CN116650710A - Mussel inspired multifunctional double-network crosslinked hydrogel wound dressing - Google Patents
Mussel inspired multifunctional double-network crosslinked hydrogel wound dressing Download PDFInfo
- Publication number
- CN116650710A CN116650710A CN202310740688.6A CN202310740688A CN116650710A CN 116650710 A CN116650710 A CN 116650710A CN 202310740688 A CN202310740688 A CN 202310740688A CN 116650710 A CN116650710 A CN 116650710A
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- hydrogel
- solution
- network
- alginic acid
- gallic acid
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a mussel inspired multifunctional double-network crosslinked hydrogel wound dressing. Forming a dynamic covalent bond crosslinked hydrogel network between carboxymethyl chitosan and oxidized sodium alginate; further introducing natural antioxidant gallic acid with catechol structure, enhancing the compactness of hydrogel network combination and endowing hydrogel with certain adhesiveness and oxidation resistance; finally, the bionic mussel adhesive liquid containing catechol and iron has strong tissue adhesion behavior under alkaline conditions, and is suitable for dynamic wound treatment, so that the multifunctional double-network crosslinked hydrogel wound dressing inspired by the mussel is prepared. In addition, catechol-Fe 3+ The metal coordination effect also shows a strong antibacterial effect, and can convert light energy into heat energy under the irradiation of near infrared light for preventing and treating wound infection, shortening the wound closing time and preventing scar formation.
Description
Technical Field
The invention belongs to the technical field of medical materials, and particularly relates to a multifunctional double-network crosslinked hydrogel wound dressing inspired by mussels and a preparation method thereof.
Background
The skin is the largest organ of the human body and plays a vital role in protecting the body from pathogen invasion and maintaining biological functions. However, due to trauma or disease, the skin barrier is easily damaged, and in particular, full-thickness wounds involving a loss of the dermis layer are currently still a major problem in clinical care. In addition, because of the frequent movement of the moving wound area (e.g., the joint wound may stretch frequently), conventional non-stretchable and non-self-healing wound dressings are prone to damage or fall off from frequent movement. Hydrogels are considered to be the most promising wound dressing because they are composed of a hydrophilic three-dimensional network that can absorb tissue exudates, providing a breathable and moist environment for the wound, and accelerating wound healing. Therefore, the design has good tissue adhesion, stretchability and self-healing property, can be adhered to the surface of wound movement, and has good application prospect in the hydrogel dressing conforming to frequent movement.
The self-healing behavior of hydrogels is achieved primarily through reversible physical non-covalent interactions and chemical covalent bonds. Physical cross-linking forms weaker bonds, but bonds are formed and dynamic equilibrium is reestablished faster. Physically crosslinked hydrogels have weak mechanical strength and are not suitable for dynamic entanglement. Chemical crosslinking can form stronger bonds, but at a slower rate of bond formation and dynamic equilibrium reestablishment. The introduction of chemical crosslinking is a method of improving the mechanical strength of hydrogels. Reversible imine bonds are a dynamic chemical covalent bond commonly used to trigger the preparation of injectable self-healing hydrogels. Inspired by mussels, catechol-based wet adhesives have attracted considerable attention over the past few years. Mussel at low pH (pH)<5) Lower secretion contains catechol and iron (Fe) 3+ ) Is dissolved in the weak single compound adhesiveLiquid, and the single complex is further transferred into seawater (pH raised to × 8) to form a double or triple complex to enhance underwater adhesion. Furthermore, catechol group-containing materials exhibit good biocompatibility and radical scavenging ability, as well as Fe 3+ After complexation, it has photo-thermal capability to inactivate bacteria, which is critical for wound healing. Therefore, the present invention aims to design a physicochemical double-crosslinked injectable self-healing hydrogel which integrates various functions including strong tissue adhesion, inherent antibacterial activity and hemostatic activity.
At present, wound dressings based on catechol structures have been widely studied, and peripheral et al graft catechol groups into a carboxymethyl chitosan skeleton, and combine modified sodium alginate to prepare a hydrogel dressing with strong adhesion performance, and the hydrogel dressing also has excellent hemostatic performance in a liver injury model of rabbits, wherein the blood loss is 0.32g and is only 54.2% of fibrin glue. Plum et al designed an injectable self-dual dynamic Schiff base hydrogel composed of modified hyaluronic acid and a benzaldehyde polymer based on melanin nanoparticles derived from cuttlefish juice having a similar catechol structure, capable of adapting to frequent movements of sports wounds. The hydrogel dressing significantly prevents wound infection in a full-thickness wound model of an animal and promotes wound healing through milder inflammation, higher granulation tissue thickness and collagen tendencies. The beam et al is made of iron (Fe 3+ ) The dual-dynamic bond crosslinking between Protocatechol (PA) containing catechol and aldehyde groups and Quaternized Chitosan (QCS) designs a series of viscous antioxidant antibacterial self-healing hydrogels with good properties, and promotes wound healing of methicillin-resistant staphylococcus aureus (MRSA) infection. In addition, poplar et al use catechol structurally modified oxidized hyaluronic acid and gelatin to form dynamic Schiff base bond and then coordinate cross-linked Fe 3+ The double-crosslinked hydrogel is prepared, and has the advantages of enhanced mechanical property, adhesive strength, injection self-healing capability, excellent shape adaptability and remarkably shortened closing time of burn wounds of rats. The chitosan, silk fibroin and tannic acid (with catechin) are selected by various weak hydrogen bonds and metal ligand coordination effectsPhenol structure) and iron ions produce a highly porous cryogel exhibiting excellent hygroscopicity and hemostatic properties, animal experiments have also shown that the cryogel effectively eradicates microorganisms at the wound site and accelerates the wound healing process. In addition, many studies report that catechol/iron-based complexation chelation has excellent photothermal bacteriostatic and adhesive properties for accelerating wound healing.
