CN104740681A - Polylactic acid-glycolic acid/adenovirus composite nano-fiber scaffold material as well as preparation method and application thereof - Google Patents
Polylactic acid-glycolic acid/adenovirus composite nano-fiber scaffold material as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a polylactic acid-glycolic acid/adenovirus composite nano-fiber scaffold material as well as a preparation method and application thereof in bone repairing, and belongs to the technical field of bone repairing materials. The method comprises the following steps: dissolving PLGA into trichloromethane and N,N-dimethylformamide, and preparing a nano spinning frame material by virtue of a high-pressure electrospinning device at a roomtemeprature; preparing an adenovirus cryoprotectant employing IM sucrose as final concentration; coating the PLGA nano spinning frame surface with sucrose/virus solution; and pre-freezing and carrying out freeze drying to obtain a PLGA/sucrose-adenovirus complex. The polylactic acid-glycolic acid/adenovirus composite nano-fiber scaffold material has good biocompatibility and relatively good biodegradability; the adenovirus can be localized on the PLGA surface, so that the concentration of the virus contacting the cells per unit area is increased; the infection efficiency is increased; the virus activity can be well stored; and once-through operation and long-time preservation can be carried out.
Description
Technical field
The invention belongs to bone renovating material technical field, be specifically related to a kind of poly lactic-co-glycolic acid (PLGA)/adenovirus (Ad) composite nano-fiber support material, preparation method and the application in Bone Defect Repari thereof.
Background technology
The method method such as the transplanting of engineering science, bone and bone substitute and Drug therapy in a organized way of current treatment Cranial defect.Wherein, bone and bone substitute transplanting can produce the problems such as the comparatively large and Integrated implant of wound is undesirable, apply the effect such as simvastatin, Diphosphonate unsatisfactory in Drug therapy.And organizational project science can become by timbering material, somatomedin and cell the method that a class can expect.
Nano fiber scaffold diameter is nanoscale, and surface area is large, thus has unique small-size effect and skin effect.Be similar to natural extracellular matrix due to it on the other hand, be conducive to cell adhesion, and then promote cell proliferation and differentiation, and be widely used.But present stage research display: in body, local cells is not enough, simple nano fiber scaffold promoting bone growing limited in one's ability.Therefore, somatomedin or cell and nano fiber scaffold compound is needed.Foreign cell is introduced to have and is caused the shortcomings such as organism adaptation immunoreation and cell can not survive.And erythropoietin (EPO) can promote that endothelial progenitor cells (EPCs) moves, promote human mesenchymal stem cell (MSCs) chemotactic of cultivation.And by increasing taxis, the animal migration of mescenchymal stem cell, activate matrix metalloproteinase, promote the formation of local vascular, for osteanagenesis provides good microenvironment.Protide somatomedin part cost is higher and have immunogenicity, is more difficult to get extensive use.Therefore, can the carrier of application load growth factor gene, express corresponding somatomedin to reach therapeutic goal by transfection into autologous cell in-situ.The adenovirus Ad-EPO of coding EPO gene can promote that rat bone marrow mesenchymal stem cells is to osteoblast differentiation in vitro.But, virus not only can be made with diffusion of body fluids in Cranial defect place application virus merely, reduce virus concentration, also likely cause ectopic infection.Current solution utilizes biomaterial by viropexis in application site.Such as: virus is mixed in electrostatic spinning solution, by high-voltage electrostatic spinning device by virus and nanofiber cospinning.Its shortcoming is that high pressure and organic solvent can reduce viral viability, and makes virus not easily quantitative owing to can lose part solution during electrostatic spinning, and then viral dosage when can not control practical application.For Ad-EPO applies in vivo, this promotes that bone defect healing causes difficulty.
