CN114259605B - Preparation method and application of acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold - Google Patents
Preparation method and application of acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold Download PDFInfo
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Abstract
The acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold is prepared by taking an acellular pig dermal matrix with high biological safety as a base material, compounding the acellular pig dermal matrix with a nano silver wire with good biocompatibility, and loading temperature-sensitive drug-loaded silicon dioxide microspheres in a physical adsorption and chemical combination mode.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a preparation method and application of a temperature-sensitive antibacterial conductive bracket of an acellular pig dermal matrix.
Background
Melanoma is one of the most aggressive skin cancers, and its incidence is increasing in recent years. As a main treatment means for such skin diseases, surgery has a high risk of recurrence and large skin defects. In addition, rapid repair of damaged tissue after tumor resection is important for long-term skin healing, and the human body cannot completely heal any full-thickness skin defect with a diameter greater than 4 cm by itself. Therefore, it is necessary to develop a medical stent which integrates the cancer treatment performance and the defective tissue regeneration promotion performance.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a preparation method and application (Ag-pADM @ TSDHSiO) of a temperature-sensitive antibacterial conductive bracket of an acellular pig dermal matrix2) The composite material has the characteristics of low immunogenicity, high biocompatibility and degradability, good mechanical strength and contribution to adhesion and growth of cells. In view of the above, first, an ideal medical skin scaffold should have disease treatment and tissue repair properties. The acellular pig dermal matrix selected as the base material has the following advantages: 1) low immunogenicity; 2) has high biocompatibility and degradability, and the degradation product can be absorbed by human body; 3) the mechanical strength is better; 4) molecules contain a large number of functional groups of different types, and the use value of the compound can be enhanced by regulating or loading drugs and the like through a chemical modification method; 5) and contains a large amount of RGD sequence, thereThe adhesion and growth of cells are facilitated; secondly, the slow release of the medicine has the advantages of reducing the administration frequency, facilitating the administration, being completely absorbed, reducing the toxic and side effects and the like, can delay the absorption, release, distribution, metabolism and excretion processes of the medicine in vivo, and can accurately administer the medicine. So the requirement of drug slow release is further provided for the stent material; furthermore, in consideration of the effect of micro-current on the stimulation of tissue regeneration, the composite conductive scaffold material is further provided. The scaffold material with conductivity can enhance the action of micro-current by periodically loading an external power supply, control the release of drugs and promote the proliferation of cells; based on the above, the invention aims to combine the advantages of the acellular dermal matrix and the micro-current on promoting cell regeneration to construct a multifunctional biomedical scaffold material, which can be used as a new generation of bionic electronic skin medical scaffold and applied to the clinical medicine for wound healing after melanoma operation.
In order to achieve the purpose, the invention adopts the technical scheme that: the preparation method of the acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold comprises the following steps:
step 1, preparing an acellular pig dermal matrix loaded with silver nanowires;
and 2, loading the adriamycin hydrochloride temperature-sensitive drug-loaded silica microspheres in the acellular pig dermal matrix loaded with the nano silver wires to obtain the medical conductive scaffold with the functions of treating the melanoma and repairing tissues.
The step 1 specifically comprises the following steps:
preparing the acellular pig dermal matrix loaded with the nano silver wires: the acellular porcine dermal matrix is cut into 3.0cm diameter circular discs using a 3.0cm diameter cutting die, and weighed as W0And immersing it in 1.0 to 5.0W0And (4) soaking in the mL of the nano silver wire for 1-24 hours to obtain the acellular pig dermal matrix loaded with the nano silver wire.
The step 2 specifically comprises the following steps: taking 0.005-0.05W0Temperature-sensitive graft modified silicon dioxide microspheres and 0.001-0.01W0The doxorubicin hydrochloride is uniformly dispersed in 5-50W in the dark0The phosphate buffer solution of (1) has a pH of =7.4, and the reaction bodyThe acellular pig dermal matrix loaded with the nano silver wires is added into the system, and the system is vibrated for 12-48 h at the constant temperature of 37 ℃ to obtain the acellular pig dermal matrix/silicon dioxide microsphere temperature-sensitive antibacterial conductive scaffold.
The silicon dioxide microspheres are hollow, and the preparation steps are as follows:
weighing 0.1-2.0 g of hexadecyl trimethyl ammonium bromide powder, and dissolving the hexadecyl trimethyl ammonium bromide powder in a mixed solution of 5.0-20.0 g of ultrapure water, 5.0-20.0 g of ethanol and 1.0-5.0 mL of ammonium hydroxide; adding 5.0-50.0 g of polystyrene emulsion under vigorous stirring, carrying out ultrasonic treatment for 5.0-50.0 min, and stirring for 10-60 min at room temperature; slowly dripping 0.1-2.0 g of tetraethoxysilane into the reaction system, and continuously stirring for 0.5-3 hours; and centrifuging the obtained mixed solution at 5000-10000 rpm for 5-30 min, washing the product with a large amount of ethanol, drying at room temperature, and calcining at 400-800 ℃ for 1-12 h to obtain the hollow silica microspheres.
