CN107865979A - A kind of three-dimensional manometer fibrous framework based on microflow control technique and electrostatic spinning technique and preparation method thereof - Google Patents
A kind of three-dimensional manometer fibrous framework based on microflow control technique and electrostatic spinning technique and preparation method thereof Download PDFInfo
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- CN107865979A CN107865979A CN201710796004.9A CN201710796004A CN107865979A CN 107865979 A CN107865979 A CN 107865979A CN 201710796004 A CN201710796004 A CN 201710796004A CN 107865979 A CN107865979 A CN 107865979A
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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
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
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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
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
-
- 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
-
- 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
- A61L27/56—Porous materials, e.g. foams or sponges
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- 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
-
- 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
- D01D5/0061—Electro-spinning characterised by the electro-spinning apparatus
-
- 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
- D01D5/0061—Electro-spinning characterised by the electro-spinning apparatus
- D01D5/0092—Electro-spinning characterised by the electro-spinning apparatus characterised by the electrical field, e.g. combined with a magnetic fields, using biased or alternating fields
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- D—TEXTILES; PAPER
- D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
- D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
- D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
- D04H1/72—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged
- D04H1/728—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged by electro-spinning
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
-
- 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
Abstract
The present invention relates to microflow control technique and electrostatic spinning technique field, there is provided the method that one kind has the three-dimensional manometer fibrous framework of " micro--to receive " composite construction.The single dispersing fibroin albumen microballoon for being loaded with size uniform is prepared by microflow control technique, slowly stable release is presented with fibroin microsphere degraded in growth factor, to give full play to its biological effect, solve in the prior art because uneven microballoon, caused dash forward made from mechanical agitation, vibration, ultrasound homogenate etc. release problem and " peak valley " phenomenon；In addition, using double shower nozzles or single nozzle to the fibroin albumen microballoon containing growth factor and the ethanol solution of PEO (PEO), and the hexafluoroisopropanol solution of fibroin albumen carries out electrostatic spinning, PEO fibers therein are then dissolved, prepare " micro--to receive " complex three-dimensional nano fiber scaffold with uniform loose structure and suitable voidage.The support has good biocompatibility and certain mechanical property, and is advantageous to cell and is grown into its inside, promotes the growth and migration of cell；With improving small-caliber artificial blood vessel long-term patency rate and remolding the dual-use function of vascular wall, suitable for damage or the reparation or displacement of lesion small-caliber vascular tissue.
Description
Technical field
The present invention relates to microflow control technique and electrostatic spinning technique field, more particularly to a kind of microflow control technique to prepare uniformly
Mono-dispersion microballoon and by electrostatic spinning technique that mono-dispersion microballoon is compound with nanofiber, preparing has " micro--to receive " compound
The method of the three-dimensional manometer fibrous framework of structure.
Background technology
Angiocardiopathy produces great threat to human health, and there are 17,000,000 people in the whole world at the beginning of 21 century because of cardiovascular and cerebrovascular
Disease death, to the year two thousand twenty, this number will be up to 25,000,000 people.With the rising of cardiovascular disease incidence rate, reconstructing blood vessel is facing
There is increasingly consequence in bed surgical operation, but autologous vein source is very limited, the various bores of urgent clinical needs
Vasotransplantation substitute.Heavy caliber artificial blood vessel is applied to clinic at present, and achieves satisfied effect.It is but small-bore
Artificial blood vessel (diameter<The demand of clinic 6mm) is not met by, its main cause is when blood and artificial blood vessel lumen contact
When, because CBF is small, flow velocity is slow, easily triggers platelet rich type thrombus, causes luminal stenosis, blood vessel embolism.Therefore,
How small-caliber artificial blood vessel prevents Acute thrombosis and luminal stenosis after implanting, improve long-term patency rate and have become
The difficult point and focus of artificial blood vessel research.
