CN108525003A - Based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent - Google Patents
Based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent Download PDFInfo
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- CN108525003A CN108525003A CN201810203150.0A CN201810203150A CN108525003A CN 108525003 A CN108525003 A CN 108525003A CN 201810203150 A CN201810203150 A CN 201810203150A CN 108525003 A CN108525003 A CN 108525003A
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- polyethylene glycol
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Classifications
-
- 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0052—Mixtures of macromolecular compounds
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/246—Intercrosslinking of at least two polymers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2371/02—Polyalkylene oxides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2471/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2471/02—Polyalkylene oxides
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Materials For Medical Uses (AREA)
Abstract
The present invention relates to hydrogel preparation fields, more particularly to based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent.Double cross joins hybridized hydrogel raw material:The hyaluronic acid HAHZ and aldehyde group modified polyethylene glycol oxide polypropylene oxide polyethylene glycol oxide PFAH of hydrazide group modification;The addition mass ratio of HAHZ and PFAH meets:Ranging from the 20 80% of hydrazide group degree of substitution/aldehyde radical degree of substitution, aqueous solvent surplus.The present invention is based on the advantages that double cross-linked hydrogels of acylhydrazone key and hydrophobe self assembly fully combine covalent cross-linking and Physical interaction, the double cross of preparation joins hybridized hydrogel, with excellent self-healing characteristics, medical gel dressing is advantageously accounted for by the frangible problem of external force;With certain temperature-responsive, there is excellent mechanical performance and formed in situ characteristic, be extremely suitable for restoration care or the treatment of the skin histology surface of a wound.
Description
Technical field
The present invention relates to hydrogel preparation fields, miscellaneous more particularly to being joined based on the double cross of acylhydrazone key and hydrophobe self assembly
Change hydrogel, preparation method and skin histology wound repair agent.
Background technology
Macromolecule hydrogel is that had after water-swellable by three-dimensional network of the high molecular component through chemically or physically preparing
There are certain mechanical strength and elasticity.Macromolecule can be divided into natural and synthesis two major classes by its source.Natural hydrophily high score
Attached bag includes polysaccharide (cellulose, starch, alginic acid, hyaluronic acid, chitosan etc.) and protide (collagen, gelatin, poly- bad ammonia
Sour, poly- Glutamic Acid etc.).The hydrophilic high mol of synthesis includes polyalcohols (polyethylene glycol), modified poly ester (polyurethane, hydrophilic modifying
Polycaprolactone, polylactic acid etc.), (polyacrylic acid, polymethylacrylic acid, polyacrylamide, poly- N- are poly- for acrylic acid and its derivative species
For acrylamide etc.) and its copolymer etc..The cross-linked structure of macromolecule hydrogel can by Physical interaction, covalent bond and
Dynamic covalent bond is completed.Physical interaction includes mainly:Chain entanglement, hydrogen bond, hydrophobic interaction, electrostatic interaction,
Supermolecule interaction etc.;Dynamic covalent bond includes cystine linkage, schiff bases and acylhydrazone key etc.;In addition, some special physics
Or chemical bonding form is also paid close attention to, such as slip ring cross-linked structure, microstructure etc..
As a kind of soft, wet stock, case of the macromolecule hydrogel for clinical treatment is no longer rare, the technology and doctor
The combination for the treatment of is mainly the following:1. anatomic implants are prepared (bone, tooth, soft tissue organs etc.);2. drug carries
Body and transmission;3. external medical material such as skin repair and nursing etc..Applied to skin burn, mechanical damage or chronic disease ulcer
The surface of a wound can be used for reducing wound temperature, obstruct bacterium, absorb sepage, mitigate pain, wounds is prevented to deepen, and accelerates
Wound healing shortens treatment cycle, mitigates scar proliferation etc..
Application of the macromolecule hydrogel in soft tissue repair at present is received significant attention and is studied, but its ingredient and structure
Complexity, there is also mechanical strength, structure and comprehensive performance etc. can not unify with jointly improve etc. challenges, need to be further improved:
1. the hydrogel for Physical interaction as crosslinking points, intensity is relatively fragile, 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 carries
When high, 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 materials is too high, degradation speed is too fast or excessively slow, uncontrollable or its life
Object compatibility 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 based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, its preparation side
Method and skin histology wound repair agent solve above-mentioned at least one technical problem.
