CN113499480A - Physical and chemical double-network hydrogel for subcutaneous filler and preparation method and application thereof - Google Patents
Physical and chemical double-network hydrogel for subcutaneous filler and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a physical and chemical double-network hydrogel for a subcutaneous filler, a preparation method and application thereof, wherein the preparation method comprises the following steps: firstly, furfurylation modification is carried out on hyaluronic acid, then freezing and unfreezing treatment is carried out on a modified hyaluronic acid solution added with a cross-linking agent, finally, hyaluronic acid double-network hydrogel which is chemically cross-linked and physically cross-linked is obtained, then, the hyaluronic acid double-network hydrogel is placed in a dialysis bag for dialysis until the pH value of the hyaluronic acid double-network hydrogel is neutral, and the obtained gel is finally used as a subcutaneous filling agent. Compared with the prior art, the hyaluronic acid double-network hydrogel prepared by the freeze-thaw physical crosslinking method and the click chemical covalent crosslinking method has good biocompatibility, mechanical property, hyaluronidase degradation resistance and long-acting subcutaneous filling and shaping effects, and can be used as a subcutaneous filler in the medical and beauty fields.
Description
Technical Field
The invention relates to the field of biomedical materials, in particular to a physical and chemical double-network hydrogel for a subcutaneous filler, and a preparation method and application thereof.
Background
Over the past decades, the need for minimally invasive surgery in cosmetic medicine has seen an exponential increase. Intracutaneous injection of fillers has become the most common method of replacing soft tissue filling plastic surgery. Fillers are injected into the skin to supplement the missing skin volume or to increase the existing skin volume. The filler is less invasive than the implant device and will immediately be effective, thus providing a more natural feel to the injected filler.
However, the greatest disadvantage of injecting bulking agents is that their effect is usually temporary. Ideally, therefore, the requirements of fillers in the field of cosmetic and medical shaping are mainly safety (i.e., biocompatibility, non-immunogenicity), efficacy (good tissue enhancement, long duration of effect, easy injection, and non-migration), and utility (cost-effective, easy to use and store).
Today the medical and cosmetic field contains many different kinds of subcutaneous fillers. Among them, a filler constructed by using Hyaluronic Acid (HA) as a base material is the best filler in the medical and cosmetic fields at present. According to the american society for cosmetic and plastic surgery, hyaluronic acid-based products are used in 85% of all subcutaneous filling procedures.
Hyaluronic acid is a linear polyanionic polysaccharide consisting of repeating units of D-glucuronic acid and N-acetylglucosamine disaccharide. Hyaluronic acid is considered to be the only mucopolysaccharide present almost in the whole animal body from bacteria to humans. The human extracellular matrix and the cell surface both contain a certain amount of hyaluronic acid. Hyaluronic acid is an ideal material for increasing skin volume, and has the advantages of high biocompatibility, non-immunogenicity, and the ability to bind large amounts of water. However, if hyaluronic acid is injected directly into dermal tissue, it is rapidly degraded by enzymatic and oxidative mechanisms (12-24 hours). In order to avoid the disadvantages of hyaluronic acid itself, the existing strategies are to increase the anti-degradation properties of hyaluronic acid and to increase its viscoelasticity by increasing the viscoelasticity of the polymer network by chemically cross-linking hyaluronic acid.
Hyaluronic acid fillers have great clinical and commercial value, and therefore since the approval of the first hyaluronic acid-based filler, many companies have introduced similar products. Hyaluronic acid hydrogels are mainly obtained by cross-linking hyaluronic acid with 1, 4-butanediol diglycidyl ether (BDDE), and are now the most commonly used subcutaneous fillers in facial rejuvenation. A variety of manufacturing techniques (i.e., vycoss, NASHA, CMP, etc.) have now been developed for the production of hyaluronic acid hydrogel fillers. Recently, as the understanding of the process of controlling facial aging has increased, the design of hyaluronic acid hydrogels is being upgraded to meet specific clinical needs. Thus, many companies now sell a range of recipes that may be based on the same technology, but adjusted to meet the specific needs of facial repair. Although the hyaluronic acid hydrogel filling agent is widely applied in the medical and aesthetic fields, the residual cross-linking agent of the chemical gel is easy to cause inflammatory reaction of skin.
