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CN109796608A - A kind of tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel preparation method - Google Patents

A kind of tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel preparation method Download PDF

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Publication number
CN109796608A
CN109796608A CN201910054447.XA CN201910054447A CN109796608A CN 109796608 A CN109796608 A CN 109796608A CN 201910054447 A CN201910054447 A CN 201910054447A CN 109796608 A CN109796608 A CN 109796608A
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solution
collagen
chitosan
peg
antibacterial
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张敏
丁翠翠
阳奇利
邓凤
郭晨晨
杨振亚
吴慧
陈礼辉
黄六莲
倪永浩
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Fujian Agriculture and Forestry University
Fujian University of Technology
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Fujian Agriculture and Forestry University
Fujian University of Technology
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Publication of CN109796608A publication Critical patent/CN109796608A/en
Priority to CN201910820532.2A priority patent/CN110343268A/en
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    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00Processes of treating or compounding macromolecular substances
    • C08J3/02Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075Macromolecular gels
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/08Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2389/00Characterised by the use of proteins; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2405/00Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
    • C08J2405/08Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2471/00Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
    • C08J2471/02Polyalkylene oxides

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
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  • Organic Chemistry (AREA)
  • Materials For Medical Uses (AREA)
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Abstract

The present invention provides a kind of pH response tool adhesiveness, antibacterial, pressure resistance quick selfreparing collagen based aquagel preparation method, the following steps are included: S1, it weighs PEG2000,4- carbamoyl benzoate and dimethyl aminopyridine is dissolved in tetrahydrofuran, N is added in nitrogen atmosphere, white solid is obtained by filtration after stirring in N'- dicyclohexylcarbodiimide;The white solid is dissolved in tetrahydrofuran and is precipitated in diethyl ether, DA-PEG is dried to obtain, it is soluble in water to be configured to DA-PEG solution;S2 weighs prepared collagen solution and chitosan solution mixing, and the mass ratio of the two is 3:1~1:3, obtains collagen/chitosan mixed solution;S3 under condition of ice bath, the DA-PEG solution is added in the collagen/chitosan mixed solution, collagen/chitosan/DA-PEG blend solution is configured to, and pH is adjusted to 3.6~4.8, is uniformly mixed;Stand, obtain the tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel.

