CN117018290B - Silk protein nanofiber nerve conduit with bionic orientation structure and preparation method thereof - Google Patents
Silk protein nanofiber nerve conduit with bionic orientation structure and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- 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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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/32—Materials or treatment for tissue regeneration for nerve reconstruction
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Abstract
The invention provides a silk fibroin nanofiber nerve conduit with a bionic orientation structure, which comprises an outer conduit and a three-dimensional support inner core, wherein the outer conduit is coated on the outer side of the three-dimensional support inner core in a tubular shape, the outer conduit and the three-dimensional support inner core are prepared from silk fibroin nanofibers obtained through physical decomposition, and the three-dimensional support inner core has the bionic orientation structure. The nerve conduit prepared by the invention is different from the nerve conduit with hollow inside, the nerve conduit with the three-dimensional orientation structure not only can provide a protective barrier for the damaged nerve, but also can support and guide the directional growth of the damaged nerve by utilizing the contact induction principle, has a repair effect similar to that of the autologous nerve, and has clinical application value.
Description
Technical Field
The invention relates to the biomedical field, in particular to a silk fibroin nanofiber nerve conduit with a bionic orientation structure and a preparation method thereof.
Background
Peripheral nerve damage is often caused by accidental injury, disease complications, and surgical side effects, and millions of people worldwide suffer from peripheral nerve damage each year, which not only severely affects the quality of life of the patient, but also causes a tremendous amount of economic loss. Currently, the treatment of peripheral nerve injury mainly includes autologous nerve transplantation and allogeneic nerve transplantation. Autologous nerve grafting is currently the "gold standard" for treating peripheral nerve injury, and the graft is removed from another part of the patient's body, typically selecting sural or epidermal nerves as the donor to bridge the defect site of the peripheral nerve. Autologous nerve transplantation is limited by many factors such as high incidence rate of donor sites, few sources of donor tissues, high risk of neuroma, insufficient recovery of nerve functions, mismatching of sizes and the like, and allograft also has the problem of rejection in vivo. Therefore, development of a new strategy as a treatment method for peripheral nerve regeneration has become an important study subject, and bridging the proximal and distal ends of a damaged nerve using a nerve guiding catheter to support guiding the growth and extension of the regenerated nerve from the proximal end to the distal end is attracting increasing attention.
Nerve conduits made from natural or synthetic high molecular weight polymers have been shown to be effective in aiding repair of damaged nerves. Document "Trends in the design of nerve guidance channels in peripheral nerve tissue engineering" introduced that over the last 20 years the U.S. Food and Drug Administration (FDA) has approved a variety of nerve conduit products for repairing peripheral nerve damage, including Neuragen, neuroflex, neuroMatrix, neuraWrap and NeuroMend prepared based on type I collagen; surgis Nerve Cuff prepared from porcine intestinal submucosa mucosa; neurolac prepared from polyglycolic acid as raw material and poly (lactide-caprolactone) as raw material. The clinical application is mainly focused on three products of Neuragen, neurotube and Neurolac, but the three products have respective defects, mainly including poor flexibility of materials, mismatch of degradation time and nerve growth speed, and lack of bionic structures for guiding peripheral nerve regeneration inside a catheter. The literature FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy discloses that the degradation time of the neurogen is too long, between 36 and 48 months, nerve compression and inflammatory reaction can be caused, the degradation time of the Neurotube is short, and about 3 months, the mechanical property of the nerve guiding catheter is insufficient, and the growth and repair of the regenerated nerve can be endangered. The main disadvantage of Neurolac is its low porosity and expansibility, which can lead to complete blockage of the lumen interior, preventing nerve regeneration. Meanwhile, the research results in documents Collagen scaffolds modified with CNTF and bFGF promote facial nerve regeneration in minipigs and matrix, scaffoldes and and carriers for protein and molecule delivery in peripheral nerve regeneration show that the hollow-structure catheter can also cause random dispersion of regenerated nerves, and the natural nerve internal nerve fiber parallel arrangement structure is inspired, and the bionic orientation structure is built in the catheter, so that the growth and functional recovery of the nerves can be more effectively promoted.
