CN110448722A - A kind of injectable is containing the temperature sensitive composite antibacterial hydrogel material of tannic acid and its preparation and application - Google Patents
A kind of injectable is containing the temperature sensitive composite antibacterial hydrogel material of tannic acid and its preparation and application Download PDFInfo
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/0066—Medicaments; Biocides
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/009—Materials resorbable by the body
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0095—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
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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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/23—Carbohydrates
- A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
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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
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
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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
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
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- A—HUMAN NECESSITIES
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- 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
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
Abstract
The present invention provides a kind of injectable containing the temperature sensitive composite antibacterial hydrogel material of tannic acid and its preparation and application.The material have temperature and pH-sensitivity, can in-situ injection it is sprayable, can be used as antiseptic dressing.Water is dissolved under polymer such as chitin derivativ low temperature first by Thermo-sensitive containing polyhydroxy, tannic acid solution is added in a liquid state and metal ion solution is uniformly mixed, gel can quickly be formed under body temperature by being injected or be ejected into wound surface, wherein tannic acid is not only used as crosslinking agent, but also antibacterial agent of the chelation as slow release occurs with metal ion.The anti-bacterial hydrogel dressing is mainly characterized by preparation simply；Low temperature flow is good, Rapid gelation under body temperature, can slow release antibacterial agent, antibacterial range is wide and antibacterial time is long；With good biocompatibility and biological degradability, the secondary injury caused when more change dressings is avoided；Be conducive to wound healing, effectively facilitate skin regeneration, reduces scar and formed, also there is anti-inflammatory antioxidation.
Description
Technical field
The invention belongs to bio-medical material and its preparation technical field, it is related to a kind of injectable containing the temperature sensitive multiple of tannic acid
Close antibacterial hydrogel material and its preparation and application.
Background technique
Skin is made of cuticula, epidermis and corium, is protection in-vivo tissue, is prevented pathogen invasion, maintains body fluid flat
The basic barrier of weighing apparatus.But the wounds such as notch, contusion, incised wound, burn can damage the function of skin, thus cause bacterium infection, egg
The problems such as white matter and excessive water are lost, endocrine and immune system disorder.Gauze, bandage, the conventional medicals dressing such as absorbent cotton are
It is made of dry fabric, the tissue of adsorbable initial stage exudation, but it cannot provide wet environment for wound, easily adhere to
On wound, when replacement, is easy to damage newly-generated tissue.Ideal wound dressing should obstruct xenobiotic pollutants and microorganism,
Moist environment is provided for wound, can be carried out gas exchanges, be not adhered wound, it is nontoxic, it does not cause allergic reaction, there is antibacterial
Property, promote wound healing etc..
Macromolecule hydrogel has three-dimensional cross-linked reticular structure and hydrophily, can absorb a large amount of water and have stronger
Water holding capacity.Hydrogel has a good through performance to water and oxygen, and property is soft, is able to maintain certain shape, and extracellular
Matrix is similar, there is good biocompatibility.Aerogel dressing can maintain surface of a wound moist environment, and absorptive tissue exudate mitigates
Patient pain.Temperature sensing polymer such as chitin base temperature-sensitive hydrogel keeps liquid in low temperature, can equably contain cell/
Drug simultaneously fills irregular wound site, and temperature rising quickly forms gel after contacting with wound, can provide one for the surface of a wound
A bacteria preventers build the good environment of a suitable tissue growth, promote tissue growth.Chitin and its derivative have
Very good biocompatibility, biodegradability and multiple biological activities, are suitable for the regeneration of skin histology.Chitin with
Carboxylated reagent reacts in sodium hydroxide-urea system, can be made the carboxy chitin with pH sensibility and Thermo-sensitive [in
State invention patent application prospectus CN201310641249.6], chitin and hydroxypropylation reagent are in sodium hydroxide-urea
It is reacted in system, Hydroxypropyl chitosan [the Chinese invention patent application prospectus with Thermo-sensitive can be made
CN201410170871.8], Hou Chunlin etc. reports Thermo-sensitive hydroxyl butyl chitosan [Chinese patent application prospectus
CN200810033699.6] and Thermo-sensitive hydroxyl amyl chitosan [Chinese patent application prospectus CN201210220246.0]
Preparation.
Microorganism infection seriously threatens organ transplant, prosthese transplanting and organizational project building.It is asked to solve this
The antibacterial materials such as antibiotic and nano silver are loaded into bracket by topic, some researchers.However, antibiotic is typically applied to carefully
Very specific site in after birth acts on very specific metabolic pathway, passes through bacterium relatively easily in this way
Natural selection, the transmitting or otherwise for encoding Drug Resistance Plasmidss develop the drug resistance to antiviral antibiotic, therefore now thin
Bacterium drug resistance problems are got worse.It is micro- that nano-Ag particles can kill most of bacteriums, fungi, mould, spore being in contact with it etc.
