CN115227866B - Injectable hydrogel wound dressing with tissue adhesion, multiple sterilization and electrical stimulation tissue regeneration functions and preparation method thereof - Google Patents
Injectable hydrogel wound dressing with tissue adhesion, multiple sterilization and electrical stimulation tissue regeneration functions and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an injectable hydrogel wound dressing with tissue adhesion, multiple sterilization and electrical stimulation tissue regeneration functions and a preparation method thereof. The preparation method comprises the following steps: (1) preparing a phytic acid-doped graphene oxide/polyaniline nanofiller; (2) polymerizing the nano-filler in a dopamine/Tris buffer solution to obtain a graphene oxide/polyaniline/polydopamine nano-filler; (3) adding the obtained nano filler into a silver nitrate solution to prepare a graphene oxide/polyaniline/polydopamine/nano silver composite nano filler; (4) adding GelMA into PBS, dissolving in 60 deg.C water bath, cooling to 30 deg.C, sequentially adding quaternized chitosan, catechol-modified chitosan, and composite nanometer filler, stirring for dissolving, centrifuging at low speed for defoaming, and in-situ photocuring. The hydrogel material has excellent wet tissue adhesion, conductivity, antibacterial property, injectability and biocompatibility, and can be used as a novel wound dressing to realize treatment of various irregular wounds.
Description
Technical Field
The invention relates to the field of hydrogel preparation, in particular to an injectable hydrogel wound dressing with tissue adhesion, multiple sterilization and electrical stimulation tissue regeneration functions and a preparation method thereof.
Background
Skin is the largest organ of the human body, and skin damage is the most common surgical wound of the human body. The wound surface infection is easy to occur due to skin injury, so that the healing of the wound is slowed down; especially large-area skin burns and scalds are easy to cause inflammatory reaction and threaten life in severe cases.
Currently, clinical treatment methods are mainly divided into two categories: the skin grafting technology is adopted for large-area burns and scalds, but secondary wound is easily caused, and scars are left at the skin taking part; the common skin trauma is treated by adopting antibacterial drugs and dressing, but the dressing has the defects of unmatched shape and wound property, poor antibacterial effect, short antibacterial time-effect, easy occurrence of secondary infection and no function of promoting tissue regeneration. In conclusion, the treatment technology of the skin wound has a larger lifting space.
The hydrogel is used as a three-dimensional water-containing polymer network, is very similar to an extracellular matrix structure, and the network structure of the hydrogel can be adjusted, so that the growth of cells is facilitated; meanwhile, active components such as an antibacterial agent, a nano functional filler and the like can be loaded in the hydrogel, so that the functions of the hydrogel are further enriched. Therefore, hydrogel dressings have become a research focus in this field.
Aiming at the defects of the common skin trauma dressing, the invention designs the injectable hydrogel wound dressing with the functions of tissue adhesion, multiple sterilization and electrical stimulation tissue regeneration, which can achieve the purposes of resisting wound infection and promoting skin regeneration, relieves the pain of patients and has great clinical significance.
Disclosure of Invention
The invention aims to provide an injectable hydrogel wound dressing with tissue adhesion, multiple sterilization and electrical stimulation tissue regeneration functions and a preparation method thereof, aiming at the defects of the prior art and combining the advantages of various materials and processes.
