CN115895280B - Photosensitive silk fibroin hydrogel and preparation method and application thereof - Google Patents
Photosensitive silk fibroin hydrogel and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of biomedical engineering, and discloses a photosensitive silk fibroin hydrogel, and a preparation method and application thereof. The photosensitive silk fibroin hydrogel comprises the following components in percentage by mass: 10% of 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin, 1% -10% of [ Ru (AAm-tpy) (Biq) (Cl) ] Cl and the balance of ultrapure water. The preparation method comprises the following steps: and uniformly mixing the components of the photosensitive silk fibroin hydrogel dressing, and irradiating ultraviolet light for 3-5min to obtain the photosensitive silk fibroin hydrogel. The photosensitive silk fibroin hydrogel can be used as a medical dressing, and the medical dressing has antibacterial and anti-tumor functions under the condition of white light or natural light irradiation.
Description
Technical Field
The invention belongs to the field of biomedical engineering, and relates to a photosensitive silk fibroin hydrogel, and a preparation method and application thereof.
Background
Currently, clinical treatment of melanoma relies mainly on surgical excision. However, residual tumor cells after surgery are extremely prone to recurrence of the patient's tumor. Meanwhile, during the operation process or the healing stage of an operation incision, the wound of a patient is extremely easy to be infected by bacteria such as staphylococcus aureus and the like, so that the wound cannot heal well, even chronic inflammation or sepsis is caused, and the life of the patient is seriously endangered. Therefore, it is necessary to develop a multifunctional wound dressing having both good anti-tumor and antibacterial properties.
Silk fibroin is a naturally occurring protein with good biological activity and can promote skin wound tissue repair, however, the lack of antibacterial function is one of the main disadvantages of most pure silk fibroin biomedical materials as wound care products. Photodynamic therapy uses photosensitizers to release active oxygen under illumination to kill bacteria or tumor cells. Compared with antibiotics, photodynamic therapy has good curative effect on drug-resistant bacteria infection.
However, existing photosensitizers often release active oxygen to kill bacteria or tumor cells upon irradiation with near infrared light (660 nm-1200 nm). In the natural world and normal living environment, the intensity of near infrared radiation is relatively low, and is insufficient to activate the photosensitizer, so that special light source equipment and complicated procedures are required for treating patients. Therefore, in clinical practical application, development of a wound dressing which is simpler and more convenient, has good anti-tumor and antibacterial properties under the white light condition, and improves wound repair of melanoma operation patients is urgently needed.
Disclosure of Invention
The invention mainly aims to develop a photosensitive silk fibroin hydrogel, the precursor solution of which can form gel at a wound site in situ under the condition of ultraviolet irradiation, and the silk fibroin hydrogel dressing which can obviously resist bacteria and kill tumor cells under the condition of white light and natural light irradiation, so that the invention can inhibit postoperative tumor recurrence, treat postoperative wound infection and promote good wound repair.
The invention provides a photosensitive silk fibroin hydrogel, which comprises the following components in percentage by mass: 10% of 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin, 1% -10% of [ Ru (AAm-tpy) (Biq) (Cl) ] Cl and the balance of ultrapure water.
The invention provides a preparation method of the photosensitive silk fibroin hydrogel, which is characterized in that after the components of the photosensitive silk fibroin hydrogel dressing are uniformly mixed, ultraviolet light is irradiated for 3-5min to obtain the photosensitive silk fibroin hydrogel.
Further, the preparation method of the 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin comprises the following steps: dissolving silk fibroin in hexafluoroisopropanol, adding 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid, stirring at room temperature in a dark place until the silk fibroin is completely dissolved, performing reaction, removing a solvent by rotary evaporation after the reaction is finished, adding water for dissolution, dialyzing, and freeze-drying to obtain the 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin.
Further, the dosage ratio of the silk fibroin, hexafluoroisopropanol and 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is 0.45g to 3mL (0.2-2 g), the reaction time of the reaction is 24 hours, and the dialysis time is 3 days.