Endothelial cellular membrane is one layer of pinacocyte for being continuously covered in whole intravascular space surface, is between vascular wall
Barrier between blood, smooth surface is provided for blood flow to maintain the normal fluidised form of blood.Endothelial cell is unique in vivo
Cell type with anti-thrombus function, it can synthesize and secrete various bioactivators, prevent platelet adhesion reaction and aggregation,
Effectively prevent thrombosis.Spontaneous endothelialization is the focus of artificial blood vessel research in recent years in small-caliber artificial blood vessel body, and
The sticking of endothelial cell, breed and migration is an important factor for small-caliber artificial blood vessel influences spontaneous endothelialization after implanting
One of.In angiogenic process, growth factor can promote angiogenesis, and the regeneration to blood vessel plays an important role.So
And the expression quantity of growth factor is too high, most probably trigger vascular defect.Therefore, the controlled release system of growth factor is established, extends it
Bioactivity in vivo simultaneously ensures steady slowly lasting release, avoids producing " peak valley " phenomenon during release, is effectively to play
The key factor of growth factor effect.
Controlled release release is to make at the uniform velocity outside at regular time and quantity such as medicine, growth factor, gene the methods of passing through clothing film
Release, makes its dosage slowly be discharged in vivo with certain speed in specific time range, to reach treatment disease, tissue
Purpose expected from regeneration etc..Controlled release delivery systems have in terms of the validity such as medicine, growth factor, gene and security is improved
The advantages of numerous, can not only effective control release speed, moreover it is possible to increase stability, maintain local concentration, improve medicine, growth
The action and efficacies such as the factor, gene simultaneously reduce toxic side effect.Microballoon is a kind of wide variety of controlled release carrier, and researchers propose
Many methods, including emulsion process, spray drying process, self-assembly method, template etc..But most method have it is certain
Limitation, it is required to act on obtaining by mechanical external forces such as mechanical agitation, vibration, ultrasound homogenate than these preparation methods as described above
Scattered emulsion droplet, this microballoon for introducing mechanical external force preparation are not sufficiently stable, and size is not uniform enough, architectural difference is big, dispersiveness
Difference, influence effective controlled release release of medicine.In addition, strong mechanical external force effect and larger shearing force, can make protein,
Polypeptide isoreactivity drug inactivation.Therefore, how to avoid mechanical external force from acting on as far as possible in preparation process, and how to prepare
Uniform particle sizes, architectural difference be small, good dispersion microballoon, for preparation long-acting can discharge, toxic side effect is small, bioavilability
High slow control-release microsphere has great importance.
Micro-fluidic (Microfluidics) is a kind of accurate control and manipulation minute yardstick fluid, especially refers in particular to sub-micron knot
The technology of structure, it is a kind of very promising method for preparing the controllable polymer microballoon of size uniform, it is possible to achieve such as
Janus, ternary, multinuclear or the microballoon of the different-shape such as hollow and composition.Therefore, we are equal using microflow control technique preparation size
Even mono-dispersion microballoon loads growth factor, and accurately controls its particle diameter and drugloading rate, to reach stably and controllable release, avoids
Side effect produces, so as to play safely and effectively and to greatest extent its biological effect.
Silk is a kind of special biomaterial to attract people's attention in recent years, and there is excellent biocompatibility and biology to drop
Xie Xing, better than traditional synthesized degradable high polymer material.Silk is made up of two kinds of albumen, and internal layer is fibroin albumen, outer layer quilt
Sericin coats.Fibroin albumen has good human body compatibility, nontoxic and biodegradable etc. premium properties, can be prepared into more
Kind form, is a kind of more satisfactory bio-medical material.This patent is by the growth factor microballoon and fibroin albumen of size uniform
Electrospun nano-fibers support is combined, to prepare the function and can reservation silk fibroin nano-fiber that can embody microballoon
The composite nano fiber scaffold of performance.
