Hard sodium hyaluronate gel particles and method for their production, composite gel preparation

Abstract

The application belongs to the technical field of biomedical materials, and particularly relates to a hard sodium hyaluronate gel particle and a preparation method and a composite gel preparation thereof, which comprises the following steps: S1, dissolving sodium hyaluronate or a salt thereof in an alkaline aqueous phase to obtain a high-concentration sodium hyaluronate or salt solution; S2, adding a condensation agent to the high-concentration sodium hyaluronate or salt solution to generate hard sodium hyaluronate gel through reaction; and S3, granulating and washing the hard sodium hyaluronate gel to obtain hard sodium hyaluronate gel particles; wherein the mass percentage concentration of the high-concentration sodium hyaluronate or salt solution is 10%-40%; and the pH value of the alkaline aqueous phase is 10-14.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a rigid sodium hyaluronate gel particle and its preparation method, as well as a composite gel formulation. Background Technology

[0002] Sodium hyaluronate gel, as a natural polymer material gel, has excellent water retention, biocompatibility and unique rheological properties, and has become one of the hot topics in biomedical materials research.

[0003] Existing self-crosslinking hyaluronic acid gels mostly employ low-concentration reaction systems combined with emulsification processes, resulting in defects such as low crosslinking density, weak mechanical strength, and high swelling rate. The EDC / NHS activation system can activate the carboxyl groups in the sodium hyaluronate structure, causing them to form intramolecular / intermolecular crosslinking structures with the hydroxyl groups in its own structure. It can also be removed by washing after the reaction to avoid adverse reactions. However, the EDC / NHS activation system must be carried out in a weakly acidic environment. When in an alkaline environment, EDC and NHS will undergo hydrolysis, and the activation sites will be deactivated. Even in a weakly acidic environment, the self-crosslinking speed of the EDC / NHS activation system is much lower than that of the traditional emulsification process.

[0004] Therefore, overcoming the incompatibility between the crosslinking rate and hydrolysis problem of sodium hyaluronate gel in the EDC / NHS activation system is a technical problem that urgently needs to be solved in this field.

[0005] It should be noted that the information disclosed in this background section is only for understanding the background technology of the present application concept, and therefore, the above description is not considered to constitute prior art information. Summary of the Invention

[0006] This disclosure provides at least one rigid sodium hyaluronate gel particle, its preparation method, and a composite gel formulation.

[0007] In a first aspect, embodiments of this disclosure provide a method for preparing rigid sodium hyaluronate gel particles, comprising the following steps: S1, dissolving sodium hyaluronate or its salt in an alkaline aqueous phase to obtain a high-concentration sodium hyaluronate or its salt solution; S2, adding a condensing agent to the high-concentration sodium hyaluronate or its salt solution to react and generate rigid sodium hyaluronate gel; S3, granulating and washing the rigid sodium hyaluronate gel to obtain rigid sodium hyaluronate gel particles; wherein the mass percentage concentration of the high-concentration sodium hyaluronate or its salt solution is 10% to 40%; and the pH value of the alkaline aqueous phase is 10 to 14.

[0008] In one optional embodiment, the condensing agent is a carbodiimide and a succinimide, and the molar ratio of the carboxyl group in the sodium hyaluronate or its salt to the carbodiimide and succinimide is 1:x:y, where x=y, x ranges from 2 to 10, and y ranges from 2 to 10.

[0009] In one optional embodiment, the carbodiimide includes at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and its salts; the succinimide includes at least one of N-hydroxysuccinimide and N-hydroxythiosuccinimide.

[0010] In one optional embodiment, the alkaline aqueous phase is any one of sodium hydroxide, potassium hydroxide, or ammonia.

[0011] In one optional embodiment, the sodium hyaluronate or its salt has a molecular weight of 50 to 3,000,000 Da.

