CN110448721A - A kind of conductive oxidation resistant injectable composite hydrogel and its preparation method and application that stops blooding of antibacterial adherency - Google Patents
A kind of conductive oxidation resistant injectable composite hydrogel and its preparation method and application that stops blooding of antibacterial adherency Download PDFInfo
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
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- 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
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- A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
Abstract
The present invention relates to a kind of antibacterials to adhere to the conductive oxidation resistant injectable composite hydrogel and its preparation method and application that stops blooding, and first dopamine is grafted on gelatin main chain and generates gelatin grafting dopamine GT-DA；Poly-dopamine coating is prepared in CNT surface using the auto polymerization of dopamine under alkaline condition, obtains CNT-PDA；GT-DA and CS are made into GT-DA/CS solution, CNT-PDA is made into CNT-PDA dispersion liquid；Under initiator effect, by the auto polymerization of the dopamine in GT-DA/CS solution and CNT-PDA dispersion liquid, the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency is obtained.Dopamine is grafted on gelatin main chain prepared hydrogel and possesses good antioxygenic property by the present invention, and hydrogel of the invention also has good biocompatibility, sticks, stops blooding, the characteristics such as photo-thermal antibacterial, medicament slow release.
Description
Technical field
The invention belongs to biomedical material technologies, and in particular to a kind of conductive hemostasis of antibacterial adherency is oxidation resistant can
Inject composite hydrogel and its preparation method and application.
Background technique
The regeneration of damaged tissues is to rebuild the most basic requirement of tissue integrity and recovery organization normal function.Many institute's weeks
Know, infection is one of major obstacle of wound healing, and has become in patient with severe symptoms's cause of death ever-increasing one
Factor.The treatment of infection brings huge burden to medical system even entire society, currently, clinically coping with the master of infection
Wanting strategy is still using antibiotic.Therefore, develop can not only efficiently and accurately by antibiotic delivery to wound location,
But also the antibacterials delivery system that can regulate and control the release of the active factors of wound healing is still full of challenge.In order to find
Not only can be to avoid wound infection, but also there is the wound dressing of facilitation for wound repair process, it has developed at present
Many Morden wound dressings with Sustained drug release performance out, such as semi-permeable membrane, thin foam, hydrocolloid and hydrogel
Deng.Wherein, have benefited from excellent hydrophily, hydrogel can be by absorbing Wound exudate and the wet of wound climate being kept to reach
To the effect for reducing infection risk, the good potentiality for improving repair of damaged tissues has been shown.
As the gelatin (GT) of protein derivatives, due to its non-immunogenic, cell adhesion behavior and Coagulability,
It combines with a large amount of synthesis or natural macromolecular and be used to manufacture wound dressing.But there is also certain for the hydrogel based on gelatin
Defect.Such as: mechanical strength is weak, degradation speed is fast etc..
Excessive active oxygen (ROS) would generally destroy corium by the ECM protein that changes or degrade in wound repair process
Fibroblast and the function of reducing keratinocyte etc. influence repairing effect.
Researcher has found that human body has endogenous biological electric system.Complete human skin surface carries than deep skin
More negative electrical charges.However, the cell and wound cell of epidermis higher depth are positively charged when defect or wound occurs in skin.
The combination of the negative electrical charge of wound positive charge and surrounding intact skin produces skin battery.It is this when wound tissue is wetted
Bioelectricity is conducive to wound healing.Facilitation of the conductive material in wound healing has also been demonstrate,proved in research before this
It is real.
Due to excellent machinery, calorifics and characteristic electron, carbon nanotube (CNTs) have led nanometer in the past few decades
The research boom of technology.However, the strong hydrophobic interaction between single CNT makes unmodified CNT be difficult to be dispersed in water.
To limit its application in the synthesis of conductive biological bracket.
Summary of the invention
In order to overcome the problems of the above-mentioned prior art, the purpose of the present invention is to provide a kind of antibacterial adherency conductions to stop
Oxidation resistant injectable composite hydrogel of blood and its preparation method and application；This method raw material sources are extensive, preparation process is simple,
Preparation cost is cheap；There is good biocompatibility, adhesiveness, hemostatic, mechanical through aerogel dressing made from this method
Performance, electric conductivity, inoxidizability, anti-microbial property and the effect for promoting infected wound reparation, can be applied to skin injury and control
Treatment field.
Preparation method of the present invention is achieved through the following technical solutions:
The following steps are included:
(1) dopamine is grafted on gelatin main chain and generates gelatin grafting dopamine GT-DA；
(2) poly-dopamine coating is prepared in CNT surface using the auto polymerization of dopamine under alkaline condition, obtains CNT-
PDA；
(3) GT-DA and CS are made into GT-DA/CS solution, CNT-PDA is made into CNT-PDA dispersion liquid；Make in initiator
Under, by the auto polymerization of the dopamine in GT-DA/CS solution and CNT-PDA dispersion liquid, it is anti-to obtain the conductive hemostasis of antibacterial adherency
The injectable composite hydrogel of oxidation.