Biology has good bactericidal effect to the tissue infection of stubborn bacteria, drug-resistant bacteria and fungus-caused higher depth, and
Drug resistance will not be generated.But in recent years researches show that nano-Ag particles have very strong cytotoxicity [Tang Jinglong, Wang Shuo,
Liu Li, Wang Chunren, Xiong Ling, Wei Lina, Xi Tingfei, the cytotoxic effect and Initial Study of Mechanism of nano-Ag particles, Beijing biology doctor
Learn engineering, 2013,32,5,485-489], nano-Ag particles are to urinary system, digestive system, respiratory system, nervous system, life
It grows system and hematological system and finds there is different degrees of side effect [Ni Fangfang, Wang Bolin, Song Tengjiao, Yuan little Feng, nanometer
The poisonous effect and study on mechanism of Argent grain are in progress, Chinese Pharmacological Bulletin, 2016,32,5,593-598], thus by
Heavy Metal Accumulation chronobiological safety issue caused by nano-Ag particles contact is widely noticed.Therefore, design and synthesis have
The injection aquagel of antibacterial activity as organizational project timbering material by expectation.
Tannic acid is the presence of a kind of extensive polynary phenolic acid of complexity in nature, and tannic acid has significant antibacterial special
Property, it can effectively inhibit the formation of staphylococcus aureus and Escherichia coli biofilm, and Wound Contraction can be made and accelerate meat
The formation [Chinese invention patent application prospectus CN201711348496] of bud tissue and collagen.Tannic acid is rich in
It in the bark and fruit of a variety of trees, can be used as food antioxidant, be one kind by food and drug administration (FDA)
Approval can be used for food additives.Although tannic acid toxicity very little itself, excessive concentration also have apparent toxicity, this hair
It is bright that tannic acid and metal ion are introduced into polymer of the Injectable temperature sensitive containing polyhydroxy such as chitin base temperature-sensitive hydrogel, it obtains
To not only there is the injectable anti-bacterial hydrogel of pH sensibility with Thermo-sensitive again, it is expected that the realization of tannic acid slow release is relatively long-term
Antimicrobial antiphlogistic antioxidation and low toxicity it is nontoxic.
Summary of the invention
Various present in existing wound dressing in order to solve the problems, such as, the object of the present invention is to provide a kind of injectables containing single
The temperature sensitive composite antibacterial hydrogel material of peaceful acid and its preparation and application.The dressing has temperature sensitivity and pH sensibility, In
When low temperature liquid have good mobility, can in-situ injection it is sprayable, irregular shape of wound can be filled.Under body temperature
Rapid gelation maintains tannic acid and is not easy to be flushed away, can slow release tannic acid antibacterial agent, reduce its toxicity, the dressing have length
The anti-microbial property and antibacterial range of time is wide, has good biocompatibility and biodegradability, in biological medicine material
Field has a wide range of applications.
A kind of temperature sensitive composite antibacterial hydrogel material of the injectable containing tannic acid, the antibacterial hydrogel material includes following
Three parts:
(1) can spontaneous physical crosslinking in situ in physiological conditions polymer solution A matrix of the Thermo-sensitive containing polyhydroxy,
It is liquid under low temperature；
(2) tannin aqueous acid；
(3) metal ion solution.
Here Thermo-sensitive can be that temperature-sensitive starch is polymer-modified, and Thermo-sensitive is cellulose modified containing polyhydroxylated polymer
Object, Thermo-sensitive chitosan modifier etc.；Here low temperature refers to 37 degree of body temperature or less.
A kind of preparation method of temperature sensitive composite antibacterial hydrogel material of the injectable containing tannic acid
(1) preparation can spontaneous physical crosslinking in situ in physiological conditions polymer solution A, In of the Thermo-sensitive containing polyhydroxy
Cryo-conservation；
(2) tannic acid solution is added into solution A under low temperature, is uniformly mixed and obtains mixed solution B；
(3) metal ion solution is added into mixed solution B under low temperature, obtains mixed solution C after mixing, acid adding or
Alkali adjusts pH, injectable composite antibacterial hydrogel precursor solution at low temperature with good fluidity is obtained, in physiological condition
Under composite antibacterial hydrogel material can be formed in situ.