Description

A kind of tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen-based water-setting The preparation method of glue
Technical field
The invention belongs to medical material manufacturing technology field more particularly to a kind of preparation methods of collagen based aquagel.
Background technique
It is dynamic that collagen is widely present in the aquatic products such as connective tissue and fish-skin, fish scale, the fish-bone of the mammals such as pig, ox, sheep It is the important object of protein resourceization comprehensive utilization in object tissue.Hydrogel as it is a kind of by covalent bond, Van der Waals force or The macromolecule network system that the interactions such as hydrogen bond are cross-linked to form swelling equilibrium and can be able to maintain its shape and three rapidly in water Dimension space network structure.As a kind of natural macromolecular material from animal body, collagen based aquagel have bio-imitability it is high, The various advantages energy such as good biocompatibility, survival and the growth for being easily absorbed by the body and cell capable of being promoted, thus receive wide General concern, and the bio-medical materials and beauty shield such as contain in medicine controlled release carrier, the building of soft tissue bracket and competent cell Wide application has been obtained in terms of skin material.
Currently, the preparation method of collagen hydrogel mainly has physical method and chemical method.Physical hydrogel is due to strand Tangle and ion, hydrogen bond, hydrophobic interaction and the network structure formed, such as by collagen accumulation self assembly, circulating freezing resistance, with The methods of other materials blending obtains collagen hydrogel.Chemical hydrogel is mainly by tropocollagen molecule or intermolecular activity Cross-bond is generated between group and forms cross-linked network structure, and common chemical cross-linking agent has carbodiimides, glutaraldehyde etc..This Outside, sometimes chemical method can also be used in combination with physical method.In general, universal with the collagen hydrogel of prior art preparation Have a problem that: toughness is insufficient, brittleness is big, cracky when by external force, and lacks autonomous repair ability.This is because The obtained collagen hydrogel intermolecular force of physical method is weaker, the destruction vulnerable to external force;And by covalently cross-linked The hydrogel of formation, stable network structure can no doubt improve mechanical property, the stability etc. of gel, but also fetter simultaneously The mobility of strand makes it show certain brittleness, and is difficult to independently repair after being destroyed.It is this can not self-healing property make It is damaged after collagen hydrogel implantation organism vulnerable to external force extruding, body fluid erosion and the intrusion of other chemical substances, from And microfissure is formed in hydrogel, the propagation of these crackles will affect the integrality and mechanical property of hydrogel structure, into And shorten the hydrogel implants service life, jeopardize patient health and safety, and impaired hydrogel is difficult to method reparation manually, It is further applied to limit collagen hydrogel material biomedical and beauty and skin care field.Therefore, seek a kind of tool There is the novel collagen hydrogel of self-healing properties to be of great significance.
Summary of the invention
The present invention provides a kind of tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel Preparation method can effectively solve the above problems.
The present invention is implemented as follows:
A kind of tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel preparation method, including Following steps:
S1 weighs 1.0~5.0g PEG2000,0.3~1.5g 4- carbamoyl benzoate and 0.015~0.075g dimethyl Aminopyridine is dissolved in 30~150mL tetrahydrofuran, and 0.5~2.5g N, N'- dicyclohexyl carbon two are added in nitrogen atmosphere Imines, stirring 12 at 23~28 DEG C~white solid is obtained by filtration afterwards for 24 hours;The white solid is dissolved in 30~150mL tetra- It in hydrogen furans, and is precipitated in diethyl ether, is dried to obtain DA-PEG;It is 20 that the DA-PEG, which is dissolved in the water, and is configured to concentration The DA-PEG solution of~80mg/mL;
Chitosan powder is dissolved in acetum by S21, is configured to the chitosan solution of 10~30mg/mL, and refrigeration is protected It deposits;
S22 under condition of ice bath, the collagen sponge of freeze-drying is dissolved in acetum, is configured to 10~30mg/mL's Collagen solution, it is stored refrigerated;