Further, in step (1), the preparation step of gelatin grafting dopamine includes:
(1A) by Gelatin in buffer solution, 50~60 DEG C of stirrings dissolve it sufficiently to obtain gelatin solution, wherein
The mass concentration of gelatin is 3~6%；
Dopamine hydrochloride is added into gelatin solution obtained by step (1A) in (1B), and dissolution is stirred at room temperature and obtains mixed liquor, mixes
The concentration for closing Dopamine hydrochloride in liquid is 44~88mg/mL；
EDC and NHS is added in (1C) mixed liquor obtained by step (1B), obtains reaction solution, reaction solution is held at 30~50 DEG C
Continuous to be stirred to react 6~18 hours, the concentration of EDC and NHS is respectively 44~89mg/mL and 27~54mg/mL in reaction solution；
(1D) after reaction, is lyophilized to step (1C) after acquired solution is dialysed, and obtains gelatin grafting dopamine.
Further, in step (1A), buffer is phosphate buffer or 2- morpholino ethanesulfonic acid buffer, buffer
PH value 5~6；In step (1D), using deionized water dialysis 48~72 hours；Pass through hydrochloric acid and sodium hydrate aqueous solution tune
The pH value of the reaction solution of step (1C) and the deionized water of step (1D) is saved always 5~6.
Further, in step (2), the specific preparation step of CNT-PDA includes:
CNT is dispersed in buffer solution by (2A), obtains the CNT dispersion that concentration is 0.5~2mg/mL；
(2B) Dopamine hydrochloride is added in the CNT dispersion of step (2A), obtains reaction solution, reaction solution is stirred at room temperature
12~48 hours, the concentration of Dopamine hydrochloride was 0.5~2mg/mL in reaction solution；
The reaction solution that (2C) step (2B) reaction terminates after post treatment, obtains CNT-PDA.
Further, the CNT of step (2A) is dispersed in Tris buffer solution, and in 0~4 DEG C of ultrasound 0.5~2h, Tris
The pH of buffer is 8~9；The post-processing of step (2C) is first to be centrifuged 5~20 minutes in 5000~10000rpm, abandons supernatant,
Respectively washed three times with distilled water and ethyl alcohol, 30~60 DEG C drying 24~72 hours.
Further, in step (3), conductive the specific of oxidation resistant injectable composite hydrogel of stopping blooding of preparation antibacterial adherency
Preparation step includes:
GT-DA/CS is dissolved in buffer by (3A), is configured to the GT-DA/CS solution that mass concentration is 5~20%；
CNT-PDA is dispersed in buffer by (3B), is configured to CNT-PDA dispersion liquid of the mass concentration 1%~4%；
(3C) is mixed the two in the ratio that every 1mL CNT-PDA dispersion liquid is added in 7.5mLGT-DA/CS solution, is added
Enter 0.25~0.65mol initiator, reaction obtains the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency；Step
10~200s is reacted in (3C).
Further, in step (3A) and step (3B), buffer is PBS；Quality accounting of the CS in GT-DA/CS
It is 5%~10%.
Further, which is characterized in that initiator includes the H that concentration is 0.1~0.3mol/mL2O2With concentration be 0.2~
0.5mg/mL horseradish peroxidase, every 1mLCNT-PDA dispersion liquid is corresponding to be added 0.5mL H2O2With 1mL horseradish peroxidase
Enzyme.
A kind of conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency made from preparation method as described above.
The conductive oxidation resistant injectable composite hydrogel that stops blooding of a kind of antibacterial adherency as described above is preparing wound dressing
In application.
Compared with prior art, the invention has the following beneficial technical effects:
Preparation method disclosed by the invention passes through chemical graft DOPA based on protein derivatives gelatin (GT)
Its tissue adhension performance and oxidation resistance are assigned on amine to main chain；Chitosan (CS), which is added in aquogel system, to be improved
The mechanical performance of hydrogel simultaneously makes up its fast disadvantage of degrading；Assign CNT introducing aquogel system to its electric conductivity；It utilizes simultaneously
The auto polymerization of dopamine under alkaline condition carries out poly-dopamine coating in CNT surface, enhances its water-soluble, electric conductivity and biology
Compatibility.
Further, the present invention is with H2O2/ HRP not only reduces conventional oxidation method bring biology peace as catalyst system
Full property problem, and make product that there is mechanical performance similar or relatively better to traditional chemical routes.
It is had the advantage that through hydrogel made from the method for the present invention
(1) dopamine is grafted to hydrogel prepared on gelatin main chain and possesses good antioxygenic property.
(2) based on the anthemorrhagic performance of chitosan itself, it is introduced into hydrogel, not only increases the hemostatic of hydrogel
Can, its mechanical performance is also improved, its fast deficiency of degrading is improved.
(3) it due to the physical bond and chemical crosslinking of dopamine or poly-dopamine group and injury tissue, is added in GT
Catechol group (deriving from dopamine) can also enhance the bio-adhesive performance based on GT-DA/CS hydrogel.In addition, good
Adhesion property can also hydrogel be made to seal wound rapidly, to reach good haemostatic effect.
(4) CNT is introduced in hydrogel, increases the electric conductivity of hydrogel, to peomote the mistake of wound reparation
Journey.
(5) auto polymerization is understood in alkaline solution using dopamine and forms strata dopamine (PDA) coating in CNT surface,
Avoid the shortcomings that modified CNT strategy of conventional oxidation is brought.Enhance CNT water-soluble, electric conductivity and biocompatibility.
