CN116212119B - Hydrogel patch for promoting bone repair and preparation method thereof - Google Patents
Hydrogel patch for promoting bone repair and preparation method thereof Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
- D01D5/00—Formation of filaments, threads, or the like
- D01D5/0007—Electro-spinning
- D01D5/0015—Electro-spinning characterised by the initial state of the material
- D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
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- Health & Medical Sciences (AREA)
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- Transplantation (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Animal Behavior & Ethology (AREA)
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- Veterinary Medicine (AREA)
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- Engineering & Computer Science (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Mechanical Engineering (AREA)
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Abstract
The invention relates to the technical field of nanofiber material and hydrogel preparation, and designs a preparation method of a PCL-PLA-HA triaxial nanofiber-supported ibuprofen patch with a coaxial structure and a degradable hyaluronic acid hydrogel coated on the same. Three solutions containing three different solutes are conveyed by using a coaxial needle with different caliber sizes, electrostatic spinning is carried out by a conventional operation method, a PCL-PLA-HA nanofiber long-acting drug release patch is obtained, and a layer of hyaluronic acid-selenium hydrogel which can be degraded in vivo and detected by IVIS in vitro is coated on the patch. The preparation method is simple, the principle is reliable, the preparation technology is mature, the operation is simple and convenient, the yield is high, the cost is low, the product performance is good, and the environment is friendly.
Description
Technical Field
The invention relates to the technical field of preparation of nanofiber materials and hydrogels, in particular to a hydrogel patch for promoting bone repair and a preparation method thereof.
Background
At present, when aiming at the treatment of broken bones, the repair treatment is mainly carried out by utilizing a surgical operation mode, and bone nails and bone plates are used for fixing bones and waiting for recovery. Metal bone nails are common fixing materials in clinic, but general metal materials have poor biocompatibility, and because of the complex biological microenvironment of human bodies, the metal materials are more or less corroded after being implanted into bodies, the corroded metal materials have certain cytotoxicity, and released metal ions often cause inflammatory reactions and anaphylactic reactions of surrounding tissues. With the progress of science and technology, more and more researchers focus on the fabrication of biocompatible nanomaterials. The electrostatic spinning technology has the advantages of low cost, various spinnability, controllable process, capability of facilitating drug delivery and intercellular information exchange, capability of facilitating tissue ingrowth and the like, and wide application prospect in the fields of biomedicine and regenerative medicine.
Disclosure of Invention
The invention aims to prepare a hydrogel patch for promoting bone repair, which is supposed to prepare triaxial electrospinning, wherein the outer layer provides mechanical strength, the middle layer provides a material suitable for stitching and fixing in bone aspect and the like as a lubricating connecting layer of the inner and outer electrospinning, and the inner layer provides a degradable material capable of being wedged with hydrogel; the hydrogel which is flowable at the initial stage of meeting water is coated on the membrane, when the membrane wraps broken bones, the joint of the broken bones is filled up, the joint is solidified after a period of time and then degraded, and the hydrogel contains photosensitive substance-selenium, can be detected by In Vivo IMAGING SYSTEM (IVIS) In vitro, and can be absorbed by the body after degradation. Therefore, the material selects PCL with high toughness and strong hydrophobicity as an outermost layer structure, can be applied to suture lines, bone nails and PLA of bone plates as a middle layer structure, HAs hydrophilic HA as an innermost layer substrate, and simultaneously coats a three-coaxial structure nanofiber scaffold of ibuprofen medicament with antibacterial and anti-inflammatory functions, and the nanofiber scaffold is coated with hyaluronic acid-selenium hydrogel which is taken as a bone regeneration repair substrate and can be detected by IVIS.