The invention is realized by adopting the following technical scheme:
the preparation method of the injectable hydrogel wound dressing with the functions of tissue adhesion, multiple sterilization and tissue regeneration by electrical stimulation comprises the following steps:
1) Firstly, uniformly stirring graphene oxide in deionized water, performing ultrasonic dispersion, adding phytic acid, performing dispersion under the three processes of vigorous stirring, vortex and ultrasound, then adding an aniline monomer, continuously performing dispersion under the three processes of vigorous stirring, vortex and ultrasound, finally dropwise adding an initiator solution, and performing in-situ free radical polymerization of aniline on the surface of the graphene oxide under the condition of vigorous stirring to prepare the graphene oxide/polyaniline nano filler with high dispersibility, washing and freeze-drying;
2) Ultrasonically dispersing the graphene oxide/polyaniline nanofiller prepared in the step 1) in 2mg/ml DA and 10mM Tris buffer solution (pH = 8.5), and reacting for 2-6 hours to realize the self-polymerization of polydopamine on the surface of the nanofiller to obtain the graphene oxide/polyaniline/polydopamine nanofiller;
3) Preparing a silver nitrate solution under a dark condition, placing the graphene oxide/polyaniline/polydopamine nanofiller in the step 2) in the solution to react for 12-24 hours, and depositing nano silver on the surface of the graphene oxide/polyaniline/polydopamine-nano silver nanofiller by virtue of the reducibility of the polydopamine to prepare the graphene oxide/polyaniline/polydopamine-nano silver nanofiller;
4) Dissolving a certain amount of GelMA in PBS (phosphate buffer solution) at 60 ℃ to obtain a uniform solution, cooling to 30 ℃, sequentially adding quaternized chitosan, catechol-modified chitosan and the graphene oxide/polyaniline/polydopamine-nano silver nano filler prepared in the step 3), dispersing uniformly, and centrifuging at a low speed to defoam;
5) Injecting the mixed solution prepared in the step 4) at the wound part by using an injection device, and curing in situ ultraviolet light to obtain the hydrogel dressing with any shape, thereby realizing accurate covering of the wound.
In the above technical scheme, further, in the step 1), the concentration of the graphene oxide is 0.01-0.05wt%; the concentration of the phytic acid is 0.12 to 0.25 weight percent; the concentration of aniline is 0.005-0.015wt%; the initiator is one or more of sodium persulfate, potassium persulfate and ammonium persulfate, and the concentration is 0.25-0.60wt%; the polymerization time is 4 to 8 hours.
Further, in the step 1), in the triple dispersion process of violent stirring, vortex and ultrasound, the violent stirring means that the stirring speed is more than 1000 revolutions per minute, and the stirring time is 10-20min; vortex for 10-20min; the ultrasonic power is more than 100W, and the ultrasonic time is 20-40min. Through the triple dispersion process, the graphene oxide with oxygen-containing functional groups on the surface can be well dispersed in an acid solution, otherwise, the graphene oxide is easy to agglomerate;
further, the concentration of the graphene oxide/polyaniline nanofiller in the step 2) is 0.05-0.15wt%.
Further, the concentration of the graphene oxide/polyaniline/polydopamine nanofiller in the step 3) is 0.05-0.15 wt%; the concentration of the silver nitrate solution is 5-15wt%; the whole operation is protected from light.
Further, the concentration of GelMA in the step 4) is 5-30wt%, and the substitution degree is 60-90%; the quaternary ammonium chitosan has a concentration of 0.5-1.5wt% and a molecular weight of 5000-20000; the catechol-modified chitosan has a concentration of 0.5-2.0wt% and a molecular weight of 500000-1500000.
Further, the ultraviolet light used in the step 5) has the excitation wavelength of 405nm and the photocuring time of 10s-5 min.