Summary of the invention
The object of the present invention is to provide a kind of composite nano-fiber support material promoting Bone Defect Repari and its production and use.Combined by the adenovirus (Ad-EPO) preparing poly lactic-co-glycolic acid nano fiber scaffold and encoding Erythropoietin gene, reach local and improve virus concentration, make virus in situ infection cell, express EPO, for osteanagenesis provides a good microenvironment.But, invisible due to EPO, determine so more difficult whether processing method has infringement to the activity of adenovirus, therefore, need one intuitively method measure virus activity.The adenovirus Ad-EGFP infection cell of encoding green fluorescent protein (EGFP) gene makes cellular expression EGFP, EGFP can green light under fluorescence microscope, can observe the activity of virus intuitively, meanwhile, the reproduction restraint of EGFP to cell does not have an impact.Therefore, the present invention adopts Ad-EGFP to detect vigor and the virus release of virus on PLGA/ adenovirus composite nano fiber scaffold in vitro.Utilize sucrose as cryoprotective agent, adopt freeze-drying by PLGA and adenovirus compound.
Poly lactic-co-glycolic acid of the present invention/adenovirus composite nano-fiber support material (PLGA/Ad), its diameter is 100 ~ 200nm, first obtain poly lactic-co-glycolic acid nanofiber by method of electrostatic spinning, then utilize freeze-drying that adenovirus is fixed on poly lactic-co-glycolic acid nanofiber surface.
The preparation method of poly lactic-co-glycolic acid of the present invention/adenovirus composite nano fiber scaffold, its step is as follows:
A) preparation quality volume fraction is the poly lactic-co-glycolic acid solution of 0.2 ~ 0.4g/mL, solvent is chloroform and N, the mixing of dinethylformamide, in mixed solvent, the volume content of chloroform is 30 ~ 50%, then stirs 4 ~ 8 hours until obtain clear solution at 20 ~ 30 DEG C of condition lower magnetic forces;
B) by step a) solution adopt high-voltage electrostatic spinning device to carry out spinning, then by spinning product vacuum drying under 20 ~ 30 DEG C of conditions, namely obtain poly lactic-co-glycolic acid nano fiber scaffold material;
C) poly lactic-co-glycolic acid nano fiber scaffold material is cut into the disk of diameter 5mm ~ 3cm, disk positive and negative carries out ultraviolet radiation disinfection (power 8 ~ 10W, wavelength 250nm ~ 260nm, irradiation time 20 ~ 30 minutes) respectively;
D) get 8.55g sucrose crystal, be dissolved in 20mL pure water, degerming through injection filter (0.22 ~ 0.45 μm of microporous filter membrane) sucking filtration with microporous filter membrane, obtain 1.25M sucrose solution; Getting concentration is again 2 × 10
10~ 2 × 10
12the adenovirus substance of VP/mL mixes with volume ratio 1:4 with 1.25M sucrose solution, obtains sucrose/adenovirus solution;
E) get 10 ~ 20 μ L sucrose/adenovirus solution to drip in step c) side of poly lactic-co-glycolic acid nano fiber scaffold material disk that obtains is on the surface; Pre-freeze 20 ~ 30h at-60 ~-80 DEG C, then lyophilizing 20 ~ 30h in the vacuum freeze drier of-60 ~-80 DEG C, obtain poly lactic-co-glycolic acid/adenovirus composite nano-fiber support material.
Further, the spinning voltage of described high-voltage electrostatic spinning device is 15 ~ 25kv, and the distance between positive and negative electrode is 10 ~ 20cm, and positive pole is the spout of electrostatic spinning apparatus, negative pole is the metal roller bearing of ground connection, and generating positive and negative voltage makes spinning liquid be 0.5mL/h ~ 1.5mL/h at the flow velocity of nozzle; The diameter of metal roller bearing is 10 ~ 20cm, and length is 20 ~ 30cm, and metal roller surface covers masking foil, and masking foil is for accepting spinning product; The diameter of spout is 0.2 ~ 0.4mm, and the diameter range of gained spinning product is 100 ~ 200nm.
In poly lactic-co-glycolic acid (PLGA), the mass percentage of polylactic acid is 30 ~ 80%, is preferably 50%.