Preferably, the polymer solution of the solution A Thermo-sensitive containing polyhydroxy is Thermo-sensitive modified chitin, specially warm
Quick property hydroxyl butyl chitosan, Thermo-sensitive hydroxyl amyl chitosan, Thermo-sensitive carboxymethyl chitin, Thermo-sensitive ethoxyl chitin, temperature
Any one of quick property Hydroxypropyl chitosan, Thermo-sensitive hydroxyl butyl chitin or their mixture.
Wherein the acetyl degree range of Thermo-sensitive hydroxyl butyl chitosan is 0.01~0.4；It is Thermo-sensitive carboxymethyl chitin, temperature sensitive
Property ethoxyl chitin, Thermo-sensitive Hydroxypropyl chitosan, Thermo-sensitive hydroxyl butyl chitin acetyl degree range be 0.7~0.92；
The molecular weight ranges of these temperature sensing polymers are 5kDa~1000kDa.
Preferably, the type that metal ion is added is iron ion, copper ion, any one of zinc ion or theirs is mixed
Close object.
Preferably, the mass concentration range of temperature sensing polymer is 0.5~20wt% in mixed solution A.
Preferably, the mass concentration range of tannic acid is 0.01~0.4wt% in mixed solution C；Metal in mixed solution C
The mass concentration range of ion is 0.001~0.5wt%.
Preferably, acid adding or alkali adjust pH in step (3), and the molar concentration that acid or alkali is added is 0.01~6mol/L, most
The pH range of mixed solution C is 4~10 afterwards.
Preferably, the preparation temperature range in step (1) (2) (3) is 2~14 DEG C, is quickly mixed each component with vortex instrument
It closes uniformly, forms the injection aquagel precursor solution with good fluidity.Step (3) physiological condition is body temperature item
Part, product do not need post-processing direct in-situ and use.
A kind of application of temperature sensitive composite antibacterial hydrogel material of the injectable containing tannic acid, the composite antibacterial hydrogel material
It is used for wound healing as antiseptic dressing, and there is anti-inflammatory antioxidation.
The material have temperature sensitivity and pH sensibility, can in-situ injection it is sprayable, can be used as antiseptic dressing.First will
Polymer of the Thermo-sensitive containing polyhydroxy such as chitin derivativ is dissolved in water at low temperature, and tannic acid solution is added in a liquid state
It being uniformly mixed with metal ion solution, gel can quickly be formed under body temperature by being injected or be ejected into wound surface, wherein
Tannic acid is not only used as crosslinking agent, but also antibacterial agent of the chelation as slow release occurs with metal ion.The anti-bacterial hydrogel
Dressing is mainly characterized by preparation simply；Low temperature flow is good, Rapid gelation under body temperature, can slow release antibacterial agent, antibacterial model
It is long to enclose wide and antibacterial time；With good biocompatibility and biological degradability, the secondary wound caused when more change dressings is avoided
Evil；Be conducive to wound healing, effectively facilitate skin regeneration, reduces scar and formed, also there is anti-inflammatory antioxidation.
Compared with prior art, this technology have it is following the utility model has the advantages that
(1) present invention is molten by the polymer such as Thermo-sensitive chitosan radical derivative directly by Thermo-sensitive containing polyhydroxy
Liquid, tannic acid and aqueous metallic ions directly mix, and preparation process is simple.Hydrogel is formed by physical crosslinking, without drawing
Enter small molecule crosslinking agent, and chitin derivativ has good biological degradability, avoids causing two to wound when more change dressings
Secondary injury.The sprayable characteristic of temperature sensitive injectable of composite antibacterial hydrogel is the liquid with good fluidity in low temperature, can
It is filled up completely irregular shape of wound, obstructs xenobiotic pollutants and microorganism.
(2) as Wound antibiotic dressing, Rapid gelation maintains tannin to the composite antibacterial hydrogel material described under body temperature
Acid is not easy to be flushed away, and sustainable slow release tannic acid antibacterial agent one week under normal physiological conditions, reduces its toxicity；Containing bacterium acid
Property under the conditions of can accelerated release in vitro tannic acid, can effectively play the broad spectrum antibacterial performance of tannic acid, reduce its toxic effect, it is effectively pre-
Anti- wound infection.
(3) composite antibacterial hydrogel material prepared by the present invention has good bio-compatible as antibacterial wound dressing
Property, composite antibacterial hydrogel material provides wet healing environment for wound, has good therapeutic effect to wound healing, promotes
Skin regeneration simultaneously reduces scar and is formed.
Detailed description of the invention
Fig. 1 is Hydroxypropyl chitosan/tannic acid/iron in 2wt% Hydroxypropyl chitosan HPCH hydrogel and embodiment 2
37 degree of lower time sweeps of rheometer test (a) temperature scanning of HPCH/TA/Fe composite hydrogel and (b).