In order to solve the technical problems, the invention adopts the following technical scheme:
A method for preparing a hydrogel patch for promoting bone repair, comprising the steps of:
A. dissolving polycaprolactone in a mixed solvent consisting of dichloromethane and N, N-dimethylformamide, and uniformly stirring to obtain PCL solution;
B. Dissolving polylactic acid in a mixed solvent consisting of dichloromethane and N, N-dimethylformamide, and uniformly stirring to obtain a PLA solution;
C. dissolving hyaluronic acid, polyethylene oxide and ibuprofen in formic acid, and uniformly stirring to obtain an HA solution;
D. Three coaxial needles with different apertures are selected for electrostatic spinning, PCL solution flows out from the outermost layer, PLA solution flows out from the middle layer, HA solution flows out from the innermost layer, and PCL-PLA-HA coaxial fibers are formed by solidification;
E. And dissolving hyaluronic acid in a mixed solvent consisting of deionized water, selenium dioxide and butanediol glycidyl ether, uniformly stirring to obtain an HA-Se-BDDE solution, standing, transferring to the PCL-PLA-HA coaxial fiber, and freeze-drying to obtain solid HA-Se-BDDE hydrogel/PCL-PLA-HA coaxial fiber, namely a hydrogel patch.
Polycaprolactone (PCL) is a common degradable stent material, has excellent biocompatibility, high strength and toughness, can well control the degradation time and microstructure of a tissue engineering stent, can hydrolyze under the conditions of enzymes and biological physiology, has low immunogenicity, and the degradation product is 6-hydroxyacetic acid, and belongs to a naturally-occurring metabolite in a human body. A 3D scaffold complex of PCL and bone marrow mesenchymal stem cells was prepared by a learner for repairing and reconstructing rabbit tracheal defects. However, PCL has certain disadvantages, and because of the hydrophobic material, PCL has poor hydrophilic properties.
Polylactic acid (PLA) is an important aliphatic polyester polymer material, is biodegradable, nontoxic and non-irritating, has good biocompatibility, can be degraded in human body, can be directly metabolized by human body to generate a final product CO 2,H2 O, and is discharged out of the body through kidneys, so that the polylactic acid is widely used as surgical suture lines, tissue engineering scaffolds, drug carriers and the like in the biomedical field. However, PLA materials are brittle, have high strength but poor toughness, which greatly limits their use in biological tissue engineering.
Hyaluronic Acid (HA) is a main component of connective tissue extracellular matrix, HAs strong hydrophilicity and HAs strong water-retaining capacity. Due to its excellent biocompatibility and biodegradability and its efficacy of promoting angiogenesis, reducing scar formation and promoting wound healing, it has been widely used in biomedical fields as a constituent of wound dressings, tissue home, drug delivery and implant materials. However, the electrospun HA itself does not have the mechanical strength and poor mechanical properties of the hernia patch.
Selenium (Selenium) is a trace mineral nutrient essential for human body, and the human body can not synthesize selenium by itself, so that selenium is a photosensitive substance. Selenium does not directly act on human body, but is used as an essential component in amino acid to assist the functions of various systems of human body and assist metabolism; in the cross-linking of the hydrogel, the time required for degradation can be prolonged, and the function of IVIS (in vivo IMAGING SYSTEM) in-vitro detection of hydrogel conditions is provided.
The PCL-PLA-HA patch HAs the advantages of strong tensile force resistance, hydrophobic PCL and strong mechanical property, and is suitable for providing tensile force and mechanical property as an external film; PLA itself HAs applications in surgical sutures, bone plates, and bone nails, here as a material joining PCL and HA with bone nails; HA itself HAs anti-adhesion, wound healing promoting and other effects, can inhibit fibroblast growth, promote epithelial cell growth, and is often used as a filler for joint surgery such as osteoarthritis and rheumatoid arthritis. HA HAs also been found to induce osteogenesis and can be a good osteoinductive scaffold material. The patch made of the three materials has good biocompatibility and anti-adhesion effect, can effectively reduce inflammatory reaction caused by microenvironment of a fracture part, can be automatically degraded and absorbed, has low complication occurrence rate of adhesion, erosion and the like at the patch, and besides, the fiber support made of the electrostatic spinning technology has the characteristics of high specific surface area and a porous structure, can be used as a carrier for releasing medicines, carries antibacterial and anti-inflammatory medicines and reduces the occurrence of inflammatory reaction of the fracture part.