[0012] Secondly, this disclosure also provides a rigid sodium hyaluronate gel particle, which is prepared by the method described above. The particle size of the rigid sodium hyaluronate gel particle is 20-200 μm, and the swelling degree ranges from 1 to 20.

[0013] Thirdly, embodiments of this disclosure also provide a composite gel formulation, comprising: rigid sodium hyaluronate gel particles as described above and a matrix, wherein the matrix comprises at least one of a solution matrix and a gel matrix; the mass concentration of the rigid sodium hyaluronate gel particles in the matrix is ​​0.1% to 60%.

[0014] In one optional embodiment, the solution matrix includes at least one of sodium hyaluronate solution, collagen solution, silk fibroin solution, cellulose and its derivatives solution, chitosan and its derivatives solution, polyethylene glycol solution, sodium alginate solution, polyvinyl alcohol solution, gelatin solution, and salt solutions of the above solutions; the gel matrix includes at least one of sodium hyaluronate gel, collagen gel, silk fibroin gel, cellulose and its derivatives gel, chitosan and its derivatives gel, polyethylene glycol gel, sodium alginate gel, polyvinyl alcohol gel, gelatin gel, and salt solutions of the above solutions.

[0015] Fourthly, embodiments of this disclosure also provide an application of the aforementioned rigid sodium hyaluronate gel particles in stimulating collagen regeneration.

[0016] Fifthly, embodiments of this disclosure also provide an application of the aforementioned composite gel formulation in the field of medical aesthetic collagen regeneration.

[0017] The beneficial effects of this invention are that the rigid sodium hyaluronate gel particles and their preparation method utilize a highly alkaline bulk reaction system of high-concentration sodium hyaluronate, combined with a large excess of condensing agent to offset hydrolysis losses, forming a high-density cross-linked network within / between molecules. The resulting gel particles, under an EDC / NHS activation system, can wash away the condensing agent, reducing adverse reactions. The resulting rigid sodium hyaluronate gel particles not only have superior collagen regeneration promotion capabilities but also a lower swelling rate, avoiding the risk of postoperative swelling after injection. Their mechanical properties are superior to traditional hyaluronic acid hydrogels, with a slower degradation rate and a longer duration of in vivo maintenance.

[0018] Other features and advantages of the invention will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the invention. The objects and other advantages of the invention are realized and obtained through the structures particularly pointed out in the description and the drawings.

[0019] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, preferred embodiments are described below in detail with reference to the accompanying drawings. Attached Figure Description

[0020] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0021] Figure 1 A schematic diagram of a rigid sodium hyaluronate gel provided in an embodiment of this disclosure; Figure 2 Mechanical compression tests of conventional sodium hyaluronate gel and rigid sodium hyaluronate gel provided in the embodiments of this disclosure; Figure 3 SEM comparison images of conventional sodium hyaluronate gel and rigid sodium hyaluronate gel provided in the embodiments of this disclosure; Figure 4 A granulation diagram of a rigid sodium hyaluronate gel screen provided in an embodiment of this disclosure; Figure 5 A microscopic schematic diagram of the rigid sodium hyaluronate gel particles provided in the embodiments of this disclosure; Figure 6 The swelling diagrams of conventional sodium hyaluronate gel particles and hard sodium hyaluronate gel particles at different time points provided in this embodiment of the present disclosure, with the purified water volume controlled at 20 mL and 0.1 g added respectively; Figure 7A schematic diagram showing the swelling of conventional sodium hyaluronate gel particles and rigid sodium hyaluronate gel particles in water, as provided in the embodiments of this disclosure. Figure 8 Data on the promotion of collagen regeneration in L929 cells by rigid sodium hyaluronate gel provided in embodiments of this disclosure; Figure 9 A diagram showing the collagen content of type I rigid sodium hyaluronate gel provided in an embodiment of this disclosure; Figure 10 A diagram showing the collagen content of type III hard sodium hyaluronate gel provided in an embodiment of this disclosure; Figure 11 Comparison of traditional sodium hyaluronate gel particles and rigid sodium hyaluronate gel in promoting collagen regeneration in mice for 0-2 weeks, as provided in the embodiments of this disclosure; Figure 12 A comparison of the effects of conventional sodium hyaluronate gel particles and rigid sodium hyaluronate gel on collagen regeneration in mice over 3 months, as provided in this embodiment of the disclosure. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] As used herein, the phrases “in one embodiment,” “according to one embodiment,” “in some embodiments,” etc., generally refer to the fact that a particular feature, structure, or characteristic following the phrase can be included in at least one embodiment of this disclosure. Therefore, a particular feature, structure, or characteristic can be included in more than one embodiment of this disclosure, such that these phrases do not necessarily refer to the same embodiment. As used herein, the terms “example,” “exemplary,” etc., are used to “serve as an example, instance, or illustration.” Any implementation, aspect, or design described herein as “example” or “exemplary” is not necessarily to be construed as preferred or superior to other implementations, aspects, or designs. Rather, the use of the terms “example,” “exemplary,” etc., is intended to present concepts in a specific manner.