The three-dimensional orientation structure bracket is filled in the nerve guiding catheter, so that the physicochemical microenvironment of nerve growth can be simulated to the greatest extent, and the orientation guiding efficiency can be greatly improved. In the document Nerve guidance conduits with hierarchical anisotropic architecture for peripheral nerve regeneration, lu and the like are filled into a catheter, an orientation structure is formed in the catheter by using an electric field, an internally oriented nerve guiding catheter is obtained after freeze drying, and cell experimental results show that the Schwann cells and PC-12 cells normally proliferate in the catheter, meanwhile, the secretion of brain-derived neurotrophic factors can be promoted, the animal experimental results have no obvious difference with an autologous nerve group, and the potential of replacing autologous nerve transplantation is provided; in the document "A bioengineered peripheral nerve construct using aligned peptide amphiphile nanofibers", li et al, a self-assembled peptide two-parent nanofiber solution was injected through a screen having a diameter of 40 μm by means of a syringe and refilled into the catheter to obtain a nerve guiding catheter in which nanofibers were aligned, and the results of animal experiments were similar to those of the autologous nerve graft group. Unidirectional freezing is a mature method for preparing an oriented scaffold, and utilizes the principle of directional growth of ice crystals to produce a scaffold with a three-dimensional oriented structure inside. In the literature "Biopolymer-nanotube nerve guidance conduit drug delivery for peripheral nerve regeneration: in vivo structural and functional assessment", ohan et al obtained a nerve guiding catheter internally filled with a chitosan scaffold having a pore size of about 60 μm by a one-way freezing method, and bridged the sciatic nerve defect model of 15 mm rats, and as a result, it was revealed that the regenerated nerve growth was excellent, and the presence of specific markers such as S100 and nerve filaments was observed. However, the nerve guiding catheter has the fatal problems of poor mechanical property and high degradation speed, and the natural silk with excellent mechanical property and excellent biocompatibility is selected as the raw material and decomposed into the nanofibers by a physical mode, so that the degradation speed of the natural silk is more matched with the regeneration repair speed of the nerve while the mechanical property and the biocompatibility are ensured, and the nerve injury is more favorably repaired.
Disclosure of Invention
The technical problems to be solved are as follows: the invention aims to provide a silk fibroin nanofiber nerve conduit with a bionic orientation structure and a preparation method thereof, and the nerve conduit with a three-dimensional orientation structure not only can provide a protective barrier for damaged nerves, but also can support and guide the directional growth of the damaged nerves by utilizing the principle of contact induction, has a repair effect similar to that of autologous nerves, and has clinical application value, unlike the nerve conduit with a hollow inside.
The technical scheme is as follows: the nerve conduit comprises an outer conduit and a three-dimensional support inner core, wherein the outer conduit is coated on the outer side of the three-dimensional support inner core in a tubular shape, the outer conduit and the three-dimensional support inner core are prepared from silk fibroin nanofibers obtained through physical decomposition, the three-dimensional support inner core is provided with three-dimensional orientation through holes in the axial direction, the inner pore diameter of each through hole is 20-150 mu m, and the size of each through hole is similar to that of a natural nerve fiber.
Preferably, the diameter of the outer conduit is 1.5-10 mm, and the length of the outer conduit is 5-50 mm.
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, degumming silk, crushing, mixing the crushed silk with water, and decomposing the mixture in a physical mode to obtain silk protein nanofiber dispersion liquid;
s2, spreading the silk fibroin nanofiber dispersion liquid prepared in the step S1 into a mold, dehydrating to obtain a silk fibroin nanofiber membrane, and winding the silk fibroin nanofiber membrane into an outer catheter;
s3, adding the silk fibroin nanofiber dispersion liquid prepared in the step S1 into a heat preservation mould, then carrying out unidirectional freezing treatment, and carrying out freeze drying treatment after unidirectional freezing treatment to obtain a three-dimensional oriented silk fibroin nanofiber scaffold, namely a three-dimensional scaffold inner core;
and S4, filling the three-dimensional stent inner core prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic orientation structure.
Preferably, the silk in the step S1 is one or a combination of two or more of tussah silk, mulberry silk, castor silk and tussah silk.
