CN108498847A - Macromolecule hydrogel, preparation method based on acylhydrazone key and skin histology adhesive - Google Patents
Macromolecule hydrogel, preparation method based on acylhydrazone key and skin histology adhesive Download PDFInfo
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- CN108498847A CN108498847A CN201810203221.7A CN201810203221A CN108498847A CN 108498847 A CN108498847 A CN 108498847A CN 201810203221 A CN201810203221 A CN 201810203221A CN 108498847 A CN108498847 A CN 108498847A
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0031—Hydrogels or hydrocolloids
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/08—Polysaccharides
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Abstract
The present invention relates to hydrogel preparation fields, more particularly to the macromolecule hydrogel based on acylhydrazone key, preparation method and skin histology adhesive.Macromolecule hydrogel raw material based on acylhydrazone key includes：The hyaluronic acid HAHZ and polyethylene glycol oxide polypropylene oxide polyethylene glycol oxide of hydrazide group modification；Hydrazide group degree of substitution is 3 100%.The present invention uses dynamic covalent bond that can have higher mechanical strength, self-repairability as hydrogel prepared by crosslinking points.Acylhydrazone key to tissue will not strong impulse wound tissue, highdensity acylhydrazone key means suitable organizational interface's adhesive strength, therefore it is a kind of material of combination aerogel dressing and Tissue adhesive advantage.
Description
Technical field
The present invention relates to hydrogel preparation fields, more particularly to the macromolecule hydrogel based on acylhydrazone key, its preparation side
Method and skin histology adhesive.
Background technology
Macromolecule hydrogel is macromolecule through three-dimensional network made of chemically or physically, has certain mechanical strength
With elasticity.Natural and synthesis macromolecule can be applied to the preparation of hydrogel.And the cross-linked structure of macromolecule hydrogel can be with
Including various covalent bonds, the physics such as chain entanglement, hydrogen bond, hydrophobic interaction, electrostatic interaction, supermolecule interaction are mutual
The cross-linked form of the special designings such as the dynamics covalent bond such as effect and cystine linkage, schiff bases and acylhydrazone key.
As a kind of soft, wet stock, case of the macromolecule hydrogel for clinical treatment is no longer rare.For example, conduct
Skin trauma dressing can be used for reducing wound temperature, obstruct bacterium, absorb sepage, mitigate pain, wounds is prevented to add
It is deep, and accelerate wound healing, shorten treatment cycle, mitigates scar proliferation etc..And as Tissue adhesive, polyvinyl alcohol
(PVA) and its compound has been used widely.However, in current clinical prods exploitation, there are two significant challenges：①
There is hydrogel material used above too high or too low tissue adhesive strength to be unfavorable for its application；2. improving macromolecule
The adhesive strength of hydrogel necessarily implies that the raising of polar groups density, but the density promotion of most polar groups can cause
The discomfort of skin wound patient or inflammatory reaction.Currently, not having macromolecule hydrogel system still, both there is suitable bond by force
Degree, and can be well protected and the nursing surface of a wound.
On the other hand, application of the macromolecule hydrogel in soft tissue repair at present is received significant attention and is studied, but its
Ingredient with it is complicated, there is also mechanical strength, structure and comprehensive performance etc. can not unify with jointly improve etc. challenges, need into
One step is perfect：1. the hydrogel for Physical interaction as crosslinking points, intensity is relatively fragile, therefore is often used a variety of friendships
Online system cooperates with to design hydrogel；But this can undoubtedly increase the complexity of hydrogel, be unfavorable for its popularization clinically
With commercialization；2. for the hydrogel that covalent bond is built as crosslinking points, do not have self-repairability and plasticity, mechanical strength
When raising, the raising of the degree of cross linking is necessarily corresponded to, but improving the degree of cross linking can cause hydrogel network scale too low, influence cell
Infiltration and migration；3. in addition, the molecular weight of most high molecular material is too high, degradation speed is too fast or excessively slow, it is uncontrollable or its
Biocompatibility is bad, also restricts its application in the field of medicine.
Invention content
(1) technical problems to be solved
The object of the present invention is to provide macromolecule hydrogel, preparation method and skin histology adherency based on acylhydrazone key
Agent solves above-mentioned at least one technical problem.