The preparation steps of the temperature-sensitive graft modified silica microspheres are as follows:
1) taking 10.0-100.0 mg of hollow silica microsphere powder and 10.0-100.0 g of ultrapure water into a reactor, carrying out ultrasonic dispersion for 10-60 min, heating the reaction system to 50-100 ℃, adding 0.1-1.0 g of liquid paraffin under vigorous stirring, continuously stirring for 10-60 min at constant temperature, filtering, and soaking in 10.0-50.0 mL of sodium hydroxide solution (1.0 mol/L) for 12-48 h to obtain the open-pore hollow silica microsphere.
2) Placing 0.1-1.0 g of open-pore hollow silica microspheres in 0.1-0.5L of ultrapure water, carrying out ultrasonic treatment for 10-60 min, adding 50.0-200.0 mg of acrylic acid, and stirring at a constant temperature of 50-100 ℃ for 1-10 h; adding 50.0-200.0 mg of N-isopropylacrylamide, 5.0-20.0 mg of N, N-methylenebisacrylamide and 10.0-50.0 mg of sodium dodecyl sulfate into a reaction system, and stirring at constant temperature for 10-60 min; slowly adding 5.0-50.0 mg of ammonium persulfate, stirring at constant temperature for 12-48 h, filtering, washing with a large amount of ethanol, and drying in vacuum at 50-80 ℃ to obtain the temperature-sensitive graft modified silicon dioxide microspheres.
The preparation steps of the polystyrene emulsion are as follows:
weighing 1.0-5.0 g of polyvinylpyrrolidone in 0.5-1.0L of ultrapure water, transferring the polyvinylpyrrolidone into a reactor after the polyvinylpyrrolidone is completely dissolved, adding 50.0-100.0 g of styrene, purging with nitrogen for 10-60 min, heating to 50-100 ℃, and stirring at constant temperature for 10-60 min; and adding 5.0-50.0 mL of 2,2' -azobisisobutyramidine hydrochloride, and performing nitrogen protection for 1-24 hours to obtain the polystyrene emulsion.
The application of the acellular porcine dermal matrix temperature-sensitive antibacterial conductive scaffold in the treatment of melanoma and the tissue repair treatment.
The polystyrene emulsion prepared by the invention has uniform size distribution and better stability.
The hollow silica microspheres prepared by the invention are of hollow structures, have larger specific surface area and can improve the drug loading rate.
The surface of the open-pore hollow silica microsphere prepared by the invention is opened to facilitate the entry of the drug and the temperature-sensitive substance into the microsphere, thereby reducing the side effect caused by the burst release of the drug.
The temperature-sensitive graft modified silica microspheres prepared by the invention have temperature sensitivity, so that the controlled release of the medicament is realized.
The acellular pig dermis matrix loaded with the nano silver wires prepared by the invention has antibacterial and conductive performances.
The acellular pig dermal matrix/silica microsphere temperature-sensitive antibacterial conductive scaffold prepared by the invention can be combined with biological micro-current to provide regular and quantitative micro-current stimulation, and the stimulation effect of the micro-current can be enhanced, so that the growth and differentiation of cells are promoted.
The acellular pig dermal matrix/silicon dioxide microsphere temperature-sensitive antibacterial conductive scaffold prepared by the invention has the performances of treating melanoma and repairing tissues.
The beneficial effects of the invention are:
compared with the prior art, the technology has the following advantages:
1) the acellular porcine dermal matrix is used as a base material, contains a large amount of RGD sequences, can promote the adhesion and growth of cells and induce the proliferation and differentiation of the cells, has a three-dimensional structure with high porosity, can provide enough space for the adhesion of the cells, the regeneration of extracellular matrix and the diffusion of the cells, has certain mechanical strength, can resist certain tissue stress, and plays a role of supporting and molding and is an excellent bionic skin scaffold base material;
2) compared with the traditional stent material, the conductive medical stent prepared by the invention has the most obvious difference that the conductive medical stent has conductivity, and the microcurrent promotes the growth, proliferation and differentiation of cells, thereby increasing the advantages of the conductive medical stent as the stent material;
3) the acellular pig dermal matrix/silicon dioxide microsphere temperature-sensitive antibacterial conductive scaffold prepared by the invention has the multiple functions of antibacterial property, temperature sensitivity, promotion of wound tissue healing, melanoma treatment and the like, and can be applied to skin melanoma treatment, postoperative repair and wound healing.
4) The SiO supported prepared by the invention2The medical bracket of the microsphere has temperature sensitivity, can accurately control the release, and has the prospect of being applied to novel intelligent medical materials for treating skin melanoma, repairing after operation and healing wounds.
In consideration of the harm of the antitumor drug to human bodies and the activity of the antitumor drug during local administration, the invention also needs to carry out the loading of the antitumor drug when preparing the tissue engineering scaffold with tumor healing performance so as to kill tumor cells, induce and stimulate tissue repair. The silicon dioxide microspheres have a large number of pore channel structures inside, so that antitumor active substances with higher concentration and larger molecular weight can be loaded. The hollow silica microsphere after temperature-sensitive grafting modification has larger specific surface area and more active sites, so that the drug can maintain activity and be released in a long-term and controlled manner in a long term during tissue repair. In addition, there are a number of studies that have demonstrated that the sustained release of silicon ions can improve cell viability and adhesion, promoting the synthesis and proliferation of type I collagen in skin fibroblasts in vitro.
The acellular pig dermal matrix after the foreign antigen is removed has a structure similar to that of a human acellular dermal matrix, provides a scaffold and a microenvironment for cell growth for regeneration and repair of skin tissues and wound healing, has high biocompatibility and biodegradability, and is widely applied to clinical wound treatment.