Therefore, the search for hyaluronic acid hydrogel with high biocompatibility, high degradation resistance and long-acting subcutaneous filling effect as medical and aesthetic plastic filling agent is urgent, and the market prospect and commercial value are huge.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a physical and chemical double-network hydrogel for subcutaneous fillers, which has high biocompatibility, high degradation resistance and long-acting subcutaneous filling shaping effect, a preparation method and application thereof.
The purpose of the invention can be realized by the following technical scheme:
the invention aims to develop a novel hyaluronic acid hydrogel which has complete biocompatibility, degradation resistance and long-acting subcutaneous filling shaping effect as a novel subcutaneous filling agent. On the basis of utilizing a freezing and thawing method, a freezing and thawing technology and a click chemical covalent crosslinking technology are further utilized to prepare novel hyaluronic acid hydrogel as a subcutaneous filler, the gel has high biocompatibility and degradation resistance, and has a long-acting subcutaneous filling and shaping effect, and the specific scheme is as follows:
a preparation method of a physical and chemical double-network hydrogel for a subcutaneous filler comprises the following steps:
(1) dissolving hyaluronic acid in deionized water to form a clear and transparent hyaluronic acid solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the hyaluronic acid solution, stirring, adding furfuryl amine, reacting, dialyzing, and freeze-drying the solution to obtain furfuryl amine modified hyaluronic acid;
(2) dissolving furfuryl amine modified hyaluronic acid in deionized water to form a furfuryl amine modified hyaluronic acid solution, adjusting the pH of the solution to acidity, adding maleimide modified polyethylene glycol (MAL-PEG) serving as a cross-linking agent to the acidic mixed solution, subpackaging the obtained acidic mixed solution into containers, hermetically freezing, taking out the containers, thawing, and repeating the freezing and thawing times to form the physically and chemically double-crosslinked hyaluronic acid hydrogel.
Freezing the mixed acidic solution, then thawing at a certain temperature, and forming a physically cross-linked gel network by the furfurylated modified hyaluronic acid. In the thawing process, the furfuryl amine groups on the hyaluronic acid and the maleimide groups on the cross-linking agent undergo a D-A click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed.
Further, the hyaluronic acid is obtained by biological fermentation or extracted from animal tissues such as cockscomb and the like; the molecular weight of the hyaluronic acid is 5-2000kDa, and the mass concentration of the hyaluronic acid solution is 0.5-10%.
Further, the molar ratio of the furfuryl amine to the hyaluronic acid repeating units is (0.05-1): 1; the mass sum of the EDC and the NHS catalysts is 10-100% of the mass of the hyaluronic acid.
Further, the method for purifying the furfuryl amine modified hyaluronic acid is an alcohol precipitation method or a dialysis freeze-drying method.
Further, the mass concentration of the furfuryl amine modified hyaluronic acid solution is 1-10%, preferably 1-5%; the pH of the solution formed by the furfuryl amine modified hyaluronic acid is 0-5, preferably 1-3.
Further, the addition amount of the cross-linking agent maleimide polyethylene glycol (MAL-PEG) is 1-50% of the mass of the furfuryl amine modified hyaluronic acid, and preferably 5-20%.
Further, the freezing temperature of the acid mixed solution is-80 to-20 ℃, preferably-30 to-20 ℃, and the time is 12 to 168 hours, preferably 48 to 72 hours; the thawing temperature is 4-70 ℃, preferably 4-30 ℃, and the time is 1-20 hours, preferably 3-5 hours; the number of times of freezing and thawing is 1-10, preferably 2-4.
Furthermore, the thawing temperature is gradient temperature rise thawing, and the temperature rise rate is 0.1-10 ℃/min.
Further, the acidic mixed solution also comprises cosmetic active molecules, specifically comprising one or more of gamma-aminobutyric acid, glucose, succinic acid, N-acetyl-D-glucosamine, D-glucuronic acid, chondroitin sulfate A, chondroitin sulfate C or glucosamine.
A physical and chemical double-network hydrogel for subcutaneous fillers prepared by the method described above.
The application of the physical and chemical double-network hydrogel for the subcutaneous filler is used for preparing the subcutaneous filler, and the specific method comprises the following steps: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, dialyzing until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filler.
Further, the acid hyaluronic acid double-network hydrogel can be immersed in phosphate buffer solution and ionized water successively for dialysis, and the acid hyaluronic acid double-network hydrogel can also be washed by water or the phosphate buffer solution.