(2) technical solution
In order to solve the above technical problem, the present invention provides a kind of macromolecule hydrogel based on acylhydrazone key, raw material packets
It includes：The hyaluronic acid HAHZ and polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide of hydrazide group modification；Hydrazide group degree of substitution is
3-100%.
In the present solution, acylhydrazone key be can inverse kinematics covalent bond, based on can inverse kinematics covalent bond prepare hydrogel crosslinking points
Chemical kinetics converted between reactant and product and reach chemistry balance state so that the hydrogel of preparation have self-healing
Characteristic, advantageously account for that current hydrogel medical dressing faces by the frangible problem of external force.Polyethylene glycol oxide (PEO)-is poly-
Propylene oxide (PPO)-polyethylene glycol oxide (PEO) triblock copolymer, each block molecule chain can adjust, and PEO segments are hydrophilic easily
It is dissolved in water, PPO segments are hydrophobic to be insoluble in water, which is easily self-assembly of micella in water.So that the hydrogel has well
Quick in situ shaping characteristic, it has multiple, high density collection polar group, including carboxyl, hydroxyl and hydrazide group etc., tool
Standby certain intensity and biological tissue's adhesion property, are pasted in skin tissue interface, which combines dressing for skin and group
The advantages of knitting binder bonds skin histology very convenient.
In some embodiments, preferably, the degree of substitution of hydrazide group is 5- in the hyaluronic acid of the hydrazide group modification
60%.
In the present solution, containing great amount of hydroxy group and carboxyl in the chemical constitution of hyaluronic acid, pass through the method for chemical modification
Introduce hydrazide group.
In some embodiments, preferably, the hyaluronic acid is by unit D-Glucose aldehydic acid and N-acetyl-glucosamine
The acid mucopolysaccharide of composition.In the present solution, hyaluronic acid is natural macromolecule amylose hyaluronic acid, there is special water conservation to make
With, be the substance that moisture retention is best in nature, have the function of promote wound healing.Can improve product water retention and
Wound self-healing effect.
In some embodiments, preferably, the raw material further includes：Aldehyde group modified polyethylene glycol oxide-polypropylene oxide-
Polyethylene glycol oxide PFAH, wherein aldehyde radical replaces the hydroxyl of the polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide end group.
In the present solution, PEO-PPO-PEO triblock polymers are a kind of synthesis macromolecules, strand is very soft, nontoxic and biological peace
The preferable polyethers of full property.A kind of micella of self assembly easy in water is provided, the intensity of product and the life compatibility of raw material are improved.
In some embodiments, preferably, the degree of substitution of the aldehyde radical is 30-100%.PEO-PPO-PEO three blocks are poly-
Closing the terminal hydroxyl of object can be replaced by aldehyde radical.
In some embodiments, preferably, the aqueous solvent includes physiological saline, buffer solution, tissue culture medium or body
Liquid.The adaptability for improving hydrogel material, can be used various modes and carries out clinical application, play skin histology adhesion function.
In some embodiments, preferably, the addition mass ratio of HAHZ and PFAH meets：Hydrazide group degree of substitution/aldehyde radical
The ranging from 10-90% of degree of substitution, aqueous solvent surplus.
The present invention also provides a kind of preparation methods of the macromolecule hydrogel based on acylhydrazone key comprising：It prepares
The hyaluronic acid HAHZ of hydrazide group modification；Under room temperature, hyaluronic acid HAHZ and the polyoxyethylene that the hydrazide group is modified
Alkene-polypropylene oxide-polyethylene glycol oxide is mixed with aqueous solvent；It stirs evenly, obtains pre-crosslinked gel；It stands, pre-crosslinked gel
Fade to flexible water-swellable three-dimensional network product or hydrogel.
In some embodiments, preferably, in the hyaluronic acid HAHZ and the polyoxyethylene for modifying the hydrazide group
Alkene-polypropylene oxide-polyethylene glycol oxide is mixed with aqueous solvent further includes before：Prepare aldehyde group modified polyethylene glycol oxide-polyoxy
Change propylene-polyethylene glycol oxide PFAH；PFAH is then participated in into the mixing.
The present invention also provides a kind of skin histology adhesives comprising the macromolecule water-setting based on acylhydrazone key
Glue.