On the other hand, the living tissue has an electric field, the trans-epidermal voltage is between 20 and 50mV, and the skin epidermal voltage is lower. Typically, when a lesion occurs, a "lesion current" is generated between the deep tissue and the skin surface. Studies have shown that "damaging currents" may be responsible for the attraction of cells involved in repair, for altering the permeability of the cell membrane, for increasing the secretion products of the cells and for directing the remodelling of the cell structure. The fiber surface in the acellular pig dermis matrix soaked with the silver nanowires adsorbs and deposits a large number of silver nanowires to form an electronic channel, and the electronic channel has antibacterial and conductive performances. In addition, the electric stimulation can accelerate the movement of drug molecules in the composite stent, increase the release concentration of the drug, and achieve multifunctional intelligent controlled release by applying the electric stimulation and the temperature difference of injured skin tissues in combination with the temperature sensitivity of silicon dioxide, thereby obtaining the medical stent integrating the cancer treatment performance and the performance of promoting the regeneration of defective tissues.
Drawings
FIG. 1(a) scanning electron micrograph of acellular porcine dermal matrix (pADM);
FIG. 1(b) shows a temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO) of acellular porcine dermal matrix2) Scanning electron micrographs of internal fibers;
FIG. 1(c) shows a temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO) of acellular porcine dermal matrix2) Scanning electron micrographs of the surface;
FIG. 1(d) shows a temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO) of acellular porcine dermal matrix2) EDS picture of scanning electron microscope;
FIG. 2(a) is a schematic view of hollow silica microspheres (HSiO)2) Transmission electron microscopy images of;
FIG. 2(b) is an open-cell silica microsphere (DHSiO)2) Transmission electron microscopy images of;
FIG. 2(c) is a diagram of temperature-sensitive graft-modified silica microspheres (TSDHSiO)2) Transmission electron microscopy images of;
FIG. 2(d) shows hollow silica microspheres (HSiO)2) Zeta particle size diagram of (a);
FIG. 2(e) is a diagram of temperature-sensitive graft-modified silica microspheres (TSDHSiO)2) Zeta granules of (A)A radial graph;
FIG. 3(a) is a hollow silica microsphere (HSiO)2) A specific surface area test chart of (1);
FIG. 3(b) is a diagram of temperature-sensitive graft-modified silica microspheres (TSDHSiO)2) Specific surface area test chart;
FIG. 4(a) is a hollow silica microsphere (HSiO)2) Open pore silica microspheres (DHSiO)2) Temperature-sensitive graft modified silicon dioxide microsphere (TSDHSiO)2) An infrared spectrogram of doxorubicin hydrochloride (DOX);
FIG. 4(b) shows acellular porcine dermal matrix (pADM) and the temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO) of acellular porcine dermal matrix2) An infrared spectrum of (2);
FIG. 5(a) shows acellular porcine dermal matrix (pADM) and temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO) of acellular porcine dermal matrix2) Histogram of OD values for biocompatibility test;
FIG. 5(b) is a fluorescence microscope image of live/dead cells of the Control group (Control) in the biocompatibility experiment;
FIG. 5(c) is a fluorescent microscope photograph of live/dead cells of acellular porcine dermal matrix (pADM) in a biocompatibility experiment;
FIG. 5(d) shows the temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO) of acellular porcine dermal matrix in biocompatibility experiment2) Live/dead cell fluorescence microscopy images of (a).
Detailed Description
While the present invention will be described in conjunction with the embodiments set forth below, it is to be understood that the present invention is not limited to the precise embodiments described herein, and that various modifications and changes may be effected therein by one skilled in the art without departing from the scope of the invention as defined by the appended claims.
Example 1
1) Preparation of polystyrene emulsion: weighing 1.0g of polyvinylpyrrolidone in 0.5L of ultrapure water, transferring the polyvinylpyrrolidone into a reactor after the polyvinylpyrrolidone is completely dissolved, adding 50g of styrene, purging with nitrogen for 10min, heating to 50 ℃, and stirring at constant temperature for 10 min; and adding 5.0mL of 2,2' -azobisisobutyramidine hydrochloride, and carrying out nitrogen protection for 1h to obtain the polystyrene emulsion.
2) Preparing hollow silica microspheres: weighing 0.1g of hexadecyl trimethyl ammonium bromide powder, and dissolving the hexadecyl trimethyl ammonium bromide powder in a mixed solution of 5.0g of ultrapure water, 5.0g of ethanol and 1.0mL of ammonium hydroxide; adding 5.0g of the polystyrene emulsion under vigorous stirring, performing ultrasonic treatment for 5min, and stirring at room temperature for 10 min; slowly dripping 0.1g of tetraethoxysilane into the reaction system, and continuously stirring for 0.5 h; and centrifuging the obtained mixed solution at 5000rpm for 5min, washing the product with a large amount of ethanol, drying at room temperature, and calcining at 400 ℃ for 1h to obtain the hollow silica microspheres.
3) Temperature-sensitive modification of hollow silica microspheres: taking 10.0mg of hollow silica microsphere powder and 10.0g of ultrapure water, placing the hollow silica microsphere powder and the ultrapure water in a reactor, carrying out ultrasonic dispersion for 10min, heating a reaction system to 50 ℃, adding 0.1g of liquid paraffin under vigorous stirring, continuously stirring for 10min at constant temperature, filtering, and placing in 10.0mL of sodium hydroxide solution (1.0 mol/L) for soaking for 12-48 h to obtain the open-cell hollow silica microsphere.