Electrospun nano-fibers support is because having bionic extracellular matrix, higher porosity and larger specific surface area
The features such as and in field of tissue engineering technology by extensive concern, but its fine and close structure is difficult to make cell grow into internal stent.For
The more preferable structure for imitating natural extracellular matrix, promotes cell to grow into nano fiber scaffold inside.We are by fibroin egg
PEO (PEO) solution of white solution and the microballoon containing fibroin albumen carries out electrostatic spinning simultaneously according to different ratios, with
After dissolve PEO fibers therein, prepare the three-dimensional manometer fibrous framework with " micro--to receive " composite construction.The support can make
Cell is internally grown into, and promotes the growth and migration of cell, has the long-term patency rate for improving small-caliber artificial blood vessel and remodeling
The dual-use function of vascular wall.
The content of the invention
In order to solve small-caliber artificial blood vessel Acute thrombosis and luminal stenosis, and long-term patency rate in the prior art
The problem of low.It is an object of the invention to provide one kind cell is grown into internal stent, promotes the growth and migration of cell,
With " micro--to receive " the complex three-dimensional Nanowire for improving small-caliber artificial blood vessel long-term patency rate and remodeling vascular wall dual-use function
Dimensional scaffold.
Technical scheme is used by the present invention solves the above problems：One kind is based on microflow control technique and electrostatic spinning technique
The method for preparing the three-dimensional manometer fibrous framework with " micro--to receive " composite construction, " micro--to receive " the complex three-dimensional nanofiber
Support is the fibroin albumen microballoon containing certain porosity and size uniform inside a kind of nanofiber.The step of the preparation method
It is rapid as follows：
Using a kind of micro flow control chip device for preparing single dispersing fibroin albumen microballoon, including micro pump, micro-fluidic core
Piece, drop receives and storage container.With in 3~10%wt% silk fibroin protein solution add needed for embedding and sustained release growth because
Son be used as dispersed phase, and the mixed liquor of surfactant and oil phase, using different flow velocity or pressure ratio, is sheared as continuous phase
Into the drop of monodispersity parcel growth factor.Then solidify drop using suitable curing, obtain size uniformity, divide
Dissipate stable fibroin albumen microballoon.And it is using electrostatic spinning technique that fibroin albumen microballoon and nanofiber is compound, spinning solution is
The alcohol mixeding liquid of fibroin albumen microballoon and PEO (PEO), and the hexafluoroisopropanol solution of fibroin albumen, collect dress
It is set to rotation circular shaft collector at a high speed.By the ethanol blended liquid of the fibroin albumen microballoon of different proportion and PEO (PEO),
And the hexafluoroisopropanol solution of fibroin albumen carries out electrostatic spinning.PEO fibers therein are then dissolved, preparing has necessarily
Porosity and good " micro--to receive " the complex three-dimensional nano fiber scaffold of mechanical property." micro--to receive " complex three-dimensional in the present invention
Nano fiber scaffold can be such that cell is grown into its inside, promote the growth and migration of cell, have and improve small-bore artificial blood
The dual-use function of pipe long-term patency rate and remodeling vascular wall.
Preferably, micro fluidic device continuous phase provided by the invention includes soybean oil, methyl-silicone oil, polyethylene glycol hydrogenated
One or more of groups in castor oil, Emulsifier EL-60, sunflower oil, sorbester p17, MCT Oil, glycerine
Compound.
Preferably, the method that the present invention prepares single dispersing fibroin microsphere using microflow control technique, mild condition, reappearance
It is good, size uniform, stable release can be achieved.
Preferably, it is of the present invention embedding and sustained release growth factor for vascular endothelial growth factor (VEGF),
Fibroblast growth factor (FGF), basic fibroblast growth factor (bFGF), EGF (EGF),
One or more combination thing in Ephrin-B2.
Preferably, scattered phase pressure of the present invention is 20mba~120mba, continuous phase pressure be 150mba~
600mba。
Preferably, single dispersing fibroin microsphere particle diameter of the present invention is at 5 μm~20 μm.