The results showed that water prepared by the present invention can be adjusted by changing the content of CNT-PDA in hydrogel
Porosity, rheological characteristic, mechanical performance, electric conductivity, swellability and degradability of gel etc..Experiment show CNT-PDA tax
Give the wide spectrum photo-thermal antibacterial activity of hydrogel, dopamine assigns the tissue adhension of hydrogel, hemostasis and the performances such as anti-oxidant.This
Outside, the drug release and Bactericidal test for enclosing the hydrogel of Doxycycline show that there is the hydrogel lasting drug to release
Put characteristic and good anti-microbial property.Hemolytic experiment and L929 cell co-culture experiments confirm it with good external biological phase
Capacitive.Histological results: collagenic supersession, granulation tissue thickness, promoting epidermization, hair follicle and revascularization and TGF-β and CD31
Immunofluorescence dyeing result confirms the good effect for promoting skin infection wound healing of hydrogel.Therefore, the more function of the series
Energy aerogel dressing has good application prospect in promotion infectious skin wound healing art.
Detailed description of the invention
Fig. 1 (a) is the swelling curve figure of hydrogel；Fig. 1 (b) is the degradation curve figure of hydrogel；Fig. 1 (c) is hydrogel
SEM image before swelling and after swelling, scale bar: 50 μm；Fig. 1 (d) is the rheological behavior figure of hydrogel.
Fig. 2 (a) is the bioadhesion performance of different hydrogels；Fig. 2 (b) is the hemostasis energy of GT-DA/CS/CNT2 hydrogel
Power；Fig. 2 (c) is the conductivity of hydrogel；Fig. 2 (d) is the DPPH clearance rate of the GT-DA/CS/CNT2 hydrogel of various concentration；
Fig. 2 (e) is Doxycycline release profiles.
Fig. 3 (a) is that luminous intensity is 1.0W/cm2When hydrogel Δ T-NIR light application time figure；Fig. 3 (b) is NIR light according to increasing
Antibacterial activity in vitro of the strong hydrogel to staphylococcus aureus；Fig. 3 (c) is its antibacterial activity in vitro to Escherichia coli；
Fig. 3 (d) is the Survival probability of bacteria of the antibacterial activity test of internal staphylococcus aureus；
Fig. 4 (a) is cell compatibility assessment, P < 0.05 *；Fig. 4 (b) is the quantitative data of hemolysis rate.
Fig. 5 (a) is TegadermTMFilm, GT-DA/CS/CNT0, GT-DA/CS/CNT2 and GT-DA/CS/CNT2/Doxy
Wound healing situation statistical chart of the hydrogel at 3 days, 7 days and 14 days.*P<0.05；Fig. 5 (b) is the hydroxyl in neoplastic skin tissue
Proline content.*P<0.05；Fig. 5 (c) is the granulation tissue thickness of the 7th day different groups；Fig. 5 (d) is that wound regenerates after 7 days
Epidermal thickness；Fig. 5 (e) is that revascularization situation counts after 7 days and 14 days；Fig. 5 (f) is the relative populations system of hair follicle after 14 days
Meter.
Specific embodiment
The present invention is described in further details with reference to the accompanying drawing.
The preparation of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial of the present invention adherency the following steps are included:
(1) in 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDC) and n-hydroxysuccinimide
(NHS) dopamine is grafted on gelatin main chain under the action of and generates gelatin grafting dopamine (GT-DA)；
Gelatin grafting dopamine preparation step include:
(1A) by Gelatin in buffer solution, 50~60 DEG C of 10~30min of stirring dissolve it sufficiently, wherein gelatin
Concentration be 3~6wt%, buffer can be in phosphate buffer (PBS) and 2- morpholino ethanesulfonic acid (MES) buffer
Any one, the pH of buffer is 5~6；
Dopamine hydrochloride is added into step (1A) acquired solution in (1B), and 10~30min is stirred at room temperature, and keeps it sufficiently molten
Solution, wherein the concentration of Dopamine hydrochloride is 44~88mg/mL；
EDC and NHS is added in (1C) in step (1B) acquired solution, and 30~50 DEG C are persistently stirred 6~18 hours, wherein
The concentration of EDC and NHS is respectively 44~89mg/mL and 27~54mg/mL；Be added EDC and NHS after, should use hydrochloric acid (1M) and
Sodium hydrate aqueous solution (1M) maintains reaction pH 5~6.
After (1D) is to step (1C), acquired solution is dialysed 48~72 hours, is lyophilized to get gelatin scion grafting DOPA is arrived
Amine (GT-DA).The pH of deionized water should use hydrochloric acid (1M) and sodium hydrate aqueous solution (1M) to be maintained at 5~6 when dialysis.
(2) CNT (CNT-PDA) of auto polymerization preparation poly-dopamine (PDA) coating using dopamine under alkaline condition；
Synthesizing, there is the specific preparation step of functional CNT of PDA coating to include:
CNT is dispersed in Tris buffer solution and in 0-4 DEG C of 0.5~2h of ultrasound by (2A), and wherein the concentration of CNT is 0.5
The pH of~2mg/mL, Tris buffer is 8~9；
(2B) Dopamine hydrochloride is added in the solution of step (2A), is stirred at room temperature 12~48 hours, wherein hydrochloric acid DOPA
The concentration of amine is 0.5~2mg/mL；
Step 5000~10000rpm of (2B) acquired solution is centrifuged 5~20 minutes by (2C), supernatant is abandoned, with distilled water and second
Alcohol respectively washs three times, 30~60 DEG C drying 24~72 hours, products therefrom is the CNT (CNT-PDA) of PDA coating.