(2) technical solution
It is miscellaneous based on the double cross of acylhydrazone key and hydrophobe self assembly connection that in order to solve the above technical problem, the present invention provides a kind of
Change hydrogel, raw material includes:The hyaluronic acid HAHZ of hydrazide group modification and aldehyde group modified polyethylene glycol oxide-polyoxygenated third
Alkene-polyethylene glycol oxide PFAH;The addition mass ratio of HAHZ and PFAH meets:The range of hydrazide group degree of substitution/aldehyde radical degree of substitution
For 20-80%, aqueous solvent surplus.
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, be more advantageous to the various irregular wounds of fitting, special construction makes possessed by the hydrogel
It has good effect for tissue repair.
In some embodiments, preferably, the degree of substitution of hydrazide group is 1.0- in the hyaluronic acid of the hydrazide group modification
50%.
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 aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide
Replace the hydroxyl of the polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide end group for aldehyde radical.In the present solution, PEO-PPO-
PEO triblock polymers are a kind of synthesis macromolecules, and strand is very soft, the preferable polyethers of nontoxic and biological safety.It carries
For a kind of micella of self assembly easy in water, 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 1.0-100%.PEO-PPO-PEO three blocks are poly-
Closing the terminal hydroxyl of object can be replaced by aldehyde radical.
In some embodiments, preferably, the solid content of the double cross connection hybridized hydrogel is 2-22%.In rated condition
The mass percent that remainder accounts for total amount after lower drying is 2-22%.
In some embodiments, preferably, the raw material further includes:Growth factor or stem cell;The aqueous solvent includes
Ultra-pure water.In the present solution, having growth factor or the stem cell promotion of bioactive ingredients by growth factor, stem cell etc.
The reparation and regrowth of skin wound.Reduce the infection probability of skin wound.
The present invention also provides a kind of systems joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly
Preparation Method comprising:Prepare the hyaluronic acid HAHZ of hydrazide group modification;Prepare aldehyde group modified polyethylene glycol oxide-polyoxygenated third
Alkene-polyethylene glycol oxide PFAH;Under room temperature, hyaluronic acid HAHZ that the hydrazide group is modified and the aldehyde radical are repaiied by preset ratio
Polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide the PFAH and aqueous solvent of decorations are mixed;It stirs evenly, it is solidifying to obtain precrosslink
Glue;It stands, pre-crosslinked gel fades to flexible water-swellable three-dimensional network product or hydrogel.In the present solution, HAHZ
Mixing is directly mixed with PFAH and can be obtained pre-crosslinked gel, and gradually becomes required product with standing.
In some embodiments, preferably, in the hyaluronic acid HAHZ for modifying the hydrazide group by preset ratio
Further include in the aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH and aqueous solvent mixing:It will
Mixing is added in the growth factor or stem cell for having life active constituent.In the present solution, passing through the tools such as growth factor, stem cell
The growth factor of standby bioactive ingredients or stem cell promote the reparation and regrowth of skin wound.
The present invention also provides a kind of skin histology wound repair agent comprising it is described based on acylhydrazone key and hydrophobe from
The double cross of assembling joins hybridized hydrogel.Be conducive to be bonded various irregular wounds, special construction makes possessed by the hydrogel
Obtain it has good effect for tissue repair.
(3) advantageous effect
Technical solution provided by the invention is fully combined based on acylhydrazone key and double cross-linked hydrogels of hydrophobe self assembly
The advantage of covalent cross-linking and Physical interaction.Acylhydrazone key as it is a kind of it is novel, typically can inverse kinematics covalent bond, based on reversible
The chemical kinetics of hydrogel crosslinking points prepared by dynamic covalent bond is converted between reactant and product and reaches chemical balance shape
State so that the hydrogel of preparation has the characteristic of self-healing, advantageously account for that current hydrogel medical dressing faces by outer
The frangible problem of power.In addition, acylhydrazone key crosslinking points are in the ceaselessly dynamic equilibrium of "on" and "off", it is similar to valve, it will not
Fetter the infiltration and migration of cell.Therefore, the hydrogel in terms of molecular structure for cell behavior and regeneration or reparation
With apparent advantage.Simultaneously as PEO-PPO-PEO triblock polymers can be self-assembled into micella at normal temperatures, assign
The more excellent mechanical property of the macromolecule hydrogel, and the introducings of the PEO-PPO-PEO triblock polymers of Thermo-sensitive
So that there is the hydrogel preferable temperature-responsive, the intensity of gel to have significant increase with the promotion of temperature so that the water
Gel has good quick in situ shaping characteristic, is more advantageous to and is bonded various irregular wounds, possessed by the hydrogel
Special construction makes it have good effect for tissue repair.