Fig. 2 be the embodiment of the present invention 2 in Hydroxypropyl chitosan/tannic acid/iron composite hydrogel HPCH/TA/Fe (b) with
Hydroxypropyl chitosan/tannic acid composite hydrogel HPCH/TA (a) in embodiment 5 tannic acid in different pH buffers is released
To one's heart's content condition.
Fig. 3 is the cytotoxicity and cell in vitro transfer ability result of study figure of hydrogel in the embodiment of the present invention 9.Respectively
Be HPCH hydrogel, HPCH/TA hydrogel, HPCH/Fe hydrogel and HPCH/TA/Fe hydrogel leaching liquor it is thin to NIH 3T3
The cell toxicity data (a) of born of the same parents, life or death cell dyeing photo (b) and cell migration effect (c).
Fig. 4 is HPCH/TA/Fe hydrogel in the embodiment of the present invention 2 to Escherichia coli (E.coli) and Staphylococcus aureus
The long-time antibacterial action of bacterium (S.aureus), respectively with the PBS solution of not aqueous gel, not the hydrogel HPCH of TA and
HPCH/Fe is as a control group.
Fig. 5 is HPCH/TA/Fe aerogel dressing in the embodiment of the present invention 2 to the BALB/c of infection of staphylococcus aureus
Back of mice through thickness cuts off wound model in different time wound photo (a), and wound area analyzes (b) and after treatment 12 days
H&E dyeing, horse pine trichrome stain and sirius red stains slice photo (c) of wound
Specific embodiment
To keep the present invention easier to understand, specific embodiments of the present invention are further illustrated below.
Below with reference to embodiment and attached drawing, the invention will be further described, and its object is to help to better understand this
The content of invention, but these specific embodiments are not in any way limit the scope of the present invention.
The preparation of 1 Thermo-sensitive chitosan derivative A of embodiment
According to the research work [Chinese invention patent application prospectus CN201410170871.8] of our early periods,
The Hydroxypropyl chitosan of low deacetylation is prepared in sodium hydroxide-urea system using homogeneous method.Weigh 2 grams of first after purification
Shell element is dispersed with stirring in 100 containing the 11wt% sodium hydroxide and 4wt% urea gram aqueous solution freezed in advance, at -30 DEG C
Lower freezing for 24 hours, takes out mechanical stirring at room temperature and is thawed the chitin water soluble liquid dissolved.It is molten to obtained chitin
11.4 grams of propylene oxide are added in liquid (100 grams, 2wt%), system stirs at 2 DEG C is warming up to reactant after mixing
5 DEG C of reactions for 24 hours, then raise temperature to 15 DEG C of reaction 6h.System is finally cooled to 2 DEG C, with 3M hydrochloric acid regulation system pH value to 7,
With deionized water dialysis, freeze-drying obtains white sponge Hydroxypropyl chitosan (HPCH), yield 87%.1H NMR spectra
The acetyl degree that product is calculated is 0.89, degree of substitution 0.84.Measuring its viscosity average molecular weigh with Ubbelohde viscometer is Mη=
410kDa.The HPCH solution of the Homogeneous synthesis has temperature sensitivity, and rheological results show the transformation of reversible sol-gel
The gel transition temperature of behavior, the HPCH solution that wherein concentration is 2wt% is 18 DEG C (Fig. 1 a).
According to the research work [Chinese invention patent application prospectus CN201310641249.6] of our early periods,
The carboxymethyl chitin of low deacetylation is prepared in sodium hydroxide-urea system using homogeneous method,1HNMR spectrogram is calculated
The acetyl degree of product is 0.87, degree of substitution by carboxymethyl 0.19.Similar, using homogeneous method in sodium hydroxide-urea system
The ethoxyl chitin and hydroxyl butyl chitin of low deacetylation are prepared, the acetyl degree range of these chitin derivativs is in 0.7-
0.92, molecular weight ranges are 5kDa~1000kDa.
The preparation of 2 Hydroxypropyl chitosans of embodiment/tannic acid/iron chloride HPCH/TA/Fe hydrogel
By the Hydroxypropyl chitosan HPCH, tannic acid TA and Iron trichloride hexahydrate of the Thermo-sensitive prepared in embodiment 1
FeCl3·6H2O is dissolved in ultrapure water respectively at 2-14 DEG C of low temperature, and configuration quality concentration is HPCH solution, the 0.75wt% of 3wt%
TA solution and 0.8wt% FeCl3·6H2O solution.Take 1g HPCH solution that 0.4g TA solution is added at 2~14 DEG C of low temperature
It is quickly vortexed and is uniformly mixed, then rapidly join 0.1g FeCl3Solution is uniform in 2~14 DEG C of vortex mixeds of low temperature, and uses 1MNaOH
Solution adjusts pH to 7.4, which has good mobility at 2-14 DEG C of low temperature, and injectable can
Injection places it in the water-bath standing 1min that temperature is 37 DEG C and quickly forms hydrogel (Fig. 1).