Poly lactic-co-glycolic acid prepared by the present invention/adenovirus composite nano fiber scaffold is mainly used in the regeneration of repairing damaged bony tissues.
The present invention compared with prior art, has the following advantages:
(1) the poly lactic-co-glycolic acid nano fiber scaffold prepared of the present invention, pattern is similar to extracellular matrix, is beneficial to adhesion and the growth of cell; By controlling blending ratio, reaction temperature, the time etc., this PLGA/Ad nanofiber had good biocompatibility because usually controlling physical and chemical performance and the degradation rate of material.
(2) after preparation, virus activity is preserved good, can express associated protein by infection cell.
(3) this preparation method is simple and feasible, has good economic benefit to equipment without particular/special requirement.
Accompanying drawing explanation
Fig. 1: the scanning electron microscope (SEM) photograph of PLGA nano fiber scaffold material prepared by embodiment 1, wherein the mass body volume concentrations of PLGA to be the amplification of 0.3g/mL, Fig. 1 (a) be 10000 ×, the amplification of Fig. 1 (b) is 5000 ×;
Fig. 2: the virus of the PLGA/Ad-EGFP composite nano fiber scaffold in embodiment 3 retains curve;
Fig. 3: the PLGA/Ad-EGFP composite nano fiber scaffold in embodiment 3 infects the fluorescence microscopy images of mesenchymal stem cells MSCs.Wherein, the fluorescence microscopy images of irradiating when A0, A1, A2, A3 are after Ad-EGFP infects BMMSCs 1,3,7,14 days; Fluorescence microscopy images when B0, B1, B2, B3 are after the PLGA/Ad-EGFP infection BMMSCs after ﹣ 70 DEG C preserves 1 day 1,3,7,14 days; Fluorescence microscopy images when C0, C1, C2, C3 are after the PLGA/Ad-EGFP infection BMMSCs after ﹣ 70 DEG C preserves 15 days 1,3,7,14 days; Fluorescence microscopy images when D0, D1, D2, D3 are after the PLGA/Ad-EGFP infection BMMSCs after ﹣ 70 DEG C preserves 28 days 1,3,7,14 days;
Fig. 4: in the PLGA/Ad-EPO composite nano fiber scaffold body in embodiment 3, osteogenic ability detects figure---Micro-CT.Wherein, A1, A2 are the Micro-CT image of matched group when the 4th week and the 8th week; B1, B2 are the Micro-CT image of experimental group when the 4th week and 8 weeks; A1, a2, b1 and b2 are the data analysis of area percentage of healing in application IPP image analysis software A1, A2, B1 and B2 of detecting.* P < 0.05 is represented.
Fig. 5: in the PLGA/Ad-EPO composite nano fiber scaffold body in embodiment 3, osteogenic ability detects figure---HE dyes.Wherein, A1, A2 are the HE colored graph picture of matched group when the 4th week and the 8th week; B1, B2 are the HE colored graph picture of experimental group when the 4th and 8 weeks, and B3 is that in B1, the image of 10 times is amplified at arrow place; B4 is that in B2, the image of 10 times is amplified at arrow place.
Detailed description of the invention
Embodiment 1:
The PLGA of 3g (is purchased from sigma company, relative molecular weight is 3.6 ten thousand) be dissolved in chloroform and the N of 10mL, in the mixed solvent of dinethylformamide (volume ratio is 4:6), magnetic agitation, after 4 hours, obtains chloroform and the dimethyl formamide mixed solution of PLGA; Then (voltage is 18KV to utilize electrostatic spinning apparatus spinning, distance is 14cm, spinning liquid is 0.5mL/h at the flow velocity of nozzle, the diameter of metal roller bearing is 10cm, length is 24cm, the diameter of spout is 0.3mm), the mass body volume concentrations preparing PLGA is the poly lactic-co-glycolic acid nano fiber scaffold material of 0.3g/mL, for subsequent use after vacuum drying 24h at 25 DEG C.Its fibre diameter is at 100nm ~ 200nm, and fiber interlocks, surface smoothing, as shown in Figure 1.