Compared with the prior art, the invention has the following advantages:
(1) the physical and chemical double-network hyaluronic acid gel prepared by the method has the characteristics of easy preparation and good tissue adhesion, and has better anti-degradation characteristic (about 12 months) compared with the commercialized subcutaneous filler (the effect is maintained for about 6 months), and the prepared hyaluronic acid double-network gel can prolong the action time of hyaluronic acid (the time is as long as more than 12 months);
(2) the hyaluronic acid gel is prepared by a freezing and thawing physical crosslinking method and a click chemistry method, and the crosslinking agent of the hyaluronic acid gel is maleimide polyethylene glycol (PEG), has good biocompatibility and long-acting subcutaneous filling and shaping effects, and can be used as a subcutaneous filling agent.
Drawings
FIG. 1 is a graph of storage modulus (G ') and loss modulus (G') versus strain sweep for hyaluronic acid double-network gels formed after dialysis in examples 1 and 3;
FIG. 2 is a plot of storage modulus (G ') and loss modulus (G') versus strain scan for the hyaluronic acid double-network gels formed after dialysis in examples 3-5;
FIG. 3 is a graph showing the biocompatibility of the hyaluronic acid double-network gel formed after dialysis in examples 3-5.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiments.
A preparation method of a physical and chemical double-network hydrogel for a subcutaneous filler comprises the following steps:
(1) dissolving hyaluronic acid in deionized water to form a clear and transparent hyaluronic acid solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the hyaluronic acid solution, stirring, adding furfuryl amine, reacting, dialyzing, and freeze-drying the solution to obtain furfuryl amine modified hyaluronic acid; wherein the hyaluronic acid is obtained by biological fermentation or extracted from animal tissues such as cockscomb; the molecular weight of the hyaluronic acid is 5-2000kDa, and the mass concentration of the hyaluronic acid solution is 0.5-10%. The molar ratio of the furfuryl amine to the hyaluronic acid repeating units is (0.05-1) to 1; the sum of the mass of the EDC and the mass of the NHS catalysts is 10-100% of the mass of the hyaluronic acid;
(2) dissolving furfuryl amine modified hyaluronic acid in deionized water to form a furfuryl amine modified hyaluronic acid solution, adjusting the pH of the solution to acidity, adding maleimide modified polyethylene glycol (MAL-PEG) serving as a cross-linking agent to the acidic mixed solution, subpackaging the obtained acidic mixed solution into containers, hermetically freezing, taking out the containers, thawing, and repeating the freezing and thawing times to form the physically and chemically double-crosslinked hyaluronic acid hydrogel.
Freezing the mixed acidic solution, then thawing at a certain temperature, and forming a physically cross-linked gel network by the furfurylated modified hyaluronic acid. In the thawing process, the furfuryl amine groups on the hyaluronic acid and the maleimide groups on the cross-linking agent undergo a D-A click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed.
Wherein, the mass concentration of the furfuryl amine modified hyaluronic acid solution is 1-10%, preferably 1-5%; the pH of the solution formed by the furfuryl amine modified hyaluronic acid is 0-5, preferably 1-3. The addition amount of the cross-linking agent maleimide polyethylene glycol (MAL-PEG) is 1-50%, preferably 5-20% of the mass of the furfuryl amine modified hyaluronic acid. The freezing temperature of the acid mixed solution is-80 to-20 ℃, preferably-30 to-20 ℃, and the time is 12 to 168 hours, preferably 48 to 72 hours; the thawing temperature is 4-70 ℃, preferably 4-30 ℃, and the time is 1-20 hours, preferably 3-5 hours; the number of times of freezing and thawing is 1-10, preferably 2-4. The thawing temperature is gradient heating thawing with a heating rate of 0.1-10 deg.C/min.
The acidic mixed solution may further comprise cosmetic active molecules, specifically including one or more of gamma-aminobutyric acid, glucose, succinic acid, N-acetyl-D-glucosamine, D-glucuronic acid, chondroitin sulfate A, chondroitin sulfate C or glucosamine.
Then, the double-network hydrogel can be applied to the preparation of subcutaneous fillers, and the specific method comprises the following steps: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, dialyzing until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filler.
Example 1
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.0g) and N-hydroxysuccinimide (NHS, 0.5g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (0.5g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 1.5), and then maleimide-modified polyethylene glycol (MAL-PEG, 0.5g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 72 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 1 time;
and step 3: the mixed acidic solution is frozen and then thawed at 4 ℃, and the furfurylated modified hyaluronic acid forms a physically cross-linked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent. The gel has effect as subcutaneous filler for 12 months.