Preferably, the physical decomposition method in the step S1 is one or two or more of high-speed shearing, high-speed grinding or ultrasonic treatment.
Preferably, the rotating speed of the high-speed shearing is 5000-60000 r/min, and the treatment time is 0.2-4 h; the rotating speed of the grinding head for high-speed grinding is 2000-30000 r/min, and the treatment time is 0.5-8 h; the ultrasonic frequency is 50-800 kHz during ultrasonic treatment, and the treatment time is 8-48 hours.
Preferably, the concentration of the silk fibroin nanofiber dispersion in the step S1 is 0.2-5 wt%.
Preferably, the dehydration treatment temperature in the step S2 is 25-110 ℃.
Preferably, the freezing temperature in the step S3 is between-40 ℃ and-196 ℃, and the freezing time is between 0.5 and 2 hours.
The beneficial effects are that: the silk fibroin nanofiber nerve conduit with the bionic orientation structure has the following advantages:
according to the invention, the natural silk nanofiber is used as a raw material to prepare the three-dimensional orientation scaffold, the natural silk has better mechanical property and slower degradation speed compared with regenerated silk fibroin, and meanwhile, the permeability of the scaffold prepared from the nanofiber is more permeable, so that regenerated nerve cells and tissues can migrate from the proximal end to the distal end;
according to the invention, the nerve conduit is prepared by adopting the structure that the three-dimensional oriented silk fibroin nanofiber stent inner core is coated by the outer conduit instead of the hollow conduit, because the hollow conduit has limited guiding and supporting effects on regenerated nerves, the regenerated nerves can be dispersed, the silk nanofiber stent with high porosity and an oriented structure is filled in the conduit based on a bionic principle according to the internal structure of natural nerves, the regenerated nerves can be better guided to grow, the high-porosity stent can not hinder the growth of the nerves, and meanwhile, the three-dimensional oriented silk fibroin nanofiber stent inner core is coated by the outer conduit, so that the regenerated nerves and the three-dimensional oriented silk fibroin nanofiber stent inner core can be protected, and the outer conduit can be sutured with nerve breaking ends, so that the applicability is strong;
the invention adopts ice crystals which form an orientation structure in silk nanofiber dispersion liquid by unidirectional temperature conduction, the ice crystals extrude nanofibers to form through holes of the orientation structure, and then freeze drying is ice crystal sublimation, so that the internally oriented nanofiber scaffold is obtained, and the prepared scaffold has high porosity and can better guide the growth of regenerated nerves.
Drawings
FIG. 1 is an optical photograph of a silk fibroin nanofiber dispersion of example 1;
FIG. 2 is a flow chart of the preparation of a three-dimensional oriented silk fibroin nanofiber scaffold;
FIG. 3 is a scanning electron microscope image of a three-dimensional oriented silk fibroin nanofiber scaffold of example 2;
FIG. 4 is a confocal laser photograph of example 3 cells growing on the surface of a silk fibroin nanofiber outer catheter;
FIG. 5 is a confocal laser photograph of example 4 cells growing inside a three-dimensional oriented silk fibroin nanofiber scaffold;
FIG. 6 is a graph of hematoxylin-eosin stained sections of example 5 cells grown in a three-dimensional oriented silk fibroin nanofiber scaffold with top-to-bottom infiltration;
fig. 7 is a photograph of a nerve conduit bridge 10mm damaged nerve operation of example 6, wherein the left image is a photograph of the bridge after nerve disruption, and the right image is a photograph of the bridge after three months;
FIG. 8 is a photograph of hematoxylin-eosin staining after three months of repair of damaged nerves of example 6, left panel is nerve conduit group, right panel is autologous nerve group;
FIG. 9 is an electrophysiological test picture of example 7 after three months of damaged nerve repair, with the left panel being the nerve conduit group and the right panel being the autologous nerve group;
FIG. 10 is a transmission electron microscope image of the remyelination of damaged nerve of example 7, the left image is a nerve conduit group, and the right image is an autologous nerve group.