Compared with the prior art, the invention has the following advantages:
1) The nano-filler in the hydrogel is a self-designed functional filler, and simultaneously uses four functional components such as graphene oxide, aniline, dopamine and silver nitrate, wherein the graphene oxide is used as an inner core and can be used as a template for aniline polymerization and can promote the dispersion of polyaniline; polyaniline is used as a conductive functional component; the introduction of dopamine can be used as a reducing agent for synthesizing nano silver to reduce silver nitrate while promoting the dispersion of the graphene oxide/polyaniline nano filler, and the nano silver is further introduced to the surface of the graphene oxide/polyaniline/polydopamine nano filler to obtain the graphene oxide/polyaniline/polydopamine-nano silver nano functional filler;
2) The matrix of the hydrogel is formed by compounding quaternized chitosan, catechol modified chitosan and GelMA, wherein the quaternized chitosan provides an antibacterial function, the catechol modified chitosan provides wet tissue adhesion performance, and the GelMA realizes the injectability of the material and conforms to the irregularity of wounds through an in-situ ultraviolet curing process so as to meet the use requirements;
3) The preparation of the composite hydrogel material simultaneously uses the combined processes of multi-step in-situ solution polymerization, in-situ reduction, nano-compounding, injectability, ultraviolet curing and the like, and the process route is formulated according to the actual preparation requirement of the gel, so that the preparation method has originality;
4) The hydrogel material has injectability, wet tissue adhesiveness, conductivity, antibacterial property and biocompatibility, and multiple functions complement each other: the material is coated on the irregular wound surface through the injectability of hydrogel, gelation is realized through an in-situ ultraviolet curing process, the first antibacterial action is realized through quaternized chitosan in a gel matrix, the second antibacterial action is realized through the nano-silver component in the nano-filler, and the third antibacterial action can be realized through the photothermal sterilization function of graphene oxide and polyaniline triggered by NIR if the wound infection degree is serious. In addition, the hydrogel has conductivity, can be externally connected with a sterile circuit and an adjustable power supply, and promotes cell proliferation and wound healing around the wound through electric signals. The hydrogel is designed according to the requirements of skin wound infection treatment and wound healing, all the components are organically combined to prepare the required hydrogel material, all the components provide all the functions required by the treatment stage respectively, and all the functions are organically cooperated to jointly complete the treatment task born by the multifunctional wound dressing.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1:
1) Firstly, preparing 0.05wt% of graphene oxide in deionized water, uniformly stirring and ultrasonically dispersing, then adding phytic acid, dispersing under the triple process of stirring at 1000 revolutions per minute for 20min, vortexing for 20min and 100w ultrasound for 20min, then adding 0.010wt% of aniline monomer, continuing to disperse under the same triple dispersion process, finally adding 0.40wt% of ammonium persulfate initiator solution, and realizing the preparation of the graphene oxide/polyaniline nano filler with high dispersibility by aniline in-situ free radical polymerization on the surface of the graphene oxide under the condition of intense magnetic stirring, washing and freeze-drying;
2) Ultrasonically dispersing the graphene oxide/polyaniline nanofiller (0.10 wt%) prepared in the step 1) into 2mg/ml DA and 10mM Tris buffer solution (pH = 8.5), and reacting for 4 hours to realize the self-polymerization of polydopamine on the surface of the nanofiller, thereby finally obtaining the graphene oxide/polyaniline/polydopamine nanofiller;
3) Preparing a 5wt% silver nitrate solution under a dark condition, placing the graphene oxide/polyaniline/polydopamine nanofiller (0.1 wt%) obtained in the step 2) in the solution for reaction for 12 hours, and depositing nano-silver on the surface of the graphene oxide/polyaniline/polydopamine-nano-silver nanofiller by virtue of the reducibility of the polydopamine to obtain the graphene oxide/polyaniline/polydopamine-nano-silver nanofiller;
4) Dissolving the GelMA in PBS at 60 ℃ by 10wt% to obtain a uniform solution, cooling to 30 ℃, then sequentially adding 0.5wt% of quaternized chitosan with the molecular weight of 5000, 0.5wt% of catechol-modified chitosan with the molecular weight of 500000 and the graphene oxide/polyaniline/polydopamine-nano silver nano filler prepared in the step 3), uniformly dispersing, and centrifuging at a low speed of 3500rpm for 3min for defoaming;
5) Injecting the mixed solution prepared in the step 4) at the wound part by using an injection device, and curing by using in-situ ultraviolet light (405 nm) for 30s to obtain the hydrogel dressing with any shape, so as to accurately cover the wound;
the 24-hour sterilization efficiency of the hydrogel is 90%, the conductivity can reach 0.54S/m, the wet adhesion strength can reach 11.3kPa, and the gel temperature can be increased from 23 ℃ to about 56 ℃ after NIR irradiation for 10 min.