S23 under condition of ice bath, weighs the collagen solution and chitosan solution mixing, and the mass ratio of the two is 3:1 ~1:3, stirring, vacuum defoamation and ultrasonic treatment obtain uniform collagen/chitosan mixed solution;
S3 under condition of ice bath, the DA-PEG solution is added in the collagen/chitosan mixed solution, the DA- is made The mass ratio of PEG solution and the collagen/chitosan mixed solution is 1~3:10, and it is total to be configured to collagen/chitosan/DA-PEG Miscible fluid;The collagen/chitosan/DA-PEG blend solution pH is adjusted to 3.6~4.8 using highly basic, is uniformly mixed;It is quiet Set, obtain the tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel.
As a further improvement of the above technical scheme:
In step S21 and S22, the concentration of the acetum is 0.01~0.5mol/L.
In step S23, the time of the vacuum defoamation is 5~15min;The time of the ultrasonic treatment is 1~3min.
In step s3, the highly basic is the sodium hydroxide solution of 0.5mol/L.
The beneficial effects of the present invention are:
1. the natural macromolecular chitosan with anti-microbial property is introduced into collagen solution by the present invention, both-end benzaldehyde is added Base polyethylene glycol (DA-PEG), between tropocollagen molecule, collagen and chitosan molecule, chitosan molecule generate dynamic reversible and The imine linkage sensitive to pH forms macromolecular three-dimensional network system, to obtain tool antibiotic property, the regulatable glue of structural behaviour Former base self-cure type hydrogel.
2. the electropositive and mobility by gel rubber system act synergistically, it can get good adhering soft tissues.
3. gel of the invention prepares simple and quick, mild condition and environmentally friendly nontoxic, have quickly from majoring in Renaturation energy has good pH intelligent response, has good antibiotic property, can widen the application range of collagen hydrogel and make Use the service life.
Detailed description of the invention
It, below will be to use required in embodiment in order to illustrate more clearly of the technical solution of embodiment of the present invention Attached drawing be briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not to be seen as It is the restriction to range, it for those of ordinary skill in the art, without creative efforts, can be with root Other relevant attached drawings are obtained according to these attached drawings.
Fig. 1 is the SEM electron microscopic picture of collagen based aquagel prepared by embodiment 1
Specific embodiment
It, below will be to embodiment party of the present invention to keep the purposes, technical schemes and advantages of embodiment of the present invention clearer Technical solution in formula is clearly and completely described, it is clear that described embodiment is a part of embodiment party of the present invention Formula, rather than whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art are not making wound Every other embodiment obtained under the premise of the property made labour, shall fall within the protection scope of the present invention.Therefore, presented below The detailed description of embodiments of the present invention is not intended to limit the range of claimed invention, but is merely representative of this hair Bright selected embodiment.Based on the embodiment in the present invention, those of ordinary skill in the art are not making creative labor Every other embodiment obtained under the premise of dynamic, shall fall within the protection scope of the present invention.
Embodiment 1
It weighs 1.0g PEG2000,0.3g 4- carbamoyl benzoate and 0.015g dimethyl aminopyridine and is dissolved in 30mL tetra- In hydrogen furans, 0.5g N is added in nitrogen atmosphere, N'- dicyclohexylcarbodiimide is obtained by filtration after stirring 12h at 23 DEG C White solid;The white solid is dissolved in 30mL tetrahydrofuran, and is precipitated in diethyl ether, DA-PEG is dried to obtain; The DA-PEG is dissolved in the water the DA-PEG solution for being configured to that concentration is 20mg/mL;
Chitosan powder is dissolved in 0.01mol/L acetum, the chitosan solution of 10mg/mL is configured to, is refrigerated It saves;Under condition of ice bath, the collagen sponge of freeze-drying is dissolved in 0.01mol/L acetum, is configured to the collagen of 10mg/mL Solution, it is stored refrigerated;Under condition of ice bath, the collagen solution and chitosan solution mixing are weighed, the mass ratio of the two is 3:1 is stirred and is obtained uniform collagen/chitosan mixed solution after vacuum defoamation 5min, ultrasonic treatment 3min;