HA itself can be prepared as a hydrogel but is easily degraded. The hyaluronic acid is crosslinked and modified by using butanediol glycidyl ether (BDDE) and selenium dioxide, the fluidity and degradation rate of the obtained HA-Se-BDDE hydrogel can be regulated, a carrier can be provided for growth factors and medicines, and the hydrogel can be used for coating the connecting part of broken bones and filling gaps due to the viscous flow characteristic of the hydrogel, so that the cell growth in the range is ensured.
The PCL-PLA-HA triaxial nanofiber with the coaxial structure HAs the same central axis, HAs a core-shell structure with three layers, and is internally loaded with ibuprofen for relieving heat, easing pain and resisting inflammation. The preparation method of the double crosslinked HA-Se-BDDE hydrogel HAs no proposal or publication of the prepared hyaluronic acid hydrogel by adopting a Se ion crosslinked structure and a BDDE covalent bond double crosslinked structure, but continuous experiments and intensive researches find that the addition of Se can cause the whole chemical structure of the hydrogel to change, and the degradation time of the hydrogel can be prolonged. In order to amplify the experimental effect, the invention designs a control group and a high-concentration selenium group to study the degradation time of the hydrogel, wherein the hydrogel in group A is crosslinked by BDDE only, and Se is not added additionally; group B adjusts the concentration of Se to 0.1%, group C adjusts the concentration of Se to 0.5%, and double crosslinking is performed on the hydrogel. The next day of the experiment, 15ml deionized water was added to each of the two groups, and degradation of the two groups of hydrogels was observed A, B. The hydrogel of the group A is changed into a semi-liquid state in the next day under the condition of adding water, and is completely hydrolyzed after 14 days; the hydrogel of the group B still maintains a colloid state after being added with water and is not degraded for more than 7 days; the group C hydrogels remained in a colloidal state after addition of water and were not degraded for more than 24 days. From this, se can prolong the degradation time of the hydrogel, and can be greatly prolonged along with the increase of Se concentration within a certain range. In addition to the prolonged degradation time, se can be detected by IVIS as a photosensitive substance, can be used as a developer, can detect the degradation degree of hydrogel in vitro, is a trace element required by human body, and can be absorbed by human body after degradation.
And D, carrying out electrostatic spinning by using three injection pumps and collecting plates with different flow rates, wherein the three injection pumps and the collecting plates correspond to three coaxial needles with different apertures.
In the step D, the aperture of the outermost layer is 17G, and the flow rate of the injection pump is 0.9-1.2 ml/h; the aperture of the middle layer is 22G, and the flow rate of the injection pump is 0.55-0.7 ml/h; the aperture of the outermost layer is 30G, and the flow rate of the injection pump is 0.2-0.4 ml/h; the voltage of the electrostatic spinning is 15-20 KV, the spinning distance is 10-15 cm, the spinning time is 5-10 hours, and the PCL-PLA-HA coaxial fiber is formed by solidifying on a collecting plate.
In the step A, the mass volume ratio of the polycaprolactone to the mixed solvent is 1.2g:10ml, wherein the mass ratio of dichloromethane to N, N dimethylformamide in the mixed solvent is 8:2; the stirring conditions in the step A are as follows: magnetically stirring at 200rpm for 5-12 hours at room temperature; and (3) standing for more than 3 hours after the stirring in the step (A) is completed.
In the step B, the mass volume ratio of the polylactic acid to the mixed solvent is 0.6g:10ml, wherein the mass ratio of dichloromethane to N, N dimethylformamide in the mixed solvent is 7:3; the stirring conditions in the step B are as follows: magnetically stirring at 200rpm for 5-12 hours at room temperature; and B, standing for more than 3 hours after stirring is completed.
In the step C, the mass-volume ratio of hyaluronic acid to polyethylene oxide to ibuprofen to formic acid is as follows: 0.2g:0.057g:0.011g:10ml; the stirring conditions in the step C are as follows: magnetic stirring is carried out for 4 to 7 days at 300rpm under the room temperature condition; and C, standing for more than 3 hours after stirring.