Taking 0.1g of open-pore hollow silica microspheres and 0.1L of ultrapure water, carrying out ultrasonic treatment for 10min, adding 50.0mg of acrylic acid, and stirring at the constant temperature of 50 ℃ for 1 h; adding 50.0mg of N-isopropyl acrylamide, 5.0mg of N, N-methylene bisacrylamide and 10.0mg of sodium dodecyl sulfate into a reaction system, and stirring for 10min at constant temperature; slowly adding 5.0 ammonium persulfate, stirring at constant temperature for 12h, filtering, washing with a large amount of ethanol, and vacuum drying at 50 ℃ to obtain the temperature-sensitive graft modified silica microspheres.
4) Preparing the acellular pig dermal matrix loaded with the nano silver wires: the acellular porcine dermal matrix is cut into 3.0cm diameter circular discs using a 3.0cm diameter circular cutting die, and weighed as W0And dipped in 1.0W0Soaking in mL of nano silver wire for 1h to obtain the acellular pig dermal matrix loaded with the nano silver wire;
5) take 0.005W0Temperature-sensitive graft modified silica microspheres, 0.001W0The adriamycin hydrochloride is uniformly dispersed in 1.0W under dark0Adding a negative into a reaction system in a phosphate buffer solutionAnd (3) vibrating the acellular pig dermis matrix carrying the nano silver wires at the constant temperature of 37 ℃ for 12h to obtain the acellular pig dermis matrix/silicon dioxide microsphere temperature-sensitive antibacterial conductive scaffold.
Example 2
1) Preparation of polystyrene emulsion: weighing 2.0g of polyvinylpyrrolidone in 0.8L of ultrapure water, transferring the polyvinylpyrrolidone into a reactor after the polyvinylpyrrolidone is completely dissolved, adding 80g of styrene, purging with nitrogen for 30min, heating to 80 ℃, and stirring at constant temperature for 30 min; and adding 10.0mL of 2,2' -azobisisobutyramidine hydrochloride, and performing nitrogen protection for 12 hours to obtain the polystyrene emulsion.
2) Preparing hollow silica microspheres: weighing 0.8g of hexadecyl trimethyl ammonium bromide powder, and dissolving the hexadecyl trimethyl ammonium bromide powder in a mixed solution of 10.0g of ultrapure water, 10.0g of ethanol and 2.0mL of ammonium hydroxide; adding 25.0g of the polystyrene emulsion under vigorous stirring, performing ultrasonic treatment for 10min, and stirring at room temperature for 30 min; slowly dripping 1.5g of tetraethoxysilane into the reaction system, and continuously stirring for 0.5 h; and centrifuging the obtained mixed solution at 7000rpm for 15min, washing the product with a large amount of ethanol, drying at room temperature, and calcining at 600 ℃ for 8h to obtain the hollow silica microspheres.
3) Temperature-sensitive modification of hollow silica microspheres: taking 50.0mg of hollow silica microsphere powder and 50.0g of ultrapure water, placing the hollow silica microsphere powder and the ultrapure water in a reactor, carrying out ultrasonic dispersion for 30min, heating a reaction system to 80 ℃, adding 0.3g of liquid paraffin under vigorous stirring, continuously stirring for 15min at constant temperature, filtering, and then placing in 30.0mL of sodium hydroxide solution (1.0 mol/L) for soaking for 24h to obtain the open-pore hollow silica microsphere.
Taking 0.5g of open-pore hollow silica microspheres and 0.2L of ultrapure water, carrying out ultrasonic treatment for 30min, adding 100.0mg of acrylic acid, and stirring at the constant temperature of 70 ℃ for 4 h; adding 100.0mg of N-isopropyl acrylamide, 10.0mg of N, N-methylene bisacrylamide and 30.0mg of sodium dodecyl sulfate into a reaction system, and stirring at constant temperature for 30 min; slowly adding 10.0mg of ammonium persulfate, stirring at constant temperature for 20h, filtering, washing with a large amount of ethanol, and vacuum drying at 60 ℃ to obtain the temperature-sensitive graft-modified silicon dioxide microspheres.
4) Preparing the acellular pig dermal matrix loaded with the nano silver wires: acellular porcine dermal matrix using a circular cutting die with a diameter of 3.0cmCutting into 3.0cm diameter circular pieces, weighing and recording as W0And dipped in 2.0W0Soaking in mL of nano silver wire for 12h to obtain the acellular pig dermal matrix loaded with the nano silver wire;
5) take 0.01W0Temperature-sensitive graft modified silica microspheres, 0.005W0The adriamycin hydrochloride is uniformly dispersed in 20.0W under dark0Adding the acellular pig dermal matrix loaded with the nano silver wires into a reaction system in a phosphate buffer solution, and oscillating for 24 hours at a constant temperature of 37 ℃ to obtain the acellular pig dermal matrix/silicon dioxide microsphere temperature-sensitive antibacterial conductive scaffold.