Embodiment 2:
Get 8.55g sucrose crystal, be dissolved in 20mL pure water, degerming through injection filter (0.22 μm of microporous filter membrane) sucking filtration, obtain 1.25M sucrose solution.(Zheng Changyu researcher presents for NIH, Lu Hemian seminar to get virus stock solution used Ad-EGFP, Ad-EPO; The public can also obtain) mix with 1:4 (V/V) with 1.25M sucrose solution respectively, method is 2 × 10 by 2 μ L concentration
12the Ad-EPO solution of virion (VP)/mL, the sucrose solution being 1.25M with 8 μ L concentration mixes, and after piping and druming mixing, Ad-EPO concentration is 4 × 10
11vP/mL, the final concentration of sucrose is 1M, and this is Ad-EPO/ sucrose solution; Getting 2 μ L concentration is 2 × 10
10vP/mL Ad-EGFP solution, the sucrose solution being 1.25M with 8 μ L concentration mixes, and after piping and druming mixing, Ad-EGFP concentration is 4 × 10
9vP/mL, the final concentration of sucrose is 1M, and this is Ad-EGFP/ sucrose solution.EGFP is green fluorescent protein, EPO is erythropoietin, and the function of the Ad-EGFP in this patent to cell has no effect, for detecting virus activity and virus release, and Ad-EPO all has certain effect to the propagation of cell and Osteoblast Differentiation, for the detection of osteogenic ability in body.
Embodiment 3:
PLGA nano fiber scaffold material (embodiment 1) is cut into the circle that diameter is 5mm and 2cm, positive and negative carries out ultraviolet (power: 8 ~ 10W, wavelength: 250nm ~ 260nm) illumination-based disinfection after 30 minutes respectively, and the Ad-EPO/ sucrose solution getting 10 μ L embodiment 2 preparations drips in the one side of the PLGA nano fiber scaffold of diameter 5mm; The Ad-EGFP/ sucrose solution getting 10 μ L embodiment 2 preparations drips on the PLGA nano fiber scaffold of diameter 2cm.At-70 DEG C, pre-freeze 24h makes liquid fully freezing, and then in the vacuum freeze drier of-70 DEG C, lyophilizing 24h makes freezing water sublimate, obtains PLGA/Ad-EGFP and PLGA/Ad-EPO two kinds of composite nano-fiber support materials.
Embodiment 4:
The PLGA/Ad-EGFP composite nano-fiber support material of 11 lyophilizing is placed in 12 orifice plates to ensure that operating condition is identical, other holes are vacant, and every hole adds 350 μ L TE (10mM Tris-HCl, 1mMEDTA, pH 7.5) buffer.The 1st, 2,4,8,15,30min and the 1st, 2,4,8,16h takes out 300 μ L supernatant and is placed in little centrifuge tube in different holes.Take out the every 100 μ L of supernatant use 15 μ L mass percentage concentration be 0.5% sodium lauryl sulphate (SDS)-TE solution (SDS is solute, TE buffer is solvent) place 15min in room temperature, lytic virus capsid, makes viral DNA come out.Supernatant after cracking establishes 3 multiple holes to be added in 33 holes of 96 orifice plates with every hole 100 μ L, each time point.To specifications by Quant-iT
tM standard substance in dsDNA quantification kit (buying in Invitrogen company) are mixed with 5 gradient concentrations (concentration is respectively 1 μ g/ml, 100ng/ml, 10ng/ml, 1ng/ml and 0ng/ml), and liquid is added in another 5 holes of above-mentioned 96 orifice plates with 100 μ l respectively.Picogreen reagent in this test kit dilutes 200 times with TE buffer, is added in the hole at above-mentioned sample and standard substance place with every hole 100 μ L.After 5min lucifuge is hatched, Picogreen reagent can be combined with double-stranded DNA and form DNA-Picogreen complex, is detected the amount of DNA by the fluorescence intensity of Picogreen.DNA-Picogreen complex in testing sample and standard substance reads data at excitation wavelength 485nm, emission wavelength 538nm respectively in microplate reader.Matched group is the Ad-EGFP/ sucrose solution of 10 μ L, and matched group operates identical with experimental group, with the Double stranded DNA concentration in matched group for 100%.As shown in Figure 3, virus discharges fast at front 1h, and along with time lengthening, viral rate of release slows down, and retains about 20% when 16h on PLGA nanometer spinning support.