In summary, the present invention utilizes natural polysaccharide materials with excellent biocompatibility, biodegradability, inherent antibacterial property, healing promoting effect, low cost and easy chemical modification to crosslink in situ to design a series of hydrogel networks with different crosslinking degrees. The carboxymethyl chitosan not only has better water solubility than chitosan, but also keeps the reversible dynamic cross-linking of amino and aldehyde group, and then sodium alginate can form corresponding aldehyde group through periodic acid oxidation, and injectable self-healing hydrogel can be formed in situ through shaking, so that the carboxymethyl chitosan has shape adaptability and is suitable for wound repair of various shapes. Secondly, the excessive generation of active oxygen in the wound repair process triggers a long-term inflammatory reaction and delays the healing speed of the wound, so that the introduction of the natural antioxidant-gallic acid increases the functional characteristics of the hydrogel, namely the enhanced mechanical property, tissue adhesiveness and antioxidant activity, and finally the active oxygen is coordinated with metal of iron ions to further endow the hydrogel with a strong photo-thermal antibacterial effect. These above-described properties, CMC/OSA/GA-Fe hydrogels, will be fully evaluated by physicochemical experiments, cytobacteriological experiments, antioxidant experiments, and animal full-thickness defect wound models.
Disclosure of Invention
The invention utilizes the hydrogel network formed by dynamic covalent bond crosslinking between carboxymethyl chitosan and oxidized sodium alginate (alginic aldehyde); further introducing natural antioxidant gallic acid with catechol structure, enhancing the compactness of hydrogel network combination and endowing hydrogel with certain adhesiveness and oxidation resistance; finally, the bionic mussel adhesive liquid containing catechol and iron has strong tissue adhesion behavior under alkaline condition, and is suitable for dynamic wound treatment, thereby preparing a mussel openerMultifunctional double-network crosslinked hydrogel wound dressing. In addition, catechol-Fe 3+ The metal coordination effect also shows a strong antibacterial effect, and can convert light energy into heat energy under the irradiation of near infrared light for preventing and treating wound infection, shortening the wound closing time and preventing scar formation. The preparation process is simple, the cost is low, and the medical material is a medical material for promoting wound healing.
In order to achieve the above purpose, the invention adopts the following technical scheme:
based on marine mussel adhesion behavior inspiring and by utilizing a material preparation technology and method, the multifunctional hydrogel adhesive with injectability, self-healing property, adhesion, hemostatic property, photo-thermal antibacterial property, oxidation resistance and angiogenesis promotion is designed to accelerate healing of full-layer skin defect wounds. Forming a dynamic covalent bond crosslinked hydrogel network between carboxymethyl chitosan and oxidized sodium alginate; further introducing natural antioxidant gallic acid with catechol structure, enhancing the compactness of hydrogel network combination and endowing hydrogel with certain adhesiveness and oxidation resistance; finally, the bionic mussel adhesive liquid containing catechol and iron has strong tissue adhesion behavior under alkaline conditions, and is suitable for dynamic wound treatment, so that the multifunctional double-network crosslinked hydrogel wound dressing inspired by the mussel is prepared.
A preparation method of a multifunctional double-network crosslinked hydrogel wound dressing inspired by mussels comprises the following steps: natural source materials such as carboxymethyl chitosan, alginic acid aldehyde and gallic acid are selected to prepare a physical and chemical double-crosslinked hydrogel network through imine bonds, metal coordination bonds and weak hydrogen bonding; different-NH 2 The hydrogel with different crosslinking degrees is prepared by the/-CHO ratio, the catechol structure is used as a bridge to connect iron ions and a polymer network, the mechanical property of the hydrogel is enhanced, and a series of multifunctional hydrogel dressings are prepared by combining the excellent biological property of natural materials and the dynamically crosslinked hydrogel network.
