Face filling composite hydrogel and preparation method thereof
By introducing nanocellulose into sodium carboxymethyl cellulose hydrogel to construct a dense cross-linked network, the problems of insufficient mechanical support and high cost of facial filler materials are solved, achieving efficient and economical facial filling results.
Patent Information
- Application Number
- CN202511435287.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-09
- Publication Date
- 2025-12-12
AI Technical Summary
Existing facial filler materials suffer from insufficient mechanical support and high manufacturing costs. In particular, polycaprolactone microspheres are expensive to manufacture and require large amounts, resulting in high product prices and limiting their widespread use in the mass beauty market.
Introducing nanocellulose into the sodium carboxymethyl cellulose hydrogel system creates a dense physical cross-linked network that partially replaces microspheres, reducing the amount of microspheres used and enhancing the mechanical properties of the hydrogel.
It significantly improves the mechanical properties and degradation stability of hydrogels, reduces preparation costs, and maintains good biocompatibility and filling effect, making it suitable for long-term filling of facial soft tissues.
Smart Images
Figure CN121102576A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of biomedical materials, and particularly relates to a facial filling composite hydrogel and a preparation method thereof. BACKGROUND
[0002] At present, the facial filling materials commonly used in clinical practice mainly include hyaluronic acid and collagen, which are single-component biomaterials. Although these materials have good biocompatibility and certain filling effect, they generally have problems such as fast degradation rate and insufficient mechanical support. Therefore, it is necessary to supplement injection multiple times to maintain the desired filling effect, which affects the patient experience. Therefore, how to improve the durability and mechanical properties of facial filling materials has become the focus of current research.
[0003] In recent years, microsphere-based composite facial filling materials composed of microspheres and hydrogel carriers have gradually emerged. Unlike the physical filling mechanism of traditional single-component materials, the gel matrix can achieve immediate plasticity and physical filling after injection, and the microspheres can be retained in the body for a long time to stimulate the adhesion, proliferation and collagen production of fibroblasts, thereby realizing the synergistic effect of "immediate filling + long-term support" and significantly improving patient satisfaction.
[0004] At present, there are such products on the market, such as soft tissue fillers composed of polycaprolactone (PCL) microspheres and carboxymethyl cellulose (CMC) hydrogel matrix which exhibit superior performance in clinical applications and have attracted widespread attention in the field of plastic and cosmetic surgery. However, the preparation cost of polycaprolactone microspheres is high and the addition amount is large (content of 30wt%), which leads to a high current market price of the product (the cost of a single injection can be as high as tens of thousands of yuan), limiting its popularization in the mass beauty market.
[0005] In order to reduce the cost and improve the material performance, it is urgent to develop alternative new functional components. As a natural polysaccharide material with abundant sources and good biocompatibility, nanocellulose (CNF) has a unique nanostructure and high aspect ratio, which can form a stable entanglement network inside the hydrogel, enhance physical crosslinking, effectively improve mechanical strength and delay degradation. In addition, nanocellulose can promote cell adhesion, growth and collagen production, which helps to improve the tissue integration of the filling site. In summary, in facial filling materials, nanocellulose has similar biological activity functions as microspheres, so it is considered to introduce nanocellulose to partially replace microspheres, which not only meets the filling effect, but also reduces the amount of microspheres, thereby effectively reducing the production cost.
[0006] In view of the above background, the present application provides a facial filling composite hydrogel. By introducing nanocellulose into the sodium carboxymethyl cellulose hydrogel system, a dense physical crosslinking network is constructed, which significantly improves the mechanical properties of the hydrogel while reducing the use amount of microspheres and effectively reducing the preparation cost, further optimizes the facial filling effect, and has good clinical transformation and market application prospect. SUMMARY
[0007] The present application aims to provide a facial filling composite hydrogel and a preparation method thereof to solve the problems of insufficient mechanical support and high preparation cost of the facial filling hydrogel in the prior art.
[0008] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions to achieve the above-mentioned purpose:
[0009] One aspect of the present application provides a facial filling composite hydrogel, comprising a gel matrix and microspheres uniformly dispersed in the gel matrix; the gel matrix is composed of sodium carboxymethyl cellulose and nanocellulose; the microspheres are polycaprolactone microspheres, or poly(lactic acid) (PLA) microspheres, or poly(lactic acid-co-glycolic acid) (PLGA) microspheres, or hydroxyapatite (HAP) microspheres; wherein the sodium carboxymethyl cellulose and nanocellulose have a specific mass ratio.