(3) advantageous effect
Technical solution provided by the invention, acylhydrazone key key are a kind of reversible dynamic chemical covalent bonds, can be certain
Reversible fracture and recombination occurs under environmental condition (such as temperature, pH value, electric field, light).As a kind of novel, typical dynamic
Covalent bond, acylhydrazone key can make up common covalent bond and physics, the deficiency of interaction.Because acylhydrazone key is different from commonly covalent
Key is similar to valve, will not fetter the infiltration and migration of cell in the ceaselessly dynamic equilibrium of "on" and "off".Dynamically
For covalent bond also different from Physical interaction, it has higher bond energy, therefore dynamic covalent bond is used to be prepared as crosslinking points
Hydrogel can have higher mechanical strength, self-repairability.What is more important, acylhydrazone key will not strong impulses to tissue
Wound tissue, highdensity acylhydrazone key means suitable organizational interface's adhesive strength, therefore it is that a kind of combination hydrogel is deposited
The material of material and Tissue adhesive advantage.
Description of the drawings
Fig. 1 is three arm PEG hydrogel of 10 hydrazides hyaluronic acid of embodiment and aldehyde radical at 37 DEG C, 1HZ, 1% stress
Lower viscosity changes with time situation；
Fig. 2 is that the swelling ratio of the HAHZ/PFAH hydrogels described in embodiment 11 changes over time situation；
Fig. 3 is tissue adhesion strength test collection of illustrative plates of the HAHZ/PFAH hydrogels described in embodiment 12 to pigskin.
Specific implementation mode
With reference to the accompanying drawings and examples, the specific implementation mode of the present invention is described in further detail.Following instance
For illustrating the present invention, but it is not limited to the scope of the present invention.
The present invention provides a kind of macromolecule hydrogel based on acylhydrazone key, raw material includes：Hydrazide group is modified transparent
Matter acid HAHZ and polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide；Hydrazide group degree of substitution is 3-100%.It is preferred that 5-60%.
Hydrazide group in hyaluronic acid hydroxyl and carboxyl replace.
Acylhydrazone key is a kind of reversible dynamic chemical covalent bond, can be in certain environmental condition (such as temperature, pH value, electricity
Field, light etc.) under reversible fracture and recombination occurs.As a kind of novel, typical dynamic covalent bond, acylhydrazone key can make up general
Valence link and physics, the deficiency of interaction in all.Because acylhydrazone key is different from common covalent bond, in ceaselessly "on" and "off"
Dynamic equilibrium in, be similar to valve, the infiltration and migration of cell will not be fettered.Dynamic covalent bond is also different from physics phase interaction
With it has higher bond energy, therefore uses dynamic covalent bond that can have higher machinery as hydrogel prepared by crosslinking points
Intensity, self-repairability.What is more important, acylhydrazone key to tissue will not strong impulse wound tissue, highdensity acylhydrazone key
Mean suitable organizational interface's adhesive strength, therefore it is a kind of material of combination aerogel dressing and Tissue adhesive advantage
Material.
Hyaluronic acid (hyaluronic acid, HA) is a kind of natural macromolecular grape glycosaminoglycan, has special guarantor
Water acts on, and is the substance that moisture retention is best in presently found nature, is referred to as ideal natural moisturizing factor (Natural
Moisturizing factor, NMF have the function of promoting wound healing.Also contain a large amount of hyaluronic acid in skin.People
Class skin maturation and ageing process change also with content and the metabolism of hyaluronic acid.In addition, it contains carboxyl and hydroxyl
Base is easy to carry out various reactions, can flexibly synthesize various derivatives.PEO-PPO-PEO triblock polymers are a kind of synthesis
Macromolecule, strand is very soft, the preferable polyethers of nontoxic and biological safety.Therefore, which has excellent
Elegant biocompatibility, is widely used in clinical application, safe.
Hyaluronic acid is a kind of acid mucopolysaccharide, is made of unit D-Glucose aldehydic acid and N-acetyl-glucosamine advanced
Polysaccharide, natural macromolecule amylose hyaluronic acid contain great amount of hydroxy group and carboxyl in chemical constitution, can pass through the side of chemical modification
Method introduces hydrazide group；The degree of substitution of hydrazide group is 3-100%, preferably 5-60% or 20- in the hyaluronic acid of hydrazide group modification
40%.