Under condition of ice bath, the DA-PEG solution is added in the collagen/chitosan mixed solution, the DA-PEG is made The mass ratio of solution and the collagen/chitosan mixed solution is 1~3, is configured to collagen/chitosan/DA-PEG blend solution; The collagen/chitosan/DA-PEG blend solution pH is adjusted to 3.6 using the sodium hydroxide solution of 0.5mol/L, mixing is equal It is even;Stand, obtain the tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel.
It is real that selfreparing effect experiment, voltage-withstand test, pH responsiveness are carried out to the collagen based aquagel that the present embodiment obtains It tests, as a result as follows:
(1) collagen based aquagel selfreparing effect experiment: the hydrogel that two panels is cut is stitched and fastened, in 5-30min It is interior to repair completion substantially, it shows as contact interface and permeates entirety, slight crack disappears or fogs, and rhodamine diffuses The other half is infiltrated into, the other half does not fall off after picking up wherein half with tweezers.
(2) collagen based aquagel voltage-withstand test: apply squeezing action 5-10s with thumb, then after decontroling, gel is substantially It can restore original form, and not rupture.
(3) collagen based aquagel pH responsiveness test: add 2mol/L hydrochloric acid solution into hydrogel after, hydrogel is because under pH It drops and becomes flowable solution state, continue plus 2mol/L sodium hydroxide solution makes pH rise to alkalinity, then aqueous solution can weigh Newly become hydrogel.
Embodiment 2
It weighs 3.0g PEG2000,0.9g 4- carbamoyl benzoate and 0.045g dimethyl aminopyridine and is dissolved in 90mL tetra- In hydrogen furans, 1.5g N is added in nitrogen atmosphere, N'- dicyclohexylcarbodiimide is obtained by filtration after stirring 15h at 25 DEG C White solid;The white solid is dissolved in 90mL tetrahydrofuran, and is precipitated in diethyl ether, DA-PEG is dried to obtain; The DA-PEG is dissolved in the water the DA-PEG solution for being configured to that concentration is 50mg/mL;
Chitosan powder is dissolved in 0.25mol/L acetum, the chitosan solution of 20mg/mL is configured to, is refrigerated It saves;Under condition of ice bath, the collagen sponge of freeze-drying is dissolved in 0.25mol/L acetum, is configured to the collagen of 20mg/mL Solution, it is stored refrigerated;Under condition of ice bath, the collagen solution and chitosan solution mixing are weighed, the mass ratio of the two is 1:1 is stirred and is obtained uniform collagen/chitosan mixed solution after vacuum defoamation 10min, ultrasonic treatment 2min;
Under condition of ice bath, the DA-PEG solution is added in the collagen/chitosan mixed solution, the DA-PEG is made The mass ratio of solution and the collagen/chitosan mixed solution is 1~5, is configured to collagen/chitosan DA-PEG blend solution; The collagen/chitosan/DA-PEG blend solution pH is adjusted to 4.8 using the sodium hydroxide solution of 0.5mol/L, mixing is equal It is even;Stand, obtain the tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel.
Embodiment 3
It weighs 5.0g PEG2000,1.5g 4- carbamoyl benzoate and 0.075g dimethyl aminopyridine and is dissolved in 150mL tetra- In hydrogen furans, 2.5g N is added in nitrogen atmosphere, N'- dicyclohexylcarbodiimide is stirred at 28 DEG C and is obtained by filtration afterwards for 24 hours White solid;The white solid is dissolved in 30mL tetrahydrofuran, and is precipitated in diethyl ether, DA-PEG is dried to obtain; The DA-PEG is dissolved in the water the DA-PEG solution for being configured to that concentration is 80mg/mL;
Chitosan powder is dissolved in 0.5mol/L acetum, the chitosan solution of 30mg/mL is configured to, refrigeration is protected It deposits;Under condition of ice bath, the collagen sponge of freeze-drying is dissolved in 0.5mol/L acetum, the collagen for being configured to 30mg/mL is molten Liquid, it is stored refrigerated;Under condition of ice bath, the collagen solution and chitosan solution mixing are weighed, the mass ratio of the two is 1: 3, it stirs and obtains uniform collagen/chitosan mixed solution after vacuum defoamation 15min, ultrasonic treatment 1min;
Under condition of ice bath, the DA-PEG solution is added in the collagen/chitosan mixed solution, the DA-PEG is made The mass ratio of solution and the collagen/chitosan mixed solution is 1~3, is configured to collagen/chitosan/DA-PEG blend solution; The collagen/chitosan/DA-PEG blend solution pH is adjusted to 4.2 using the sodium hydroxide solution of 0.5mol/L, mixing is equal It is even;Stand, obtain the tool adhesiveness of pH response, antibacterial, pressure resistance quick selfreparing collagen based aquagel.
The foregoing is merely the preferred embodiment of the present invention, are not intended to restrict the invention, for this field For technical staff, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any Modification, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.