Example 2:
1) Firstly, preparing 0.05wt% of graphene oxide in deionized water, uniformly stirring and ultrasonically dispersing, then adding phytic acid, dispersing under the triple process of stirring at 1000 revolutions per minute for 20min, vortexing for 20min and 100w ultrasound for 20min, then adding 0.01wt% of aniline monomer, continuing to disperse under the same triple dispersion process, finally adding 0.40wt% of ammonium persulfate initiator solution, and realizing the preparation of the graphene oxide/polyaniline nano filler with high dispersibility by aniline in-situ free radical polymerization on the surface of the graphene oxide under the condition of intense magnetic stirring, washing and freeze-drying;
2) Ultrasonically dispersing the graphene oxide/polyaniline nanofiller (0.10 wt%) prepared in the step 1) into 2mg/ml DA and 10mM Tris buffer solution (pH = 8.5), and reacting for 4 hours to realize the self-polymerization of polydopamine on the surface of the nanofiller, thereby finally obtaining the graphene oxide/polyaniline/polydopamine nanofiller;
3) Preparing 15wt% of silver nitrate solution under a dark condition, placing the graphene oxide/polyaniline/polydopamine nanofiller (0.1 wt%) in the step 2) in the solution for reaction for 12 hours, and depositing nano-silver on the surface of the graphene oxide/polyaniline/polydopamine-nano-silver nanofiller by virtue of reducibility of the polydopamine to prepare the graphene oxide/polyaniline/polydopamine-nano-silver nanofiller;
4) Dissolving the GelMA in PBS at 60 ℃ by 10wt% to obtain a uniform solution, cooling to 30 ℃, then sequentially adding 0.5wt% of quaternized chitosan with the molecular weight of 5000, 0.5wt% of catechol-modified chitosan with the molecular weight of 500000 and the graphene oxide/polyaniline/polydopamine-nano silver nano filler prepared in the step 3), uniformly dispersing, and centrifuging at a low speed of 3500rpm for 3min for defoaming;
5) Injecting the mixed solution prepared in the step 4) at the wound part by using an injection device, and curing by using in-situ ultraviolet light (405 nm) for 30s to obtain the hydrogel dressing with any shape, so as to accurately cover the wound;
compared with the example 1, the dosage of the silver nitrate in the step 3) is increased, the sterilization efficiency of the hydrogel for 24 hours is 99%, the electric conductivity can reach 0.58S/m, the wet adhesion strength can reach 109kPa, and the gel temperature can be increased from 23 ℃ to about 57 ℃ after NIR irradiation for 10 min.
