CN105833346A - Injected self-healing hydrogel material capable of realizing ordered release of medicine - Google Patents
Injected self-healing hydrogel material capable of realizing ordered release of medicine Download PDFInfo
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Abstract
The invention discloses an injected self-healing hydrogel material capable of realizing ordered release of a medicine as well as a preparation method and applications of the injected self-healing hydrogel material. The injected self-healing hydrogel material is composed of aminated gelatin, oxidized dextran, hydrogel prepared by adipic dihydrazide, antibiotic and PLGA microspheres loaded with growth factors. The hydrogel material prepared by the method provided by invention has the self-healing and ordered releasing functions, and the release of the antibiotic is rapid, so that the rapid inflammation diminishing effect can be realized; the growth factors wrapped by the microspheres release slowly, the tissue regeneration can be induced, and the injected self-healing hydrogel material is suitable for repairing the defected tissues such as the skin tissue, the periodontal tissue and the cartilage tissue.
Description
Technical field
The invention belongs to biology medical material technical field, be specifically related to a kind of realize injection-type self-healing hydrogel material that medicine discharges in order and its preparation method and application.
Background technology
The sick normal concomitant infections of defect of tissue, will realize the reproducibility reparation of disease defective tissue, first have to diminish inflammation.Therefore, urgent clinical needs exploitation is a kind of realizes the pharmaceutical carrier that somatomedin and antibiotic discharge in order, thus the Regeneration and Repair of successive induction disease defective tissue while quickly suppression inflammation.
Macromolecule hydrogel is hydrophilic polymer network, can absorb large quantity of moisture, simultaneously because physics and chemical crosslinking effect between polymer chain and water insoluble, there is its shape of maintenance and the function of three-dimensional space network structure.Injection aquagel has a wide range of applications at biomedical sectors such as pharmaceutical carrier, tissue repair, cell transplantations.At present, the natural macromolecular material that injection aquagel uses includes collagen, gelatin, hyaluronic acid, chitosan and glucosan etc..But, inject the hydrogel after organism owing to being vulnerable to external force extruding, body fluid corrode and the intrusion of other chemical substances and impaired, form microfissure, thus affect integrity and the mechanical property of gel structure, shorten the gel life-span.And the appearance of self-healing hydrogel is expected to repair the microfissure of such material, recover the original mechanics of gel and biological function, extend the gel life-span.
The present invention combines the advantage that self-healing hydrogel discharges system in order with medicine, the injectable self-healing hydrogel load antibiotic utilizing amination gelatin, oxidized dextran and adipic dihydrazide to prepare and the PLGA microsphere carrying somatomedin, constructing a kind of cocoa and realize the injection-type self-healing hydrogel material that medicine discharges in order, it can maintain the original mechanics of gel and biological function and realize the purpose that quick antiinflammatory is repaired with successive induction disease defective tissue.
Summary of the invention
It is an object of the invention to provide and a kind of realize the injection-type self-healing hydrogel material that medicine discharges in order, it not only has self-healing function, can the microfissure of self-regeneration gel, recover the original mechanics of gel and biological function, extend the gel life-span, and the orderly release of antibiotic and somatomedin can be realized, quickly while suppression inflammation, successive induction disease defective tissue is repaired.
For achieving the above object, the present invention adopts the following technical scheme that
A kind of realizing the injection-type self-healing hydrogel material that medicine discharges in order, its hydrogel, antibiotic and growth factor-loaded PLGA(Poly(D,L-lactide-co-glycolide of being prepared by amination gelatin, oxidized dextran, adipic dihydrazide) microsphere forms；Wherein, the concentration of antibiotic is 0.01-1 g/mL；The concentration of PLGA microsphere is 5-25 mg/m.
In described hydrogel, the total mass fraction of amination gelatin, adipic dihydrazide and oxidized dextran is 5 ~ 20%；Wherein, amination gelatin is 1:4-10:1 with the mass ratio of oxidized dextran, and adipic dihydrazide is 1:5-1:40 with the mass ratio of oxidized dextran.
Described antibiotic is for acting on G+Or G-Any one water soluble antibiotics of antibacterial, including beta-lactam, Macrolide, aminoglycoside, Tetracyclines, chloromycetin.