Claims (4)

1.一种pH响应的具粘附性、抗菌、耐压的快速自修复胶原基水凝胶的制备方法,其特征在于,包括以下步骤:1. the preparation method of the fast self-repairing collagen-based hydrogel of pH response with adhesion, antibacterial, pressure resistance, is characterized in that, comprises the following steps: S1,称取1.0~5.0g PEG2000、0.3~1.5g 4-甲酰苯甲酸和0.015~0.075g二甲基氨基吡啶溶解于30~150mL四氢呋喃中,在氮气氛围中加入0.5~2.5g N,N'-二环己基碳二亚胺,23~28℃下搅拌12~24h后过滤得到白色固体;将所述白色固体溶解于30~150mL四氢呋喃中,并在二乙醚中沉淀,干燥得到DA-PEG;将所述DA-PEG溶解于水中配制成浓度为20~80mg/mL的DA-PEG溶液;S1, weigh 1.0~5.0g PEG2000, 0.3~1.5g 4-formylbenzoic acid and 0.015~0.075g dimethylaminopyridine and dissolve them in 30~150mL tetrahydrofuran, add 0.5~2.5g N,N in nitrogen atmosphere '-dicyclohexylcarbodiimide, stirred at 23-28 °C for 12-24 h, and filtered to obtain a white solid; the white solid was dissolved in 30-150 mL of tetrahydrofuran, precipitated in diethyl ether, and dried to obtain DA-PEG ; Dissolving the DA-PEG in water to prepare a DA-PEG solution with a concentration of 20-80 mg/mL; S21,将壳聚糖粉末溶解于醋酸溶液中,配制成10~30mg/mL的壳聚糖溶液,冷藏保存;S21, dissolve the chitosan powder in the acetic acid solution, prepare a chitosan solution of 10-30 mg/mL, and store it under refrigeration; S22,冰浴条件下,将冻干的胶原海绵溶解于醋酸溶液中,配制成10~30mg/mL的胶原溶液,冷藏保存;S22, under the condition of ice bath, dissolve the freeze-dried collagen sponge in acetic acid solution, prepare a collagen solution of 10-30 mg/mL, and store it under refrigeration; S23,冰浴条件下,称取所述胶原溶液和所述壳聚糖溶液混合,二者的质量比为3:1~1:3,搅拌,真空脱泡并超声处理得到均匀的胶原/壳聚糖混合溶液;S23, under ice bath condition, weigh the collagen solution and the chitosan solution and mix, the mass ratio of the two is 3:1~1:3, stir, vacuum defoaming and ultrasonic treatment to obtain uniform collagen/shell Glycan mixed solution; S3,冰浴条件下,将所述DA-PEG溶液加入所述胶原/壳聚糖混合溶液中,使所述DA-PEG溶液与所述胶原/壳聚糖混合溶液的质量比为1~3:10,配制成胶原/壳聚糖/DA-PEG共混溶液;使用强碱将所述胶原/壳聚糖/DA-PEG共混溶液的pH调至3.6~4.8,混合均匀;静置,得到所述pH响应的具粘附性、抗菌、耐压的快速自修复胶原基水凝胶。S3, under ice bath conditions, add the DA-PEG solution to the collagen/chitosan mixed solution, so that the mass ratio of the DA-PEG solution to the collagen/chitosan mixed solution is 1-3 : 10, prepare a collagen/chitosan/DA-PEG blend solution; use a strong base to adjust the pH of the collagen/chitosan/DA-PEG blend solution to 3.6-4.8, mix evenly; The pH-responsive fast self-healing collagen-based hydrogel with adhesion, antibacterial, and pressure resistance is obtained. 2.根据权利要求1所述的制备方法,其特征在于,在步骤S21和S22中,所述醋酸溶液中醋酸的浓度为0.01~0.5mol/L。2 . The preparation method according to claim 1 , wherein in steps S21 and S22 , the concentration of acetic acid in the acetic acid solution is 0.01-0.5 mol/L. 3 . 3.根据权利要求1所述的制备方法,其特征在于,在步骤S23中,所述真空脱泡的时间为5~15min;所述超声处理的时间为1~3min。3 . The preparation method according to claim 1 , wherein, in step S23 , the time of the vacuum defoaming is 5-15 minutes; the time of the ultrasonic treatment is 1-3 minutes. 4 . 4.根据权利要求1所述的制备方法,其特征在于,在步骤S3中,所述强碱为0.5mol/L的氢氧化钠溶液。4. preparation method according to claim 1, is characterized in that, in step S3, described strong base is the sodium hydroxide solution of 0.5mol/L.
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CN118986860A (en) * 2024-08-20 2024-11-22 黑龙江中医药大学 Glycyrrhetinic acid chitosan self-healing hydrogel and preparation method and application thereof

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