[0010] Another aspect of the present application provides a preparation method of a facial filling composite hydrogel, comprising the following steps:
[0011] (1) gradually adding a nanocellulose dispersion liquid to a sodium carboxymethyl cellulose aqueous solution, stirring uniformly under heating conditions to obtain a gel matrix;
[0012] (2) uniformly dispersing polycaprolactone microspheres, or poly(lactic acid) microspheres, or poly(lactic acid-co-glycolic acid) microspheres, or hydroxyapatite microspheres in the gel matrix obtained in step (1), and cooling and standing to gel to obtain the composite hydrogel.
[0013] The preparation method of the facial filling composite hydrogel, wherein the organic solvent is one of dichloromethane (DCM), chloroform (CF), ethyl acetate (EAC), and acetone (AC).
[0014] The preparation method of the facial filling composite hydrogel, wherein the aqueous phase is a solution containing an emulsifier, wherein the emulsifier is one of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and polysorbate (Tween 80), and the solvent is one of deionized water and phosphate buffered saline (PBS).
[0015] The preparation method of the facial filling composite hydrogel, wherein the oil phase and water phase mixing emulsification method is one of mechanical stirring emulsification method, microfluidic emulsification method and membrane emulsification method.
[0016] The preparation method of the facial filling composite hydrogel, wherein the concentration of the nanocellulose dispersion solution is 1wt%-5wt%.
[0017] The preparation method of the facial filling composite hydrogel, wherein the concentration of the sodium carboxymethyl cellulose solution is 1wt%-10wt%.
[0018] The preparation method of the facial filling composite hydrogel, wherein the mass ratio of the nanocellulose and sodium carboxymethyl cellulose is 2:1-1:10.
[0019] The preparation method of the facial filling composite hydrogel, wherein the heating temperature of the heating stirring process is 50-80 DEG C, and the stirring speed is 300-1000 rpm.
[0020] The preparation method of the facial filling composite hydrogel, wherein the content of the microspheres is 1wt%-25wt%.
[0021] Compared with the prior art, the present application has the following beneficial effects:
[0022] The present application discloses a kind of facial filling composite hydrogel and preparation method thereof, for the insufficient mechanical support of existing facial filling material and the problems such as high preparation cost. By introducing nanocellulose in sodium carboxymethyl cellulose hydrogel system to construct dense physical crosslinking network, not only the mechanical properties of hydrogel are significantly enhanced, but also microspheres can be partially replaced, to reduce its usage amount, to effectively reduce the preparation cost. The material obtained by the present application has excellent biocompatibility and filling durability, is suitable for the filling repair of facial soft tissue, has good application value and industrialization prospect. BRIEF DESCRIPTION OF DRAWINGS
[0023] Figure 1 The scanning electron microscope graph of the hydrogel prepared for example 1;
[0024] Figure 2 The actual object graph of the hydrogel prepared for example 1;
[0025] Figure 3 The rheological property graph of the hydrogel prepared for example 1, comparative example 1 and comparative example 2;
[0026] Figure 4 The biocompatibility results of the hydrogel prepared for example 1;
[0027] Figure 5Test results of the hydrogels prepared for Example 1, Comparative Example 1 and Comparative Example 2 on the rat dorsal filling model. DETAILED DESCRIPTION
[0028] The examples given below serve to illustrate the application without limiting it, the scope of the application being defined by the claims.
[0029] Example 1:
[0030] The present embodiment provides a preparation method of a facial filling composite hydrogel, comprising the following steps:
[0031] (1) CMC powder was dissolved in water, heated and stirred at 70°C and 800 rpm to prepare a CMC solution (5wt%); then 2wt% CNF dispersion was slowly added at a CNF: CMC mass ratio of 1:3, and heated and stirred until uniform to obtain a gel matrix;
[0032] (2) 0.5g PCL was dissolved in 10mL DCM as an oil phase, and 100mL PBS containing 2wt% PVA was used as an aqueous phase, which were injected into a microfluidic chip, respectively, and an emulsion was formed by controlling the flow rate (0.25mL / h for the oil phase and 5mL / h for the aqueous phase) using a syringe pump, and then PCL microspheres were obtained after solidification, washing and freeze-drying. Then the PCL microspheres were uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 20wt%, and the composite hydrogel was obtained after cooling and gelation.