Further, the preparation method of [ Ru (AAm-tpy) (Biq) (Cl) ] Cl comprises the following steps:
S1-Synthesis of NH2-tpy: potassium hydroxideDissolving in DMSO, heating to 65deg.C, dropwise adding 3-amino-1-propanol under stirring, stirring for a while, adding 4 '-chloro-2, 2':6',2' -terpyridine, reacting, cooling to room temperature, pouring into deionized water, extracting with dichloromethane, drying with anhydrous sodium sulfate, drying under reduced pressure, recrystallizing with ethyl acetate to obtain NH 2 -tpy；
S2. Synthesis of AAM-tpy: dissolving NH2-tpy and triethylamine in tetrahydrofuran, adding acryloyl chloride under ice water bath condition and nitrogen protection, reacting completely at room temperature, removing solvent by rotary evaporation after the reaction is finished, dissolving in dichloromethane, washing with saturated saline water to remove impurities, drying, removing dichloromethane by rotary evaporation to obtain a crude product, and purifying the crude product by using an alumina column chromatography to obtain AAM-tpy;
S3.Ru(Aam-tpy)Cl 3 is synthesized by the following steps: ruCl is to be processed 3 Dissolving H2O and AAm-tpy in ethanol for reflux reaction, cooling to room temperature after the reaction is finished, filtering, washing the filtered solid with ethanol and diethyl ether in sequence, and then vacuum drying to obtain Ru (Aam-tpy) Cl 3 ；
S4.[Ru(AAm-tpy)(Biq)(Cl)]Synthesis of Cl: ru (Aam-tpy) Cl 3 And 2,2' -biquinoline is dissolved in a mixed solvent of ethanol and water, nitrogen is degassed for 5min, light is prevented from refluxing under the protection of nitrogen, after the reaction is finished, the solution is filtered by heat, the filtrate is collected, the solvent is removed by decompression, and then the solution is purified to obtain [ Ru (AAm-tpy) (Biq) (Cl)]Cl。
Further, in step S1, the dosage ratio of potassium hydroxide, DMSO, 3-amino-1-propanol, 4 '-chloro-2, 2':6',2' -terpyridine was 0.298g:20mL:0.42g:0.75g.
Further, in step S2, NH2-tpy, triethylamine, tetrahydrofuran and acryloyl chloride were used in a ratio of 0.362g to 1.8mL to 40mL to 0.16g.
Further, in step S3, ruCl 3 The ratio of H2O, AAm-tpy to ethanol was 0.163g:0.26g:50mL.
Further, in step S4, ru (Aam-tpy) Cl 3 2,2' -biquinoline and mixture of said ethanol and waterThe dosage ratio of the solvent is 0.33g to 0.149g to 30mL, and the volume ratio of the ethanol to the water in the mixed solvent of the ethanol and the water is 1:1.
Furthermore, the invention provides application of the photosensitive silk fibroin hydrogel or the photosensitive silk fibroin hydrogel prepared by the preparation method in medical dressing, and the medical dressing has antibacterial and anti-tumor functions under the condition of white light or natural light irradiation.
Further, the white light is 100mWcm -2 Is a white light of (c).
Compared with the prior art, the precursor solution of the hydrogel can form gel at a wound in situ under the condition of ultraviolet irradiation, can kill more than 85% of tumor cells in an in vitro experiment within 10min under white light or natural light, effectively inhibit tumor recurrence, treat wound bacterial infection, and promote wound repair after tumor resection, wherein the irradiation sterilization rate of staphylococcus aureus at the wound is more than 95%.
Drawings
FIG. 1 is a graph showing the results of in vitro light tumor cell killing performance test of the hydrogel prepared in example 2;
FIG. 2 is a graph showing the results of in vivo antibacterial property test of the hydrogel prepared in example 2.
Detailed Description
The invention will be better understood from the following examples. However, it will be readily appreciated by those skilled in the art that the description of the embodiments is provided for illustration only and should not limit the invention as described in detail in the claims.
Example 1
0.45g of silk fibroin is dissolved in 3mL of hexafluoroisopropanol, 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid (0.2 g) is added, the mixture is stirred at room temperature until the silk fibroin is completely dissolved, the mixture is reacted for 24h, water is added for dissolving after the solvent is removed by rotary evaporation, the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is obtained by dialysis for 3 days, the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is dissolved in ultrapure water to obtain a solution with the concentration of 10w/v percent, and [ Ru (AAm-tpy) (Biq) (Cl) ] Cl is added into the solution according to the mass ratio of the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid to [ Ru (AAm-tpy) (Biq) (Cl) ] Cl) of 1:1, and the mixture is stirred until the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is completely dissolved. Hydrogels were formed under irradiation with 365nm UV light (50 mW/cm 2) for 5 min.