Embodiment 5:
Rat bone marrow mesenchymal stem cells BMMSCs (Jilin University's preclinical medicine portion animal experimental center is extracted with the full bone marrow extraction method of femur, Wistar male rat, 4 ~ 5 weeks, body weight 80 ~ 100g), the 3rd generation (Jin H is passaged in culture bottle, Zhang K, Qiao C, et al.Efficiently engineered cell sheetusing a complex of polyethylenimine – alginate nanocomposites plus bonemorphogenetic protein 2gene to promote new bone formation [J] .Internationaljournal of nanomedicine, 2014, 9:2179.), with every hole 1.5 × 10
5individual cell, every hole 2ml culture medium is laid on six orifice plates.After 24h cell attachment, culture medium is replaced by the culture medium of serum-free.Matched group be not with the viral liquid of Material cladding, virus quantity is identical with the virus quantity in PLGA/Ad-EGFP prepared by embodiment 3, the PLGA/Ad-EGFP of preparation in the embodiment 3 that experimental group takes out when being and preserving 1,15,30 day at-70 DEG C, be covered in by PLGA/Ad-EGFP on cell, each time point establishes three multiple holes.Then be placed in containing volume fraction 5%CO
237 DEG C of constant temperature cell culture incubators (the promising air in cell culture incubator Central Plains, artificially inputs CO
2, make its volume fraction reach 5%) and middle cultivation, after 12h, culture medium is replaced by the culture medium of serum.Then, every two days change a volume is the cell culture medium of 2mL, comprising volume fraction in cell culture medium is 85%-90% LG-Dole uncle section MEM L-DMEM (buying in Gibco company), and hyclone (buying in BI company), hyclone volume fraction is 10% ~ 15%.Observed under inverted fluorescence microscope at the 1st, 3,7,14 day and take pictures.As shown in Figure 4, preserving after 30 days virus at-70 DEG C still can infected rats BMMSCs, makes cellular expression green fluorescent protein (in Fig. 4 light).Illustrate that Ad-EGFP still has activity after cryopreservation.In addition, compared with matched group, the fluorescence area of experimental group is larger, virus and Material cladding are described, the local concentration of virus can be made to improve, and the reduction virus sedimentation time in the medium, increase the number of unit interval cell entry cell, thus reach the effect improving transfection efficiency.
Embodiment 6:
At Wistar male rat (Jilin University's preclinical medicine portion animal experimental center, 8 ~ 10 weeks, body weight 280 ~ 300g) head ear edge after do length be 1cm walk crosswise otch, be separated periosteum, bone by annular at a slow speed and be drilled in skull lambdoid suture region and prepare the round defect that diameter is 5mm, experimental group be PLGA/Ad-EPO composite nano fiber scaffold prepared by embodiment 3 with 1/only implant defect place, only to carry out the rat of performing the operation as a control group, often organize 5.Continuous normal saline flushing in operating process, finally uses 3/0 operation stitching suturing with thread management.After rat heart perfusion fixation (quality volume fraction is the paraformaldehyde of 40mg/mL) being put to death in postoperative eight weeks, skull is taken out, fixes process with paraformaldehyde and measure for Micro-CT after 48 hours.As shown in Figure 4, by areal calculation, can find to promote that Cranial defect obviously reduces at the 4th week experimental group, defect edge is rough, and at the 8th week, experimental group promoted that Cranial defect reduces further.Confirm through HE dyeing, as shown in Figure 5, at the 4th week experimental group due to the effect of Ad-EPO, make defect local produce a large amount of erythrocyte, and occur osteanagenesis at the 8th week Cranial defect edge.Illustrate that product of the present invention has the effect promoting osteanagenesis.