The method specifically comprises the following steps:
(1) Dissolving sodium alginate in deionized water, and adding oxidant sodium periodate to generate alginic acid aldehyde OSA;
(2) Terminating the oxidation of the alginic acid aldehyde solution obtained in the step (1) by using ethylene glycol;
(3) Placing the alginic acid aldehyde solution obtained in the step (2) in a cellulose dialysis bag, and dialyzing and purifying;
(4) Freeze-drying the purified alginic acid aldehyde solution obtained in the step (3);
(5) Weighing the freeze-dried alginic acid aldehyde powder obtained in the step (4), and adding PBS buffer solution for dissolution under the condition of constant-temperature magnetic stirring;
(6) Under the constant temperature magnetic stirring condition, dissolving carboxymethyl chitosan in PBS buffer solution;
(7) Weighing gallic acid, placing in a PBS buffer solution with alkalescence, and fully stirring until the gallic acid is dissolved;
(8) Adding ferric trichloride hexahydrate powder into the solution obtained in the step (7) under the magnetic stirring condition, and fully stirring to completely and uniformly mix the ferric trichloride powder to obtain a mixed solution of gallic acid chelated iron ions;
(9) Uniformly mixing the mixed solution obtained in the step (8) with the alginic acid aldehyde solution obtained in the step (5) by vortex to obtain hydrogel precursor liquid;
(10) Uniformly vortex-dispersing the carboxymethyl chitosan solution obtained in the step (6) and the hydrogel precursor liquid obtained in the step (9), and standing to obtain the carboxymethyl chitosan/alginic aldehyde/gallic acid-iron-based double-network crosslinked adhesion type hydrogel dressing.
Further, in the step (1), the concentration of the sodium alginate solution is 2wt%, the dissolution temperature is 50 ℃, and the molar ratio of sodium alginate to sodium periodate is 1:1, the oxidation time in the dark is 6h.
Further, in the step (2), the mass ratio of the added amount of ethylene glycol to sodium alginate is 1.5:1, the termination reaction time was 1h.
Further, in the step (3), the cellulose dialysis bag retention amount was 3500Da, the dialysis purification time was 3 days, and water was changed every 6 hours.
Further, in the step (4), the temperature of the freeze dryer is-80 ℃ and the drying time is 72 hours.
Further, the concentration of the alginic acid aldehyde solution prepared in the step (5) is 10wt%, and the pH value of the PBS buffer solution is 7.0-7.4.
Further, in the step (6), the mass to volume ratio of the carboxymethyl chitosan to the PBS buffer solution is 0.05g:1ml, constant temperature of 55 ℃ and magnetic stirring time of 2-4h.
Further, in the gallic acid solution prepared in the step (7), the concentration of the PBS buffer solution is 0.2mol/L, the pH value is 8.5, and the concentration of the gallic acid solution is 1wt%.
Further, in the step (8), the molar ratio of ferric trichloride hexahydrate to gallic acid is 1:6,1:3 or 2:3.
further, in the hydrogel precursor liquid obtained in the step (9), the volume ratio of the mixed liquid of the gallic acid chelated iron ions to the alginic acid aldehyde solution is 3:5.
further, in the physicochemical double-crosslinked adhesive hydrogel obtained in the step (10), the volume ratio of the gallic acid-iron solution to the alginic acid aldehyde solution to the carboxymethyl chitosan solution is 3:5:10, and a vortex time of about 15s.
A mussel-inspired multifunctional double-network crosslinked hydrogel wound dressing prepared by the method.
The invention has the remarkable advantages that:
(1) The invention is based on the adhesion behavior of marine mussels, and is a multifunctional hydrogel dressing suitable for dynamic wounds.
(2) The invention selects the green renewable marine polysaccharide to form a dynamic covalent bond, and combines the natural antioxidant and the metal coordination bond of iron ions to prepare the physical-chemical double-crosslinked injectable self-healing hydrogel adhesive, which can be suitable for wound repair of various shapes.
(3) The prepared hydrogel has good biocompatibility and in vivo degradability, and can avoid secondary injury caused by dressing replacement.
(4) Bacterial infection at a wound is a main cause of difficult wound healing, traditional antibiotic treatment bacteria are easy to generate drug resistance, and photothermal therapy adopted by the invention has the advantages of spectral antibacterial property, remote control and drug resistance avoidance.
(5) The invention has low synthesis cost, simple method and outstanding effect, and can be produced in batch and large scale.