(3) it takes a certain amount of GT-DA and chitosan (CS) to dissolve in a solvent, GT-DA/CS solution is made, make in initiator
Under, is obtained by the auto polymerization of dopamine in GT-DA/CS solution and CNT-PDA dispersion liquid with antibiotic property, electric conductivity, resisted
The injectable composite hydrogel dressing of oxidisability.Specifically preparation step includes:
GT-DA/CS is dissolved in PBS by (3A), is configured to certain density solution, wherein matter of the CS in GT-DA/CS
Amount accounting is 5wt%~10wt%, and the concentration range of GT-DA/CS is 5~20wt%；
CNT-PDA is dispersed in PBS by (3B), is configured to dispersion liquid, wherein the concentration range of CNT-PDA be 1wt%~
4wt%；
1mL CNT-PDA dispersion liquid is added in 7.5mL GT-DA/CS solution by (3C), after mixing well, successively plus
Enter 0.5mL initiator A and 1mL initiator B, arrives water-setting of the present invention by the sol-gel transition of 10~200s
Glue；Initiator A is H2O2, concentration is 0.1~0.3mol/mL；Initiator B is horseradish peroxidase (HRP), and concentration is
0.2~0.5mg/mL.
The conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency produced by the present invention can be applied in infection
During dermal tissue insult is repaired, in terms of wound dressing.
Below with reference to specific embodiment, the present invention is described in further detail, it is described be explanation of the invention and
It is not to limit.
Embodiment 1
(1) in 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDC) and n-hydroxysuccinimide
(NHS) dopamine is grafted on gelatin main chain under the action of and generates gelatin grafting dopamine (GT-DA):
It is stirred at 50 DEG C, gelatin (0.5g, the A type from pigskin, Sigma-Aldrich) is dissolved in 10mL phosphate
In buffer (PBS, pH=5.0).Then dopamine hydrochloride (0.741g, Sigma-Aldrich) is added thereto, room temperature is stirred
30min is mixed, dissolves it sufficiently.Add EDC (0.749g, Sigma-Aldrich) and NHS (0.45g, Sigma-
Aldrich).At 37 DEG C, persistently stir 12 hours.Finally above-mentioned reaction solution is dialysed 48 hours in deionized water, so
After be lyophilized to get to gelatin-scion grafting-dopamine.After EDC and NHS is added, and deionized water when dialysis, use hydrochloric acid
(1M) and sodium hydrate aqueous solution (1M) maintain pH 5.
(2) CNT (CNT-PDA) of auto polymerization preparation poly-dopamine (PDA) coating using dopamine under alkaline condition:
30mg CNT is dispersed in the Tris buffer solution that 30mL and pH are 8.5, and be ultrasonically treated 2 hours in 2 DEG C.So
Afterwards, dopamine hydrochloride (30mg) is added in above-mentioned solution, stir 48 hours reacts it sufficiently at room temperature, and is attached to
CNT surface.Above-mentioned solution is centrifuged 10 minutes in 8000rpm again, abandons supernatant, respectively washs precipitating three times with distilled water and ethyl alcohol,
40 DEG C oven drying 12 hours, products therefrom is to have the CNT (CNT-PDA) of PDA coating.
(3) it under initiator effect, is obtained by the auto polymerization of the dopamine in GT-DA/CS and CNT-PDA with antibacterial
Property, electric conductivity, antioxidative injectable composite hydrogel dressing:
GT-DA/CS (95:5) is dissolved in PBS by (3A), is configured to the solution of 13.3wt%.
CNT-PDA is dispersed in PBS by (3B), is configured to the CNT-PDA dispersion liquid of 1wt%.
The above-mentioned CNT-PDA dispersion liquid of 1mL is added in the GT-DA/CS solution of 7.5mL by (3C).After mixing completely, it is added
0.5mL H2O2(0.1mol/mL) and 1mL HRP (0.25mg/mL) are prepared by the sol-gel transition of 50s
The hydrogel of 10wt%GT-DA/CS, 0.1wt%CNT-PDA, are named as GT-DA/CS/CNT1.
Embodiment 2
Unlike the first embodiment, 1wt%CNT-PDA in (3) (3B) step of step is substituted for 2wt%, water-setting is made
Glue is also named as GT-DA/CS/CNT2.
Embodiment 3
Unlike the first embodiment, 13.3wt%GT-DA/CS in (3) (3A) step of step is substituted for 20wt%, made
It obtains hydrogel and is also named as (GT-DA/CS) 15/CNT1.
Embodiment 4
Unlike the first embodiment, by GT-DA/CS (95:5) in (3) (3A) step of step be substituted for GT-DA/CS (90:
10) hydrogel, is made and is also named as GT-DA 90/CS/CNT1.
Embodiment 5
(1) in 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDC) and n-hydroxysuccinimide
(NHS) dopamine is grafted on gelatin main chain under the action of and generates gelatin grafting dopamine (GT-DA):
It is stirred at 55 DEG C, it is slow that gelatin (0.3g, the A type from pigskin, Sigma-Aldrich) is dissolved in 10mLMES
In fliud flushing (pH=5.25).Then dopamine hydrochloride (0.44g, Sigma-Aldrich) is added thereto, is stirred at room temperature
20min dissolves it sufficiently.Add EDC (0.44g, Sigma-Aldrich) and NHS (0.27g, Sigma-Aldrich).