Further include in raw material：Aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH, wherein aldehyde radical
Replace the hydroxyl of the polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide end group.In some embodiments, polyethylene glycol oxide-
Polypropylene oxide-polyethylene glycol oxide can also replace with aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide completely
PFAH。
Polyethylene glycol oxide (PEO)-polypropylene oxide (PPO)-polyethylene glycol oxide (PEO), i.e. PEO-PPO-PEO three blocks are poly-
Micella can be self-assembled at normal temperatures by closing object, impart the more excellent mechanical property of the macromolecule hydrogel, and temperature sensitive
Property PEO-PPO-PEO triblock polymers introducing make the hydrogel have preferable temperature-responsive, the intensity of gel
There is significant increase with the promotion of temperature so that the hydrogel has good quick in situ shaping characteristic.Triblock polymer
For high-molecular copolymer, each block molecule chain can adjust, and polyethylene glycol oxide PEO segments are hydrophilic soluble easily in water, polypropylene oxide
PPO segments are hydrophobic to be insoluble in water, which is easily self-assembly of micella in water；The end group of poloxamer is hydroxyl, Ke Yijing
Chemical modification generates aldehyde radical；The degree of substitution of aldehyde radical is 30-100%.It is preferred that 40-75% or 55-85% or 40-80% etc..
The addition mass ratio of HAHZ and PFAH meets：The ranging from 10-90% of hydrazide group degree of substitution/aldehyde radical degree of substitution,
Aqueous solvent surplus.The sum of mass concentration percentage of all raw materials is 100%.Wherein, aqueous solvent include physiological saline, buffering it is molten
Liquid, tissue culture medium or body fluid.
In view of the deficiencies of the prior art, the present invention is intended to provide a kind of being based on acylhydrazone key, in conjunction with aerogel dressing and tissue
The macromolecule hydrogel of binder advantage：
(1) acylhydrazone key is different from common covalent bond, in the ceaselessly dynamic equilibrium of "on" and "off", is similar to valve
Door, will not fetter the infiltration and migration of cell.In addition, acylhydrazone key has higher bond energy, acylhydrazone key is used to be prepared as crosslinking points
Hydrogel can have higher mechanical strength, self-healing properties, with irregular surface of a wound stickiness.
(2) HA all has very outstanding histocompatbility with poloxamer；HAHZ presents certain after being mixed with PFAH
Mobility can directly be applied to the tissue surface of a wound of skin injury, quickly become the material with some strength, function similarly to
The effect of dressing for skin.Therefore, the hydrogel can " original position " be applied to dressing for skin, it is very convenient for clinical application.
(3) there is very strong water imbibition, it can be with absorptive tissue sepage；With certain mechanical strength and tissue adhesion；
It is extremely suitable for restoration care or the treatment of the skin histology surface of a wound；
(4) acylhydrazone key to tissue will not strong impulse wound tissue, highdensity acylhydrazone key means suitably to organize
Interfacial adhesion strength, therefore it is a kind of material of combination aerogel dressing and Tissue adhesive advantage；
(5) original ingredient, micro-structure and bioactivity can be stored and kept under 0-37 degree, only regulated and controled with simple temperature
Physical mixed can rapid shaping, be free of photoactive substance, it is safer, be more suitable for daily-use chemical industry, scientific research, clinical medicine,
Application in translational medicine.It is same as the application of nursing field with absolute predominance in skin repair.
The present invention also provides a kind of preparation methods of the macromolecule hydrogel based on acylhydrazone key comprising：
Step 110, the hyaluronic acid HAHZ of hydrazide group modification is prepared；
Step 112, under room temperature, the hyaluronic acid HAHZ and polyethylene glycol oxide-polyoxy that modify hydrazide group by preset ratio
Change propylene-polyethylene glycol oxide and aqueous solvent mixing；
Step 114, it stirs evenly, obtains pre-crosslinked gel；
Step 116, pre-crosslinked gel fades to flexible water-swellable three-dimensional network product or hydrogel.
Wherein, HAHZ and part aqueous agent can be mixed to get mixture one in step 112, by three block high polymer with
Part aqueous agent is mixed to get mixture two, then mixes mixture one and two, is uniformly mixing to obtain pre-crosslinked gel.