Example 3
1) Preparation of polystyrene emulsion: weighing 5.0g of polyvinylpyrrolidone in 1.0L of ultrapure water, transferring the polyvinylpyrrolidone into a reactor after the polyvinylpyrrolidone is completely dissolved, adding 100.0g of styrene, purging with nitrogen for 60min, heating to 100 ℃, and stirring at constant temperature for 60 min; and adding 50.0mL of 2,2' -azobisisobutyramidine hydrochloride, and performing nitrogen protection for 24 hours to obtain the polystyrene emulsion.
2) Preparing hollow silica microspheres: weighing 2.0g of hexadecyl trimethyl ammonium bromide powder, and dissolving the hexadecyl trimethyl ammonium bromide powder in a mixed solution of 20.0g of ultrapure water, 20.0g of ethanol and 5.0mL of ammonium hydroxide; adding 50.0g of the polystyrene emulsion under vigorous stirring, performing ultrasonic treatment for 50min, and stirring at room temperature for 60 min; slowly dripping 2.0g of tetraethoxysilane into the reaction system, and continuously stirring for 3.0 hours; and centrifuging the obtained mixed solution at 1000rpm for 30min, washing the product with a large amount of ethanol, drying at room temperature, and calcining at 800 ℃ for 12h to obtain the hollow silica microspheres.
3) Temperature-sensitive modification of hollow silica microspheres: and (2) putting 100.0mg of hollow silica microsphere powder and 100.0g of ultrapure water into a reactor, performing ultrasonic dispersion for 60min, heating a reaction system to 100 ℃, adding 1.0g of liquid paraffin under vigorous stirring, continuously stirring at constant temperature for 60min, filtering, and soaking in 50.0mL of sodium hydroxide solution (1.0 mol/L) for 48h to obtain the open-pore hollow silica microsphere.
Taking 1.0g of open-pore hollow silica microspheres and 0.5L of ultrapure water, carrying out ultrasonic treatment for 60min, adding 200.0mg of acrylic acid, and stirring at constant temperature of 100 ℃ for 10 h; adding 200.0mg of N-isopropyl acrylamide, 20.0mg of N, N-methylene bisacrylamide and 50.0mg of sodium dodecyl sulfate into a reaction system, and stirring at constant temperature for 60 min; slowly adding 50.0mg of ammonium persulfate, stirring at constant temperature for 48h, filtering, washing with a large amount of ethanol, and vacuum drying at 80 ℃ to obtain the temperature-sensitive graft-modified silicon dioxide microspheres.
4) Preparing the acellular pig dermal matrix loaded with the nano silver wires: the acellular porcine dermal matrix is cut into 3.0cm diameter circular discs using a 3.0cm diameter circular cutting die, and weighed as W0And dipped in 5.0W0Soaking in mL of the silver nanowire for 24 hours to obtain the acellular pig dermal matrix loaded with the silver nanowire;
5) take 0.05W0Temperature-sensitive graft modified silica microspheres, 0.01W0The doxorubicin hydrochloride is uniformly dispersed in 50.0W under dark0Adding the acellular pig dermal matrix loaded with the nano silver wires into a reaction system in a phosphate buffer solution, and oscillating at the constant temperature of 37 ℃ for 48 hours to obtain the acellular pig dermal matrix/silicon dioxide microsphere temperature-sensitive antibacterial conductive scaffold.
Example four
A preparation method of a temperature-sensitive antibacterial conductive scaffold of an acellular pig dermal matrix comprises the following steps:
step 1, preparing an acellular pig dermal matrix loaded with silver nanowires;
and 2, loading doxorubicin hydrochloride thermosensitive drug-loaded silica microspheres in the acellular pig dermal matrix loaded with the nano silver wires to obtain the medical conductive scaffold with melanoma treatment and tissue repair functions.
The step 1 specifically comprises the following steps:
preparing the acellular pig dermal matrix loaded with the nano silver wires: the acellular porcine dermal matrix is cut into 3.0cm diameter circular discs using a 3.0cm diameter cutting die, and weighed as W0And immersing it in 3.0W0And (3) soaking the mL of the nano silver wire for 12 hours to obtain the acellular pig dermal matrix loaded with the nano silver wire.
The step 2 specifically comprises the following steps: take 0.03W0Temperature-sensitive graft modified silicon dioxide microsphere and 0.006W0The adriamycin hydrochloride is uniformly dispersed in 28W under dark0And (3) adding the acellular pig dermal matrix loaded with the nano silver wires into the phosphate buffer solution, wherein the pH of the phosphate buffer solution is =7.4, and oscillating the acellular pig dermal matrix loaded with the nano silver wires at the constant temperature of 37 ℃ for 30 hours to obtain the acellular pig dermal matrix/silica microsphere temperature-sensitive antibacterial conductive scaffold.
The silicon dioxide microspheres are hollow, and the preparation steps are as follows:
weighing 1.1g of hexadecyl trimethyl ammonium bromide powder, and dissolving the hexadecyl trimethyl ammonium bromide powder in a mixed solution of 13.0g of ultrapure water, 13.0g of ethanol and 3.0mL of ammonium hydroxide; adding 28g of polystyrene emulsion under vigorous stirring, performing ultrasonic treatment for 28min, and stirring at room temperature for 35 min; slowly dripping 1.1g of tetraethoxysilane into the reaction system, and continuously stirring for 1.8 h; and centrifuging the obtained mixed solution at 8000rpm for 18min, washing the product with a large amount of ethanol, drying at room temperature, and calcining at 600 ℃ for 6h to obtain the hollow silica microspheres.