At 30 DEG C, persistently stir 6 hours.Finally above-mentioned reaction solution is dialysed 60 hours in deionized water, be then lyophilized to get
To gelatin-scion grafting-dopamine.After EDC and NHS is added, and deionized water when dialysis, use hydrochloric acid (1M) and sodium hydroxide
Aqueous solution (1M) maintains pH 5.5.
(2) CNT (CNT-PDA) of auto polymerization preparation poly-dopamine (PDA) coating using dopamine under alkaline condition:
15mg CNT is dispersed in the Tris buffer solution that 30mL and pH are 9, and be ultrasonically treated 1 hour in 4 DEG C.So
Afterwards, dopamine hydrochloride (15mg) is added in above-mentioned solution, stir 24 hours reacts it sufficiently at room temperature, and is attached to
CNT surface.Above-mentioned solution is centrifuged 5 minutes in 5000rpm again, abandons supernatant, respectively washs precipitating three times with distilled water and ethyl alcohol, In
30 DEG C oven drying 24 hours, products therefrom is to have the CNT (CNT-PDA) of PDA coating.
(3) it under initiator effect, is obtained by the auto polymerization of the dopamine in GT-DA/CS and CNT-PDA with antibacterial
Property, electric conductivity, antioxidative injectable composite hydrogel dressing:
GT-DA/CS (95:5) is dissolved in PBS by (3A), is configured to the solution of 13.3wt%.
CNT-PDA is dispersed in PBS by (3B), is configured to the CNT-PDA dispersion liquid of 1wt%.
The above-mentioned CNT-PDA dispersion liquid of 1mL is added in the GT-DA/CS solution of 7.5mL by (3C).After mixing completely, it is added
0.5mL H2O2(0.2mol/mL) and 1mL HRP (0.5mg/mL) are prepared by the sol-gel transition of 35s
The hydrogel of 10wt%GT-DA/CS, 0.1wt%CNT-PDA.
Embodiment 6
(1) in 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDC) and n-hydroxysuccinimide
(NHS) dopamine is grafted on gelatin main chain under the action of and generates gelatin grafting dopamine (GT-DA):
It is stirred at 60 DEG C, it is slow that gelatin (0.6g, the A type from pigskin, Sigma-Aldrich) is dissolved in 10mL MES
In fliud flushing (pH=6).Then dopamine hydrochloride (0.88g, Sigma-Aldrich) is added thereto, 10min is stirred at room temperature,
Dissolve it sufficiently.Add EDC (0.89g, Sigma-Aldrich) and NHS (0.54g, Sigma-Aldrich).At 50 DEG C
Under, persistently stir 18 hours.Above-mentioned reaction solution is dialysed 72 hours in deionized water finally, is then lyophilized bright to get arriving
Glue-scion grafting-dopamine.After EDC and NHS is added, and deionized water when dialysis, it is water-soluble using hydrochloric acid (1M) and sodium hydroxide
Liquid (1M) maintains pH 6.
(2) CNT (CNT-PDA) of auto polymerization preparation poly-dopamine (PDA) coating using dopamine under alkaline condition:
60mg CNT is dispersed in the Tris buffer solution that 30mL and pH are 8, and be ultrasonically treated 0.5 hour in 0 DEG C.So
Afterwards, dopamine hydrochloride (60mg) is added in above-mentioned solution, stir 12 hours reacts it sufficiently at room temperature, and is attached to
CNT surface.Above-mentioned solution is centrifuged 20 minutes in 10000rpm again, abandons supernatant, respectively washs precipitating three times with distilled water and ethyl alcohol,
60 DEG C oven drying 72 hours, products therefrom is to have the CNT (CNT-PDA) of PDA coating.
(3) it under initiator effect, is obtained by the auto polymerization of the dopamine in GT-DA/CS and CNT-PDA with antibacterial
Property, electric conductivity, antioxidative injectable composite hydrogel dressing:
GT-DA/CS (92:8) is dissolved in PBS by (3A), is configured to the solution of 5wt%.
CNT-PDA is dispersed in PBS by (3B), is configured to the CNT-PDA dispersion liquid of 4wt%.
The above-mentioned CNT-PDA dispersion liquid of 1mL is added in the GT-DA/CS solution of 7.5mL by (3C).After mixing completely, it is added
0.5mL H2O2(0.3mol/mL) and 1mL HRP (0.2mg/mL) are prepared by the sol-gel transition of 40s
The hydrogel of 3.75wt%GT-DA/CS, 0.4wt%CNT-PDA.