Detailed Description
The invention will be further described with reference to the accompanying drawings and examples, which are illustrative of the invention and not intended to limit the invention to the examples below:
example 1
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, putting 100 g tussah raw silk into 5L Na with the concentration of 0.5-wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and cleaning with 60deg.C deionized water. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 2 g degummed silk into pieces with a length of about 5 mm, adding 100 mL water, placing into a high-speed shearing machine for treatment at a shearing machine rotating speed of 30000 r/min, and treating for 10, 20 and 30 min (10 TSF, 20TSF and 30 TSF) to obtain nanofiber dispersion;
s2, spreading 20 g nanofiber dispersion liquid in a round die with the diameter of 100 mm, drying at 60 ℃ to form a film, cutting the nanofiber film into proper dimensions, and winding to form an outer catheter with the diameter of 1.5 mm and the length of 10 mm;
s3, injecting the nanofiber dispersion liquid into a heat-preserving mold with an opening at one end, putting into liquid nitrogen, performing unidirectional freezing for 40min, and performing freeze drying treatment for 48 and h to obtain the three-dimensional oriented silk fibroin nanofiber scaffold;
s4, filling the three-dimensional oriented silk fibroin nanofiber scaffold prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic oriented structure.
As shown in FIG. 1, the silk is uniformly dispersed in water after high-speed shearing treatment, the treatment time is respectively 10min, 20min and 30 min, and respectively corresponds to 10TSF, 20TSF and 30TSF in the figure, and it can be seen from the figure that the nanofiber dispersion liquid is more uniform along with the increase of the treatment time.
Example 2
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, placing 100 g mulberry silk into 5L Na with concentration of 0.05 wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and cleaning with 60deg.C deionized water. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 5 g degummed silk into pieces with a length of about 2 mm, adding 300 mL water, placing into a high-speed grinding machine, and processing at a grinding head rotation speed of 10000 r/min for 50 min to obtain nanofiber dispersion;
s2, taking 30 g nanofiber dispersion liquid, spreading the nanofiber dispersion liquid in a circular die with the diameter of 150 mm, drying the nanofiber dispersion liquid at the temperature of 25 ℃ to form a film, cutting the nanofiber film into a proper size, and winding and forming to obtain an outer catheter with the diameter of 2 mm and the length of 15 mm;
s3, injecting the nanofiber dispersion liquid into a heat-insulating mold with one end open, and placing the mold in an environment of-80 ℃ for unidirectional freezing for 50 min, and performing freeze drying treatment on the mold for 24 h to obtain the three-dimensional oriented silk fibroin nanofiber scaffold;
s4, filling the three-dimensional oriented silk fibroin nanofiber scaffold prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic oriented structure.
As shown in FIG. 2, which is a flow chart of preparing three-dimensional oriented silk protein nanofiber scaffolds from silk, it can be seen from FIG. 3 that the internal orientation structure of the scaffolds is obvious after unidirectional freezing, the pore walls of the scaffolds are formed by interweaving nanofibers, and the pore diameters are between 20 and 80 mu m, which is beneficial to cell growth and proliferation.
Example 3
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, putting 100 g castor silkworms into 5L Na with the concentration of 0.5-wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and subsequently adding deionized water at 60deg.C to obtain Morus albaAnd (5) cleaning raw silk of silkworms. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 6 g degummed silk into pieces with a length of about 1 mm, adding 200 mL water, placing into a high-speed grinding machine for treatment, wherein the grinding head rotating speed is 20000 r/min, treating for 50 min, and then placing into a cell ultrasonic pulverizer with a frequency of 100 kHz for treating 8 h to obtain nanofiber dispersion;
s2, spreading 15 g nanofiber dispersion liquid in a circular die with the diameter of 50 mm, drying to form a film at the temperature of 40 ℃, cutting the nanofiber film into proper dimensions, and winding to form an outer catheter with the diameter of 3 mm and the length of 12 mm;
s3, injecting the nanofiber dispersion liquid into a heat-preserving mold with one end open, and placing the mold into an environment of-40 ℃ for unidirectional freezing for 120 min, and performing freeze drying treatment for 30 h to obtain the three-dimensional oriented silk fibroin nanofiber scaffold;
s4, filling the three-dimensional oriented silk fibroin nanofiber scaffold prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic oriented structure.