Embodiment 3: Hydroxypropyl chitosan/tannic acid/iron chloride HPCH/TA/Fe hydrogel preparation
By the Hydroxypropyl chitosan HPCH, tannic acid TA and Iron trichloride hexahydrate of the Thermo-sensitive prepared in embodiment 1
FeCl3·6H2O is dissolved in ultrapure water respectively at 4 DEG C of low temperature, and configuration quality concentration is the HPCH solution of 3wt%, 0.75wt%
The FeCl of TA solution and 9.6wt%3·6H2O solution.Take 1g HPCH solution that 0.4g TA solution is added quick at 2~15 DEG C of low temperature
Vortex mixed is uniform, then rapidly joins 0.1g FeCl3Solution is uniform in 2~10 DEG C of vortex mixeds of low temperature.With 1M NaOH solution
PH to 7.4 is adjusted, which has good mobility at 2-10 DEG C of low temperature, and injectable is sprayable,
It places it in the water-bath standing 1min that temperature is 37 DEG C and quickly forms hydrogel.It is molten using the HPCH that mass concentration is 0.75wt%
It is that the HPCH solution of 3wt% obtains similar result that liquid, which replaces mass concentration,.Use the HPCH solution (M of lower molecular weightη=
When 40kDa), the HPCH solution that mass concentration is 30wt% can be used, similar injectable is made containing the temperature sensitive compound of tannic acid
Antibacterial hydrogel material.
The preparation of 4 Hydroxypropyl chitosans of embodiment/tannic acid/iron chloride HPCH/TA/Fe hydrogel
By the Hydroxypropyl chitosan HPCH, tannic acid TA and Iron trichloride hexahydrate of the Thermo-sensitive prepared in embodiment 1
FeCl3·6H2O is dissolved in ultrapure water respectively at 4 DEG C of low temperature, and configuration quality concentration is HPCH solution, the 1.125wt% of 3wt%
TA solution and 14.4wt% FeCl3·6H2O solution.Take 1g HPCH solution that 0.4g TA solution is added at 2~15 DEG C of low temperature
It is quickly vortexed and is uniformly mixed, then rapidly join 0.1g FeCl3Solution is uniform in 2~10 DEG C of vortex mixeds of low temperature.With 1M NaOH
Solution adjusts pH to 7.4, which has good mobility at 2-10 DEG C of low temperature, and injectable can
Injection places it in the water-bath standing 1min that temperature is 37 DEG C and quickly forms hydrogel.The tannin of C solution before adjusting pH
The mass concentration range of acid is 0.01~0.4wt%, and metal ion iron speciation range is equal when being 0.001~0.5wt%
Similar temperature sensitive composite antibacterial hydrogel material of the injectable containing tannic acid can be made.
The preparation of 5 Hydroxypropyl chitosans of embodiment/tannic acid HPCH/TA hydrogel
The Hydroxypropyl chitosan HPCH of the Thermo-sensitive prepared in embodiment 1 and tannic acid TA is dissolved in respectively at 4 DEG C of low temperature
In ultrapure water, configuration quality concentration is the TA solution of the HPCH solution of 3wt%, 0.75wt%.1g HPCH solution is taken to be added
0.4g TA solution is quickly vortexed at 2~15 DEG C of low temperature and is uniformly mixed, then rapidly joins 0.1g pure water and be vortexed at 2~15 DEG C of low temperature
It is uniformly mixed.PH to 7.4 is adjusted with 1M NaOH solution, the water-bath standing 1min that temperature is 37 DEG C is placed it in and quickly forms water
Gel, but do not have here without the neutral hydrogel containing tannic acid of addition metal ion at 2-10 DEG C of low temperature good
Mobility and lose reversible Thermo-sensitive and syringeability.