[0033] Example 2:
[0034] The present embodiment provides a preparation method of a facial filling composite hydrogel, comprising the following steps:
[0035] (1) CMC powder was dissolved in water, heated and stirred at 80°C and 300 rpm to prepare a CMC solution (10wt%); then 1wt% CNF dispersion was slowly added at a CNF: CMC mass ratio of 1:10, and heated and stirred until uniform to obtain a gel matrix;
[0036] (2) 0.5g PLA was dissolved in 10mL CF as an oil phase, which was added dropwise into 100mL PBS containing 2wt% PVP, and an emulsion was formed by mechanical stirring (3000rpm, 3min), and then the organic solvent was volatilized by continuing stirring (300rpm, 3h) to achieve solidification. After repeated washing with water, PLA microspheres were obtained by freeze-drying. Then the PLA microspheres were uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 1wt%, and the composite hydrogel was obtained after cooling and gelation.
[0037] Example 3:
[0038] The embodiment provides a preparation method of a facial filling composite hydrogel, and comprises the following steps:
[0039] (1) CMC powder is dissolved in water, and a CMC solution (1wt%) is prepared by heating and stirring under the condition of 50 DEG C and 1000 rpm. Then, 5wt% CNF dispersion liquid is slowly added in the mass ratio of CNF to CMC 1:1, and uniform heating and stirring are continued to obtain a gel matrix;
[0040] (2) 0.5g PLGA is dissolved in 10mL EAC as an oil phase, and then the oil phase is extruded through a hydrophobic membrane under a constant pressure condition and dropped into 100mL water containing 2wt% Tween 80 to be emulsified by stirring. Volatile organic solvent is used for solidification, and after repeated washing with water, PLGA microspheres are obtained by freeze-drying. Then, the PLGA microspheres are uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 25wt%, and the composite hydrogel is obtained by cooling and standing to gel.
[0041] Example 4:
[0042] The embodiment provides a preparation method of a facial filling composite hydrogel, and comprises the following steps:
[0043] (1) CMC powder is dissolved in water, and a CMC solution (1wt%) is prepared by heating and stirring under the condition of 50 DEG C and 1000 rpm. Then, 5wt% CNF dispersion liquid is slowly added in the mass ratio of CNF to CMC 1:1, and uniform heating and stirring are continued to obtain a gel matrix;
[0044] (2) 0.75g HAP is dissolved in 10mL AC as an oil phase, and 100mL water solution containing 2wt% PVA is used as an aqueous phase, which are respectively injected into a microfluidic chip to form an emulsion by controlling the flow rate (0.5mL / h for the oil phase and 10mL / h for the aqueous phase) through an injection pump. After solidification, washing and freeze-drying treatment, HAP microspheres are obtained. Then, the HAP microspheres are uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 15wt%, and the composite hydrogel is obtained by cooling and standing to gel.
[0045] Example 5:
[0046] The embodiment provides a preparation method of a facial filling composite hydrogel, and comprises the following steps:
[0047] (1) CMC powder is dissolved in water, and a CMC solution (1wt%) is prepared by heating and stirring under the condition of 50 DEG C and 1000 rpm. Then, 5wt% CNF dispersion liquid is slowly added in the mass ratio of CNF to CMC 1:1, and uniform heating and stirring are continued to obtain a gel matrix;
[0048] (2) 0.75 g PCL was dissolved in 10 mL EAC as oil phase, which was added dropwise into 100 mL PBS containing 2 wt% PVP, and emulsified by mechanical stirring (4000 rpm, 5 min) to form an emulsion, and then the stirring (200 rpm, 4 h) was continued to volatilize the organic solvent to achieve solidification. After repeated washing with water and freeze-drying, PCL microspheres were obtained. Then the PCL microspheres were uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 12 wt%, and the gelation was achieved by cooling and standing to obtain a composite hydrogel.
[0049] Example 6:
[0050] The present example provides a preparation method of a facial filling composite hydrogel, comprising the following steps:
[0051] (1) CMC powder was dissolved in water, and a CMC solution (6 wt%) was prepared by heating and stirring at 60°C and 700 rpm. Then 2 wt% CNF dispersion was slowly added at a CNF to CMC mass ratio of 1:5, and uniform heating and stirring were continued to obtain a gel matrix;
[0052] (2) 0.6 g PLA was dissolved in 10 mL CF as oil phase, which was then extruded through a hydrophobic membrane under constant pressure and dropped into 100 mL water containing 1 wt% Tween 80 to form an emulsion by stirring. The organic solvent was volatilized to achieve solidification. After repeated washing with water and freeze-drying, PLA microspheres were obtained. Then the PLA microspheres were uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 10 wt%, and the gelation was achieved by cooling and standing to obtain a composite hydrogel.