Described somatomedin is any one in basic fibroblast growth factor, transforming growth factor, epidermal growth factor, bone morphogenetic protein, insulin like growth factor, platelet derived growth factor, VEGF.
The viscosity of described PLGA is 0.4-2.0 dL/g；Wherein, lactic acid is 50:50-85:15 with the molar percentage of hydroxyacetic acid.
The described preparation method realizing the injection-type self-healing hydrogel material that medicine discharges in order, comprises the following steps:
1) aqueous solution with 1-50 μ g/mL somatomedin be interior aqueous phase, 30-80 mg/mL PLGA dichloromethane solution as oil phase, the PVA aqueous solution of 1-5wt% be outer aqueous phase, prepare growth factor-loaded PLGA microsphere by multi-emulsion method；
2) adding the ethylenediamine of its volume 2.5-6.5% in the gelatin solution of 5-20wt%, regulating pH value of solution after mix homogeneously is 4.0-6.0, and the amount then pressing 0.5-2 g/L adds EDC, reaction system is after 37 DEG C of reaction 2-8 h, deionized water is dialysed, lyophilization, obtain amination gelatin；
3) amount pressing 0.05-0.2 g/L in the dextran solution of 5-20wt% adds sodium metaperiodate, after 42 DEG C of lucifuge reaction 4-16 h, it is that 1:4-1:20 adds diethylene glycol termination reaction by the volume ratio with dextran solution, deionized water is dialysed, lyophilization, obtains oxidized dextran；
4) amination gelatin and adipic dihydrazide are dissolved in phosphate buffer, add 0.5-10 mg/mL antibiotic and the growth factor-loaded PLGA microsphere of 1-20 mg/mL, add oxidized dextran after mix homogeneously, stand 0.5-20
Described injection-type self-healing hydrogel material is obtained after min.
Described realize the injection-type self-healing hydrogel material that medicine discharges in order and can be used for preparing disease defect skin histology, periodontal tissue or cartilaginous tissue repair vector material.
The remarkable advantage of the present invention is: it is healedmyocardial that self-healing hydrogel material prepared by the present invention has good biocompatibility, biodegradability and oneself, the prominent of somatomedin can be reduced release, and the quickly release of antibiotic and the slow release of somatomedin, successive induction disease defective tissue reparation while reaching quick antiinflammatory can be realized.
Accompanying drawing explanation
Fig. 1 is the SEM figure of injection-type self-healing hydrogel material of the present invention.
Fig. 2 is the antibacterial figure of injection-type self-healing hydrogel material of the present invention.
Detailed description of the invention
In order to make content of the present invention easily facilitate understanding, below in conjunction with detailed description of the invention, technical solutions according to the invention are described further, but the present invention is not limited only to this.
Embodiment 1: a kind of preparation method realizing the injection-type self-healing hydrogel material that medicine discharges in order
1) aqueous solution with 5 μ g/mL bFGF be interior aqueous phase, 40 mg/mL PLGA dichloromethane solution as oil phase, the PVA aqueous solution of 2wt% be outer aqueous phase, prepare growth factor-loaded PLGA microsphere by multi-emulsion method；
2) adding 18mL ethylenediamine in the gelatin solution of 10wt%, adding concentrated hydrochloric acid regulation pH after mix homogeneously is 5.0, is subsequently adding 5.35g EDC, and reaction system is after 37 DEG C of reaction 6 h, and in deionized water, dialysis, lyophilization, obtain amination gelatin；
3) adding 3.0g sodium metaperiodate in the dextran solution of 10wt%, after 42 DEG C of lucifuges react 8 h, add 10 mL diethylene glycols and terminate reaction, in deionized water, dialysis, lyophilization, obtain oxidized dextran；
4) 75 mg amination gelatin and 5 mg adipic dihydrazides are dissolved in phosphate buffer, add 1mg antibiotic and the growth factor-loaded PLGA microsphere of 2 mg, add 75 mg oxidized dextrans after mix homogeneously, after standing 20 min, obtain described injection-type self-healing hydrogel material.