As shown in figure 4, cells are inoculated on the surface of a silk fibroin nanofiber outer catheter, the growth condition of the cells is observed by using a laser confocal microscope after 7 days, the cells are normal in morphology and form of a shuttle or triangle, and the cells can normally grow and reproduce on the surface of the catheter, so that the material has no biotoxicity.
Example 4
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, placing 100 g natural silk of Bombyx mori L into 5L Na with concentration of 0.05 wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and cleaning with 60deg.C deionized water. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 3 g degummed silk into pieces with length of about 6 mm, adding 100 mL water, placing into a high-speed shearing machine, treating at blade rotation speed of 32000 r/min for 60 min, placing into a high-speed grinding machine, and treating at grinding head rotation speed of 10000 r/min for 30 min to obtain nanofiber dispersionA liquid;
s2, spreading 40 g nanofiber dispersion liquid in a circular die with the diameter of 150 mm, drying to form a film at 80 ℃, cutting the nanofiber film into proper dimensions, and winding to form an outer catheter with the diameter of 2.5 mm and the length of 15 mm;
s3, injecting the nanofiber dispersion liquid into a heat-insulating mold with one end open, and placing the mold in an environment of-80 ℃ for unidirectional freezing for 30 min, and performing freeze drying treatment for 48 h to obtain the three-dimensional oriented silk fibroin nanofiber scaffold;
s4, filling the three-dimensional oriented silk fibroin nanofiber scaffold prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic oriented structure.
As shown in figure 5, cells are inoculated in the three-dimensional oriented silk fibroin nanofiber scaffold, the growth condition of the cells is observed by using a laser confocal microscope after 5 days, the cells are normal in morphology and form of a shuttle, normal adhesion and proliferation can be realized on the surface of a pore wall, and meanwhile, the oriented growth of the cells along the pore wall can be observed, so that the scaffold has the capability of directionally guiding the oriented growth and repair of cells and tissues.
Example 5
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, putting 100 g tussah raw silk into 5L Na with the concentration of 0.5-wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and cleaning with 60deg.C deionized water. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 2 g degummed silk into pieces with a length of about 2 mm, adding 200 mL water, placing into a high-speed shearing machine for treatment, and treating at a blade rotation speed of 43000 r/min for 60 min to obtain nanofiber dispersion;
s2, spreading 200 g nanofiber dispersion liquid in a round die with the diameter of 90 mm, drying to form a film at the temperature of 60 ℃, cutting the nanofiber film into proper dimensions, and winding to form an outer catheter with the diameter of 1.5 mm and the length of 10 mm;
s3, injecting the nanofiber dispersion liquid into a heat-preserving mold with an opening at one end, putting into liquid nitrogen, performing unidirectional freezing for 60 min, and performing freeze drying treatment for 72 h to obtain the three-dimensional oriented silk fibroin nanofiber scaffold;
s4, filling the three-dimensional oriented silk fibroin nanofiber scaffold prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic oriented structure.
As shown in FIG. 6, cells were seeded on top of a three-dimensional oriented silk fibroin nanofiber scaffold, and the infiltration growth condition of the cells into the interior of the scaffold was observed after 15 days by hematoxylin-eosin staining, and as a result, it was found that cell growth was observed in both the middle and bottom of the scaffold, indicating that the scaffold was excellent in permeability, favorable for cell migration, and did not hinder the growth of regenerated tissues.
Example 6
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, placing 100 g mulberry silk into 5L Na with concentration of 0.05 wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and cleaning with 60deg.C deionized water. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 4 g degummed silk into pieces with a length of about 3 mm, adding 200 mL water, and processing in a cell ultrasonic pulverizer with a frequency of 500 kHz for 24 h to obtain nanofiber dispersion;
s2, taking 30 g nanofiber dispersion liquid, spreading the nanofiber dispersion liquid in a circular die with the diameter of 120mm, drying the nanofiber dispersion liquid at the temperature of 90 ℃ to form a film, cutting the nanofiber film into a proper size, and winding and forming to obtain an outer catheter with the diameter of 2 mm and the length of 5 mm;
s3, injecting the nanofiber dispersion liquid into a heat-preserving mold with an opening at one end, putting into liquid nitrogen, unidirectional freezing for 45 min, and performing freeze drying treatment for 48 and h to obtain the three-dimensional oriented silk fibroin nanofiber scaffold;
s4, filling the three-dimensional oriented silk fibroin nanofiber scaffold prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic oriented structure.