[0053] Example 7:
[0054] The present example provides a preparation method of a facial filling composite hydrogel, comprising the following steps:
[0055] (1) CMC powder was dissolved in water, and a CMC solution (4.5 wt%) was prepared by heating and stirring at 80°C and 500 rpm. Then 1.5 wt% CNF dispersion was slowly added at a CNF to CMC mass ratio of 1:6, and uniform heating and stirring were continued to obtain a gel matrix;
[0056] (2) 0.4 g PLGA was dissolved in 10 mL DCM as oil phase, and 100 mL aqueous solution containing 2.5 wt% PVA was used as water phase, which were injected into a microfluidic chip respectively, and an emulsion was formed by controlling the flow rate of the oil phase (0.25 mL / h) and the water phase (10 mL / h) through a syringe pump. After solidification, washing and freeze-drying, PLGA microspheres were obtained. Then the PLGA microspheres were uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 8 wt%, and the gelation was achieved by cooling and standing to obtain a composite hydrogel.
[0057] Example 8:
[0058] The embodiment provides a preparation method of a facial filling composite hydrogel, and comprises the following steps:
[0059] (1) CMC powder is dissolved in water, and a CMC solution (2wt%) is prepared by heating and stirring at 60°C and 600rpm. Then, 2.5wt% CNF dispersion liquid is slowly added in a CNF-to-CMC mass ratio of 1:1, and uniform heating and stirring are continued to obtain a gel matrix;
[0060] (2) 0.5g HAP is dissolved in 10mL EAC as an oil phase, and the oil phase is added dropwise into 100mL PBS containing 2wt% Tween 80, and emulsified by mechanical stirring (5000rpm, 10min) to form an emulsion, and stirring (250rpm, 3h) is continued to volatilize organic solvents to achieve solidification, and the HAP microspheres are obtained after repeated washing with water and freeze-drying, and then the HAP microspheres are uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 12.5wt%, and the gel is cooled and placed to gelate, to obtain the composite hydrogel.
[0061] Example 9:
[0062] The embodiment provides a preparation method of a facial filling composite hydrogel, and comprises the following steps:
[0063] (1) CMC powder is dissolved in water, and a CMC solution (4wt%) is prepared by heating and stirring at 70°C and 1000rpm. Then, 5wt% CNF dispersion liquid is slowly added in a CNF-to-CMC mass ratio of 1:6, and uniform heating and stirring are continued to obtain a gel matrix;
[0064] (2) 0.5g PCL is dissolved in 10mL DCM as an oil phase, and 100mL aqueous solution containing 3wt% PVA is used as an aqueous phase, and the oil phase and the aqueous phase are respectively injected into a microfluidic chip, and an emulsion is formed by controlling the flow rate (0.35mL / h for the oil phase and 14mL / h for the aqueous phase) of an injection pump, and PCL microspheres are obtained after solidification, washing and freeze-drying treatment, and then the PCL microspheres are uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 2wt%, and the gel is cooled and placed to gelate, to obtain the composite hydrogel.
[0065] Example 10:
[0066] The embodiment provides a preparation method of a facial filling composite hydrogel, and comprises the following steps:
[0067] (1) CMC powder was dissolved in water, heated and stirred at 80℃, 300 rpm to prepare a CMC solution (2wt%); then 1wt% CNF dispersion was slowly added according to a CNF to CMC mass ratio of 1:1, and heated and stirred until uniform to obtain a gel matrix;
[0068] (2) 0.75g PCL was dissolved in 10mL DCM as an oil phase, and 100mL aqueous solution containing 2wt% PVA as an aqueous phase, which were respectively injected into a microfluidic chip, and an emulsion was formed by controlling the flow rate (0.4mL / h for the oil phase and 8mL / h for the aqueous phase) through a syringe pump, and PCL microspheres were obtained after solidification, washing and freeze-drying treatment, then the PCL microspheres were uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 22wt%, and the composite hydrogel was obtained after cooling and gelling.
[0069] Comparative Example 1:
[0070] The embodiment provides a preparation method of a facial filling composite hydrogel, comprising the following steps:
[0071] (1) CMC powder was dissolved in water, heated and stirred at 70℃, 800 rpm to prepare a CMC solution (5wt%), and a gel matrix was obtained;
[0072] (2) 0.5g PCL was dissolved in 10mL DCM as an oil phase, and 100mL PBS containing 2wt% PVA as an aqueous phase, which were respectively injected into a microfluidic chip, and an emulsion was formed by controlling the flow rate (0.25mL / h for the oil phase and 5mL / h for the aqueous phase) through a syringe pump, and PCL microspheres were obtained after solidification, washing and freeze-drying treatment, then the PCL microspheres were uniformly dispersed in the gel matrix obtained in step (1) at a mass fraction of 30wt%, and the composite hydrogel was obtained after cooling and gelling.