Or directly HAHZ and three block high polymer are directly mixed with aqueous solvent.
Room temperature, i.e., the natural temperature in the case of any temperature not being added to adjust disturbing factor are mentioned in step 114.Preferably
Temperature value in the range of 22-37 DEG C.
In the hyaluronic acid HAHZ for modifying the hydrazide group by preset ratio and the aldehyde group modified polyoxygenated
Further include before ethylene-polypropylene oxide-polyethylene glycol oxide PFAH and aqueous solvent mixing：Prepare aldehyde group modified polyoxyethylene
Alkene-polypropylene oxide-polyethylene glycol oxide PFAH；PFAH is then participated in into the mixing.
The present invention also provides a kind of skin histology adhesives comprising the above-mentioned macromolecule hydrogel based on acylhydrazone key.
This skin histology adhesive is in use, based on hyaluronic acid and polyethylene glycol oxide-polypropylene oxide-polyoxyethylene
Alkene all has very outstanding histocompatbility；After the HAHZ obtained after hydrazide group modification is mixed with aldehyde group modified obtained PFAH
Certain mobility is presented, quickly becomes the material with some strength, and paste in organizational interface.Therefore, the water-setting is cementing
The advantages of having closed dressing for skin and Tissue adhesive, it is very convenient for clinical application.
The present invention is intended to provide a kind of hydrogel based on acylhydrazone key, by the application in skin histology adherency field come
Illustrate that it has unique technical advantage and wide application prospect in medical domain.Below by the mode of embodiment to this hair
It is bright to be further described, but it is not limited to following embodiments.
Embodiment 1
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, aldehyde radical is modified poly-
Ethylene oxide (PEO)-polypropylene oxide (PPO)-polyethylene glycol oxide (PEO), also referred to as poloxamer (PFAH) are dissolved in water, are made into
10% PFAH solution, by 10% HAHZ solution and 10% PFAH solution by volume 9:1, ratio is uniformly mixed to obtain gel
Precursor solution, mixture gradually become water-swellable three-dimensional network or hydrogel with certain elasticity.
Embodiment 2
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, the pool that aldehyde radical is modified
Luo Shamu (PFAH) is dissolved in water, is made into 10% PFAH solution, and the PFAH solution of 10% HAHZ solution and 10% is pressed volume
Than 8:2, ratio is uniformly mixed to obtain gel precursor solution, and mixture gradually becomes the water-swellable three-dimensional network with certain elasticity
Or hydrogel.
Embodiment 3
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, the pool that aldehyde radical is modified
Luo Shamu (PFAH) is dissolved in water, is made into 10% PFAH solution, and the PFAH solution of 10% HAHZ solution and 10% is pressed volume
Than 7:3, ratio is uniformly mixed to obtain gel precursor solution, and mixture gradually becomes the water-swellable three-dimensional network with certain elasticity
Or hydrogel.
Embodiment 4
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, the pool that aldehyde radical is modified
Luo Shamu (PFAH) is dissolved in water, is made into 10% PFAH solution, and the PFAH solution of 10% HAHZ solution and 10% is pressed volume
Than 6:4, ratio is uniformly mixed to obtain gel precursor solution, and mixture gradually becomes the water-swellable three-dimensional network with certain elasticity
Or hydrogel.
Embodiment 5
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, the pool that aldehyde radical is modified
Luo Shamu (PFAH) is dissolved in water, is made into 10% PFAH solution, and the PFAH solution of 10% HAHZ solution and 10% is pressed volume
Than 5:5, ratio is uniformly mixed to obtain gel precursor solution, and mixture gradually becomes the water-swellable three-dimensional network with certain elasticity
Or hydrogel.
Embodiment 6
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, the pool that aldehyde radical is modified
Luo Shamu (PFAH) is dissolved in water, is made into 10% PFAH solution, and the PFAH solution of 10% HAHZ solution and 10% is pressed volume
Than 4:6, ratio is uniformly mixed to obtain gel precursor solution, and mixture gradually becomes the water-swellable three-dimensional network with certain elasticity
Or hydrogel.