Example 3:
1) Firstly, 0.05wt% of graphene oxide is prepared in deionized water, stirring and ultrasonic dispersion are carried out uniformly, phytic acid is added, dispersion is carried out under the triple process of stirring at 1000 r/min for 20min, vortex for 20min and 100w ultrasonic for 20min, then 0.05wt% of aniline monomer is added, dispersion is carried out under the same triple dispersion process, finally 0.60wt% of ammonium persulfate initiator solution is added, and the preparation of the graphene oxide/polyaniline nano filler with high dispersibility is realized through aniline in-situ free radical polymerization on the surface of the graphene oxide under the condition of vigorous magnetic stirring, and washing and freeze-drying are carried out;
2) Ultrasonically dispersing the graphene oxide/polyaniline nanofiller (0.10 wt%) prepared in the step 1) into 2mg/ml DA and 10mM Tris buffer solution (pH = 8.5), and reacting for 4 hours to realize the self-polymerization of polydopamine on the surface of the nanofiller, thereby finally obtaining the graphene oxide/polyaniline/polydopamine nanofiller;
3) Preparing a 5wt% silver nitrate solution under a dark condition, placing the graphene oxide/polyaniline/polydopamine nanofiller (0.1 wt%) obtained in the step 2) in the solution for reaction for 12 hours, and depositing nano-silver on the surface of the graphene oxide/polyaniline/polydopamine-nano-silver nanofiller by virtue of reducibility of the polydopamine to obtain the graphene oxide/polyaniline/polydopamine-nano-silver nanofiller;
4) Dissolving the GelMA in PBS at 60 ℃ by 10wt% to obtain a uniform solution, cooling to 30 ℃, then sequentially adding 0.5wt% of quaternized chitosan with the molecular weight of 5000, 0.5wt% of catechol-modified chitosan with the molecular weight of 500000 and the graphene oxide/polyaniline/polydopamine-nano silver nano filler prepared in the step 3), uniformly dispersing, and centrifuging at a low speed of 3500rpm for 3min for defoaming;
5) Injecting the mixed solution prepared in the step 4) at the wound part by using an injection device, and curing by using in-situ ultraviolet light (405 nm) for 30s to obtain the hydrogel dressing with any shape, so as to accurately cover the wound;
compared with the example 1, the dosage of the aniline in the step 1) is increased, the sterilization efficiency of the hydrogel is 91% in 24 hours, the conductivity can reach 0.84S/m, the wet adhesion strength can reach 10.9kPa, and the gel temperature can be increased from 23 ℃ to about 59 ℃ by NIR irradiation for 10 min.
Example 4:
1) Firstly, preparing 0.05wt% of graphene oxide in deionized water, uniformly stirring and ultrasonically dispersing, then adding phytic acid, dispersing under the triple process of stirring at 1000 revolutions per minute for 20min, vortexing for 20min and 100w ultrasound for 20min, then adding 0.010wt% of aniline monomer, continuing to disperse under the same triple dispersion process, finally adding 0.40wt% of ammonium persulfate initiator solution, and realizing the preparation of the graphene oxide/polyaniline nano filler with high dispersibility by aniline in-situ free radical polymerization on the surface of the graphene oxide under the condition of intense magnetic stirring, washing and freeze-drying;
2) Ultrasonically dispersing the graphene oxide/polyaniline nanofiller (0.10 wt%) prepared in the step 1) into 2mg/ml DA and 10mM Tris buffer solution (pH = 8.5), and reacting for 4 hours to realize the self-polymerization of polydopamine on the surface of the nanofiller, thereby finally obtaining the graphene oxide/polyaniline/polydopamine nanofiller;
3) Preparing a 5wt% silver nitrate solution under a dark condition, placing the graphene oxide/polyaniline/polydopamine nanofiller (0.1 wt%) obtained in the step 2) in the solution for reaction for 12 hours, and depositing nano-silver on the surface of the graphene oxide/polyaniline/polydopamine-nano-silver nanofiller by virtue of reducibility of the polydopamine to obtain the graphene oxide/polyaniline/polydopamine-nano-silver nanofiller;
4) Dissolving the GelMA in PBS at 60 ℃ by 10wt% to obtain a uniform solution, cooling to 30 ℃, then sequentially adding 1.5wt% of quaternized chitosan with the molecular weight of 5000, 1.5wt% of catechol-modified chitosan with the molecular weight of 500000 and the graphene oxide/polyaniline/polydopamine-nano silver nano filler prepared in the step 3), uniformly dispersing, and centrifuging at a low speed of 3500rpm for 3min for defoaming;
5) Injecting the mixed solution prepared in the step 4) at the wound part by using an injection device, and curing by using in-situ ultraviolet light (405 nm) for 30s to obtain the hydrogel dressing with any shape, so as to accurately cover the wound;
compared with the example 1, the concentration of the quaternized chitosan and the catechol-modified chitosan in the step 4) is increased, the 24-hour sterilization efficiency of the hydrogel is 93%, the conductivity can reach 0.49S/m, the wet adhesion strength can reach 14.5kPa, and the gel temperature can be increased from 23 ℃ to about 53 ℃ by NIR irradiation for 10 min.