Description of the drawings
Fig. 1 is that the gel strength of embodiment 8HAHZ/PFAH double crosses connection hybridized hydrogel changes with time;
Fig. 2 is that the HAHZ/PFAH double crosses described in embodiment 9 join healing and stretching of the hybridized hydrogel under no environmental stimuli
Picture;
Fig. 3 is the dermatopathology H&E staining analysis when burn described in embodiment 10 is repaired 21 days.
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.
Hybridized hydrogel, raw material packet are joined based on the double cross of acylhydrazone key and hydrophobe self assembly the present invention provides a kind of
It includes:The hyaluronic acid HAHZ and aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH of hydrazide group modification;
The addition mass ratio of HAHZ and PFAH meets:The ranging from 20-80% of hydrazide group degree of substitution/aldehyde radical degree of substitution, more than aqueous solvent
Amount.Hydrazide group in hyaluronic acid hydroxyl and carboxyl replace, aldehyde radical is to polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide
The hydroxyl of the ends PFAH is replaced.
Double cross-linked hydrogels based on acylhydrazone key and hydrophobe self assembly fully combine covalent cross-linking and physics phase interaction
Advantage.Acylhydrazone key as it is a kind of it is novel, typically can inverse kinematics covalent bond, based on can the water-setting for preparing of inverse kinematics covalent bond
The chemical kinetics of glue crosslinking points is converted between reactant and product and reaches chemistry balance state so that the hydrogel of preparation has
The characteristic for having self-healing, advantageously account for that current hydrogel medical dressing faces by the frangible problem of external force.In addition, acylhydrazone key
Crosslinking points are in the ceaselessly dynamic equilibrium of "on" and "off", are similar to valve, will not be fettered the infiltration and migration of cell.Cause
This, which for cell behavior and regeneration or repairs with apparent advantage in terms of molecular structure.
Simultaneously as PEO-PPO-PEO triblock polymers can be self-assembled into micella at normal temperatures, the high score is imparted
The more excellent mechanical property of sub- hydrogel, and the introducing of the PEO-PPO-PEO triblock polymers of Thermo-sensitive makes the water
There is gel preferable temperature-responsive, the intensity of gel to have significant increase with the promotion of temperature so that the hydrogel has
Good quick in situ shaping characteristic is more advantageous to and is bonded various irregular wounds, special construction possessed by the hydrogel
So that it has good effect for tissue repair.
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.
What this technology obtained joins hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly, has excellent self-healing
Characteristic is closed, advantageously accounts for medical gel dressing by the frangible problem of external force;With certain temperature-responsive, have excellent
Mechanical performance and formed in situ characteristic are extremely suitable for restoration care or the treatment of the skin histology surface of a wound.
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;Hydrazide group modification hyaluronic acid in hydrazide group degree of substitution be 1.0-50%, preferably 10-25%, or
20-40%.
Polyethylene glycol oxide (PEO)-polypropylene oxide (PPO)-polyethylene glycol oxide (PEO) triblock copolymer, macromolecule are total
Polymers, each block molecule chain can adjust, and polyethylene glycol oxide PEO segments are hydrophilic soluble easily in water, and polypropylene oxide PPO segments are hydrophobic
It is insoluble in water, which is easily self-assembly of micella in water;The end group of poloxamer is hydroxyl, chemically modified can be generated
Aldehyde radical;The degree of substitution of aldehyde radical is 1.0-100%.It is preferred that 10-35% or 55-85% or 40-80% etc..
The solid content that the double cross joins hybridized hydrogel is 2-22%.Its raw material is additionally added the growth for having bioactive ingredients
The factor or stem cell etc.;For aqueous solvent as surplus, aqueous solvent includes ultra-pure water, and the sum of mass concentration percentage of all raw materials is
100%.