Embodiment 7
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, the pool that aldehyde radical is modified
Luo Shamu (PFAH) is dissolved in water, is made into 10% PFAH solution, and the PFAH solution of 10% HAHZ solution and 10% is pressed volume
Than 3:7, ratio is uniformly mixed to obtain gel precursor solution, and mixture gradually becomes the water-swellable three-dimensional network with certain elasticity
Or hydrogel.
Embodiment 8
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, the pool that aldehyde radical is modified
Luo Shamu (PFAH) is dissolved in water, is made into 10% PFAH solution, and the PFAH solution of 10% HAHZ solution and 10% is pressed volume
Than 2:8, ratio is uniformly mixed to obtain gel precursor solution, and mixture gradually becomes the water-swellable three-dimensional network with certain elasticity
Or hydrogel.
Embodiment 9
Under room temperature, the HA (HAHZ) that hydrazide group is modified is dissolved in water, is made into 10% HAHZ solution, the pool that aldehyde radical is modified
Luo Shamu (PFAH) is dissolved in water, is made into 10% PFAH solution, and the PFAH solution of 10% HAHZ solution and 10% is pressed volume
Than 1:9, ratio is uniformly mixed to obtain gel precursor solution, and mixture gradually becomes the water-swellable three-dimensional network with certain elasticity
Or hydrogel.
The degree of substitution of hydrazide group is 3-100% in HAHZ in embodiment 1-9, such as：10%, 45%, 70%, 85%；
The degree of substitution of aldehyde radical is 30-100% in PFAH in embodiment 1-9, such as：40%, 55%, 70%, 85% etc..
Moreover, hydrazide group and aldehyde radical degree of substitution ratio meet 10-90%, such as 10%, 50%, 75% etc..
The preparation of HAHZ and PFAH is given below：
Embodiment 1-9-1,
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 10%.
Embodiment 1-9-2
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 45%.
Embodiment 1-9-3
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 70%.
Embodiment 1-9-4
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 85%.
Embodiment 1-9-5
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 100%.
Embodiment 1-9-6
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 30% PFAH.
Embodiment 1-9-7
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 40% PFAH.
Embodiment 1-9-8
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 55% PFAH.
Embodiment 1-9-9
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 85% PFAH.
Embodiment 1-9-10
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 10% respectively are 100%
The two is sufficiently mixed by solution, stands be cross-linked to form gel at room temperature.
Embodiment 1-9-11
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 9% respectively are 30% is molten
The two is sufficiently mixed by liquid, stands be cross-linked to form gel at room temperature.
Embodiment 1-9-12
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 54% respectively are 90%
Solution is added stem cell, is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 1-9-13
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 25% respectively are 50%
Solution is added biotic factor, is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 10
Hydrogel precursor solution 300ul in embodiment 5 is added drop-wise on rheometer tablet, silicone oil is used in combination to encapsulate, is surveyed
Its viscosity under 37 DEG C, 1HZ, 1% stress is tried to change with time situation.
As a result it is three arm PEG of the hydrazides hyaluronic acid and aldehyde radical described in the embodiment of the present invention 10 referring to Fig. 1, Fig. 1
Hydrogel viscosity under 37 DEG C, 1HZ, 1% stress changes with time situation.As shown in Figure 1, the increasing of the viscosity of sample at any time
Add continuous increase, be finally reached a platform (about 400pa), illustrates that gel precursor solution is constantly crosslinked and finally crosslinking is completed
Form stable hydrogel three-dimensional network.
Embodiment 11
The HAHZ/PFAH hydrogels obtained in embodiment 5 are lyophilized, are soaked in PBS buffer solutions, 37 DEG C incubate
It educates, aqueous solution is carefully sucked out to particular point in time, the residual moisture of gel surface is gently sucked with filter paper and is precisely weighed, count
Swelling ratio is calculated to change with time situation.
As a result it is that the swelling ratio of the HAHZ/PFAH hydrogels described in the embodiment of the present invention 11 becomes at any time referring to Fig. 2, Fig. 2
Change situation.As shown in Figure 2, the swelling ratio of gel, which changes with time, dramatically increases, and the swelling ratio of hydrogel material reaches in 3h
2000%, be equivalent to the moisture for absorbing 20 times of its own weight, in addition, with the extension of time, the swelling ratio of hydrogel still
When being slowly increased 8h, which can be stabilized and its swelling ratio has reached 2500% or so.Sepage it is timely absorption and
Removing is a current burn dressing field clinical problem urgently to be resolved hurrily, and the higher swelling behavior of the hydrogel is conducive to clinic
The absorption of upper sepage, this is most important to preventing infection and skin repair.