The preparation steps of the temperature-sensitive graft modified silica microspheres are as follows:
1) taking 55mg of hollow silica microsphere powder and 55g of ultrapure water, carrying out ultrasonic dispersion for 30min, heating a reaction system to 80 ℃, adding 0.5g of liquid paraffin under vigorous stirring, continuously stirring for 30min at constant temperature, filtering, and soaking in 30.0mL of sodium hydroxide solution (1.0 mol/L) for 30h to obtain the hollow silica microspheres with open pores.
2) Placing 0.50g of open-pore hollow silica microspheres in 0.3L of ultrapure water, carrying out ultrasonic treatment for 35min, adding 125mg of acrylic acid, and stirring at the constant temperature of 75 ℃ for 5 h; adding 125mg of N-isopropylacrylamide, 13mg of N, N-methylenebisacrylamide and 30.0mg of sodium dodecyl sulfate into a reaction system, and stirring at constant temperature for 35 min; slowly adding 27.5mg of ammonium persulfate, stirring at constant temperature for 30h, filtering, washing with a large amount of ethanol, and vacuum drying at 65 ℃ to obtain the temperature-sensitive graft-modified silicon dioxide microspheres.
The preparation steps of the polystyrene emulsion are as follows:
weighing 3.0g of polyvinylpyrrolidone in 0.8L of ultrapure water, transferring the polyvinylpyrrolidone into a reactor after the polyvinylpyrrolidone is completely dissolved, adding 80.0g of styrene, purging with nitrogen for 35min, heating to 80 ℃, and stirring at constant temperature for 35 min; and adding 28.0mL of 2,2' -azobisisobutyramidine hydrochloride, and performing nitrogen protection for 13 hours to obtain the polystyrene emulsion.
EXAMPLE five
A preparation method of a temperature-sensitive antibacterial conductive scaffold of an acellular pig dermal matrix comprises the following steps:
step 1, preparing an acellular pig dermal matrix loaded with silver nanowires;
and 2, loading doxorubicin hydrochloride thermosensitive drug-loaded silica microspheres in the acellular pig dermal matrix loaded with the nano silver wires to obtain the medical conductive scaffold with melanoma treatment and tissue repair functions.
The step 1 specifically comprises the following steps:
preparing the acellular pig dermal matrix loaded with the silver nanowires: the acellular porcine dermal matrix was cut into 3.0cm diameter discs using a 3.0cm diameter cutting die and weighed as W0And immersing it in 1.0W0And (4) soaking the nano silver wire in the mL of nano silver wire for 1h to obtain the acellular pig dermal matrix loaded with the nano silver wire.
The step 2 specifically comprises the following steps: take 0.005W0Temperature-sensitive graft modified silica microspheres, 0.001W0The adriamycin hydrochloride is uniformly dispersed in 5W under dark0Adding the acellular pig dermal matrix loaded with the nano silver wires into the phosphate buffer solution, wherein the pH of the phosphate buffer solution is =7.4, and oscillating at the constant temperature of 37 ℃ for 12 hours to obtain the acellular pig dermal matrix/silica microsphere temperature-sensitive antibacterial conductive scaffold.
The silica microspheres are hollow, and the preparation steps are as follows:
weighing 0.1g of hexadecyl trimethyl ammonium bromide powder, and dissolving the hexadecyl trimethyl ammonium bromide powder in a mixed solution of 5.0g of ultrapure water, 5.0g of ethanol and 1.0mL of ammonium hydroxide; adding 5.0g of polystyrene emulsion under vigorous stirring, performing ultrasonic treatment for 5.0min, and stirring at room temperature for 10 min; slowly dripping 0.1g of tetraethoxysilane into the reaction system, and continuously stirring for 0.5 h; and centrifuging the obtained mixed solution at 5000rpm for 5min, washing the product with a large amount of ethanol, drying at room temperature, and calcining at 400 ℃ for 1h to obtain the hollow silica microspheres.
The preparation steps of the temperature-sensitive graft modified silicon dioxide microsphere are as follows:
1) taking 10.0mg of hollow silica microsphere powder and 10.0g of ultrapure water, placing the hollow silica microsphere powder and the ultrapure water in a reactor, carrying out ultrasonic dispersion for 10min, heating a reaction system to 50 ℃, adding 0.1g of liquid paraffin under vigorous stirring, continuously stirring for 10min at constant temperature, filtering, and then placing in 10.0mL of sodium hydroxide solution (1.0 mol/L) for soaking for 12h to obtain the open-pore hollow silica microsphere.
2) Placing 0.1g of open-pore hollow silica microspheres in 0.1L of ultrapure water, performing ultrasonic treatment for 10min, adding 50.0mg of acrylic acid, and stirring at the constant temperature of 50 ℃ for 1 h; adding 50.0mg of N-isopropyl acrylamide, 5.0mg of N, N-methylene bisacrylamide and 10.0mg of sodium dodecyl sulfate into a reaction system, and stirring for 10min at constant temperature; slowly adding 5.0mg of ammonium persulfate, then stirring at constant temperature for 12h, filtering, washing with a large amount of ethanol, and drying in vacuum at 50 ℃ to obtain the temperature-sensitive graft modified silicon dioxide microspheres.