In view of the deficiencies of the prior art, the present invention is intended to provide a kind of joined based on the double cross of acylhydrazone key and hydrophobe self assembly
Hybridized hydrogel illustrates that it has unique technical advantage in medical domain by the application in skin ultrastructure field
With wide application prospect.The system will utilize physicochemical properties of dynamic covalent bond and hydrophobe self assembly itself, natural
The characteristics of macromolecule and hydrogel itself, regenerates for medical tissue engineering and provides one kind newly with reparation especially skin tissue engineering
Clever and reliable material.Advantage is as follows:
(1) double cross-linked hydrogels based on acylhydrazone key and hydrophobe self assembly fully combine covalent cross-linking and physics is mutual
The advantage of effect.Acylhydrazone key has great advantage as a kind of novel, typical dynamic covalent bond for hydrogel performance.It can
Inverse kinematics covalent bond is similar to valve in the ceaselessly dynamic equilibrium of "on" and "off", will not fetter the infiltration of cell with
Migration.Based on can the chemical kinetics of hydrogel crosslinking points for preparing of inverse kinematics covalent bond convert and reach between reactant and product
To chemistry balance state so that the hydrogel of preparation has self-healing properties and surface of a wound adhesiveness, advantageously accounts for current water
Gel medical dressing face by external force is frangible and problem easy to fall off.Simultaneously as PEO-PPO-PEO triblock polymers are normal
It can be self-assembled into micella under temperature, impart the more excellent mechanical property of the macromolecule hydrogel, and the PEO- of Thermo-sensitive
The introducing of PPO-PEO triblock polymers makes the hydrogel have preferable temperature-responsive, and the intensity of gel is with temperature
Promotion has significant increase so that the hydrogel has good quick in situ shaping characteristic, is more advantageous to fitting and various does not advise
Wound then.
(2) HA all has very outstanding histocompatbility with PEO-PPO-PEO triblock polymers;What hydrazide group was modified
Certain mobility is presented after being mixed with the poloxamer (PFAH) that aldehyde radical is modified in HA (HAHZ), can directly be applied to skin damage
The tissue surface of a wound of wound, quickly becomes the material with some strength, functions similarly to the effect of dressing for skin.Therefore, the water-setting
Glue is applied to dressing for skin, 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) 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 sides joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly
Method comprising:
Step 110, the hyaluronic acid HAHZ of hydrazide group modification is prepared;
Step 112, aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH is prepared;
Step 114, the hyaluronic acid HAHZ for modifying hydrazide group by preset ratio under room temperature and aldehyde group modified polyoxygenated
Ethylene-polypropylene oxide-polyethylene glycol oxide PFAH and aqueous solvent mixing;
Step 116, it stirs evenly, obtains pre-crosslinked gel;
Step 118, 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 114, by PFAH and 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 PFAH 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 order to increase the bioactivity that double cross joins hybridized hydrogel, reparation, revival in raising application to skin wound
Fruit, it is poly- in the hyaluronic acid HAHZ and aldehyde group modified polyethylene glycol oxide-polypropylene oxide-for modifying hydrazide group by preset ratio
Further include in ethylene oxide PFAH and aqueous solvent mixing:It will be provided with the growth factor of life active constituent or stem cell be added and mix
It closes.
The present invention also provides a kind of skin histology wound repair agent comprising above-mentioned acylhydrazone key and the hydrophobe of being based on is from group
The double cross of dress joins hybridized hydrogel.
The wound repair agent of this skin histology is in use, based on hyaluronic acid and polyethylene glycol oxide-polypropylene oxide-polyoxy
Change ethylene and all has very outstanding histocompatbility;The HAHZ and aldehyde group modified obtained PFAH obtained after hydrazide group modification is mixed
Certain mobility is presented after conjunction, can directly be applied to the tissue surface of a wound of skin injury, quickly become with some strength
Material functions similarly to the effect of dressing for skin.Therefore, which is applied to dressing for skin, very square for clinical application
Just.
The preparation of a kind of double cross-linked hydrogels based on acylhydrazone key and hydrophobe self assembly disclosed by the invention and its in skin
Application in skin tissue wound repair, especially burn reparation, wherein acylhydrazone key is a kind of dynamic covalent bond, it is a kind of reversible
The chemical kinetics of key, the hydrogel crosslinking points based on the preparation of dynamic covalent bond is converted between reactant and product and reaches chemistry
Equilibrium state so that the hydrogel of preparation has the characteristic of self-healing, advantageously accounts for current hydrogel medical dressing and faces
By the frangible problem of external force.In addition, acylhydrazone key crosslinking points are in the ceaselessly dynamic equilibrium of "on" and "off", it is similar to valve
Door, will not fetter the infiltration and migration of cell.Therefore, the hydrogel in terms of molecular structure for cell behavior and regeneration
Or it repairs with apparent advantage.Simultaneously as PEO-PPO-PEO triblock polymers at normal temperatures being capable of self assembly plastic
Beam imparts the more excellent mechanical property of the macromolecule hydrogel, and the PEO-PPO-PEO triblock polymers of Thermo-sensitive
Introducing to change hydrogel there is preferable temperature-responsive, the intensity of gel to make with the significant increase of promotion of temperature
Hydrogel, which must be changed, has good formed in situ characteristic, is more advantageous to the various wounds of different shapes of fitting, which is had
Some special constructions make it have good effect for tissue repair.The hydrogel selected materials have outstanding biofacies
Capacitive is widely used in clinical application, safe.