Embodiment 12
Fresh porcine skin (2.5cm*3cm) is chosen, hair and fat are rejected, the gel precursor solution in embodiment 5 is equal
It is even to be applied on pigskin (2.5cm*2.5cm), then another piece of pigskin is covered into its surface, the area that two pieces of pigskins overlap ensures
For (2.5cm*2.5cm), 30min is placed at room temperature, it is ensured that its plastic is complete, then tests its adhesive strength with tensilon.
As a result it is tissue adhesion of the HAHZ/PFAH hydrogels described in the embodiment of the present invention 12 to pigskin referring to Fig. 3, Fig. 3
Strength test collection of illustrative plates, the adhesive strength that platform area reflects the hydrogel are about 1Kpa.Since the hydrogel has skin histology
Adhesive force advantageously accounts at present the clinically caducous problem of burn dressing.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail can carry out a variety of simple variants to technical scheme of the present invention within the scope of the technical concept of the present invention, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should also be regarded as the disclosure of the present invention.
Claims (10)
1. a kind of macromolecule hydrogel based on acylhydrazone key, which is characterized in that its raw material includes：The hyaluronic acid of hydrazide group modification
HAHZ and polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide；Hydrazide group degree of substitution is 3-100%.
2. the macromolecule hydrogel as described in claim 1 based on acylhydrazone key, which is characterized in that the hydrazide group is modified saturating
The degree of substitution of hydrazide group is 5-60% in bright matter acid.
3. the macromolecule hydrogel as described in claim 1 based on acylhydrazone key, which is characterized in that the hyaluronic acid is by list
The acid mucopolysaccharide of position D-Glucose aldehydic acid and N-acetyl-glucosamine composition.
4. the macromolecule hydrogel as described in any one of claims 1-3 based on acylhydrazone key, which is characterized in that the raw material is also
Including：Aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH, wherein aldehyde radical replaces the polyoxyethylene
The hydroxyl of alkene-polypropylene oxide-polyethylene glycol oxide end group.
5. the macromolecule hydrogel as claimed in claim 4 based on acylhydrazone key, which is characterized in that the degree of substitution of the aldehyde radical is
30-100%.
6. the macromolecule hydrogel as claimed in claim 5 based on acylhydrazone key, which is characterized in that the addition matter of HAHZ and PFAH
Amount ratio meets：The ranging from 10-90% of hydrazide group degree of substitution/aldehyde radical degree of substitution, aqueous solvent surplus.
7. the macromolecule hydrogel as claimed in claim 6 based on acylhydrazone key, which is characterized in that the aqueous solvent includes physiology
Brine, buffer solution, tissue culture medium or body fluid.
8. a kind of preparation method of macromolecule hydrogel of the claim 1-9 any one of them based on acylhydrazone key, feature exist
In, including：
Prepare the hyaluronic acid HAHZ of hydrazide group modification；
Under room temperature, hyaluronic acid HAHZ and the polyethylene glycol oxide-polypropylene oxide-polyoxyethylene that the hydrazide group is modified
Alkene is mixed with aqueous solvent；
It stirs evenly, obtains pre-crosslinked gel；
It stands, pre-crosslinked gel fades to flexible water-swellable three-dimensional network product or hydrogel.
9. preparation method as claimed in claim 8, which is characterized in that
In the hyaluronic acid HAHZ for modifying the hydrazide group and the polyethylene glycol oxide-polypropylene oxide-polyoxyethylene
Alkene is mixed with aqueous solvent further includes before：Prepare aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH；
PFAH is then participated in into the mixing.
10. a kind of skin histology adhesive, which is characterized in that it includes that claim 1-9 any one of them is based on acylhydrazone key
Macromolecule hydrogel.
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| CN115895467B (en) * | 2022-11-16 | 2023-11-10 | 江西昊泽光学膜科技有限公司 | Preparation method of optical OCA adhesive and application of optical OCA adhesive in mobile phone folding screen |
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