Example 2
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 2.0g) and N-hydroxysuccinimide (NHS, 1.0g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (1.0g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 1.5), and then maleimide-modified polyethylene glycol (MAL-PEG, 1.0g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 72 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 1 time;
and step 3: the mixed acidic solution is frozen and then thawed at 4 ℃, and the furfurylated modified hyaluronic acid forms a physically cross-linked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent. The gel has an effect as a subcutaneous filler for up to 13 months.
Example 3
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 4.0g) and N-hydroxysuccinimide (NHS, 2.0g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (2.0g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 1.5), and then maleimide-modified polyethylene glycol (MAL-PEG, 2.0g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 72 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 1 time;
and step 3: the mixed acidic solution is frozen and then thawed at 4 ℃, and the furfurylated modified hyaluronic acid forms a physically cross-linked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent. The gel has long-term effect as subcutaneous filler for 15 months.
As can be seen from examples 1-3, as shown in FIG. 1, as the addition amount of furfuryl amine is increased, the crosslinking degree of the gel is improved, so that the mechanical property is improved, the action effect is prolonged, and the application potential of the gel can be further widened.
Example 4
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.0g) and N-hydroxysuccinimide (NHS, 0.5g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (0.5g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 1.5), and then maleimide-modified polyethylene glycol (MAL-PEG, 0.5g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 72 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 2 times;
and step 3: the mixed acidic solution is frozen and then thawed at 4 ℃, and the furfurylated modified hyaluronic acid forms a physically cross-linked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent. The gel has an effect as a subcutaneous filler for up to 13 months.
Example 5
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.0g) and N-hydroxysuccinimide (NHS, 0.5g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (0.5g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 1.5), and then maleimide-modified polyethylene glycol (MAL-PEG, 0.5g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 72 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 3 times;
and step 3: the mixed acidic solution is frozen and then thawed at 4 ℃, and the furfurylated modified hyaluronic acid forms a physically cross-linked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent. The gel has 14 months of effect as subcutaneous filler.
From examples 1,4 and 5, as shown in fig. 1-2, the application potential of the gel can be further widened as the repeated thawing times are increased, the mechanical property is improved, and the action effect is prolonged.
This is because the degradation time of the hyaluronic acid double-network gel is gradually prolonged as the number of times of freeze-thawing increases. Mainly because hydrogen bonds are formed in the hyaluronic acid network in the freezing and thawing process, the more the freezing and thawing times are, the more the hydrogen bonds are formed in the hyaluronic acid network, and the degradation resistance of the hyaluronic acid double-network gel is enhanced.
As shown in fig. 3, it can be seen that the gel has excellent biocompatibility, and the cells proliferate as the incubation time increases, as can be seen from the gradual increase of the optical density value, and the biocompatibility is not affected by the increase of the number of repeated freeze thawing.
Example 6
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.0g) and N-hydroxysuccinimide (NHS, 0.5g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (0.5g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 1.5), and then maleimide-modified polyethylene glycol (MAL-PEG, 0.5g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 72 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 3 times;
and step 3: the mixed acidic solution is frozen and then thawed at the temperature of 20 ℃, and the furfurylated modified hyaluronic acid forms a physically cross-linked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent. The gel has an effect as a subcutaneous filler for up to 13 months.
Example 7
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.0g) and N-hydroxysuccinimide (NHS, 0.5g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (0.5g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 1.5), and then maleimide-modified polyethylene glycol (MAL-PEG, 0.5g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 72 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 3 times;
and step 3: freezing the mixed acidic solution, gradually heating and thawing at 4-70 deg.C, and allowing furfurylated modified hyaluronic acid to form physically crosslinked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent.
Example 8
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.0g) and N-hydroxysuccinimide (NHS, 0.5g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (0.5g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 2.0), and then maleimide-modified polyethylene glycol (MAL-PEG, 0.5g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 72 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 3 times;
and step 3: the mixed acidic solution is frozen and then thawed at the temperature of 20 ℃, and the furfurylated modified hyaluronic acid forms a physically cross-linked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent. The gel has effect as subcutaneous filler for 12 months.