In the step E, the mass volume ratio of the hyaluronic acid to the mixed solvent is 1g:10ml, wherein the mass ratio of deionized water, selenium dioxide and butanediol glycidyl ether in the mixed solvent is 99.989:0.001:0.01; the stirring conditions in the step E are as follows: magnetically stirring for 24 hours at room temperature; and E, after stirring, standing for 24 hours, cleaning for three times by using deionized water, transferring to the PCL-PLA-HA coaxial fiber, placing in a refrigerator at the temperature of 80 ℃ below zero for 24 hours, and freeze-drying by using a freeze dryer to obtain the solid HA-Se-BDDE hydrogel/PCL-PLA-HA coaxial fiber, namely the hydrogel patch
A hydrogel patch obtained according to the above method for producing a hydrogel patch for promoting bone repair.
In the hydrogel patch, PCL-PLA-HA triaxial nanofibers with coaxial structures have the same central axis and have three layers of core-shell structures.
The invention designs a preparation method of a PCL-PLA-HA triaxial nanofiber-supported ibuprofen patch with a coaxial structure, and a degradable hyaluronic acid hydrogel is coated on the ibuprofen patch. The preparation method is simple, the principle is reliable, the preparation technology is mature, the operation is simple and convenient, the yield is high, the cost is low, the product performance is good, the non-invasive observation can be realized, and the environment is friendly.
Compared with the prior art, the implementation of the invention has the following beneficial effects:
Compared with the prior art, the invention prepares the nanofiber scaffold with three different material core-shell structures by adopting a coaxial electrostatic spinning method. The PCL of the outer layer and the PLA of the middle layer serve as materials with high toughness strength, firstly, to provide physical support, and secondly, serve as hydrophobic materials to prevent the approach of fibroblasts to cause adhesion of surrounding connective tissues. The innermost HA layer is wrapped with ibuprofen, which is a non-steroidal antipyretic analgesic anti-inflammatory drug, and the synthesis of the prostacyclin is reduced by inhibiting cyclooxygenase in a human body, so that the analgesic anti-inflammatory effect is achieved. The absorption rate is not affected by the age, and 90% of metabolites are metabolized in the liver and excreted with urine. Due to the hydrophilic characteristic of HA, HA can be gradually disintegrated after being transplanted into a body, the three-dimensional space structure of a stent is increased, the growth of self newly-born tissues is promoted, and medicines can be gradually released through a cavity, middle-layer PLA and a large-aperture structure formed by outer-layer PCL, so that the medicine can be used for resisting bacteria, diminishing inflammation and relieving pain, reducing the occurrence of inflammatory reaction and relieving pain of a patient, and helping the patient to recover better. The three-dimensional nano patch prepared by the method has the excellent characteristics of good biocompatibility, multiple holes, large specific surface area, light weight and the like, and the preparation method is simple, reliable in principle, simple and convenient to operate, mature in technology, low in cost and environment-friendly. The hydrogel is formed by bonding hyaluronic acid and selenium ions and covalent bonding with BDDE, when the hydrogel is changed into colloid from solid state when meeting water, the hydrogel is distributed into layers on electrospinning, and then the membrane is used for coating broken bones, 1. The colloid can flow to fill gaps, reduce holes and promote bone hyperplasia; 2. selenium is a photosensitive material, and the content of the selenium can be measured in vitro by IVIS equipment to confirm the content of hydrogel in vivo; BDDE is used as cross-linking agent to prolong the degradation time of hydrogel and form long-acting degradable bone hyperplasia rack. Together with the above 3 effects, se is crosslinked with hyaluronic acid ion, and then the hyaluronic acid ion is covalently crosslinked with BDDE, so that the whole body generates a synergistic effect to form hydrogel, and the hydrogel is an in-vivo degradable long-acting bone hyperplasia bracket which can be detected in vitro, is environment-friendly in vivo and has low cost. The combination of electrospinning and hydrogel can be used as a biomedical material for effectively treating broken bones and promoting bone hyperplasia.
Drawings
FIG. 1 is a diagram of a triaxial electrospinning apparatus according to the present invention;
FIG. 2 is a view showing the internal structure of a needle of the electrostatic spinning device of the present invention;
FIG. 3 is a PCL-PLA-HA triaxial fiber scanning electron microscope image of the present invention;
FIG. 4 is a schematic illustration of the solid HA-Se-BDDE hydrogel/PCL-PLA-HA coaxial electrospinning structure of the present invention;
FIG. 5 shows a process for preparing a solid HA-Se-BDDE hydrogel according to the invention and its possible chemical structural formula
FIG. 6 is a schematic representation of a hydrogel patch of the present invention promoting bone repair.