Embodiment 2: a kind of preparation method realizing the injection-type self-healing hydrogel material that medicine discharges in order
1) aqueous solution with 1 μ g/mL bFGF be interior aqueous phase, 30 mg/mL PLGA dichloromethane solution as oil phase, the PVA aqueous solution of 1wt% be outer aqueous phase, prepare growth factor-loaded PLGA microsphere by multi-emulsion method；
2) adding 10mL ethylenediamine in the gelatin solution of 5wt%, adding concentrated hydrochloric acid regulation pH after mix homogeneously is 6.0, is subsequently adding 1.35g EDC, and reaction system is after 37 DEG C of reaction 4 h, and in deionized water, dialysis, lyophilization, obtain amination gelatin；
3) adding 1.5g sodium metaperiodate in the dextran solution of 5wt%, after 42 DEG C of lucifuges react 6 h, add 2 mL diethylene glycols and terminate reaction, in deionized water, dialysis, lyophilization, obtain oxidized dextran；
4) 50 mg amination gelatin and 1 mg adipic dihydrazide are dissolved in phosphate buffer, add 1mg antibiotic and the growth factor-loaded PLGA microsphere of 2 mg, add 50 mg oxidized dextrans after mix homogeneously, after standing 0.5 min, obtain described injection-type self-healing hydrogel material.
Embodiment 3: a kind of preparation method realizing the injection-type self-healing hydrogel material that medicine discharges in order
1) with 10 μ g/mL
The aqueous solution of hEGF be interior aqueous phase, 80
The dichloromethane solution of mg/mL PLGA be oil phase, the PVA aqueous solution of 2wt% be outer aqueous phase, prepare growth factor-loaded PLGA microsphere by multi-emulsion method；
2) adding 25mL ethylenediamine in the gelatin solution of 20wt%, adding concentrated hydrochloric acid regulation pH after mix homogeneously is 4.0, is subsequently adding 8.0g EDC, and reaction system is after 37 DEG C of reaction 8 h, and in deionized water, dialysis, lyophilization, obtain amination gelatin；
3) adding 6g sodium metaperiodate in the dextran solution of 20wt%, after 42 DEG C of lucifuges react 8 h, add 10mL diethylene glycol and terminate reaction, in deionized water, dialysis, lyophilization, obtain oxidized dextran；
4) 100mg amination gelatin and 5 mg adipic dihydrazides are dissolved in phosphate buffer, add 1mg antibiotic and the growth factor-loaded PLGA microsphere of 2 mg, add 50mg oxidized dextran after mix homogeneously, after standing 20 min, obtain described injection-type self-healing hydrogel material.
Fig. 1 is the SEM figure of injection-type self-healing hydrogel material of the present invention.From figure 1 it appears that microsphere is evenly distributed in the loose structure of hydrogel.
Embodiment 4: bacteriostatic experiment
1) by staphylococcus aureus at 37 DEG C of incubator (80%N2, 10%CO2, 10% H2Cultivate 24 h, the single bacterial clone of picking in), be diluted to the turbid liquid of bacterium with physiological saline solution, and to adjust bacterial concentration be 5000 CFU；
2) turbid for normal saline bacterium liquid is spread evenly across on culture dish, the most after drying, the sterile injectable self-healing hydrogel material of a diameter of 6 mm is placed in culture dish surface；And using the hydrogel of not added with antibiotic as negative control；
3) being positioned over culture dish in incubator overnight to observe and measure inhibition zone size, its result is shown in Fig. 2.
Experimental result shows, after cultivating 12 h, injection-type self-healing hydrogel material has Partial digestion, but compared with negative control, it has obvious fungistatic effect, and inhibition zone size is at about 10 mm.
Embodiment 5: cell proliferation experiment
1) 3T3 NIH cell cultivate to digesting after logarithmic (log) phase, centrifugal, with stand-by after culture medium Eddy diffusion.
2) oxidized dextran, amination gelatin, adipic dihydrazide solution are prepared respectively with complete medium, degerming with 0.22 μm microfilter filtering solution in super-clean bench.
3) it is that 100:50:5 prepares mixed solution according to amination gelatin, oxidized dextran, the mass ratio of adipic dihydrazide, according to the cell density of 5,000,000/mL, cell suspending liquid is joined in above-mentioned mixed solution, mixing rapidly, it is added in 48 orifice plates according to the density in 300 μ L/ holes with liquid-transfering gun, add 100 μ L complete mediums in gel surface afterwards to soak, it is placed in 37 DEG C, 5%CO2Constant incubator is cultivated.