The preparation of 6 Hydroxypropyl chitosans of embodiment/tannic acid/zinc chloride HPCH/TA/Zn hydrogel
By the Hydroxypropyl chitosan HPCH, tannic acid TA and zinc chloride ZnCl of the Thermo-sensitive prepared in embodiment 12Respectively at
4 DEG C of low temperature are dissolved in ultrapure water, and configuration quality concentration is the TA solution and 0.8wt% of the HPCH solution of 3wt%, 0.75wt%
ZnCl2Solution.It takes 1g HPCH solution that 0.4g TA solution is added to be uniformly mixed in 2~15 DEG C of low temperature quick are vortexed, then quickly
0.1g ZnCl is added2Solution is uniform in 2~15 DEG C of vortex mixeds of low temperature.PH to 7.4 is adjusted with 1M NaOH solution, this contains list
The neutral solution of peaceful acid has good mobility at 2-15 DEG C of low temperature, and injectable is sprayable, and placing it in temperature is 37 DEG C
Water-bath stand 1min quickly form hydrogel.
7 Hydroxypropyl chitosans of embodiment/tannic acid/copper chloride HPCH/TA/CuCl2The preparation of hydrogel
By the Hydroxypropyl chitosan HPCH, tannic acid TA and copper chloride CuCl of the Thermo-sensitive prepared in embodiment 12Respectively at
4 DEG C of low temperature are dissolved in ultrapure water, and configuration quality concentration is the TA solution and 0.8wt% of the HPCH solution of 3wt%, 0.75wt%
CuCl2Solution.It takes 1g HPCH solution that 0.4g TA solution is added to be uniformly mixed in 2~15 DEG C of low temperature quick are vortexed, then quickly
0.1g CuCl is added2Solution is uniform in 2~15 DEG C of vortex mixeds of low temperature.PH to 7.4 is adjusted with 1M NaOH solution, this contains list
The neutral solution of peaceful acid has good mobility at 2-15 DEG C of low temperature, and injectable is sprayable, and placing it in temperature is 37 DEG C
Water-bath stand 1min quickly form hydrogel.
8 polymer of other Thermo-sensitives containing polyhydroxy of embodiment replace the preparation of Thermo-sensitive Hydroxypropyl chitosan containing tannic acid and
Iron ion hydrogel
The carboxymethyl chitin CMCH of the Thermo-sensitive prepared in embodiment 2 is dissolved in 0.5M NaOH in 4 DEG C of low temperature, is used
3M HCl solution adjusts pH to 7.4, tannic acid TA and Iron trichloride hexahydrate FeCl3·6H2O is dissolved in ultrapure water respectively at 4 DEG C of low temperature
In, configuration quality concentration is CMCH solution, the TA solution of 0.75wt% and the FeCl of 0.8wt% of 3wt%3·6H2O solution.It takes
1g CMCH solution is added 0.4g TA solution and is uniformly mixed in 2~10 DEG C of low temperature quick are vortexed, then rapidly joins 0.1g FeCl3
Solution is uniform in 2~10 DEG C of vortex mixeds of low temperature.It places it in the water-bath standing 1min that temperature is 37 DEG C and quickly forms hydrogel.
Polymer such as Thermo-sensitive collagen, the modified temperature sensitive water-setting of xyloglucan using other Thermo-sensitives containing polyhydroxy
Glue, Thermo-sensitive hydroxypropyl cellulose, Thermo-sensitive hydroxypropyl methyl cellulose, Thermo-sensitive hydroxybutyl cellulose, Thermo-sensitive hydroxyl butyl
Chitosan, Thermo-sensitive hydroxyl amyl chitosan, Thermo-sensitive ethoxyl chitin or Thermo-sensitive hydroxyl butyl chitin replace Thermo-sensitive
Tannin aqueous acid and aqueous metallic ions are added in Hydroxypropyl chitosan at low temperature, and injectable can be made containing tannic acid
Temperature-sensitivcomposite composite hydrogel antiseptic dressing.
9 performance test of embodiment
1. release behavior of the antibacterial agent TA in different pH buffers
The 500 μ L hydrogel precursor solution prepared in above-described embodiment 2 and 5 are placed 30 minutes at 37 DEG C coagulates it
Then glue is separately immersed in the centrifuge tube of the different pH buffer solutions containing 15mL pH 3.0,5.0,5.5,7.4 and 9.0.