FIG. 7 is a schematic representation of the stirring of the hydrogels of the present invention at 45℃and 500rpm for 1 hour, wherein: a is HA-BDDE, B is HA-01Se-BDDE, and C is HA-05Se-BDDE.
FIG. 8 is a schematic representation of the stirring of the hydrogels of the present invention at 45℃and 500rpm for 5 hours, wherein: a is HA-BDDE, B is HA-01Se-BDDE, and C is HA-05Se-BDDE.
FIG. 9 is a schematic representation of a hydrogel of the invention after 1 day in PBS, wherein: a is HA-BDDE, B is HA-01Se-BDDE, and C is HA-05Se-BDDE.
FIG. 10 is a schematic representation of a hydrogel of the present invention after 7 days in PBS, wherein: a is HA-BDDE, B is HA-01Se-BDDE, and C is HA-05Se-BDDE.
FIG. 11 is a schematic representation of a hydrogel of the present invention after 14 days in PBS, wherein: a is HA-BDDE, B is HA-01Se-BDDE, and C is HA-05Se-BDDE.
FIG. 12 is a schematic representation of the hydrogels of the present invention after 24 days in PBS, wherein: a is HA-BDDE, B is HA-01Se-BDDE, and C is HA-05Se-BDDE.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings, for the purpose of making the objects, technical solutions and advantages of the present invention more apparent.
Example 1
1) Preparing a solution: a conventional electrostatic spinning device suitable for the spinning solution is selected, and a preparation occasion with the environment temperature of 25 ℃ and the humidity of 25% is selected. 1.2g of Polycaprolactone (PCL) was weighed under a fume hood using an electronic balance and dissolved in 10ml of a mixed solvent of Dichloromethane (DCM) and N, N dimethylformamide in a mass ratio of 8:2. Magnetically stirring for 5-12 hours at room temperature to obtain a uniform and transparent PCL solution with the concentration of 12% w/v; polylactic acid (PLA) and ibuprofen-containing Hyaluronic Acid (HA) solutions were prepared under the same environment. 0.6gPLA was weighed out and dissolved in 10ml of a mixed solvent consisting of Dichloromethane (DCM) and N, N Dimethylformamide (DMF) in a mass ratio of 7:3. Magnetically stirring for 5-12 hours at room temperature to obtain a uniform and transparent PLA solution with the concentration of 6% w/v; 0.2g HA,0.057g polyethylene oxide (PEO) and 0.011g ibuprofen (30% w/w) were weighed out and dissolved in 10ml formic acid solution. After magnetic stirring at room temperature for 4-7 days a homogeneous transparent 2% w/v HA solution was obtained.
2) And (3) electrostatic spinning: and standing the prepared solution for at least 3 hours, and then carrying out electrostatic spinning in a laminar flow hood by using three injection pumps and collecting plates with different flow rates by using a high-voltage power supply according to a conventional operation method by using an electrostatic spinning device. Three coaxial needles with the aperture sizes are selected, and the inner diameter and the outer diameter are respectively 30G/22G/17G from small to large. The needle and 10ml syringe were connected using a teflon hose and a 1.6mm PP internal screw fitting as shown in fig. 1 and 2. The flow rate of the three injection pumps is regulated according to the size of the inner diameter and the outer diameter, PCL liquid flows out from a channel with the caliber of the outermost layer 17G, and the flow rate of the injection pumps is 0.9ml/h; the outflow of the passage with the caliber of the middle layer 22G is PLA liquid, and the flow rate of the injection pump is 0.55ml/h; the flow of HA liquid out of the channel with the caliber of the innermost layer 30G is 0.3ml/h of the flow rate of the injection pump. Setting the voltage to 15KV, the spinning distance to 12cm, carrying out electrostatic spinning for 5-10 hours, forming tiny jet flow by the polymer solution under the action of high-voltage electricity, and finally solidifying the mixture solvent on a collecting plate after volatilizing the mixture solvent to obtain the triaxial PCL-PLA-HA fiber, as shown in figure 3.