Drawings
FIG. 1 is a SEM image (400×) of a hydrogel wound dressing prepared in example 1;
FIG. 2 is a SEM image (400X) of a hydrogel wound dressing prepared in example 2;
FIG. 3 is an SEM image (400X) of a mussel-inspired multifunctional dual-network crosslinked hydrogel wound dressing prepared in example 3;
FIG. 4 is an SEM image (400X) of a mussel-inspired multifunctional dual-network crosslinked hydrogel wound dressing prepared in example 4;
FIG. 5 is an SEM image (400X) of a mussel-inspired multifunctional dual-network crosslinked hydrogel wound dressing prepared in example 5;
FIG. 6 is a mechanical property test of the hydrogel wound dressings prepared in examples 1-5;
FIG. 7 is a compression cycle unloading experiment of the hydrogel wound dressing prepared in examples 1-5;
FIG. 8 is the macroscopic deformation recovery capability of the multifunctional dual-network crosslinked hydrogel wound dressing inspired by preparation of example 4;
fig. 9, 10 are macroscopic and microscopic adhesive effects of different materials of the multifunctional dual-network crosslinked hydrogel wound dressing inspired by the preparation of mussel in example 4;
FIG. 11 is a hydrogel wound dressing prepared in examples 1-5 in NIR (806 nm,1w/cm 2 ) Heating response data under stimulation;
FIG. 12 is an infrared imaging photograph of temperature changes at different powers for a multifunctional dual-network crosslinked hydrogel wound dressing inspired by preparation of mussel from example 4;
FIG. 13 is a real-time monitoring of temperature changes after cycling the NIR of the switch for example 4 preparation of a mussel-inspired multifunctional dual-network crosslinked hydrogel wound dressing;
FIG. 14 is a microscopic evaluation of the bactericidal effect of the multifunctional dual-network crosslinked hydrogel wound dressing inspired by the preparation of mussel in example 4 on E.coli and Staphylococcus aureus in NIR response;
FIG. 15 is a graph of DPPH radical, ABTS radical and hydroxyl radical scavenging test for hydrogel wound dressings prepared in examples 1-5.
Detailed Description
In order to make the contents of the present invention easier to understand, the technical solutions of the present invention will be further described with reference to the specific embodiments, but the following examples are only examples of the present invention and do not represent the scope of the present invention defined by the claims.
Example 1
The preparation method of carboxymethyl chitosan/alginic acid aldehyde adhesion type hydrogel (CMC/OSA) comprises the following steps:
(1) Sodium alginate is dissolved in deionized water according to the mole ratio of 1:1 adding oxidant sodium periodate to generate alginic acid aldehyde (OSA), and oxidizing in the dark for 6 hours;
(2) Terminating oxidation of the alginic acid aldehyde solution obtained in the step (1) by using glycol, wherein the mass ratio of the glycol to the sodium alginate is 1.5:1, terminating oxidation for 1h;
(3) Placing the alginic acid aldehyde solution obtained in the step (2) into a cellulose dialysis bag with cutoff of 3500Da, dialyzing and purifying for 3 days, and changing water every 6 hours;
(4) Placing the purified alginic acid aldehyde solution obtained in the step (3) in a freeze dryer at the temperature of minus 80 ℃ for freeze drying for 72 hours;
(5) Weighing the freeze-dried alginic aldehyde powder obtained in the step (4), adding PBS buffer solution (pH=7.0-7.4) under the constant temperature magnetic stirring condition for dissolution, and preparing 10wt% alginic aldehyde solution;
(6) Under the constant temperature magnetic stirring condition, carboxymethyl chitosan is dissolved in PBS buffer solution, and the mass to volume ratio is 0.05g:1ml of the mixture is magnetically stirred for 2 to 4 hours at 55 ℃;
(7) Mixing a 0.2mol/L PBS buffer solution with alkalescence (pH=8.5) with the alginic acid aldehyde solution obtained in the step (5) according to a volume ratio of 3: vortex mixing evenly;
(8) Vortex dispersing the carboxymethyl chitosan solution obtained in the step (6) and the mixed solution obtained in the step (7), wherein the volume ratio of the alkalescent PBS buffer solution to the alginic acid aldehyde solution to the carboxymethyl chitosan solution is 3:5:10, vortex for 15s, and stand to obtain carboxymethyl chitosan/alginic acid aldehyde adhesion type hydrogel.
Example 2
The preparation method of gallic acid modified carboxymethyl chitosan/alginic acid aldehyde adhesion type hydrogel (CMC/OSA/GA) comprises the following steps:
(1) Sodium alginate is dissolved in deionized water according to the mole ratio of 1:1 adding oxidant sodium periodate to generate alginic acid aldehyde (OSA), and oxidizing in the dark for 6 hours;
(2) Terminating oxidation of the alginic acid aldehyde solution obtained in the step (1) by using glycol, wherein the mass ratio of the glycol to the sodium alginate is 1.5:1, terminating oxidation for 1h;
(3) Placing the alginic acid aldehyde solution obtained in the step (2) into a cellulose dialysis bag with cutoff of 3500Da, dialyzing and purifying for 3 days, and changing water every 6 hours;
(4) Placing the purified alginic acid aldehyde solution obtained in the step (3) in a freeze dryer at the temperature of minus 80 ℃ for freeze drying for 72 hours;
(5) Weighing the freeze-dried alginic aldehyde powder obtained in the step (4), adding PBS (phosphate buffer solution) (pH=7.0-7.4) under the constant temperature magnetic stirring condition for dissolution, and preparing 10wt% alginic aldehyde solution;
(6) Under the constant temperature magnetic stirring condition, carboxymethyl chitosan is dissolved in PBS buffer solution, and the mass to volume ratio is 0.05g:1ml of the mixture is magnetically stirred for 2 to 4 hours at 55 ℃;
(7) Gallic acid is weighed and placed in a 0.2mol/L PBS buffer solution with alkalescence (pH=8.5), and fully stirred until the gallic acid is dissolved, so as to prepare 1wt% gallic acid solution;
(8) Mixing the solution obtained in the step (7) with the alginic acid aldehyde solution obtained in the step (5) according to a volume ratio of 3: vortex mixing evenly;
(9) Vortex dispersing the carboxymethyl chitosan solution obtained in the step (6) and the mixed solution obtained in the step (8), wherein the mass ratio of gallic acid, alginic acid aldehyde and carboxymethyl chitosan is 0.17:2.78:2.78, vortex for 15s, and stand to obtain gallic acid modified carboxymethyl chitosan/alginic acid aldehyde adhesion type hydrogel.