It is 37 DEG C that centrifuge tube, which is placed in temperature, and oscillation rate is in the shaking table of 60rpm.1.0mL solution is taken out in certain time interval,
And the fresh buffer of same volume is added.Passed through in the absorbance measurement solution at 278nm using ultraviolet specrophotometer
The release of TA.As shown in Fig. 2, HPCH/TA hydrogel in 48 hours there is similar sustained release TA to reach at various ph values
To 40% or more, without apparent pH sensibility；And in HPCH/TA/Fe hydrogel the rate of release of TA with the variation of pH value and
Variation, acid lower release is faster, has apparent pH sensibility.In pH3.0, HPCH/TA/Fe hydrogel release profiles class
It is similar to the TA curve of HPCH/TA hydrogel release, and from the TA of HPCH/TA/Fe hydrogel release about 50% after 48 hours.When
When pH value increases to 5.5,7.4 and 9.0,10% TA is only discharged in 7 days, this shows in faint acid, neutral and alkaline ring
TA under border in hydrogel can long-term slow release, inhibit bacterial growth, play long-term antimicrobial antiphlogistic antioxidation, and
Meeting accelerated release in vitro tannic acid, can effectively play the broad spectrum antibacterial performance of tannic acid under acid condition containing bacterium.
2. the cytotoxicity and cell in vitro transfer ability of hydrogel are studied.
Pass through the cell in vitro of Cell counting Kit CCK-8 measurement assessment hydrogel using NIH 3T3 fibroblast
Toxicity.Life or death dyeing is carried out to NIH 3T3 cell, green represents living cells, and red represents dead cell, sees by laser co-focusing
It examines.Such as Fig. 3, the results show that the cell number of HPCH, HPCH/Fe, HPCH/TA/Fe group all shows sustainable growth, this three groups
Red dead cell number is considerably less, this, which shows HPCH/TA/Fe hydrogel not, influences the growth of 3T3 NIH cell, and does not add metal
The HPCH/TA hydrogel of ion has overt toxicity to cell.It is repaired in addition, carrying out cell migration assay with the wound for assessing hydrogel
Reactivation power.The measurement of 2D scratch wound is carried out on NIH 3T3 fibroblast monolayer to simulate the different hydrogel condition trainings of monitoring
The influence in 48 hours to wound closure in vitro of feeding base.The cell cultivated in HPCH/TA/Fe hydrogel culture medium, which is shifted to, to be drawn
Trace region faster than other groups, and nearly reaches 100% after 24 hours and converges.Illustrate that HPCH/TA/Fe hydrogel can be with
Accelerating wound healing process.
3. long-time anti-microbial property test
The antibacterial of HPCH/TA/Fe hydrogel is assessed by colony counting method using Escherichia coli and staphylococcus aureus
Activity, respectively by the PBS of 200 μ L of not aqueous gel, hydrogel HPCH and the HPCH/ Fe of TA is not as a control group.By water
Gel precursors solution (200 μ L) is added in 48 porocyte culture plates, is subsequently placed in 37 DEG C until forming hydrogel.By HPCH/
TA/Fe hydrogel impregnates in the sterile PBS of 1mL in 37 DEG C 24 hours, and the PBS after then being impregnated with the fresh PBS replacement of 1mL should
Process repeats.10 μ L are contained 106CFU mL-1The PBS suspension of Escherichia coli or staphylococcus aureus is upper
It states and impregnates on the hydrogel of different number of days that (the original hydrogel that will not impregnate respectively impregnates and changes liquid 3 times water through PBS solution
The hydrogel that gel and immersion change liquid 6 times is denoted as D1, D4 and D7).By the hydrogel of these inoculated bacterias in wet atmosphere
It is incubated 24 hours in 37 DEG C.Then, 1mL PBS is added into each hole and retains bacterium to be resuspended, and take 10 μ L bacterium therein
Suspension is on Luria-Bertani agar plate, after 37 DEG C incubate 24 hours, counts Luria-Bertani agar
The bacterium colony formed on plate, as shown in figure 4, illustrating that HPCH/TA/Fe gel has good prolonged antibacterial action.To bacterium
Life or death dyeing is carried out, green represents bacterium living, and red represents dead bacterium, observes by laser co-focusing, as a result illustrates HPCH/
TA/Fe gel can kill Escherichia coli and staphylococcus aureus (red), and the bacterium of control group is substantially that green is deposited
Living.