Possess adherency, hemostasis, conduction, oxidation resistant injection aquagel dressing in the present invention, performance is stablized, antibiotic property
Can performance is good in antibacterial test in vivo and in vitro, mechanical performance and electric conductivity are excellent in testing, Blank gel and
The gel for loading Doxycycline has the promotion Healing better than commercial dressing (TegadermTM) to mouse skin wound, and
And the hydrogel of this method preparation can remarkably promote the adherency of fibroblast (L929), proliferation, show good biology
Compatibility, with reference to the accompanying drawing and experimental data detailed analysis:
It is 95:5, H that attached drawing part Experiment, which chooses GT-DA/CS concentration 10wt%, GT-DA and CS mass ratio,2O2Concentration is
0.2mol/mL and HRP concentration is that 0.5mg/mL is representative, according to the concentration of CNT-PDA in hydrogel from 0wt% to 1wt%,
Sample is once named as GT-DA/CS/CNT0, GT-DA/CS/CNT1, GT-DA/CS/CNT2 and GT-DA/ by 2wt%, 4wt%
CS/CNT4。
The swelling behavior test result of Fig. 1 (a) hydrogel shows the increase with CNT-PDA content in hydrogel, water-setting
The swelling ratio of glue gradually increases.
The degradation behavior test result of Fig. 1 (b) hydrogel shows the increase with CNT-PDA content in hydrogel, water-setting
The degradation rate of glue slows down gradually.
The hydrogel SEM image being lyophilized before Fig. 1 (c) display swelling and after swelling, showing has the uniform pore size of interconnection micro-
Structure.
The time quilt in the crosspoint of storage modulu (G') and loss modulus (G ") that Fig. 1 (d) is obtained by rheology test
It is considered gelation time.When the mass percent of CNT-PDA increases to 1wt%, 2wt% and 4wt% from 0wt%, when plastic
Between from 120s be gradually reduced to 60s, 36s and 17s, show that the concentration of the CNT-PDA in hydrogel network the high more is conducive to mention
High gelation efficiency.Meanwhile with the increase of CNT-PDA content in hydrogel, the final strength (storage modulu) of hydrogel
It gradually increases.
Fig. 2 (a) is the adherency test experiments of aerogel dressing produced by the present invention as a result, having estimated these water by experiment
Adhesion property of the gel to skin.Test result shows that the made hydrogel of the present invention has good bio-adhesive performance.And
And increase the adhesion property that CNT-PDA concentration improves synthetic hydrogel from 1wt%2wt%4wt%.
The anthemorrhagic performance test result of Fig. 2 (b) aerogel dressing produced by the present invention, experiment show and do not take any arrange
The control group applied is compared, and hydrogel has the effect for being significantly reduced blood loss.
Fig. 2 (c) is the conductivity test result of aerogel dressing produced by the present invention, GT-DA/CS/CNT0 hydrogel tool
There is the minimum conductivity of 2.5 × 10-2S/m.When adding CNT-PDA, the conductance of GT-DA/CS/CNT 1, GT-DA/CS/CNT2
Rate is increased to 6.7 × 10-2 and 7.2 × 10-2S/m from 6.2 × 10-2.Illustrate that the addition of CNT-PDA has been obviously improved hydrogel
Electric conductivity.
Fig. 2 (d) is the radicals scavenging experimental result of aerogel dressing produced by the present invention, and 3mg/mL copolymer removes
Nearly 86.5% free radical, when hydrogel concentration increases to 5mg/mL, nearly all free radical is all removed.Demonstrate GT-
The antioxidant activity of DA/CS/CNT hydrogel.
Fig. 2 (e) is the drug release test result of aerogel dressing produced by the present invention, when starting, four hydrogels
Group Doxycycline comparatively quickly discharges, and almost half drug discharges in first 20 hours.Later, although how western ring
The rate of release of element slows down, but entire drug release process continues nearly 100 hours, and finally nearly 80% Doxycycline is from water-setting
The release of glue kind.Entire experiment shows the good medicament slow release performance of hydrogel.
Fig. 3 (a) is the light thermal property test result of aerogel dressing produced by the present invention, is irradiated 10 minutes in NIR
(1.0W/cm2) after, GT-DA/CS/CNT0 hydrogel temperature increases about 10 DEG C, this result is from oxidation catechol group shape
At quinone have certain photo-thermal ability.When the CNT-PDA concentration being added in hydrogel from 1wt% increase to 2wt% and
When 4wt%, after illumination 10min, Δ Ts increases to 21.3 DEG C and 23.3 DEG C from 17.2 DEG C respectively.All results confirm containing
The excellent photo-thermal effect of the GT-AD/CS/CNT hydrogel of CNT-PDA.
Fig. 3 (b) and Fig. 3 (c) is aerogel dressing produced by the present invention in vitro to staphylococcus aureus and Escherichia coli
Photo-thermal antibacterial effect test, as the result is shown 3min irradiation just can significantly reduce Survival probability of bacteria, 5min almost kills major part
Bacterium, 10min can kill all bacteriums with 100%.Experimental result shows the good external photo-thermal anti-microbial property of hydrogel.
Staphylococcus aureus photo-thermal antibacterial effect is tested in Fig. 3 (d) aerogel dressing body produced by the present invention, as a result
Wound location Survival probability of bacteria can be significantly reduced in display 10min irradiation, it was demonstrated that hydrogel good internal photo-thermal antibiotic property
Energy.
Fig. 4 (a) is the Cyto-compatibility in vitro of aerogel dressing produced by the present invention as a result, co-culturing 1 day and 3 days, institute
There is cell survival rate between group not show notable difference, shows the nontoxicity of GT-DA/CS/CNT hydrogel.It co-cultures 5 days
Afterwards, although entire hydrogel group average cell proliferation is lower than TCP, only GT-DA/CS/CNT4 hydrogel shows to show with TCP
It writes difference (P < 0.05).Demonstrate the good cell compatibility of hydrogel.