Example 3
A preparation method of a mussel inspired multifunctional double-network crosslinked hydrogel wound dressing (CMC/OSA/GA-Fe2.5) comprises the following steps:
(1) Sodium alginate is dissolved in deionized water according to the mole ratio of 1:1 adding oxidant sodium periodate to generate alginic acid aldehyde (OSA), and oxidizing in the dark for 6 hours;
(2) Terminating oxidation of the alginic acid aldehyde solution obtained in the step (1) by using glycol, wherein the mass ratio of the glycol to the sodium alginate is 1.5:1, terminating oxidation for 1h;
(3) Placing the alginic acid aldehyde solution obtained in the step (2) into a cellulose dialysis bag with cutoff of 3500Da, dialyzing and purifying for 3 days, and changing water every 6 hours;
(4) Placing the purified alginic acid aldehyde solution obtained in the step (3) in a freeze dryer at the temperature of minus 80 ℃ for freeze drying for 72 hours;
(5) Weighing the freeze-dried alginic aldehyde powder obtained in the step (4), adding PBS (phosphate buffer solution) (pH=7.0-7.4) under the constant temperature magnetic stirring condition for dissolution, and preparing 10wt% alginic aldehyde solution;
(6) Under the constant temperature magnetic stirring condition, carboxymethyl chitosan is dissolved in PBS buffer solution, and the mass to volume ratio is 0.05g:1ml of the mixture is magnetically stirred for 2 to 4 hours at 55 ℃;
(7) Gallic acid is weighed and placed in a 0.2mol/L PBS buffer solution with alkalescence (pH=8.5), and fully stirred until the gallic acid is dissolved, so as to prepare 1wt% gallic acid solution;
(8) Under the magnetic stirring condition, adding ferric trichloride hexahydrate powder into the solution obtained in the step (7), and fully stirring to completely and uniformly mix the ferric trichloride powder to obtain a mixed solution of gallic acid chelated iron ions, wherein the molar ratio of ferric trichloride hexahydrate to gallic acid is 1:6, preparing a base material;
(9) Mixing the mixed solution obtained in the step (8) with the alginic acid aldehyde solution obtained in the step (5) according to the volume ratio of 3: vortex mixing uniformly to obtain hydrogel precursor liquid;
(10) Uniformly vortex-dispersing the carboxymethyl chitosan solution obtained in the step (6) and the hydrogel precursor solution obtained in the step (9), wherein the volume ratio of the gallic acid-iron solution to the alginic acid aldehyde solution to the carboxymethyl chitosan solution is 3:5:10, vortex 15s, and stand to obtain the double-network crosslinking adhesion type hydrogel dressing based on carboxymethyl chitosan/alginic aldehyde/gallic acid-iron.
Example 4
A preparation method of a mussel inspired multifunctional double-network crosslinked hydrogel wound dressing (CMC/OSA/GA-Fe 5) comprises the following steps:
(1) Sodium alginate is dissolved in deionized water according to the mole ratio of 1:1 adding oxidant sodium periodate to generate alginic acid aldehyde (OSA), and oxidizing in the dark for 6 hours;
(2) Terminating oxidation of the alginic acid aldehyde solution obtained in the step (1) by using glycol, wherein the mass ratio of the glycol to the sodium alginate is 1.5:1, terminating oxidation for 1h;
(3) Placing the alginic acid aldehyde solution obtained in the step (2) into a cellulose dialysis bag with cutoff of 3500Da, dialyzing and purifying for 3 days, and changing water every 6 hours;
(4) Placing the purified alginic acid aldehyde solution obtained in the step (3) in a freeze dryer at the temperature of minus 80 ℃ for freeze drying for 72 hours;
(5) Weighing the freeze-dried alginic aldehyde powder obtained in the step (4), adding PBS (phosphate buffer solution) (pH=7.0-7.4) under the constant temperature magnetic stirring condition for dissolution, and preparing 10wt% alginic aldehyde solution;
(6) Under the constant temperature magnetic stirring condition, carboxymethyl chitosan is dissolved in PBS buffer solution, and the mass to volume ratio is 0.05g:1ml of the mixture is magnetically stirred for 2 to 4 hours at 55 ℃;
(7) Gallic acid is weighed and placed in a 0.2mol/L PBS buffer solution with alkalescence (pH=8.5), and fully stirred until the gallic acid is dissolved, so as to prepare 1wt% gallic acid solution;
(8) Under the magnetic stirring condition, adding ferric trichloride hexahydrate powder into the solution obtained in the step (7), and fully stirring to completely and uniformly mix the ferric trichloride powder to obtain a mixed solution of gallic acid chelated iron ions, wherein the molar ratio of ferric trichloride hexahydrate to gallic acid is 1:3, a step of;
(9) Mixing the mixed solution obtained in the step (8) with the alginic acid aldehyde solution obtained in the step (5) according to the volume ratio of 3: vortex mixing uniformly to obtain hydrogel precursor liquid;
(10) Uniformly vortex-dispersing the carboxymethyl chitosan solution obtained in the step (6) and the hydrogel precursor solution obtained in the step (9), wherein the volume ratio of the gallic acid-iron solution to the alginic acid aldehyde solution to the carboxymethyl chitosan solution is 3:5:10, vortex 15s, and stand to obtain the double-network crosslinking adhesion type hydrogel dressing based on carboxymethyl chitosan/alginic aldehyde/gallic acid-iron.