4. bacterial infections in vivo wound healing assay
The female BAl BIc of 8 week old/c mouse is anaesthetized by intraperitoneal injection chloraldurate, and is shaved using razor small
The dorsal body setae of mouse.Through thickness circular wound (diameter 5mm) is prepared in rat dorsum skin by biopsy punch.20 μ L are golden yellow
Color staphylococcus suspension (2 × 108CFUmL-1) be added wound location 5 minutes, then use PBS, TA solution (0.2wt%) or
HPCH (2wt%), HPCH/TA/Fe (composite hydrogel prepared by embodiment 2, HPCH 2wt%, TA 0.2wt%, Fe ion
0.01wt%) hydrogel covers.It is fixed with transparent membrane.More change dressings and every 2 days measurement wound sizes.Wound healing 12
Mouse is implemented to be euthanized after it, the skin histology of wound area is collected, is then attached in 4% paraformaldehyde.Then, it will receive
To study tissue appearance, Masson Ma Songsan color and Picro-Sirius red are used for skin biopsy hematoxylin and eosin (H&E) dyeing obtained
In histologic analysis.Fig. 5 illustrates that HPCH/TA/Fe group shows that apparent wound size reduces after processing 6 days, this shows
HPCH/TA/Fe hydrogel, which has, organizes better debridement and antibacterial effect than other.Histotomy result also indicates that HPCH/TA/Fe
Hydrogel is more advantageous to wound healing, effectively facilitates skin regeneration, reduces scar and is formed.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
Claims (10)
1. a kind of temperature sensitive composite antibacterial hydrogel material of injectable containing tannic acid, which is characterized in that the composite antibacterial water-setting
Glue material includes:
(1) can spontaneous physical crosslinking in situ in physiological conditions polymer solution A matrix of the Thermo-sensitive containing polyhydroxy, under low temperature
It is liquid；
(2) tannin aqueous acid；
(3) metal ion solution.
2. a kind of preparation method of temperature sensitive composite antibacterial hydrogel material of injectable containing tannic acid, it is characterised in that:
(1) preparation can spontaneous physical crosslinking in situ in physiological conditions polymer solution A of the Thermo-sensitive containing polyhydroxy, in low temperature
It saves；
(2) tannic acid solution is added into solution A under low temperature, is uniformly mixed and obtains mixed solution B；
(3) metal ion solution is added into mixed solution B under low temperature, obtains mixed solution C, acid adding or alkali tune after mixing
PH is saved, injectable antibacterial composite hydrogel precursor solution at low temperature with good fluidity is obtained, in physiological conditions may be used
Composite antibacterial hydrogel material is formed in situ.
3. temperature sensitive composite antibacterial hydrogel material or claim of a kind of injectable according to claim 1 containing tannic acid
A kind of 2 preparation methods of temperature sensitive composite antibacterial hydrogel material of the injectable containing tannic acid, which is characterized in that the solution
Polymer of the Thermo-sensitive containing polyhydroxy is Thermo-sensitive modified chitin in A.
4. temperature sensitive composite antibacterial hydrogel material or one kind of a kind of injectable according to claim 3 containing tannic acid can be infused
Penetrate the preparation method of the temperature sensitive composite antibacterial hydrogel material containing tannic acid, which is characterized in that the Thermo-sensitive modified chitin
For Thermo-sensitive hydroxyl butyl chitosan, Thermo-sensitive hydroxyl amyl chitosan, Thermo-sensitive carboxymethyl chitin, Thermo-sensitive ethoxy crust
Any one of element, Thermo-sensitive Hydroxypropyl chitosan, Thermo-sensitive hydroxyl butyl chitin or their mixture.
5. temperature sensitive composite antibacterial hydrogel material or claim of a kind of injectable according to claim 1 containing tannic acid
2 a kind of preparation methods of temperature sensitive composite antibacterial hydrogel material of the injectable containing tannic acid, which is characterized in that metal is added
The type of ion is iron ion, copper ion, any one of zinc ion or their mixture.
6. a kind of preparation side of temperature sensitive composite antibacterial hydrogel material of the injectable according to claim 2 containing tannic acid
Method, which is characterized in that the mass concentration range of polymer is 0.5~20wt% in solution A.
7. a kind of preparation side of temperature sensitive composite antibacterial hydrogel material of the injectable according to claim 2 containing tannic acid
Method, which is characterized in that the mass concentration range of tannic acid is 0.01~0.4wt% in mixed solution C；Metal in mixed solution C
The mass concentration range of ion is 0.001~0.5wt%.
8. a kind of preparation side of temperature sensitive composite antibacterial hydrogel material of the injectable according to claim 2 containing tannic acid
Method, which is characterized in that acid adding or alkali adjust pH in step (3), and the pH range of last mixed solution is 4-10.
9. a kind of preparation side of temperature sensitive composite antibacterial hydrogel material of the injectable according to claim 2 containing tannic acid
Method, which is characterized in that the preparation temperature range in step (1) (2) (3) is 2~14 DEG C, each component is quickly uniformly mixed, shape
At the injectable composite antibacterial hydrogel precursor solution with good fluidity；Step (3) physiological condition is body temperature,
Product does not need post-processing direct in-situ and uses.
10. a kind of application of temperature sensitive composite antibacterial hydrogel material of the injectable according to claim 1 containing tannic acid,
It is characterized in that, which is used for wound healing as antiseptic dressing.
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