The preparation steps of the polystyrene emulsion are as follows:
weighing 1.0g of polyvinylpyrrolidone in 0.5L of ultrapure water, transferring the polyvinylpyrrolidone into a reactor after the polyvinylpyrrolidone is completely dissolved, adding 50.0g of styrene, purging with nitrogen for 10min, heating to 50 ℃, and stirring at constant temperature for 10 min; and adding 5.0mL of 2,2' -azobisisobutyramidine hydrochloride, and carrying out nitrogen protection for 1h to obtain the polystyrene emulsion.
EXAMPLE six
A preparation method of a acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold comprises the following steps:
step 1, preparing an acellular pig dermal matrix loaded with silver nanowires;
and 2, loading doxorubicin hydrochloride thermosensitive drug-loaded silica microspheres in the acellular pig dermal matrix loaded with the nano silver wires to obtain the medical conductive scaffold with melanoma treatment and tissue repair functions.
The step 1 specifically comprises the following steps:
preparing the acellular pig dermal matrix loaded with the nano silver wires: the decellularized pig is cut by using a cutting die with the diameter of 3.0cmThe skin substrate was cut into 3.0cm diameter disks and weighed W0And immersing it in 5.0W0And (3) soaking the mL of the nano silver wire for 24 hours to obtain the acellular pig dermal matrix loaded with the nano silver wire.
The step 2 specifically comprises the following steps: take 0.05W0Temperature-sensitive graft modified silica microspheres, 0.01W0The adriamycin hydrochloride is uniformly dispersed in 50W under dark0And (3) adding the acellular pig dermal matrix loaded with the nano silver wires into the phosphate buffer solution, wherein the pH of the phosphate buffer solution is =7.4, and oscillating at the constant temperature of 37 ℃ for 48h to obtain the acellular pig dermal matrix/silica microsphere temperature-sensitive antibacterial conductive scaffold.
The silicon dioxide microspheres are hollow, and the preparation steps are as follows:
weighing 2.0g of hexadecyl trimethyl ammonium bromide powder, and dissolving the hexadecyl trimethyl ammonium bromide powder in a mixed solution of 20.0g of ultrapure water, 20.0g of ethanol and 5.0mL of ammonium hydroxide; adding 50.0g of polystyrene emulsion under vigorous stirring, performing ultrasonic treatment for 50.0min, and stirring at room temperature for 60 min; 2.0g of tetraethoxysilane is slowly dripped into the reaction system, and the stirring is continued for 3 hours; and centrifuging the obtained mixed solution at 10000rpm for 30min, washing a product by using a large amount of ethanol, drying at room temperature, and calcining at 800 ℃ for 12h to obtain the hollow silica microspheres.
The preparation steps of the temperature-sensitive graft modified silica microspheres are as follows:
1) taking 100.0mg of hollow silica microsphere powder and 100.0g of ultrapure water in a reactor, carrying out ultrasonic dispersion for 60min, heating the reaction system to 100 ℃, adding 1.0g of liquid paraffin under vigorous stirring, continuously stirring for 60min at constant temperature, filtering, and soaking in 50.0mL of sodium hydroxide solution (1.0 mol/L) for 48h to obtain the open-pore hollow silica microsphere.
2) Placing 1.0g of open-pore hollow silica microspheres in 0.5L of ultrapure water, performing ultrasonic treatment for 60min, adding 200.0mg of acrylic acid, and stirring at constant temperature of 100 ℃ for 10 h; adding 200.0mg of N-isopropyl acrylamide, 20.0mg of N, N-methylene bisacrylamide and 50.0mg of sodium dodecyl sulfate into a reaction system, and stirring at constant temperature for 60 min; slowly adding 50.0mg of ammonium persulfate, stirring at constant temperature for 48h, filtering, washing with a large amount of ethanol, and vacuum drying at 80 ℃ to obtain the temperature-sensitive graft-modified silicon dioxide microspheres.
The preparation steps of the polystyrene emulsion are as follows:
weighing 5.0g of polyvinylpyrrolidone in 1.0L of ultrapure water, transferring the polyvinylpyrrolidone into a reactor after the polyvinylpyrrolidone is completely dissolved, adding 100.0g of styrene, purging with nitrogen for 60min, heating to 100 ℃, and stirring at constant temperature for 60 min; and adding 50.0mL of 2,2' -azobisisobutyramidine hydrochloride, and performing nitrogen protection for 24 hours to obtain the polystyrene emulsion.
The acellular porcine dermal matrix is provided by Jiangyin running Xiang biotechnology limited in Jiangsu province.
Referring to fig. 1(a) - (D), fig. 1(b) and fig. 1(c) scanning electron microscope images of the acellular porcine dermal matrix temperature-sensitive antibacterial conductive scaffold, it can be observed that the preparation method still maintains the 3D network structure inside the acellular porcine dermal matrix, and the silica microspheres are uniformly deposited on the surface of the collagen fibers in a physical adsorption and chemical combination manner.
Referring to FIGS. 2(a) to (e), FIGS. 2(a), 2(b) and 2(c) are hollow silica microspheres (HSiO) respectively2) Open pore silica microspheres (DHSiO)2) Temperature-sensitive graft modified silicon dioxide microsphere (TSDHSiO)2) FIG. 2(d) and FIG. 2(e) are respectively a transmission electron micrograph of hollow silica microspheres (HSiO)2) Temperature-sensitive graft modified silicon dioxide microsphere (TSDHSiO)2) Zeta particle size diagram of (a); according to TEM results, the prepared silicon dioxide microspheres are hollow structures with the size of 200-300 nm, the wall thickness is about 50nm, and the detection result is consistent with that of Zeta particle size.