Example 5
A preparation method of a mussel inspired multifunctional double-network crosslinked hydrogel wound dressing (CMC/OSA/GA-Fe 10) comprises the following steps:
(1) Sodium alginate is dissolved in deionized water according to the mole ratio of 1:1 adding oxidant sodium periodate to generate alginic acid aldehyde (OSA), and oxidizing in the dark for 6 hours;
(2) Terminating oxidation of the alginic acid aldehyde solution obtained in the step (1) by using glycol, wherein the mass ratio of the glycol to the sodium alginate is 1.5:1, terminating oxidation for 1h;
(3) Placing the alginic acid aldehyde solution obtained in the step (2) into a cellulose dialysis bag with cutoff of 3500Da, dialyzing and purifying for 3 days, and changing water every 6 hours;
(4) Placing the purified alginic acid aldehyde solution obtained in the step (3) in a freeze dryer at the temperature of minus 80 ℃ for freeze drying for 72 hours;
(5) Weighing the freeze-dried alginic aldehyde powder obtained in the step (4), adding PBS (phosphate buffer solution) (pH=7.0-7.4) under the constant temperature magnetic stirring condition for dissolution, and preparing 10wt% alginic aldehyde solution;
(6) Under the constant temperature magnetic stirring condition, carboxymethyl chitosan is dissolved in PBS buffer solution, and the mass to volume ratio is 0.05g:1ml of the mixture is magnetically stirred for 2 to 4 hours at 55 ℃;
(7) Gallic acid is weighed and placed in a 0.2mol/L PBS buffer solution with alkalescence (pH=8.5), and fully stirred until the gallic acid is dissolved, so as to prepare 1wt% gallic acid solution;
(8) Under the magnetic stirring condition, adding ferric trichloride hexahydrate powder into the solution obtained in the step (7), and fully stirring to completely and uniformly mix the ferric trichloride powder to obtain a mixed solution of gallic acid chelated iron ions, wherein the molar ratio of ferric trichloride hexahydrate to gallic acid is 2:3, a step of;
(9) Mixing the mixed solution obtained in the step (8) with the alginic acid aldehyde solution obtained in the step (5) according to the volume ratio of 3: vortex mixing uniformly to obtain hydrogel precursor liquid;
(10) Uniformly vortex-dispersing the carboxymethyl chitosan solution obtained in the step (6) and the hydrogel precursor solution obtained in the step (9), wherein the volume ratio of the gallic acid-iron solution to the alginic acid aldehyde solution to the carboxymethyl chitosan solution is 3:5:10, vortex 15s, and stand to obtain the double-network crosslinking adhesion type hydrogel dressing based on carboxymethyl chitosan/alginic aldehyde/gallic acid-iron.
SEM images of hydrogel (CMC/OSA) wound dressings prepared in this example 1 are shown in fig. 1, respectively.
SEM images of hydrogel (CMC/OSA/GA) wound dressings prepared in this example 2 are shown in fig. 2, respectively.
SEM images of the multifunctional dual-network crosslinked hydrogel (CMC/OSA/GA-fe2.5) wound dressing elicited by mussels prepared in this example 3 are shown in fig. 3, respectively.
SEM images of the multifunctional dual-network crosslinked hydrogel (CMC/OSA/GA-Fe 5) wound dressing elicited by mussel prepared in this example 4 are shown in fig. 4, respectively.
SEM images of the multifunctional dual-network crosslinked hydrogel (CMC/OSA/GA-Fe 10) wound dressing elicited by mussel prepared in this example 5 are shown in fig. 5, respectively.
As the concentration of the gallic acid-iron precursor solution increases, the hydrogels of examples 3,4 and 5 show a tighter network structure, and particularly the gel network prepared in example 4 is more uniform, and the phenomenon of network collapse caused by too fast crosslinking does not occur. The porosity of the hydrogel is calculated to be more than 70%, which is beneficial to exudation of wound tissue fluid and gas exchange.