[0024] It should be noted that similar labels and letters in the following figures indicate similar items. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures.

[0025] The following detailed description of some embodiments of the present invention is provided in conjunction with the accompanying drawings. Unless otherwise specified, the following embodiments and features can be combined with each other.

[0026] This disclosure provides a method for preparing rigid sodium hyaluronate gel particles, comprising the following steps: S1, dissolving sodium hyaluronate or its salt in an alkaline aqueous phase to obtain a high-concentration sodium hyaluronate or its salt solution; S2, adding a condensing agent to the high-concentration sodium hyaluronate or its salt solution to react and generate rigid sodium hyaluronate gel; S3, granulating and washing the rigid sodium hyaluronate gel to obtain rigid sodium hyaluronate gel particles; wherein the mass percentage concentration of the high-concentration sodium hyaluronate or its salt solution is 10% to 40%; and the pH value of the alkaline aqueous phase is 10 to 14.

[0027] In some embodiments, specifically, the condensing agent is a carbodiimide and a succinimide, and the molar ratio of the carboxyl group in the sodium hyaluronate or its salt to the carbodiimide and succinimide is 1:x:y, where x=y, x ranges from 2 to 10, and y ranges from 2 to 10.

[0028] In some embodiments, specifically, the carbodiimide includes at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and its salts; the succinimide includes at least one of N-hydroxysuccinimide and N-hydroxythiosuccinimide.

[0029] In some embodiments, specifically, the alkaline aqueous phase is any one of sodium hydroxide, potassium hydroxide, or ammonia.

[0030] In some embodiments, specifically, the molecular weight of the sodium hyaluronate or its salt is 50 to 3,000,000 Da.

[0031] This disclosure also provides a rigid sodium hyaluronate gel particle, which is prepared by the method described above. The particle size of the rigid sodium hyaluronate gel particle is 20-200 μm, and the swelling degree ranges from 1 to 20.

[0032] This disclosure also provides a composite gel formulation, comprising: rigid sodium hyaluronate gel particles as described above and a matrix, wherein the matrix comprises at least one of a solution matrix and a gel matrix; the mass concentration of the rigid sodium hyaluronate gel particles in the matrix is ​​0.1% to 60%.

[0033] In some embodiments, specifically, the solution matrix includes at least one of sodium hyaluronate solution, collagen solution, silk fibroin solution, cellulose and its derivatives solution, chitosan and its derivatives solution, polyethylene glycol solution, sodium alginate solution, polyvinyl alcohol solution, gelatin solution, and salt solutions of the above solutions; the gel matrix includes at least one of sodium hyaluronate gel, collagen gel, silk fibroin gel, cellulose and its derivatives gel, chitosan and its derivatives gel, polyethylene glycol gel, sodium alginate gel, polyvinyl alcohol gel, gelatin gel, and salt solutions of the above solutions.