See FIGS. 3(a) - (b) for hollow silica microspheres (HSiO)2) And temperature-sensitive graft-modified silica microspheres (TSDHSiO)2) A specific surface area test chart of (1); the low pressure area is convex, the high pressure area is capillary condensation, the absorption and desorption are not coincident, the aperture belongs to mesopores and is between 2 and 50 nm.
Referring to FIGS. 4(a) - (b), FIG. 4(a) shows hollow silica microspheres (HSiO)2) Open-cell silica microspheres (a)DHSiO2) Thermo-sensitive graft modified silicon dioxide microsphere (TSDHSiO)2) An infrared spectrogram of doxorubicin hydrochloride (DOX); FIG. 4(b) shows acellular porcine dermal matrix (pADM) and temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO) of acellular porcine dermal matrix2) Infrared spectrum of (2).
Referring to fig. 5(a) - (d), fig. 5(a) is the OD value of the result of the biocompatibility experiment of the acellular pig dermal matrix (pADM) and the acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO 2), and fig. 5(b) - (d) are the fluorescence microscope images of the living/dead cells of the Control group (Control), the acellular pig dermal matrix (pADM) and the acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold (Ag-pADM @ TSDHSiO 2) in the biocompatibility experiment: the scaffold material has higher biocompatibility.
Claims (4)
1. The preparation method of the acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold is characterized by comprising the following steps:
step 1, preparing an acellular pig dermal matrix loaded with nano silver wires;
step 2, loading doxorubicin hydrochloride thermosensitive drug-loaded silica microspheres in the acellular pig dermal matrix loaded with the nano silver wires to obtain the medical conductive scaffold with melanoma treatment and tissue repair functions;
the silica microspheres are hollow, and the preparation steps are as follows:
weighing 0.1-2.0 g of hexadecyl trimethyl ammonium bromide powder, and dissolving the hexadecyl trimethyl ammonium bromide powder in a mixed solution of 5.0-20.0 g of ultrapure water, 5.0-20.0 g of ethanol and 1.0-5.0 mL of ammonium hydroxide; adding 5.0-50.0 g of polystyrene emulsion under vigorous stirring, carrying out ultrasonic treatment for 5.0-50.0 min, and stirring for 10-60 min at room temperature; slowly dripping 0.1-2.0 g of tetraethoxysilane into the reaction system, and continuously stirring for 0.5-3 hours; and centrifuging the obtained mixed solution at 5000-10000 rpm for 5-30 min, washing the product with a large amount of ethanol, drying at room temperature, and calcining at 400-800 ℃ for 1-12 h to obtain the hollow silica microspheres.
2. The preparation method of the acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold according to claim 1, wherein the silica microspheres are subjected to temperature-sensitive graft modification, and the preparation steps are as follows:
1) taking 10.0-100.0 mg of hollow silica microsphere powder and 10.0-100.0 g of ultrapure water, placing the hollow silica microsphere powder and the ultrapure water in a reactor, carrying out ultrasonic dispersion for 10-60 min, heating a reaction system to 50-100 ℃, adding 0.1-1.0 g of liquid paraffin under vigorous stirring, continuously stirring for 10-60 min at constant temperature, filtering, and soaking in 1.0mol/L of 10.0-50.0 mL of sodium hydroxide solution for 12-48 h to obtain open-cell hollow silica microspheres;
2) placing 0.1-1.0 g of open-pore hollow silica microspheres in 0.1-0.5L of ultrapure water, carrying out ultrasonic treatment for 10-60 min, adding 50.0-200.0 mg of acrylic acid, and stirring at a constant temperature of 50-100 ℃ for 1-10 h; adding 50.0-200.0 mg of N-isopropylacrylamide, 5.0-20.0 mg of N, N-methylenebisacrylamide and 10.0-50.0 mg of sodium dodecyl sulfate into a reaction system, and stirring at constant temperature for 10-60 min; slowly adding 5.0-50.0 mg of ammonium persulfate, stirring at constant temperature for 12-48 h, filtering, washing with a large amount of ethanol, and drying in vacuum at 50-80 ℃ to obtain the temperature-sensitive graft modified silicon dioxide microspheres.
3. The preparation method of the acellular pig dermal matrix temperature-sensitive antibacterial conductive scaffold according to claim 1, wherein the polystyrene emulsion is prepared by the following steps:
weighing 1.0-5.0 g of polyvinylpyrrolidone in 0.5-1.0L of ultrapure water, transferring the polyvinylpyrrolidone into a reactor after the polyvinylpyrrolidone is completely dissolved, adding 50.0-100.0 g of styrene, purging with nitrogen for 10-60 min, heating to 50-100 ℃, and stirring at constant temperature for 10-60 min; and adding 5.0-50.0 mL of 2,2' -azobisisobutyramidine hydrochloride, and performing nitrogen protection for 1-24 hours to obtain the polystyrene emulsion.
4. The use of the scaffold obtained by the method for preparing the acellular porcine dermal matrix temperature-sensitive antibacterial conductive scaffold according to any one of claims 1 to 3 in melanoma treatment materials and tissue repair materials.
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