Mechanical property test of mussel inspired multifunctional double-network crosslinked hydrogel wound dressing:
hydrogels were prepared as cylindrical samples with a diameter of 10 mm and a height of 10 mm. The hydrogel material was subjected to compression test in the axial direction using a universal tester at a compression rate of 5 mm/min during the test, and the maximum compressive strength that the hydrogel material could withstand was measured, and the results are shown in fig. 6. Through compression testing, each set of hydrogels exhibited good mechanical strength, with the example 4 hydrogel set having the best mechanical strength, since the incorporation of gallic acid and iron ions increased the degree of network binding within the hydrogel. In addition, the results obtained by subjecting each set of hydrogels to a compression cycle of 50% deformation are shown in FIG. 7 (CMC/OSA, CMC/OSA/GA, CMC/OSA/GA-Fe2.5, CMC/OSA/GA-Fe5, CMC/OSA/GA-Fe10 in this order from left to right). By the deformation recovery ability, we can find that compared with CMC/OSA hydrogel groups formed only by simple imine bonds, CMC/OSA/GA and CMC/OSA/GA-Fe hydrogels have a good energy dissipation effect by the presence of multiple hydrogen bonds and metal coordination bonds, which indicates that the hydrogel group of example 4 has both rigid network and flexible structure, and can well adapt to the recovery ability of the wound after multiple deformations due to movement, and the result is shown in fig. 8.
Adhesion capability of mussel-inspired multifunctional dual-network crosslinked hydrogel wound dressing:
example 4 macroscopic effects of hydrogels on adhesion of various materials such as metal, plastic, glass, skin and rat viscera, the results are shown in figure 9. Subsequently, the microscopic morphology of the hydrogel-adhered sample interface was observed with a scanning electron microscope, and the result is shown in fig. 10. The hydrogel has certain adhesion effect on various materials, and the hydrogel dressing can be well adhered to the wound surface without falling off because the aldehyde group, the quinone group and the phenolic hydroxyl group which are polymerized in the hydrogel can have corresponding physical and chemical bond action with the surface of the material.
Photo-thermal capability and antibacterial effect of multifunctional double-network crosslinked hydrogel wound dressing inspired by mussels:
the photo-thermal conversion properties of the hydrogels were evaluated using NIR irradiation. The same volume of hydrogel was placed in a 5 ml EP tube with 1w/cm 2 The 808 and nm laser irradiation was continued for 10 min, and the temperature change was recorded in real time by a thermal infrared imager (chinese UTi 160D), and the result is shown in fig. 11. Metal coordination bond between catechol and iron ions in hydrogelsIn this case, the device has a good capability of converting light energy into temperature. Furthermore, by setting the power density of NIR from 1w/cm 2 Changed to 2.5 w/cm 2 Photo-thermal tunability of the hydrogels of example 4 was studied and the results are shown in figure 12. The temperature change of the photothermograph shows that the hydrogel of example 4 has good thermal response capability to light sources with different intensities. Photo-thermal stability was tested by measuring the temperature change of the hydrogel of example 4 under three on/off irradiation cycles, the results are shown in fig. 13. In addition, we determined the hydrogel of example 4 with gram positive bacteria [ ]S.aures) And gram-negative bacteriaE.coli) After the bacteria are cultured together, the survival condition of the bacteria is treated by NIR, the corresponding bacterial microscopic morphology is observed by a scanning electron microscope, the result is shown in figure 14, and the cell membrane structure of the thalli can be destroyed by heating, so that the good sterilization effect is achieved.
Mussel-inspired free radical scavenging ability of multifunctional dual-network crosslinked hydrogel wound dressing:
excessive free radicals at the wound site often lead to strong oxidative stress, causing normal cells to undergo enzyme inactivation, lipid peroxidation and DNA damage, thereby delaying wound healing. Thus, wound dressings with radical scavenging properties are beneficial for wound healing. The oxidation resistance of the hydrogel dressing is evaluated by simulating the generation of free radicals in vitro and then by the change of the content of the corresponding free radicals after material treatment. As shown in FIG. 15, we found that the hydrogel group containing plant polyphenol gallic acid has good scavenging effect on both nitrogen free radicals (DPPH or ABTS) and hydroxyl free radicals, especially the hydrogel group containing plant polyphenol gallic acid can reach more than 80%, which can accelerate the inflammation stage of the wound to overgrow to accelerate the wound healing time.
The foregoing description is only of the preferred embodiments of the invention, and all changes and modifications that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (10)
1. A preparation method of a multifunctional double-network crosslinked hydrogel wound dressing inspired by mussels is characterized by comprising the following steps of: natural source materials are selected: carboxylic acidMethyl chitosan, alginic acid aldehyde and gallic acid, and preparing a physical and chemical double-crosslinked hydrogel network through imine bonds, metal coordination bonds and weak hydrogen bonds; different-NH 2 The hydrogel with different crosslinking degrees is prepared by the/-CHO ratio, the catechol structure is used as a bridge to connect iron ions and a polymer network, the mechanical property of the hydrogel is enhanced, and a series of multifunctional hydrogel dressings are prepared by combining the excellent biological property of natural materials and the dynamically crosslinked hydrogel network.