Fig. 4 (b) is the hemolysis in vitro experimental result of aerogel dressing produced by the present invention, by positive group (0.1%
Triton when hemolysis rate) is set as 100%, the hemolysis rate of all hydrogel groups is respectively less than 4%, it is shown that good blood phase
Capacitive.
Fig. 5 (a) is the wound closure rate system in the skin infection wound repair experiment of aerogel dressing produced by the present invention
Meter is as a result, after treatment in 3 days, with TegadermTMFilm group is compared, GT-DA/CS/CNT0, GT-DA/CS/CNT2 and GT-
The wound closure degree of DA/CS/Doxy hydrogel is considerably higher (P < 0.05).Show that GT-DA/CS/CNT hydrogel is preferably hurt
Mouth healing effect.In addition, GT-DA/CS/CNT2/Doxy hydrogel is also than GT-DA/CS/CNT0 and GT-DA/CS/CNT2 water-setting
The wound area of glue is substantially reduced (P < 0.05), it was demonstrated that antibiotic has positive effect to infected wound is repaired.
Fig. 5 (b) is the hydroxyproline content in the skin infection wound repair experiment of aerogel dressing produced by the present invention
Statistical result.Collagen deposition is indispensable process during union of wounded skin, is the important indicator for evaluating healing effect.
Therefore, the content of our hydroxyprolines using in neoplastic skin tissue detects its repairing effect as the representative of collagen deposition.Such as
Shown in Fig. 5 (b), collagen deposition level day has a larger increase from the 3rd day to the 7th, slightly increases within the 14th day.In addition, with
TegadermTMFilm group is compared, and all hydrogel groups all show higher collagen level the 3rd day of repair process and the 7th day.
And the 7th day collagen deposition of GT-DA/CS/CNT2/Doxy, GT-DA/CS/CNT2 group be apparently higher than GT-DA/CS/CNT0 group (p <
0.05) hydrogel group, is shown, the hydrogel for being especially added to conductive component plays the role of significantly promoting collagenic supersession.
Fig. 5 (c) is the granulation tissue thickness in the skin infection wound repair experiment of aerogel dressing produced by the present invention
Statistical result.The thickness of granulation tissue can reflect the quality of wound repair.As shown in Fig. 5 (c), three kinds of hydrogel group granulation groups
It knits thick (P < 0.05) compared with control group.In addition, GT-DA/CS/CNT2/Doxy hydrogel granulation tissue compared with GT-DA/CS/CNT0 and
GT-DA/CS/CNT2 hydrogel granulation tissue is thicker, illustrates that its Wound Healing Effect is more preferable.
Fig. 5 (d) is the epidermal thickness statistics in the skin infection wound repair experiment of aerogel dressing produced by the present invention.
The results show that all hydrogel groups were showed at the 7th day compares TegadermTMThe thicker epidermis of film (P < 0.05), especially GT-
DA/CS/CNT2 and GT-DA/CS/CNT2/Doxy group.GT-DA/CS/CNT2 group is compared with GT-DA/CS/CNT0 group, due to adding
Add CNT-PDA and shows thicker epidermal thickness.
Fig. 5 (e) is the revascularization statistics in the skin infection wound repair experiment of aerogel dressing produced by the present invention.
Increase trend is presented in defect skin wound medium vessels regeneration in the 7th day to the 14th day after handling as the result is shown.And GT-DA/CS/CNT2
With GT-DA/CS/CNT2/Doxy hydrogel group ratio TegadermTMFilm group and GT-DA/CS/CNT0 group have preferably improvement blood
The effect (P < 0.05) of pipe formation speed.
Fig. 5 (f) is the hair follicle regeneration statistics in the skin infection wound repair experiment of aerogel dressing produced by the present invention.
With TegadermTMFilm group is compared, and the hair follicle in hydrogel group dermal tissue is more, it is shown that better repairing effect.
A kind of method processed that the conductive oxidation resistant injectable composite hydrogel that stops blooding is adhered to the invention discloses antibacterial it is standby and
Its application in terms of wound dressing.Firstly, in 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDC) and
Dopamine is grafted on gelatin under the action of n-hydroxysuccinimide (NHS) and generates gelatin grafting dopamine (GT-DA)；Its
It is secondary, utilize the CNT (CNT-PDA) of polymerization preparation poly-dopamine (PDA) coating of dopamine under alkaline condition；Finally, by GT-
DA/CS solution and the mixing of CNT-PDA dispersion liquid, utilize H2O2/ HRP obtains the water as initiator, by the polymerization of dopamine
Gel.Concentration by changing CNT-PDA can porosity, degradation, swelling, rheology, machinery and electric conductivity to hydrogel
Etc. being fine-tuned.Aerogel dressing of the invention have good biocompatibility, stick, stop blooding, is anti-oxidant, photo-thermal it is anti-
The characteristics such as bacterium, medicament slow release.