[0073] Comparative Example 2:
[0074] The embodiment provides a preparation method of a facial filling composite hydrogel, comprising the following steps:
[0075] CMC powder was dissolved in water, heated and stirred at 70℃, 800 rpm to prepare a CMC solution (5wt%). Then 2wt% CNF dispersion was slowly added according to a CNF to CMC mass ratio of 1:3, and heated and stirred until uniform to obtain a gel matrix, and the composite hydrogel was obtained after cooling and gelling.
[0076] Application Example 1:
[0077] Rheological property test: The hydrogels prepared by Example 1, Comparative Example 1 and Comparative Example 2 were placed on the rheometer platform, and the 25mm parallel plate measurement mode was used to scan at 25℃. The frequency scanning was carried out at a fixed strain (0.1-100 rad / s), and the relationship between the storage modulus (G') and the loss modulus (G") with the frequency was recorded to evaluate the structural stability and mechanical properties of the hydrogel.
[0078] The test results are shown in Figure 3 The viscoelastic properties of the hydrogels of different components were tested by the rheometer, and the results showed that the storage modulus (G') of all samples was always greater than the loss modulus (G") in the test frequency range, indicating that the hydrogel system had an elastic dominant physical property. In addition, by comparing the size of the storage modulus and the loss modulus among different samples, the composite hydrogel of Example 1 showed the highest modulus, indicating that its internal network structure was the most compact, had higher mechanical strength and structural stability, and could more firmly support the tissue in facial filling application, helping to maintain the shaping effect after injection.
[0079] Application Example 2:
[0080] Biocompatibility test: The hydrogel prepared by Example 1 was incubated with DMEM culture medium for 24h to obtain a hydrogel extract. L929 fibroblasts were inoculated in a 96-well plate and the hydrogel extract was added for further culture. Then CCK-8 reagent was added for incubation, and the absorbance was measured at 450nm wavelength using a microplate reader to calculate the cell survival rate.
[0081] The test results are shown in Figure 4 The cell survival rate after treatment with the hydrogel extract for different times was higher than 90%, indicating that the composite hydrogel of Example 1 had no obvious cytotoxicity and good biocompatibility, and was suitable for facial filling application.
[0082] Application Example 3:
[0083] Rat subcutaneous implantation experiment: Healthy SD rats were selected, and the hydrogels prepared by Example 1, Comparative Example 1 and Comparative Example 2 were injected subcutaneously on the back under anesthesia. The rats were sacrificed at 8 weeks, and the skin tissue of the injection area was taken for H&E staining to observe the histological changes, and to evaluate the biocompatibility, collagen generation, etc.
[0084] The test results are shown in Figure 5 The H&E staining results showed that the three hydrogels all showed good biocompatibility after implantation, and no obvious inflammatory reaction or granulation tissue formation was observed. Further analysis found that the dermal thickness of the composite hydrogel of Example 1 was the highest at 8 weeks, indicating that it had better filling durability.
Claims
1. A facial filler composite hydrogel, characterized in that, The invention comprises a gel matrix and microspheres uniformly dispersed in the gel matrix; the gel matrix is composed of sodium carboxymethyl cellulose and nanocellulose; the microspheres are polycaprolactone microspheres, polylactic acid microspheres, poly(lactic-glycolic acid) copolymer microspheres, or hydroxyapatite microspheres; wherein the sodium carboxymethyl cellulose and nanocellulose have a specific mass ratio.
2. A method for preparing the facial filling composite hydrogel as described in claim 1, characterized in that, Includes the following steps: (1) The nanocellulose dispersion was gradually added to the sodium carboxymethyl cellulose aqueous solution and stirred evenly under heating conditions to obtain a gel matrix; (2) Polycaprolactone microspheres, or polylactic acid microspheres, or poly(lactic acid-hydroxyacetic acid) copolymer microspheres, or hydroxyapatite microspheres are uniformly dispersed in the gel matrix obtained in step (1), and cooled and allowed to stand to gel, so as to obtain the composite hydrogel.
3. The method according to claim 2, characterized in that, The oil-water phase mixing and emulsification method is mechanical stirring emulsification, microfluidic emulsification, or membrane emulsification.
4. The facial filling composite hydrogel according to claim 1, characterized in that, The microspheres in the composite hydrogel contain 1 wt% to 25 wt%.
5. The facial filling composite hydrogel according to claim 1, characterized in that, The concentration of sodium carboxymethyl cellulose in the aqueous solution is 1 wt% to 10 wt%.
6. The facial filling composite hydrogel according to claim 1, characterized in that, The mass ratio of nanocellulose to sodium carboxymethyl cellulose is 2:1 to 1:10.