Example 9
Step 1: firstly, dissolving hyaluronic acid (5g) in deionized water (500mL) to form a clear and transparent hyaluronic acid solution, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.0g) and N-hydroxysuccinimide (NHS, 0.5g) into the hyaluronic acid solution and stirring for a certain time, then adding furfuryl amine (0.5g) and reacting for 24 hours, dialyzing the solution and freeze-drying to obtain furfuryl amine modified hyaluronic acid;
step 2: the furfuryl amine-modified hyaluronic acid obtained in step 1 was dissolved in deionized water to form a furfuryl amine-modified hyaluronic acid solution (1%), followed by adjusting the pH of the solution to acidity (pH 1.5), and then maleimide-modified polyethylene glycol (MAL-PEG, 0.5g) was added as a crosslinking agent to the above acidic mixed solution. Subpackaging the obtained acidic mixed solution into containers, sealing and freezing for 96 hours, taking out the containers, thawing for 10 hours, and repeatedly freezing and thawing for 3 times;
and step 3: the mixed acidic solution is frozen and then thawed at the temperature of 20 ℃, and the furfurylated modified hyaluronic acid forms a physically cross-linked gel network. In the thawing process, the furfuryl amine group on the hyaluronic acid and the maleimide group on the cross-linking agent are subjected to click chemical reaction to form a chemically cross-linked hyaluronic acid gel network, and finally, the physically and chemically double-cross-linked hyaluronic acid hydrogel is formed;
and 4, step 4: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, sequentially immersing the hyaluronic acid hydrogel into buffer solution and ionized water for dialysis for 72 hours until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filling agent. The gel has effect as subcutaneous filler for 12 months.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (10)
1. A preparation method of a physical and chemical double-network hydrogel for a subcutaneous filler is characterized by comprising the following steps:
(1) dissolving hyaluronic acid in deionized water to form a clear and transparent hyaluronic acid solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the hyaluronic acid solution, stirring, adding furfuryl amine, reacting, dialyzing, and freeze-drying the solution to obtain furfuryl amine modified hyaluronic acid;
(2) dissolving furfuryl amine modified hyaluronic acid in deionized water to form a furfuryl amine modified hyaluronic acid solution, adjusting the pH of the solution to acidity, adding maleimide modified polyethylene glycol (MAL-PEG) serving as a cross-linking agent to the acidic mixed solution, subpackaging the obtained acidic mixed solution into containers, hermetically freezing, taking out the containers, thawing, and repeating the freezing and thawing times to form the physically and chemically double-crosslinked hyaluronic acid hydrogel.
2. The method for preparing the physical and chemical double-network hydrogel for the subcutaneous filler according to claim 1, wherein the hyaluronic acid is obtained by biological fermentation or is extracted from animal tissues such as cockscomb; the molecular weight of the hyaluronic acid is 5-2000kDa, and the mass concentration of the hyaluronic acid solution is 0.5-10%.
3. The method for preparing a physical and chemical double-network hydrogel for a subcutaneous filler according to claim 1, wherein the molar ratio between the furfuryl amine and the hyaluronic acid repeating units is (0.05-1): 1; the mass sum of the EDC and the NHS catalysts is 10-100% of the mass of the hyaluronic acid.
4. The method for preparing the physical and chemical double-network hydrogel for the subcutaneous filler according to claim 1, wherein the mass concentration of the furfuryl amine modified hyaluronic acid solution is 1-10%; the pH value of the solution formed by the furfuryl amine modified hyaluronic acid is 0-5.
5. The method for preparing a physical and chemical double-network hydrogel for a subcutaneous filler according to claim 1, wherein the cross-linking agent maleimide polyethylene glycol (MAL-PEG) is added in an amount of 1-50% by mass of the furfuryl amine-modified hyaluronic acid.
6. The preparation method of the physical and chemical double-network hydrogel for the subcutaneous filling agent, according to claim 1, is characterized in that the freezing temperature of the acidic mixed solution is-80 to-20 ℃, and the time is 12-168 hours; the thawing temperature is 4-70 ℃, and the time is 1-20 h; the number of times of freezing and thawing is 1-10.
7. The method for preparing the physical and chemical double-network hydrogel for the subcutaneous filler according to claim 6, wherein the thawing temperature is gradient temperature-rising thawing, and the temperature-rising rate is 0.1-10 ℃/min.