3) Hydrogel: a conventional glass bottle suitable for the hydrogel solution of the invention is selected, and a preparation occasion with the environment temperature of 25 ℃ and the humidity of 25% is selected. Under a fume hood, 2g of Hyaluronic Acid (HA) was weighed by an electronic balance and dissolved in 20ml of a mixed solvent consisting of deionized water (H2O), selenium dioxide (SeO 2) and butanediol glycidyl ether (BDDE) in a mass ratio of 99.989:0.001:0.01. Magnetic stirring is carried out for 24 hours at room temperature to obtain a uniform and transparent HA-Se-BDDE solution, the solution is poured into a 15cm glass culture dish, the solution is kept stand for 24 hours, deionized water is used for cleaning three times, hydrogel is put on a coaxial electrospinning device, the coaxial electrospinning device is placed in a refrigerator at-80 ℃ for 24 hours for lyophilization, and solid HA-Se-BDDE hydrogel/PCL-PLA-HA coaxial electrospinning device can be obtained, as shown in figure 4; the HA-Se-BDDE hydrogel preparation process and possible chemical structural formula, se cross-links with hyaluronic acid ion, and then the hyaluronic acid ion cross-links with BDDE covalently, so that the whole generates synergistic effect to form hydrogel, as shown in fig. 5.
The solid HA-Se-BDDE hydrogel/PCL-PLA-HA co-axial electrospinning obtained can be used for promoting bone repair, as shown in figure 6.
Example 2
The influence of Se on the degradation time of the hydrogel is explored, and a comparison test is designed.
The method comprises the following steps:
Step 1: a, B, C groups were set up, 0.5g HA, 0.05g NaOH and 5ml deionized water (10% HA, 1% NaOH) were added, respectively, and stirred at 500r/min for 1 hour at 45 ℃.
Step 2: then adding 0.05ml of BDDE into each of A, B, C groups to crosslink, wherein the group A hydrogel is crosslinked by BDDE only, and Se, abbreviated as HA-BDDE, is not added additionally; group B additionally contains 0.005gSeO 2, i.e. 0.1% concentration of SeO 2, abbreviated as HA-01Se-BDDE; group C was added with 0.025gSeO 2 to adjust the concentration of SeO 2 to 0.5%, abbreviated as HA-05Se-BDDE, and the hydrogel was double crosslinked.
Group a shown in fig. 7 (left, body without obvious mark, with obvious abrasion), with bubbles after stirring; group B (in which the body is written with 0.005, the mass of SeO 2) has higher hardness than group A; group C (body written with 0.025) had significant hydrogel agglomeration.
Step 3: stirring was continued for 5 hours under the above conditions, and the results were shown in FIG. 8, wherein the A, B, C groups were all liquid and the color of group C was significantly different from that of the other groups. The next day it is seen that A, B, C groups are all solid,
Step 4: as shown in FIG. 9, 15ml deionized water was added to each of the A, B, C groups, and the hydrolysis was observed.
Step 5: after 7 days, it was observed that all three groups remained good, and only group a had a tendency to hydrolyze, as shown in fig. 10.
Step 6: group A (without SeO 2 added) was essentially hydrolyzed after 14 days with only a small amount of agglomerated colloid. The hydrolysis trend was evident in group B and no significant change was seen in group C, as shown in fig. 11.
Step 7: after 24 days no hydrogel was observed in group a, the hydrolysis was evident in group B, but the morphology remained barely good in group C, as shown in figure 12.
Therefore, se can effectively prolong the degradation time of the hydrogel, and the degradation time can be greatly prolonged along with the increase of Se concentration within a certain range.
The foregoing disclosure is merely illustrative of the preferred embodiments of the present invention and is not intended to limit the scope of the claims herein, as equivalent changes may be made in the claims herein without departing from the scope of the invention.