Claims (10)
1. a kind of preparation method of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency, which is characterized in that including
Following steps:
(1) dopamine is grafted on gelatin main chain and generates gelatin grafting dopamine GT-DA；
(2) poly-dopamine coating is prepared in CNT surface using the auto polymerization of dopamine under alkaline condition, obtains CNT-PDA；
(3) GT-DA and CS are made into GT-DA/CS solution, CNT-PDA is made into CNT-PDA dispersion liquid；Under initiator effect,
By the auto polymerization of the dopamine in GT-DA/CS solution and CNT-PDA dispersion liquid, it is anti-oxidant to obtain the conductive hemostasis of antibacterial adherency
Injectable composite hydrogel.
2. a kind of preparation side of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency according to claim 1
Method, which is characterized in that in step (1), the preparation step of gelatin grafting dopamine includes:
(1A) by Gelatin in buffer solution, 50~60 DEG C of stirrings dissolve it sufficiently to obtain gelatin solution, wherein gelatin
Mass concentration be 3~6%；
Dopamine hydrochloride is added into gelatin solution obtained by step (1A) in (1B), and dissolution is stirred at room temperature and obtains mixed liquor, mixed liquor
The concentration of middle Dopamine hydrochloride is 44~88mg/mL；
EDC and NHS is added in (1C) mixed liquor obtained by step (1B), obtains reaction solution, reaction solution is persistently stirred at 30~50 DEG C
Mix reaction 6~18 hours, the concentration of EDC and NHS is respectively 44~89mg/mL and 27~54mg/mL in reaction solution；
(1D) after reaction, is lyophilized to step (1C) after acquired solution is dialysed, and obtains gelatin grafting dopamine.
3. a kind of preparation side of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency according to claim 2
Method, which is characterized in that in step (1A), buffer is phosphate buffer or 2- morpholino ethanesulfonic acid buffer, buffer
PH value is 5~6；In step (1D), using deionized water dialysis 48~72 hours；It is adjusted by hydrochloric acid and sodium hydrate aqueous solution
The pH value of the deionized water of the reaction solution and step (1D) of step (1C) is always 5~6.
4. a kind of preparation side of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency according to claim 1
Method, which is characterized in that in step (2), the specific preparation step of CNT-PDA includes:
CNT is dispersed in buffer solution by (2A), obtains the CNT dispersion that concentration is 0.5~2mg/mL；
(2B) Dopamine hydrochloride is added in the CNT dispersion of step (2A), obtains reaction solution, and reaction solution is stirred at room temperature 12~
48 hours, the concentration of Dopamine hydrochloride was 0.5~2mg/mL in reaction solution；
The reaction solution that (2C) step (2B) reaction terminates after post treatment, obtains CNT-PDA.
5. a kind of preparation side of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency according to claim 4
Method, which is characterized in that the CNT of step (2A) is dispersed in Tris buffer solution, and slow in 0~4 DEG C of ultrasound 0.5~2h, Tris
The pH of fliud flushing is 8~9；The post-processing of step (2C) is first to be centrifuged 5~20 minutes in 5000~10000rpm, abandons supernatant, uses
Distilled water and ethyl alcohol respectively wash three times, 30~60 DEG C drying 24~72 hours.
6. a kind of preparation side of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency according to claim 1
Method, which is characterized in that in step (3), the specific system of the conductive oxidation resistant injectable composite hydrogel that stops blooding of preparation antibacterial adherency
Include: for step
GT-DA/CS is dissolved in buffer by (3A), is configured to the GT-DA/CS solution that mass concentration is 5~20%；
CNT-PDA is dispersed in buffer by (3B), is configured to CNT-PDA dispersion liquid of the mass concentration 1%~4%；
(3C) is mixed the two in the ratio that every 1mL CNT-PDA dispersion liquid is added in 7.5mL GT-DA/CS solution, is added
0.25~0.65mol initiator, reaction obtain the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency.
7. a kind of preparation side of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency according to claim 6
Method, which is characterized in that in step (3A) and step (3B), buffer is PBS；Quality accounting of the CS in GT-DA/CS be
5%~10%.
8. a kind of system of the conductive oxidation resistant injectable composite hydrogel that stops blooding of antibacterial adherency according to claim 1 or 6
Preparation Method, which is characterized in that initiator includes the H that concentration is 0.1~0.3mol/mL2O2It is that 0.2~0.5mg/mL is peppery with concentration
Root peroxidase, every 1mL CNT-PDA dispersion liquid is corresponding to be added 0.5mL H2O2With 1mL horseradish peroxidase；Step (3C)
10~200s of middle reaction.
9. a kind of conductive oxidation resistant injectable Compound Water that stops blooding of antibacterial adherency made from preparation method as described in claim 1
Gel.
10. the conductive oxidation resistant injectable composite hydrogel that stops blooding of a kind of antibacterial adherency as claimed in claim 9 is hurt in preparation
Application in mouth dressing.
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| CN113773688A (en) * | 2021-09-26 | 2021-12-10 | 北京理工大学 | Functionalized nano composite electromagnetic shielding coating and preparation method and application thereof |
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| CN116327640B (en) * | 2023-03-08 | 2024-04-26 | 大连理工大学 | Bioadhesive hydrotalcite-polydopamine skin composite light shielding agent and preparation method thereof |
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| CN116589862A (en) * | 2023-05-19 | 2023-08-15 | 福建优壳生物科技有限公司 | Degradable biological gel and preparation method and application thereof |
| CN116589862B (en) * | 2023-05-19 | 2024-01-30 | 福建优壳生物科技有限公司 | Degradable biological gel and preparation method and application thereof |
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