Preferably, the micro-sphere method of the present invention for preparing solves traditional skills such as mechanical agitation, vibration, ultrasound homogenate
Art prepares being such as not sufficiently stable in microballoon, and size is not uniform enough, architectural difference is big, bad dispersibility, and protein, polypeptide etc.
The problems such as active component inactivates.
Preferably, electrospun material of the present invention, can be fibroin albumen, polycaprolactone (PCL), collagen,
One or more combination thing in chitosan, polylactic acid (PLA), polyglycolic acid (PLLA), PEO (PEO).Solvent
For the one or more combination thing in chloroform, acetone, hexafluoroisopropanol, ethanol, tetrahydrofuran, N,N-dimethylformamide.
Preferably, electrostatic spinning of the present invention is using 2 electrostatic spinning nozzles (double shower nozzles) or by 2 electrostatic
Spinning nozzle interflow is a single nozzle.
Preferably, electrospinning device device of the present invention, comprising carrying out electrostatic spinning with equidirectional, and
Relative direction carries out electrostatic spinning.
Preferably, electrospinning parameters of the present invention are preferably：Voltage 5KV~20KV, spinning solution inject speed
Reception distance 10cm~20cm of 0.5mL/h~2mL/h, syringe needle and metal shaft, high speed rotating collecting device rotating speed 500rpm~
3500rpm, electrostatic spinning total time 3h~5h.
Preferably, present invention incorporates micro-fluidic and two kinds of technologies of electrostatic spinning, it is prepared for that there is uniform porous knot
" micro--to receive " complex three-dimensional nano fiber scaffold of structure, the hole of small size and good mechanical property.
The present invention compared with prior art, has advantages below and effect：Utilize microflow control technique and electrostatic spinning technique
Prepare " micro--to receive " complex three-dimensional nano fiber scaffold with good biocompatibility and certain mechanical property.The support carries
There is the single dispersing fibroin albumen microballoon of size uniform, slowly stable release is presented with fibroin microsphere degraded in growth factor, to fill
Distribution wave its biological effect, solve in the prior art because mechanical agitation, vibration, ultrasound homogenate etc. made from uneven microballoon,
Caused dash forward releases problem and " peak valley " phenomenon；In addition, uniform loose structure and suitable voidage, be advantageous to cell to its
Inside is grown into, and promotes the growth and migration of cell.The support, which has, improves small-caliber artificial blood vessel long-term patency rate and remodeling blood
The dual-use function of tube wall, suitable for damage or the reparation or displacement of lesion small-caliber vascular tissue.
Brief description of the drawings
Fig. 1 is " micro--to receive " complex three-dimensional nano fiber scaffold exterior appearance figure prepared by implementation column 1 of the present invention.A is logical
Cross microflow control technique and prepare the fibroin albumen droplet figure for loading growth factor；B is " micro--to receive " complex three-dimensional nano fiber scaffold
Electron microscope；CD is the outside drawing of " micro--to receive " complex three-dimensional nano fiber scaffold；
Fig. 2 is the schematic diagram that the embodiment of the present invention 2 prepares " micro--to receive " complex three-dimensional nano fiber scaffold；
Embodiment
Below in conjunction with the accompanying drawings and the present invention is described in further detail by embodiment.Following examples are to this hair
Bright explanation and the invention is not limited in following examples.