8. The method for preparing a physical and chemical double-network hydrogel for subcutaneous fillers according to claim 1, wherein the acidic mixed solution further comprises a cosmetic active molecule, specifically comprising one or more of γ -aminobutyric acid, glucose, succinic acid, N-acetyl-D-glucosamine, D-glucuronic acid, chondroitin sulfate a, chondroitin sulfate C, or glucosamine.
9. A physical and chemical double-network hydrogel for a subcutaneous filler prepared by the method of any one of claims 1 to 8.
10. The use of a physical and chemical double-network hydrogel for a subcutaneous filler according to claim 9, wherein the double-network hydrogel is used for preparing the subcutaneous filler by the following specific method: and (3) placing the physically and chemically double-crosslinked hyaluronic acid hydrogel into a dialysis bag, dialyzing until the pH of the hyaluronic acid double-network hydrogel is neutral, and taking out the hyaluronic acid gel from the dialysis bag to be finally used as a subcutaneous filler.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115068671A (en) * | 2022-06-20 | 2022-09-20 | 常州华联医疗器械集团股份有限公司 | Preparation method of sodium alginate hydrogel dressing |
| CN115463622A (en) * | 2022-08-03 | 2022-12-13 | 广东纤友朵美生物科技有限公司 | Gel based on oxidized pectin and preparation method thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102772823A (en) * | 2012-07-25 | 2012-11-14 | 华南理工大学 | Preparation method of hyaluronic acid/gelatin/chondroitin sulfate bone repair bionic scaffold |
| CN102784414A (en) * | 2012-08-02 | 2012-11-21 | 东华大学 | Preparation method of injectable double-cross-linked hydrogel for tissue engineering |
| CN103611184A (en) * | 2013-11-27 | 2014-03-05 | 长春吉原生物科技有限公司 | Hydrogel of composite semipermeable membrane and preparation method thereof |
| CN110038161A (en) * | 2019-04-29 | 2019-07-23 | 上海交通大学 | A kind of novel transparent matter acid flow-gel and its preparation method and application |
| US20200262939A1 (en) * | 2017-11-15 | 2020-08-20 | Zhongshan Guanghe Medical Technology Co., Ltd. | Photo-coupled synergistically crosslinked hydrogel material and its composition, preparation method, use, product, and preparation kit |
| US20210015967A1 (en) * | 2018-03-23 | 2021-01-21 | Kaohsiung Medical University | Method for preparing hyaluronic acid hydrogel microparticles and use thereof in repairing articular cartilage defects |
| CN112920425A (en) * | 2021-01-22 | 2021-06-08 | 华东数字医学工程研究院 | Medical hydrogel composition, medical hydrogel and preparation method thereof |
-
2021
- 2021-07-13 CN CN202110787657.7A patent/CN113499480A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102772823A (en) * | 2012-07-25 | 2012-11-14 | 华南理工大学 | Preparation method of hyaluronic acid/gelatin/chondroitin sulfate bone repair bionic scaffold |
| CN102784414A (en) * | 2012-08-02 | 2012-11-21 | 东华大学 | Preparation method of injectable double-cross-linked hydrogel for tissue engineering |
| CN103611184A (en) * | 2013-11-27 | 2014-03-05 | 长春吉原生物科技有限公司 | Hydrogel of composite semipermeable membrane and preparation method thereof |
| US20200262939A1 (en) * | 2017-11-15 | 2020-08-20 | Zhongshan Guanghe Medical Technology Co., Ltd. | Photo-coupled synergistically crosslinked hydrogel material and its composition, preparation method, use, product, and preparation kit |
| US20210015967A1 (en) * | 2018-03-23 | 2021-01-21 | Kaohsiung Medical University | Method for preparing hyaluronic acid hydrogel microparticles and use thereof in repairing articular cartilage defects |
| CN110038161A (en) * | 2019-04-29 | 2019-07-23 | 上海交通大学 | A kind of novel transparent matter acid flow-gel and its preparation method and application |
| CN112920425A (en) * | 2021-01-22 | 2021-06-08 | 华东数字医学工程研究院 | Medical hydrogel composition, medical hydrogel and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115068671A (en) * | 2022-06-20 | 2022-09-20 | 常州华联医疗器械集团股份有限公司 | Preparation method of sodium alginate hydrogel dressing |
| CN115463622A (en) * | 2022-08-03 | 2022-12-13 | 广东纤友朵美生物科技有限公司 | Gel based on oxidized pectin and preparation method thereof |
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