Claims (7)
1. a preparation method for poly lactic-co-glycolic acid/adenovirus composite nano-fiber support material, its step is as follows:
A) preparation quality volume fraction is the poly lactic-co-glycolic acid solution of 0.2 ~ 0.4g/mL, solvent is chloroform and N, the mixing of dinethylformamide, in mixed solvent, the volume content of chloroform is 30 ~ 50%, then stirs 4 ~ 8 hours until obtain clear solution at 20 ~ 30 DEG C of condition lower magnetic forces;
B) by step a) solution adopt high-voltage electrostatic spinning device to carry out spinning, then by spinning product vacuum drying under 20 ~ 30 DEG C of conditions, namely obtain poly lactic-co-glycolic acid nano fiber scaffold material;
C) poly lactic-co-glycolic acid nano fiber scaffold material is cut into the disk of diameter 5mm ~ 3cm, disk positive and negative carries out ultraviolet radiation disinfection respectively;
D) get 8.55g sucrose crystal, be dissolved in 20mL pure water, degerming through the injection filter sucking filtration with microporous filter membrane, obtain 1.25M sucrose solution; Getting concentration is again 2 × 10
10~ 2 × 10
12the adenovirus substance of VP/mL mixes with volume ratio 1:4 with 1.25M sucrose solution, obtains sucrose/adenovirus solution;
E) get 10 ~ 20 μ L sucrose/adenovirus solution to drip in step c) side of poly lactic-co-glycolic acid nano fiber scaffold material disk that obtains is on the surface; Pre-freeze 20 ~ 30h at-60 ~-80 DEG C, then lyophilizing 20 ~ 30h in the vacuum freeze drier of-60 ~-80 DEG C, obtain poly lactic-co-glycolic acid/adenovirus composite nano-fiber support material.
2. the preparation method of a kind of poly lactic-co-glycolic acid/adenovirus composite nano-fiber support material as claimed in claim 1, it is characterized in that: the spinning voltage of high-voltage electrostatic spinning device is 15 ~ 25kv, distance between positive and negative electrode is 10 ~ 20cm, positive pole is the spout of electrostatic spinning apparatus, negative pole is the metal roller bearing of ground connection, and generating positive and negative voltage makes spinning liquid be 0.5mL/h ~ 1.5mL/h at the flow velocity of nozzle; The diameter of metal roller bearing is 10 ~ 20cm, and length is 20 ~ 30cm, and metal roller surface covers masking foil, and masking foil is for accepting spinning product; The diameter of spout is 0.2 ~ 0.4mm, and the diameter range of gained spinning product is 100 ~ 200nm.
3. the preparation method of a kind of poly lactic-co-glycolic acid/adenovirus composite nano-fiber support material as claimed in claim 1, is characterized in that: in poly lactic-co-glycolic acid, and the mass percentage of polylactic acid is 30 ~ 80%.
4. the preparation method of a kind of poly lactic-co-glycolic acid/adenovirus composite nano fiber scaffold as claimed in claim 3, is characterized in that: in poly lactic-co-glycolic acid, and the mass percentage of polylactic acid is 50%.
5. the preparation method of a kind of poly lactic-co-glycolic acid/adenovirus composite nano-fiber support material as claimed in claim 1, is characterized in that: the power of ultraviolet radiation disinfection is 8 ~ 10W, wavelength is 250nm ~ 260nm, irradiation time 20 ~ 30 minutes.
6. poly lactic-co-glycolic acid/adenovirus composite nano-fiber support material, is characterized in that: prepared by the method for Claims 1 to 5 described in any one.
7. a kind of poly lactic-co-glycolic acid according to claim 6/application of adenovirus composite nano-fiber support material in Bone Defect Repari.
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Cited By (1)
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