As shown in fig. 7 and 8, the nerve conduit was bridged at the ischial nerve defect of SD rat 5 mm, and the nerve was recovered to be normal after three months, and the hematoxylin-eosin staining result found that a certain number of regenerated axons and regenerated blood vessels exist in both the nerve conduit group and the autologous nerve group, which indicates that the nerve conduit has similar repair ability as the autologous nerve.
Example 7
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, putting 100 g castor silkworms into 5L Na with the concentration of 0.5-wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and cleaning with 60deg.C deionized water. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 3 g degummed silk into pieces with a length of about 5 mm, adding 300 mL water, placing into a high-speed shearing machine for treatment, and treating for 80 min at a blade rotation speed of 36000 r/min to obtain nanofiber dispersion;
s2, spreading 50 g nanofiber dispersion liquid in a round die with the diameter of 160mm, drying to form a film at the temperature of 30 ℃, cutting the nanofiber film into proper dimensions, and winding to form an outer catheter with the diameter of 1.5 mm and the length of 10 mm;
s3, injecting the nanofiber dispersion liquid into a heat-insulating mold with one end open, and placing the mold in an environment of-80 ℃ for unidirectional freezing for 60 min, and performing freeze drying treatment on the mold for 72 h to obtain the three-dimensional oriented silk fibroin nanofiber scaffold;
s4, filling the three-dimensional oriented silk fibroin nanofiber scaffold prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic oriented structure.
As shown in fig. 9 and 10, the nerve conduit is bridged at the ischial nerve defect of SD rat 10mm, and the three months electrophysiological test result shows that the nerve conduit group has no significant difference in muscle action composite potential and nerve conduction speed from the autologous nerve group, the regenerated myelin sheath can be observed under a transmission electron microscope, and the myelin sheath diameter and the myelin sheath wall thickness are close, which indicates that the nerve conduit repair capability is similar to that of a 'gold standard' autologous nerve, and has clinical application value.
Comparative example 1
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, placing 100 g mulberry silk into 5L Na with concentration of 0.05 wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and cleaning with 60deg.C deionized water. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 3 g degummed silk into pieces with a length of about 5 mm, adding 300 mL water, placing into a high-speed shearing machine for treatment, and treating for 80 min at a blade rotation speed of 36000 r/min to obtain nanofiber dispersion;
s2, spreading 50 g nanofiber dispersion liquid in a round die with the diameter of 160mm, drying to form a film at the temperature of 30 ℃, cutting the nanofiber film into proper dimensions, and winding to form an outer catheter with the diameter of 1.5 mm and the length of 10 mm;
the hollow outer catheter is bridged at the ischial nerve defect of the SD rat 10mm, the sole of the experimental side of the rat in three months is obviously ulcerated and degenerated, and the movement function is almost lost.
Comparative example 2
The preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, putting 100 g tussah raw silk into 5L Na with the concentration of 0.5-wt% 2 CO 3 Boiling in solution at 100deg.C for 30 min, and cleaning with 60deg.C deionized water. Repeating the process for three times to remove sericin on the surface of raw silk, and then drying in a 60 ℃ oven to obtain degummed silk; cutting 2 g degummed silk into pieces with a length of about 5 mm, adding 300 mL water, placing into a high-speed grinding machine, and treating at a blade rotation speed of 20000 r/min for 60 min to obtain nanofiber dispersion;
s2, spreading 40 g nanofiber dispersion liquid in a round die with the diameter of 120mm, drying at the temperature of 30 ℃ to form a film, cutting the nanofiber film into proper dimensions, and winding and forming to obtain an outer catheter with the diameter of 1.5 mm and the length of 10 mm;
s3, putting the nanofiber dispersion liquid into an environment of-80 ℃ for freezing 24 h, and carrying out freeze drying treatment on the nanofiber dispersion liquid 72 h to obtain the three-dimensional unordered silk protein nanofiber scaffold;
s4, filling the three-dimensional disordered silk fibroin nanofiber scaffold prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic orientation structure.