The invention provides a kind of " micro--to receive " complex three-dimensional nano fiber scaffold, specific implementation step are as follows：
(1) the fibroin albumen microballoon for loading growth factor is prepared using microflow control technique
Using the micro flow control chip device that can prepare single dispersing fibroin albumen microballoon, including micro pump, micro-fluidic chip, liquid
Drop receives and storage container.Made with adding the growth factor of required embedding and sustained release in 3~10%wt% silk fibroin protein solution
For dispersed phase；It is preferably 20%~0.5% using the mixture of surfactant and oil as continuous phase, its mixed proportion.Using
Different flow velocitys or pressure ratio, micro-fluidic parameter are preferably：Dispersed phase is 20mba~120mba, continuous phase be 150mba~
600mba, cut into the drop of monodispersity parcel growth factor.Then drop is entered by collecting pipe fills sorbester p17 oil phase
Collecting pit in.Obtained drop is cooled to 4 DEG C, under 4 DEG C of cryogenic conditions, adds a certain amount of organic solvent, is mixed
Uniformly.After 4 hours, the particulate of sedimentation is washed 2 times using petroleum ether, absolute ethyl alcohol respectively, fibroin egg is obtained after freeze-drying
Bai Weiqiu.
(2) it is using electrostatic spinning technique that fibroin albumen microballoon and silk fibroin nano-fiber is compound
Using fibroin albumen microballoon and the compound electrostatic spinning apparatus equipment of nanofiber, spinning solution is fibroin albumen microballoon
With the ethanol solution of PEO (PEO) blending, its concentration is preferably 25~105Microballoon/mL；And the hexafluoro of fibroin albumen
Aqueous isopropanol, its total concentration are preferably 5%~15%, and more preferably 8%~12%；Collection device is received for rotation circular shaft at a high speed
Storage.Using double shower nozzles or single nozzle by the fibroin albumen microballoon of different proportion and PEO (PEO) blended liquid, Yi Jisi
The hexafluoroisopropanol solution of fibroin carries out electrostatic spinning.Electrospinning parameters are preferably：Voltage 5KV~20KV, spinning solution push away
Note speed 0.5mL/h~2mL/h, syringe needle and metal shaft reception distance 10cm~20cm, high speed rotating collecting device rotating speed
500rpm~3500rpm, electrostatic spinning total time 3h~5h.Electrostatic spinning is soaked in absolute ethyl alcohol after terminating, and is carried out
Fibroin albumen be modified, drying is taken out after immersion, is then soaked in deionized water, remove PEO produce thickness for 0.25mm~
0.45mm " micro--to receive " complex three-dimensional nano fiber scaffold.
For a further understanding of the present invention, with reference to embodiment to " micro--to receive " complex three-dimensional nanometer provided by the invention
Fibrous framework is described in detail.
Embodiment 1.
(1) sericin on silk fiber surface is removed：
Domestic silkworm silk is placed in 0.1% Na2CO3In solution, handled 30 minutes in 98~100 DEG C, in triplicate, to slough
The sericin on silk fiber surface, dries in air at room temperature.
(2) silk fibroin protein solution is prepared：
Boiled silk is pressed into 27g：100mL ratio is dissolved in 9.3mol/L lithium bromide water solutions, is put in 60 DEG C of baking ovens
4h is dissolved, silk fibroin protein solution is produced after dialysis, it is standby.And take a part of silk fibroin protein solution to be freeze-dried, produce fibroin egg
Bai Haimian, it is standby.
(3) micro-fluidic chip is prepared：
The SU-8 templates of vertical microchannel are made using soft lithography, A glue and B glue are stirred and evenly mixed, are poured on SU-8 moulds
On plate and blank template, 30 minutes are placed on horizontal experimental bench to exclude bubble, is subsequently placed in 75 DEG C of constant temperature ovens, take out
Dimethyl silicone polymer (PDMS) and blank PDMS of the cutting with passage after cooling, and punched in chip import and export, put
Cleaned 1.5 minutes in plasma cleaner, take out rapid bonding, produce.
(4) the fibroin albumen droplet for loading growth factor is prepared：
Using the micro flow control chip device that can prepare single dispersing fibroin albumen droplet, including micro pump, micro-fluidic chip, liquid
Drop receives and storage container.Made with adding the growth factor of required embedding and sustained release in 3~10%wt% silk fibroin protein solution
For dispersed phase；Using the mixture of sorbester p17 and soybean oil as continuous phase, its mixed proportion is 5%.Using different flow velocitys or
Person's pressure ratio, micro-fluidic parameter are preferably：Dispersed phase is 20mba~120mba, and continuous phase is 150mba~600mba, is cut into
Monodispersity wraps up the drop of growth factor (shown in Figure 1A).Then drop enters the receipts for filling sorbester p17 oil phase by collecting pipe
Collect in pond.
