light-shielding conditions. The absorbance of each sample was measured at a wavelength of 450nm with a microplate reader.
Statistical treatment: all data were statistically processed using SPSS12.0 statistical software, and comparisons between groups were by t-test, with P <0.05 indicating significant differences.
And (4) analyzing results: as shown in FIG. 3, the cells cultured in the HPMC/HA/Gyl group and the HPMC/HA/Gyl-FP group promoted proliferation at 3d, 5d and 7d compared to the blank group and the HPMC/Gyl group; the result shows that the hydrogel has no toxicity to gingival fibroblasts, and the addition of the hyaluronic acid also has the function of promoting proliferation of cells.
Experimental example 3 the antibacterial performance test of the hydrogel having the optimal gel temperature obtained in experimental example 1 specifically includes:
the experimental method comprises the following steps: the antibacterial activity of the HPMC/HA/Gyl-FP hydrogel was determined by colony counting using Porphyromonas gingivalis (Pg, ATCC33277) as a model strain. 200 μ L of the hydrogel precursor solution was added to a 48-well plate, grouped as in Experimental example 2, and placed at 37 ℃ until the solution completely formed a hydrogel. Thereafter, 10. mu.L of the suspension of the Western bacteria (10)6CFU/mL) was placed on the hydrogel surface, and the seeded hydrogel was incubated in a humidified environment at 37 ℃ for 4 hours. Then 1ml PBS was added to each well to resuspend the bacteria, and 10. mu.L of the bacterial suspension (10)6 CFU mL-1) Suspended in 1ml PBS as a negative control. After incubation at 37 ℃ for 24 hours, the number of colony forming units on the petri dish was counted.
Statistical treatment: all data were statistically processed using SPSS12.0 statistical software, and comparisons between groups were by t-test, with P <0.05 indicating significant differences.
And (4) analyzing results: as shown in fig. 4, colonies formed on the culture dishes of the HPMC/Gyl group and the HPMC/HA/Gyl group, but the colonies formed were less than those formed in the control group, and colonies formed on the hydrogel group carrying the phenformin polypeptide were not formed, indicating that the hydrogel carrying the phenformin polypeptide had an effective antibacterial effect on periodontal and peri-implant bacteria.
Claims (5)
1. The preparation method of the injectable temperature-sensitive hydrogel is characterized by comprising the following preparation steps: (1) heating double distilled water to not less than 80 ℃, mixing hydroxypropyl methyl cellulose powder with the heated double distilled water, fully stirring, and balancing at 4 ℃ overnight to obtain hydroxypropyl methyl cellulose solution; respectively adding hyaluronic acid powder and Fingermine polypeptide powder into double distilled water, continuously stirring at room temperature, and completely dissolving to obtain hyaluronic acid solution and Fingermine polypeptide solution; (2) mixing a hydroxypropyl methyl cellulose solution with a hyaluronic acid solution, and uniformly stirring to obtain a solution A; (3) adding the fenugreek polypeptide solution into the solution A, and uniformly stirring to obtain a solution B; (4) dropwise adding glycerol into the solution B under stirring, and fully and uniformly stirring to finally obtain a hydroxypropylmethylcellulose/hyaluronic acid/glycerol temperature-sensitive hydrogel system carrying the phenthoate polypeptide; according to the percentage content of the total weight of the hydrogel, the content of the hydroxypropyl methylcellulose is 5-10%, the content of the hyaluronic acid is 1-2%, the content of the Fenugen polypeptide is 0.01-0.1%, the content of the glycerol is 10-25%, and the balance is water.
2. The method for preparing the injectable temperature-sensitive hydrogel according to claim 1, wherein: the content of the hydroxypropyl methylcellulose is 7 percent, the content of the hyaluronic acid is 2 percent, the content of the Fenugen polypeptide is 0.05 percent, the content of the added glycerol is 20 percent, and the balance is water.
3. An injectable temperature-sensitive hydrogel prepared by the preparation method according to claim 1 or 2.
4. The injectable temperature-sensitive hydrogel according to claim 3, wherein: is flowable sol at room temperature, non-flowable gel at 37 deg.C, and has a phase transition temperature of 35-37 deg.C.
5. Use of the injectable temperature-sensitive hydrogel according to claim 3 for the preparation of a material for the treatment of periodontal and peri-implant diseases and wounds.
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