2. The method for preparing the mussel-inspired multifunctional double-network crosslinked hydrogel wound dressing, which is characterized by comprising the following steps of: the method comprises the following steps:
(1) Dissolving sodium alginate in deionized water, and adding oxidant sodium periodate to generate alginic acid aldehyde OSA;
(2) Terminating the oxidation of the alginic acid aldehyde solution obtained in the step (1) by using ethylene glycol;
(3) Placing the alginic acid aldehyde solution obtained in the step (2) in a cellulose dialysis bag, and dialyzing and purifying;
(4) Freeze-drying the purified alginic acid aldehyde solution obtained in the step (3);
(5) Weighing the freeze-dried alginic acid aldehyde powder obtained in the step (4), and adding PBS buffer solution for dissolution under the condition of constant-temperature magnetic stirring;
(6) Under the constant temperature magnetic stirring condition, dissolving carboxymethyl chitosan in PBS buffer solution;
(7) Weighing gallic acid, placing in a PBS buffer solution with alkalescence, and fully stirring until the gallic acid is dissolved;
(8) Adding ferric trichloride hexahydrate powder into the solution obtained in the step (7) under the magnetic stirring condition, and fully stirring to completely and uniformly mix the ferric trichloride powder to obtain a mixed solution of gallic acid chelated iron ions;
(9) Uniformly mixing the mixed solution obtained in the step (8) with the alginic acid aldehyde solution obtained in the step (5) by vortex to obtain hydrogel precursor liquid;
(10) Uniformly vortex-dispersing the carboxymethyl chitosan solution obtained in the step (6) and the hydrogel precursor liquid obtained in the step (9), and standing to obtain the carboxymethyl chitosan/alginic aldehyde/gallic acid-iron-based double-network crosslinked adhesion type hydrogel dressing.
3. The preparation method according to claim 2, characterized in that: in the step (1), the concentration of the sodium alginate solution is 2wt%, the dissolution temperature is 50 ℃, and the mole ratio of sodium alginate to sodium periodate is 1:1, the oxidation time in the dark is 6h.
4. The preparation method according to claim 2, characterized in that: in the step (2), the mass ratio of the added amount of the glycol to the sodium alginate is 1.5:1, terminating the reaction for 1h; in the step (3), the cellulose dialysis bag retention amount is 3500Da, the dialysis purification time is 3 days, and water is changed every 6 hours.
5. The preparation method according to claim 2, characterized in that: in the step (4), the temperature of the freeze dryer is-80 ℃ and the drying time is 72 hours.
6. The preparation method according to claim 2, characterized in that: the concentration of the alginic acid aldehyde solution prepared in the step (5) is 10wt%, and the pH value of the PBS buffer solution is 7.0-7.4; in the step (6), the mass to volume ratio of the carboxymethyl chitosan to the PBS buffer solution is 0.05g:1ml, constant temperature of 55 ℃ and magnetic stirring time of 2-4h.
7. The preparation method according to claim 2, characterized in that: the concentration of the gallic acid solution prepared in the step (7) is 1wt%, the concentration of the PBS buffer solution is 0.2mol/L, and the pH value is 8.5.
8. The preparation method according to claim 2, characterized in that: in the step (8), the mole ratio of ferric trichloride hexahydrate to gallic acid is 1:6,1:3 or 2:3.
9. the preparation method according to claim 2, characterized in that: in the hydrogel precursor liquid obtained in the step (9), the volume ratio of the mixed liquid of the gallic acid chelated iron ions to the alginic acid aldehyde solution is 3:5, a step of; in the step (10), the volume ratio of the hydrogel precursor solution to the carboxymethyl chitosan solution is 8:10, vortex time 15s.
10. A multifunctional dual-network crosslinked hydrogel wound dressing made by the method of any one of claims 1-9.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114181066A (en) * | 2021-11-12 | 2022-03-15 | 安徽理工大学 | Gallic acid analogue, and preparation method and application thereof |
| CN117159786A (en) * | 2023-08-30 | 2023-12-05 | 广州贝奥吉因生物科技股份有限公司 | Preparation method of chitosan hydrogel for regenerating wound healing |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114181066A (en) * | 2021-11-12 | 2022-03-15 | 安徽理工大学 | Gallic acid analogue, and preparation method and application thereof |
| CN117159786A (en) * | 2023-08-30 | 2023-12-05 | 广州贝奥吉因生物科技股份有限公司 | Preparation method of chitosan hydrogel for regenerating wound healing |
| CN117159786B (en) * | 2023-08-30 | 2024-03-26 | 广州贝奥吉因生物科技股份有限公司 | Preparation method of bioactive hydrogel for regenerating wound healing |
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