(5) preparation of fibroin albumen microballoon：
The drop of above-mentioned collection is cooled to 4 DEG C, under 4 DEG C of cryogenic conditions, adds a certain amount of organic solvent, is mixed
Uniformly.It is cold by the particulate of sedimentation respectively using petroleum ether, absolute ethyl alcohol washing centrifugation 2 times, rotating speed 9000rpm after 4 hours
It is lyophilized it is dry after obtain fibroin albumen microballoon.
(6) it is using electrostatic spinning technique that fibroin albumen microballoon and silk fibroin nano-fiber is compound：
Fibroin albumen microballoon is dispersed in 95% ethanol solution of 5% PEO (PEO) as spinning solution
A, and fibroin albumen sponge is dissolved in hexafluoroisopropanol solution, the solution that obtained concentration is 10% is as spinning solution B.Using silk
Fibroin microballoon and the compound double nozzle electrospinning appliance arrangements of nanofiber, collection device are collected for rotation circular shaft at a high speed
Device.It is 10 by concentration395% ethanol spinning solution A of microballoon/mL fibroin albumen microballoon and PEO (PEO) carries out quiet
Electrospun, syringe pump fltting speed is set to 0.5mL/L during electrostatic spinning, and voltage is set to 6KV, and syringe needle is set with metal shaft distance
For 15cm, the rotating speed of collector is adjusted to 2000rpm, and electrostatic spinning total time is 4h；And the hexafluoroisopropanol of fibroin albumen is spun
Silk liquid carries out electrostatic spinning simultaneously with relative direction.Syringe pump fltting speed is set to 1.0mL/L during electrostatic spinning, and voltage is set
For 20KV, syringe needle is set to 15cm with metal shaft distance, and the rotating speed of collector is adjusted to 2000rpm, and electrostatic spinning total time is 4h；It is quiet
Electrospun is soaked in absolute ethyl alcohol after terminating, and carries out fibroin albumen modification, drying is taken out after immersion, is then soaked in
In ionized water, " micro--to receive " complex three-dimensional nano fiber scaffold is made after removing PEO (shown in Figure 1B CD).
Embodiment 2.
(1) the fibroin albumen droplet for loading growth factor is prepared using microflow control technique：
Using the micro flow control chip device that can prepare single dispersing fibroin albumen droplet, including micro pump, micro-fluidic chip, liquid
Drop receives and storage container.The growth factor that the silk fibroin protein solution prepared in embodiment 1 is added to required embedding and sustained release is made
For dispersed phase；Using the mixture of sorbester p17 and Medium chain fatty triglycerides as continuous phase, its mixed proportion is 2%.Using not
With flow velocity or pressure ratio, micro-fluidic parameter be preferably：Dispersed phase is 20mba~120mba, continuous phase be 150mba~
600mba, cut into the drop of monodispersity parcel growth factor.Then drop is entered by collecting pipe fills sorbester p17 oil phase
Collecting pit in.(2) preparation of fibroin albumen microballoon：
The drop of above-mentioned collection is cooled to 4 DEG C, under 4 DEG C of cryogenic conditions, adds a certain amount of organic solvent, is mixed
Uniformly.After 4 hours, by the particulate of sedimentation using absolute ethyl alcohol washing centrifugation 4 times, rotating speed 6000rpm, obtained after freeze-drying
To fibroin albumen microballoon.