Claims (9)
1. A method for preparing a hydrogel patch for promoting bone repair, comprising the steps of:
A. Dissolving polycaprolactone in a mixed solvent consisting of dichloromethane and N, N-dimethylformamide, and uniformly stirring to obtain PCL solution;
B. Dissolving polylactic acid in a mixed solvent consisting of dichloromethane and N, N-dimethylformamide, and uniformly stirring to obtain a PLA solution;
C. Dissolving hyaluronic acid, polyethylene oxide and ibuprofen in formic acid, and uniformly stirring to obtain an HA solution;
D. Three coaxial needles with different apertures are selected for electrostatic spinning, PCL solution flows out from the outermost layer, PLA solution flows out from the middle layer, HA solution flows out from the innermost layer, and PCL-PLA-HA coaxial fibers are formed by solidification;
E. And dissolving hyaluronic acid in a mixed solvent consisting of deionized water, selenium dioxide and butanediol glycidyl ether, uniformly stirring to obtain an HA-Se-BDDE solution, standing, transferring to the PCL-PLA-HA coaxial fiber, and freeze-drying to obtain solid HA-Se-BDDE hydrogel/PCL-PLA-HA coaxial fiber, namely a hydrogel patch.
2. The method of claim 1, wherein in step D, three syringe pumps and collection plates with different flow rates are used to perform the electrospinning corresponding to three coaxial needles with different apertures.
3. The method for preparing a hydrogel patch for promoting bone repair according to claim 2, wherein in the step D, the outermost pore diameter is 17G, and the flow rate of the syringe pump is 0.9-1.2 ml/h; the aperture of the middle layer is 22G, and the flow rate of the injection pump is 0.55-0.7 ml/h; the aperture of the innermost layer is 30G, and the flow rate of the injection pump is 0.2-0.4 ml/h; the voltage of the electrostatic spinning is 15-20 KV, the spinning distance is 10-15 cm, the spinning time is 5-10 hours, and the PCL-PLA-HA coaxial fiber is formed by solidifying on a collecting plate.
4. The method of preparing a hydrogel patch for promoting bone repair according to claim 1, wherein in step a, the mass to volume ratio of polycaprolactone to mixed solvent is 1.2g:10ml, wherein the mass ratio of dichloromethane to N, N dimethylformamide in the mixed solvent is 8:2; the stirring conditions in the step A are as follows: magnetically stirring at 200rpm for 5-12 hours at room temperature; and (3) standing for more than 3 hours after the stirring in the step (A) is completed.
5. The method of preparing a hydrogel patch for promoting bone repair according to claim 1, wherein in step B, the mass to volume ratio of polylactic acid to mixed solvent is 0.6g:10ml, wherein the mass ratio of dichloromethane to N, N dimethylformamide in the mixed solvent is 7:3; the stirring conditions in the step B are as follows: magnetically stirring at 200rpm for 5-12 hours at room temperature; and B, standing for more than 3 hours after stirring is completed.
6. The method for preparing a hydrogel patch for promoting bone repair according to claim 1, wherein in the step C, the mass-to-volume ratio of hyaluronic acid, polyethylene oxide, ibuprofen, and formic acid is: 0.2g:0.057g:0.011g:10ml; the stirring conditions in the step C are as follows: magnetically stirring at 300rpm for 4-7 days at room temperature; and C, standing for more than 3 hours after stirring.
7. The method of preparing a hydrogel patch for promoting bone repair according to claim 1, wherein in step E, the mass to volume ratio of hyaluronic acid to mixed solvent is 1g:10ml, wherein the mass ratio of deionized water, selenium dioxide and butanediol glycidyl ether in the mixed solvent is 99.989:0.001:0.01; the stirring conditions in the step E are as follows: magnetically stirring for 24 hours at room temperature; and E, standing for 24 hours after stirring, cleaning for three times by using deionized water, transferring to the PCL-PLA-HA coaxial fiber, and freeze-drying in a refrigerator at the temperature of 80 ℃ below zero for 24 hours to obtain the solid HA-Se-BDDE hydrogel/PCL-PLA-HA coaxial fiber, namely the hydrogel patch.
8. A hydrogel patch obtained according to the method of preparing a hydrogel patch for promoting bone repair of claim 1.
9. The hydrogel patch according to claim 8 wherein the PCL-PLA-HA triaxial nanofibers of coaxial structure have the same central axis and have a three-layered core-shell structure.
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