Embodiment 1
The polymer solution of the PFAH of the HAHZ and 5% (w/v) of accurate formulation 5% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
Embodiment 2
The polymer solution of the PFAH of the HAHZ and 10% (w/v) of accurate formulation 5% (w/v) respectively, increases in the solution
Growth factor is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 3
The polymer solution of the PFAH of the HAHZ and 15% (w/v) of accurate formulation 5% (w/v) respectively, increases in the solution
Stem cell is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 4
The polymer solution of the PFAH of the HAHZ and 20% (w/v) of accurate formulation 5% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
Embodiment 5
The polymer solution of the PFAH of the HAHZ and 10% (w/v) of accurate formulation 10% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
Embodiment 6
The polymer solution of the PFAH of the HAHZ and 15% (w/v) of accurate formulation 10% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
Embodiment 7
The polymer solution of the PFAH of the HAHZ and 20% (w/v) of accurate formulation 10% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
The degree of substitution of hydrazide group is 1-50% in HAHZ in embodiment 1-7, such as:10%, 25%, 20% or 40%;
The degree of substitution of aldehyde radical is 1-100% in PFAH in embodiment 1-7, such as:10%, 35%, 55%, 85% etc..
Moreover, hydrazide group and aldehyde radical degree of substitution ratio meet 20-80%, such as 30%, 50%, 75% etc..
The preparation of HAHZ and PFAH is given below:
Embodiment 1-7-1,
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 1%.
Embodiment 1-7-2
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 10%.
Embodiment 1-7-3
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 20%.
Embodiment 1-7-4
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 25%.
Embodiment 1-7-5
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 40%.
Embodiment 1-7-6
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 1% PFAH.
Embodiment 1-7-7
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 35% PFAH.
Embodiment 1-7-8
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 1-7-9
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 100% PFAH.
Embodiment 1-7-10
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 20% respectively are 100%
The two is sufficiently mixed by solution, stands be cross-linked to form gel at room temperature.
Embodiment 1-7-11
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 40% respectively are 50%
The two is sufficiently mixed by solution, stands be cross-linked to form gel at room temperature.
Embodiment 1-7-12
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 32% respectively are 80%
Solution is added stem cell, is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 1-7-12
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 6% respectively are 20% is molten
Liquid is added biotic factor, is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 8
Mixed liquor 300ul in embodiment 6 is added on rheometer test platform, under 37 DEG C, 1HZ, 10% stress
The intensity of test gel changes with time.
As a result it is that HAHZ/PFAH double crosses described in embodiment 8 join the gel strength of hybridized hydrogel at any time referring to Fig. 1, Fig. 1
Between variation.As shown in Figure 1, the crosspoint of storage modulus G ' and loss modulus G " are gel point, gel can shape in 5 minutes
At being conducive to be formed in situ gel, that is, illustrate that time gel has the characteristic of formed in situ.As time increases, gel is strong
Degree dramatically increases, and gel strength reaches 1100Pa when 90min, shows that the hydrogel has excellent mechanical strength, can conduct
Dressing for skin provides mechanical support.
Embodiment 9
Mixed liquor 300ul in embodiment 6 is added in the Teflon mould of a diameter of 1cm, crosslinking west is stood
Guo Cheng gels, are drawn off after gel-forming, are arbitrarily divided into three parts, then gel is put into mold, and observation is taken out after 30min
And it stretches.