(3) it is using electrostatic spinning technique that fibroin albumen microballoon and silk fibroin nano-fiber is compound：
Fibroin albumen microballoon is dispersed in 90% ethanol solution of 10% PEO (PEO) as spinning solution
A, and fibroin albumen sponge is dissolved in hexafluoroisopropanol solution, the solution that obtained concentration is 10% is as spinning solution B.Using silk
Fibroin microballoon and the compound double nozzle electrospinning appliance arrangements of nanofiber, collection device use planar collecting.By concentration
For 5 × 102Microballoon/mL fibroin albumen microballoon carries out electrostatic spinning with 90% ethanol spinning solution A of PEO (PEO),
Syringe pump fltting speed is set to 0.5mL/L during electrostatic spinning, and voltage is set to 8KV, and syringe needle is set to planar collecting distance
15cm, electrostatic spinning total time are 4h；And the hexafluoroisopropanol spinning solution of fibroin albumen is subjected to electrostatic simultaneously with equidirectional
Spinning.Syringe pump fltting speed is set to 1.0mL/L during electrostatic spinning, and voltage is set to 15KV, syringe needle and planar collecting distance
15cm is set to, electrostatic spinning total time is 4h；Electrostatic spinning is soaked in absolute ethyl alcohol after terminating, and is carried out fibroin albumen and is changed
Property, drying is taken out after immersion, is then soaked in deionized water, " micro--to receive " complex three-dimensional nanofiber is made after removing PEO
Support (shown in Fig. 2).
Embodiment 3.
(1) the fibroin albumen droplet for loading growth factor is prepared using microflow control technique：
Using the micro flow control chip device that can prepare single dispersing fibroin albumen droplet, including micro pump, micro-fluidic chip, liquid
Drop receives and storage container.The growth factor that the silk fibroin protein solution prepared in embodiment 1 is added to required embedding and sustained release is made
For dispersed phase；Using the mixture of Crodaret and sunflower oil as continuous phase, its mixed proportion is 2%.Adopt
With different flow velocity or pressure ratio, micro-fluidic parameter is preferably：Dispersed phase is 20mba~120mba, continuous phase 150mba
~600mba, cut into the drop of monodispersity parcel growth factor.Then drop is entered by collecting pipe fills polyoxyethylene
In the collecting pit of rilanit special oil phase.
(2) preparation of fibroin albumen microballoon：
The drop of above-mentioned collection is cooled to 4 DEG C, under 4 DEG C of cryogenic conditions, adds a certain amount of organic solvent, is mixed
Uniformly.It is cold by the particulate of sedimentation respectively using petroleum ether, absolute ethyl alcohol washing centrifugation 2 times, rotating speed 5000rpm after 4 hours
It is lyophilized it is dry after obtain fibroin albumen microballoon.
(3) it is using electrostatic spinning technique that fibroin albumen microballoon and silk fibroin nano-fiber is compound：
Fibroin albumen microballoon is dispersed in 90% ethanol solution of 10% PEO (PEO) as spinning solution
A, and fibroin albumen sponge is dissolved in hexafluoroisopropanol solution, the solution that obtained concentration is 10% is as spinning solution B.Using silk
The fibroin microballoon double shower nozzles interflow compound with nanofiber is a single nozzle electrostatic spinning apparatus equipment, and collection device uses
Planar collecting.It is 10 by concentration290% ethanol spinning solution A of microballoon/mL fibroin albumen microballoon and PEO (PEO) enters
Row electrostatic spinning, syringe pump fltting speed is set to 0.5mL/L during electrostatic spinning, and voltage is set to 8KV；And by fibroin albumen
Hexafluoroisopropanol spinning solution carries out electrostatic spinning simultaneously with equidirectional, and syringe pump fltting speed is set to during electrostatic spinning
1.0mL/L, voltage are set to 20KV；It is a single nozzle by 2 electrostatic spinning nozzle interflow, single nozzle is set with planar collecting distance
For 15cm, electrostatic spinning total time is 4h；Electrostatic spinning is soaked in absolute ethyl alcohol after terminating, and is carried out fibroin albumen and is changed
Property, drying is taken out after immersion, is then soaked in deionized water, " micro--to receive " complex three-dimensional nanofiber is made after removing PEO
Support.