4), after adding culture medium culturing 15 h, sucking-off culture medium, PBS washs 3 times, and the glutaraldehyde of 2.5% fixes 0.5 h, then removes remaining glutaraldehyde, metal spraying after lyophilization, sem observation cell growth conditions on hydrogel with PBS.
Experimental result: 3T3 NIH cell adheres on hydrogel, and grow in its cavernous structure, hydrogel has promotion 3T3 NIH cell adhesion, the function of growth, illustrates that it has good biocompatibility.
The foregoing is only presently preferred embodiments of the present invention, all impartial changes done according to scope of the present invention patent and modification, all should belong to the covering scope of the present invention.
Claims (7)
1. one kind can realize the injection-type self-healing hydrogel material that medicine discharges in order, it is characterised in that: its hydrogel, antibiotic and growth factor-loaded PLGA microsphere prepared by amination gelatin, oxidized dextran, adipic dihydrazide forms；
Wherein, the concentration of antibiotic is 0.01-1
g/mL；The concentration of PLGA microsphere is 5-25 mg/mL.
The injection-type self-healing hydrogel material that medicine discharges in order can be realized the most according to claim 1, it is characterised in that: in described hydrogel, the total mass fraction of amination gelatin, adipic dihydrazide and oxidized dextran is 5 ~ 20%；Wherein, amination gelatin is 1:4-10:1 with the mass ratio of oxidized dextran, and adipic dihydrazide is 1:5-1:40 with the mass ratio of oxidized dextran.
The injection-type self-healing hydrogel material that medicine discharges in order can be realized the most according to claim 1, it is characterised in that: described antibiotic is for acting on G+Or G-Any one water soluble antibiotics of antibacterial, including beta-lactam, Macrolide, aminoglycoside, Tetracyclines, chloromycetin.
The injection-type self-healing hydrogel material that medicine discharges in order can be realized the most according to claim 1, it is characterised in that: described somatomedin is any one in basic fibroblast growth factor, transforming growth factor, epidermal growth factor, bone morphogenetic protein, insulin like growth factor, platelet derived growth factor, VEGF.
The injection-type self-healing hydrogel material that medicine discharges in order can be realized the most according to claim 1, it is characterised in that: the viscosity of described PLGA is 0.4-2.0 dL/g；Wherein, lactic acid is 50:50-85:15 with the molar percentage of hydroxyacetic acid.
6. the preparation method that can realize the injection-type self-healing hydrogel material that medicine discharges in order as claimed in claim 1, it is characterised in that: comprise the following steps:
1) aqueous solution with 1-50 μ g/mL somatomedin be interior aqueous phase, 30-80 mg/mL PLGA dichloromethane solution as oil phase, the PVA aqueous solution of 1-5wt% be outer aqueous phase, prepare growth factor-loaded PLGA microsphere by multi-emulsion method；
2) adding the ethylenediamine of its volume 2.5-6.5% in the gelatin solution of 5-20wt%, regulating pH value of solution after mix homogeneously is 4.0-6.0, and the amount then pressing 0.5-2 g/L adds EDC, reaction system is after 37 DEG C of reaction 2-8 h, deionized water is dialysed, lyophilization, obtain amination gelatin；
3) amount pressing 0.05-0.2 g/L in the dextran solution of 5-20wt% adds sodium metaperiodate, after 42 DEG C of lucifuge reaction 4-16 h, it is that 1:4-1:20 adds diethylene glycol termination reaction by the volume ratio with dextran solution, deionized water is dialysed, lyophilization, obtains oxidized dextran；
4) amination gelatin and adipic dihydrazide are dissolved in phosphate buffer, add 0.5-10 mg/mL antibiotic and the growth factor-loaded PLGA microsphere of 1-20 mg/mL, add oxidized dextran after mix homogeneously, after standing 0.5-20 min, obtain described injection-type self-healing hydrogel material.
7.
A kind of application that can realize the injection-type self-healing hydrogel material that medicine discharges in order as claimed in claim 1, it is characterised in that: it is used for preparing disease defect skin histology, periodontal tissue or cartilaginous tissue repair vector material.
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