As a result join hybridized hydrogel under no environmental stimuli referring to such as 2, Fig. 2 for the HAHZ/PFAH double crosses described in embodiment 9
Healing and stretch picture.As shown in Fig. 2, gel, which is arbitrarily divided into three points, places into mold, taken out after 30min, gel energy
Enough healings completely are an entirety, and pipette tips can not be separated, easily can integrally hang gel without falling, show
The excellent healing properties of gel.Further, the gel after healing is stretched, gel not fragmentation and can be stretched, shown
There is gel excellent self-healing performance and tensile property, good mechanical performance to be conducive to the practical application of gel.
Embodiment 10
Deep second degree burn model is established, experimental group and control group are randomly divided into, control group is only covered with gauze, and experimental group is used
Gel for treating described in embodiment 6.At 7 days, 14 days, 21 days, 11 the skin of surface of a wound part is taken to carry out H&E dyeing respectively, carried out
Pathological analysis.
As a result it is the dermatopathology H&E staining analysis burnt when repairing 21 days described in embodiment 10 referring to Fig. 3, Fig. 3
(the left side:Control group, the right:Experimental group).As shown in figure 3, experimental group is compared with control group:The scar area of experimental group relatively compares
The scar area range of group is obviously reduced, and inflammatory cell infiltration is significantly reduced compared with control group, and collagen structure form is close normal, real
There is a small amount of inflammatory cell infiltration in subregion when though testing group 21D, has clearly skin three-decker and skin corium has skin
Accessory structure exists;And have a large amount of inflammatory cell infiltrations when control group 21D, and have apparent skin ulcer (ulcer) appearance
And epidermis thickens.Therefore, animal skin burn experiment is the result shows that materials on skin tissue repair has positive effect.
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 joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly, which is characterized in that its raw material includes:Acyl
The hyaluronic acid HAHZ and aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH of diazanyl modification;HAHZ and
The addition mass ratio of PFAH meets:The ranging from 20-80% of hydrazide group degree of substitution/aldehyde radical degree of substitution, aqueous solvent surplus.
2. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as described in claim 1, which is characterized in that
The degree of substitution of hydrazide group is 1.0-50% in the hyaluronic acid of the hydrazide group modification.
3. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as described in claim 1, which is characterized in that
The hyaluronic acid is the acid mucopolysaccharide being made of unit D-Glucose aldehydic acid and N-acetyl-glucosamine.
4. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as described in claim 1, which is characterized in that
Aldehyde group modified polyethylene glycol oxide-polypropylene oxide-the polyethylene glycol oxide is that aldehyde radical replaces the polyethylene glycol oxide-polyoxygenated
The hydroxyl of propylene-polyethylene glycol oxide end group.
5. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as claimed in claim 4, which is characterized in that
The degree of substitution of the aldehyde radical is 1.0-100%.
6. as described in any one in claim 1-5 join hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly,
It is characterized in that, the solid content of the double cross connection hybridized hydrogel is 2-22%.
7. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as claimed in claim 6, which is characterized in that
The raw material further includes:Growth factor or stem cell;The aqueous solvent includes ultra-pure water.
8. a kind of claim 1-7 any one of them joins hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly
Preparation method, which is characterized in that including:
Prepare the hyaluronic acid HAHZ of hydrazide group modification;
Prepare aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH;
Under room temperature, the hyaluronic acid HAHZ and the aldehyde group modified polyoxyethylene that modify the hydrazide group by preset ratio
Alkene-polypropylene oxide-polyethylene glycol oxide PFAH is mixed to get mixture one, mixture two with aqueous solvent respectively;
Mixture one and mixture two are mixed, stirred evenly, pre-crosslinked gel is obtained;
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 by preset ratio modified the hydrazide group described
Hyaluronic acid HAHZ and the aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH and aqueous solvent are mixed
Further include in conjunction:Mixing is added in the growth factor or stem cell that will be provided with life active constituent.
10. a kind of skin histology wound repair agent, which is characterized in that it includes that claim 1-7 any one of them is based on acyl
The double cross of hydrazone bond and hydrophobe self assembly joins hybridized hydrogel.
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CN113827501A (en) * | 2021-10-09 | 2021-12-24 | 湖南大学 | Hyaluronic acid hydrogel mask with skin repairing function and preparation method thereof |
CN114432493A (en) * | 2021-12-23 | 2022-05-06 | 南方医科大学顺德医院(佛山市顺德区第一人民医院) | Injectable biodegradable temperature-sensitive hydrogel and application thereof |
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CN110522948B (en) * | 2019-08-29 | 2021-08-06 | 南京工业大学 | Injectable hydrogel and preparation method and application thereof |
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