The hollow outer catheter is bridged at the ischial nerve defect of the SD rat 10mm, the foot sole part of the three-month mouse experiment side is ulcerated and degenerated, the nerve regeneration and repair effect is not ideal, the gastrocnemius muscle is seriously atrophic, and the electrophysiological result is obviously lower than the effect after repairing the nerve by the three-dimensional oriented silk protein nanofiber scaffold.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (8)
1. A silk fibroin nanofiber nerve conduit with a bionic orientation structure, which is characterized in that: the nerve conduit comprises an outer conduit and a three-dimensional bracket inner core, wherein the outer conduit is coated on the outer side of the three-dimensional bracket inner core in a tubular shape, the outer conduit and the three-dimensional bracket inner core are prepared from silk fibroin nanofibers obtained through physical decomposition, the three-dimensional bracket inner core is provided with a three-dimensional orientation through hole in the axial direction, the inner aperture of the through hole is 20-150 mu m, and the size of the through hole is similar to that of a natural nerve fiber;
the preparation method of the silk fibroin nanofiber nerve conduit with the bionic orientation structure comprises the following steps:
s1, degumming silk, crushing, mixing the crushed silk with water, and decomposing the mixture in a physical mode to obtain silk protein nanofiber dispersion liquid;
s2, spreading the silk fibroin nanofiber dispersion liquid prepared in the step S1 into a mold, dehydrating to obtain a silk fibroin nanofiber membrane, and winding the silk fibroin nanofiber membrane into an outer catheter;
s3, adding the silk fibroin nanofiber dispersion liquid prepared in the step S1 into a heat preservation mould, then carrying out unidirectional freezing treatment, and carrying out freeze drying treatment after unidirectional freezing treatment to obtain a three-dimensional oriented silk fibroin nanofiber scaffold, namely a three-dimensional scaffold inner core;
and S4, filling the three-dimensional stent inner core prepared in the step S3 into the outer catheter prepared in the step S2 to obtain the silk fibroin nanofiber nerve catheter with the bionic orientation structure.
2. The silk fibroin nanofiber nerve conduit with a biomimetic orientation structure of claim 1, wherein: the diameter of the outer conduit is 1.5-10 mm, and the length of the outer conduit is 5-50 mm.
3. The silk fibroin nanofiber nerve conduit with a biomimetic orientation structure of claim 1, wherein: the silk in the step S1 is one or a combination of two or more of tussah silk, mulberry silk, castor silk and tussah silk.
4. The silk fibroin nanofiber nerve conduit with a biomimetic orientation structure of claim 1, wherein: the physical decomposition method in the step S1 is one or two or more of high-speed shearing, high-speed grinding or ultrasonic treatment.
5. The silk fibroin nanofiber nerve conduit with a biomimetic orientation structure of claim 4, wherein: the rotating speed of the high-speed shearing is 5000-60000 r/min, and the treatment time is 0.2-4 h; the rotating speed of the grinding head for high-speed grinding is 2000-30000 r/min, and the treatment time is 0.5-8 h; the ultrasonic frequency is 50-800 kHz during ultrasonic treatment, and the treatment time is 8-48 hours.
6. The silk fibroin nanofiber nerve conduit with a biomimetic orientation structure of claim 1, wherein: the concentration of the silk fibroin nanofiber dispersion liquid in the step S1 is 0.2-5 wt%.
7. The silk fibroin nanofiber nerve conduit with a biomimetic orientation structure of claim 1, wherein: and the dehydration treatment temperature in the step S2 is 25-110 ℃.
8. The silk fibroin nanofiber nerve conduit with a biomimetic orientation structure of claim 1, wherein: the freezing temperature in the step S3 is between-40 ℃ and-196 ℃, and the freezing time is 0.5-2 h.
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