" micro--to receive " complex three-dimensional nano fiber scaffold prepared by the present invention has good mechanical property and bio-compatible
Property.Meanwhile the support is loaded with the single dispersing fibroin albumen microballoon of size uniform, growth factor presents slow with fibroin microsphere degraded
Stable release, to give full play to its biological effect.And uniform loose structure and suitable voidage, be advantageous to cell to
Grown into inside it, promote the growth and migration of cell.The support, which has, improves small-caliber artificial blood vessel long-term patency rate and remodeling
The dual-use function of vascular wall, suitable for damage or the reparation or displacement of lesion small-caliber vascular tissue.
The explanation of above example is only intended to help the method and its core concept for understanding the present invention.It should be pointed out that this
Invention is not limited to above-mentioned embodiment, in the case of without departing substantially from the substantive content of the present invention, is familiar with the technology of this technology
Personnel, in the change and retouching made without departing from the spirit and scope of the invention, protection scope of the present invention all should be belonged to.
Claims (8)
1. a kind of " micro--to receive " complex three-dimensional nano fiber scaffold, it is characterised in that electrostatic spinning nano microfibre is compound uniformly
The single dispersing fibroin albumen microballoon for being loaded with growth factor, it is and uniform more with good biocompatibility and certain mechanical property
Hole three-dimensional manometer fibrous framework.
2. " micro--to receive " complex three-dimensional nano fiber scaffold according to claim 1, it is characterised in that utilize micro-fluidic dress
Put and prepare the uniform single dispersing fibroin albumen microballoon for being loaded with growth factor, and use electrostatic spinning apparatus by the microballoon and fibroin
Protein nano fiber composite is made.
3. " micro--to receive " complex three-dimensional nano fiber scaffold according to claim 1, it is characterised in that shelf inner diameter exists
Between 2mm~6mm, backing thickness is between 0.25mm~0.45mm.
4. " micro--to receive " complex three-dimensional nano fiber scaffold according to claim 1, it is characterised in that be loaded with growth factor
Fibroin albumen microballoon and nanofiber it is compound, the particle diameter of fibroin albumen microballoon is between 5 μm~20 μm；The particle diameter of nanofiber
Between 300nm-1000nm.
5. " micro--to receive " complex three-dimensional nano fiber scaffold according to claim 1, it is characterised in that utilize micro-fluidic skill
Continuous phase in art device is soybean oil, methyl-silicone oil, Crodaret, Emulsifier EL-60, sunflower oil,
Sorbester p17, MCT Oil, glycerine and above two two or more mix in varing proportions.
6. " micro--to receive " complex three-dimensional nano fiber scaffold according to claim 1, it is characterised in that fibroin albumen microballoon
The growth factor for embedding and being sustained is vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), alkali
Property fibroblast growth factor (bFGF), EGF (EGF), Ephrin-B2 and above two or two or more
Mix in varing proportions.
7. " micro--to receive " complex three-dimensional nano fiber scaffold according to claim 1, it is characterised in that utilize electrostatic spinning
The nano fiber scaffold of preparation, the solute of spinning solution used is fibroin albumen, polycaprolactone (PCL), collagen, chitosan, poly
Lactic acid (PLA), polyglycolic acid (PLLA), PEO (PEO) and above two two or more mix in varing proportions.
Solvent is chloroform, acetone, hexafluoroisopropanol, ethanol, tetrahydrofuran and above two or two or more mixed in varing proportions.
8. " micro--to receive " complex three-dimensional nano fiber scaffold according to claim 1, it is characterised in that have uniform more
Pore structure and suitable voidage, be advantageous to cell and grown into its inside, promote the growth and migration of cell, suitable for damage or
The reparation or displacement of lesion small-caliber vascular tissue.
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