Claims (8)
1. A preparation method of an injectable hydrogel wound dressing with tissue adhesion, multiple sterilization and electrical stimulation tissue regeneration functions is characterized by comprising the following steps:
1) Firstly, uniformly stirring graphene oxide in deionized water, performing ultrasonic dispersion, adding phytic acid, performing dispersion under the three processes of vigorous stirring, vortex and ultrasound, then adding an aniline monomer, continuously performing dispersion under the three processes of vigorous stirring, vortex and ultrasound, finally dropwise adding an initiator solution, and performing in-situ free radical polymerization of aniline on the surface of the graphene oxide under the condition of vigorous stirring to prepare the graphene oxide/polyaniline nano filler with high dispersibility, washing and freeze-drying;
2) Ultrasonically dispersing the graphene oxide/polyaniline nanofiller prepared in the step 1) in 2mg/ml DA and 10mM Tris buffer solution with pH =8.5, and reacting for 2-6 hours to obtain the graphene oxide/polyaniline/polydopamine nanofiller;
3) Preparing a silver nitrate solution under a dark condition, and placing the graphene oxide/polyaniline/polydopamine nanofiller obtained in the step 2) in the silver nitrate solution to react for 12-24 hours to obtain the graphene oxide/polyaniline/polydopamine-nano silver nanofiller;
4) Dissolving a certain amount of GelMA in PBS (phosphate buffer solution) at 60 ℃ to obtain a uniform solution, cooling to 30 ℃, sequentially adding quaternized chitosan, catechol-modified chitosan and the graphene oxide/polyaniline/polydopamine-nano silver nano filler prepared in the step 3), dispersing uniformly, and centrifuging at a low speed to defoam;
5) Injecting the mixed solution prepared in the step 4) at the wound part by using an injection device, and curing in situ ultraviolet light to obtain the hydrogel dressing with any shape, thereby realizing accurate covering of the wound.
2. The preparation method according to claim 1, wherein in the step 1), the concentration of the graphene oxide is 0.01-0.05wt%; the concentration of the phytic acid is 0.12-0.25wt%; the concentration of aniline is 0.005-0.015wt%; the initiator is one or more of sodium persulfate, potassium persulfate and ammonium persulfate, and the concentration is 0.25-0.60wt%; the polymerization time is 4 to 8 hours.
3. The method of claim 1, wherein: in the step 1), in the processes of intensive stirring, vortex and ultrasonic triple dispersion, the intensive stirring means that the stirring speed is more than 1000 revolutions per minute and the stirring time is 10-20min; vortex for 10-20min; the ultrasonic power is more than 100W, and the ultrasonic time is 20-40min.
4. The production method according to claim 1, characterized in that: in the step 2), the concentration of the graphene oxide/polyaniline nanofiller is 0.05-0.15wt%.
5. The method of claim 1, wherein: in the step 3), the concentration of the graphene oxide/polyaniline/polydopamine nanofiller is 0.05-0.15 wt%; the concentration of the silver nitrate solution is 5-15wt%; the whole operation is protected from light.
6. The method of claim 1, wherein: step 4), the concentration of GelMA is 5-30wt%, and the substitution degree is 60-90%; the concentration of the quaternized chitosan is 0.5-1.5wt percent, and the molecular weight is 5000-20000; the catechol-modified chitosan has a concentration of 0.5-2.0wt% and a molecular weight of 500000-1500000.
7. The method of claim 1, wherein: the ultraviolet light used in the step 5) has the excitation wavelength of 405nm and the photocuring time of 10s-5 min.
8. An injectable hydrogel wound dressing having tissue adhesion, multiple sterilization and electro-stimulation tissue regeneration functions, prepared by the method of any one of claims 1-7.
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