Example 2
0.45g of silk fibroin is dissolved in 3mL of hexafluoroisopropanol, and 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid (2 g) is added, the mixture is stirred at room temperature until the silk fibroin is completely dissolved, the mixture is reacted for 24h, water is added for dissolving after the solvent is removed by rotary evaporation, the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is dialyzed for 3 days, the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is obtained by freeze-drying, the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is dissolved in ultrapure water to obtain a solution with the concentration of 10w/v%, and the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid and [ Ru (AAm-tpy) (Biq) (Cl) ] Cl) are added into the solution according to the mass ratio of 1:1, and the solution is stirred until the silk fibroin modified by [ Ru (AAm-tpy) (Biq) (Cl) ] Cl) is completely dissolved. Hydrogels were formed under irradiation with 365nm UV light (50 mW/cm 2) for 5 min.
Example 3
0.45g of silk fibroin is dissolved in 3mL of hexafluoroisopropanol, and 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid (2 g) is added, the mixture is stirred at room temperature until the silk fibroin is completely dissolved, the mixture is reacted for 24h, water is added for dissolving after the solvent is removed by rotary evaporation, the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is obtained after dialysis for 3 days, the 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin is obtained after freeze drying, the 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin is dissolved in ultrapure water to obtain a solution with the concentration of 10w/v percent, and the silk fibroin modified by 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid and [ Ru (AAm-tpy) (Biq) (Cl) ] Cl) are added into the solution according to the mass ratio of 1:0.1, and the mixture is stirred until the silk fibroin modified by [ Ru (AAm-tpy) (Biq) (Cl) ] Cl) is completely dissolved. Hydrogels were formed under irradiation with 365nm UV light (50 mW/cm 2) for 5 min.
Test example 1
Compression strength test of hydrogels: the hydrogels obtained in examples 1 to 3 were prepared into cylinders having a diameter of 1.5cm and a height of 1cm, and the cylinders were compressed at a displacement rate of 5mm/min until the hydrogels disintegrated by using an electronic universal material tester, and the compressive strengths were measured and were 0.03MPa, 0.1MPa and 0.89MPa, respectively.
Test example 2
The product is tested for the performance of killing tumor cells under white light by using in vitro tumor cell culture. B16F10 melanoma cells were seeded on the hydrogel prepared in example 2 using LED white light (100 mWcm -2 ) And after 10 minutes of irradiation of the hydrogel with natural light, cell viability was measured using the Cell counting kit-8 kit and compared to the non-irradiated hydrogel. Due to [ Ru (AAm-tpy) (Biq) (Cl)]Cl can absorb visible light and release active oxygen to kill bacteria and tumor cells, as shown in figure 1, the product is white light (100 mWcm) -2 ) Or more than 85% of tumor cells can be killed by irradiation with natural light for 10 min.
Test example 3
The product is tested for the performance of killing staphylococcus aureus under white light by using a drug-resistant bacteria infection model of back skin injury of a mouse. The back wound of the rat infected with staphylococcus aureus was filled with the hydrogel prepared in example 2, and the wound was wound-packed with LED white light (100 mWcm -2 ) And irradiating the affected area with natural light for 10 minutes, and after 3 days, taking the tissue of the affected area for bacterial culture, and comparing with the tissue of a mouse which is not treated by irradiation. As shown in figure 2, after white light or natural light treatment, the number of drug-resistant bacteria at the wound is obviously reduced, and the sterilization rate of the product under white light or natural light is over 90 percent, so that the product has obvious antibacterial effect.
Claims (10)
1. The photosensitive silk fibroin hydrogel is characterized by comprising the following components in percentage by mass: 10% of 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin, 1% -10% of [ Ru (AAm-tpy) (Biq) (Cl) ] Cl and the balance of ultrapure water; the preparation method of the photosensitive silk fibroin hydrogel comprises the following steps: and uniformly mixing the components of the photosensitive silk fibroin hydrogel dressing, and irradiating with ultraviolet light for 3-5 min.
2.A method for preparing the photosensitive silk fibroin hydrogel according to claim 1, wherein after the components of the photosensitive silk fibroin hydrogel dressing are uniformly mixed, ultraviolet light is irradiated for 3-5min, so as to obtain the photosensitive silk fibroin hydrogel.
3. The preparation method of the 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin according to claim 2, wherein the preparation method comprises the following steps: dissolving silk fibroin in hexafluoroisopropanol, adding 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid, stirring at room temperature in a dark place until the silk fibroin is completely dissolved, performing reaction, removing a solvent by rotary evaporation after the reaction is finished, adding water for dissolution, dialyzing, and freeze-drying to obtain the 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid modified silk fibroin.
4. The method according to claim 3, wherein the ratio of the amount of silk fibroin, hexafluoroisopropanol and 4- (4-hydroxymethyl-2-methoxy-5-nitrophenoxy) butyric acid is 0.45: 0.45g:3mL (0.2-2) g, the reaction time of the reaction is 24: 24h, and the dialysis time is 3 days.
5. The preparation method according to claim 2, wherein the preparation method of [ Ru (AAm-tpy) (Biq) (Cl) ] Cl comprises the steps of:
S1-Synthesis of NH2-tpy: dissolving potassium hydroxide in DMSO, heating to 65deg.C, dropwise adding 3-amino-1-propanol under stirring, stirring for a while, adding 4 '-chloro-2, 2':6',2' -terpyridine, reacting, cooling to room temperature, pouring into deionized water, extracting with dichloromethane, drying with anhydrous sodium sulfate, drying under reduced pressure, recrystallizing with ethyl acetate to obtain NH 2 -tpy；
S2. Synthesis of AAM-tpy: dissolving NH2-tpy and triethylamine in tetrahydrofuran, adding acryloyl chloride under ice water bath condition and nitrogen protection, reacting completely at room temperature, removing solvent by rotary evaporation after the reaction is finished, dissolving in dichloromethane, washing with saturated saline water to remove impurities, drying, removing dichloromethane by rotary evaporation to obtain a crude product, and purifying the crude product by using an alumina column chromatography to obtain AAM-tpy;
S3. Ru(Aam-tpy)Cl 3 is synthesized by the following steps: ruCl is to be processed 3 Dissolving H2O and AAm-tpy in ethanol for reflux reaction, cooling to room temperature after the reaction is finished, filtering, washing the filtered solid with ethanol and diethyl ether in sequence, and then vacuum drying to obtain Ru (Aam-tpy) Cl 3 ；
S4. [Ru(AAm-tpy)(Biq)(Cl)]Synthesis of Cl: ru (Aam-tpy) Cl 3 And 2,2' -biquinoline is dissolved in a mixed solvent of ethanol and water, nitrogen is degassed for 5min, light is prevented from refluxing under the protection of nitrogen, after the reaction is finished, the solution is filtered by heat, the filtrate is collected, the solvent is removed by decompression, and then the solution is purified to obtain [ Ru (AAm-tpy) (Biq) (Cl)]Cl。
6. The method according to claim 5, wherein in the step S1, the ratio of potassium hydroxide, DMSO, 3-amino-1-propanol, 4 '-chloro-2, 2':6',2' -terpyridine is 0.298g:20mL:0.42g:0.75g.
7. The method according to claim 5, wherein in step S2, NH2-tpy, triethylamine, tetrahydrofuran and acrylic acid chloride are used in a ratio of 0.362 and 0.362g:1.8 and 1.8mL:40 and 40mL:0.16 and g.
8. The method according to claim 5, wherein in step S3, ruCl is added 3 The ratio of H2O, AAm-tpy to ethanol was 0.163g:0.26g:50mL.
9. The process according to claim 5, wherein in step S4, ru (Aam-tpy) Cl is contained 3 The dosage ratio of the 2,2' -biquinoline to the mixed solvent of the ethanol and the water is 0.33, g, 0.149, g and 30, mL, and the volume ratio of the ethanol to the water in the mixed solvent of the ethanol and the water is 1:1.
10. The use of the photosensitive silk fibroin hydrogel according to claim 1 or the photosensitive silk fibroin hydrogel prepared by the preparation method according to any one of claims 2-9 in the preparation of medical dressings, wherein the medical dressings have antibacterial and antitumor functions under the condition of white light or natural light irradiation.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107987287A (en) * | 2017-11-15 | 2018-05-04 | 华东理工大学 | Photic nitroso cross-linked hydrogel material and preparation method and application |
| CN115028903A (en) * | 2022-07-07 | 2022-09-09 | 广州创赛生物医用材料有限公司 | Hydrogel and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107987287A (en) * | 2017-11-15 | 2018-05-04 | 华东理工大学 | Photic nitroso cross-linked hydrogel material and preparation method and application |
| CN115028903A (en) * | 2022-07-07 | 2022-09-09 | 广州创赛生物医用材料有限公司 | Hydrogel and preparation method and application thereof |
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