[0034] This disclosure also provides an application of the aforementioned hard sodium hyaluronate gel particles in stimulating collagen regeneration.

[0035] This disclosure also provides an application of the aforementioned composite gel formulation in the field of medical aesthetic collagen regeneration.

[0036] Example 1: Preparation method of rigid sodium hyaluronate gel and composite gel formulation: S1, Dissolve 3g of sodium hyaluronate powder in 20mL of sodium hydroxide aqueous solution with pH=14; Specifically, the molecular weight of the sodium hyaluronate powder is 2,000,000 Da; S2, with the carboxyl group in sodium hyaluronate being added to carbodiimide and succinimide in a molar ratio of 1:3:3, and allowed to stand to react, to obtain a hard sodium hyaluronate gel. S3, the hard sodium hyaluronate gel obtained from the reaction is granulated, washed and collected to obtain hard sodium hyaluronate gel particles with an average particle size of 50 μm. S4. Add 1% by weight of hard sodium hyaluronate gel particles to the sodium hyaluronate solution and mix evenly to obtain a composite gel formulation.

[0037] Please see Figure 1 ,like Figure 1 The diagram shown is a schematic diagram of the rigid sodium hyaluronate gel provided in an embodiment of this disclosure.

[0038] Traditional methods for preparing sodium hyaluronate gel: S1, Dissolve 1g of sodium hyaluronate powder in 20mL of aqueous solution with pH=7; Specifically, the molecular weight of the sodium hyaluronate powder is 1,000,000 Da; S2, with the carboxyl group in sodium hyaluronate and the molar ratio of carbodiimide and succinimide substances being 1:0.1:0.1, EDC and NHS were added, and the mixture was allowed to stand to react, thus obtaining the traditional sodium hyaluronate gel. S3, the traditional sodium hyaluronate gel obtained from the reaction is granulated, washed and collected to obtain traditional sodium hyaluronate gel particles with an average particle size of 200μm. S4. Add 2% by weight of traditional sodium hyaluronate gel particles to the sodium hyaluronate solution and mix evenly to obtain a composite gel formulation.

[0039] Please see Figure 2 ,like Figure 2 As shown, the mechanical compression test of the conventional sodium hyaluronate gel and the rigid sodium hyaluronate gel provided in Embodiment 1 of this disclosure is shown. It can be seen that the compression modulus of the rigid sodium hyaluronate gel is much greater than that of the conventional sodium hyaluronate gel. The compression modulus of the rigid gel is about 10 times that of the conventional gel.

[0040] Please see Figure 3 ,like Figure 3 The image shown is a SEM comparison image of the traditional sodium hyaluronate gel and the rigid sodium hyaluronate gel provided in Embodiment 1 of this disclosure. It can be seen that the pores of the rigid sodium hyaluronate gel are smaller than those of the traditional sodium hyaluronate gel.

[0041] Please see Figure 4-5 ,like Figure 4-5 The images shown are a granulation diagram of the rigid sodium hyaluronate gel screen and a microscopic schematic diagram of the rigid sodium hyaluronate gel particles provided in Embodiment 1 of this disclosure.

[0042] Please see Figure 6 ,like Figure 6 The figure shows the swelling diagrams of traditional sodium hyaluronate gel particles and hard sodium hyaluronate gel particles at different time points, with the volume of purified water controlled at 20 mL. It can be seen that the swelling rate of hard sodium hyaluronate gel particles is much lower than that of traditional sodium hyaluronate gel particles.

[0043] Please see Figure 7 ,like Figure 7 The diagram shown illustrates the swelling of conventional sodium hyaluronate gel particles and rigid sodium hyaluronate gel particles in water, as provided in Embodiment 1 of this disclosure.

[0044] After co-culturing the gel particles with L929 cells for 24 hours, quantitative analysis of type I and type III collagen was performed. As the content of gel particles increased, the content of both type I and type III collagen increased, indicating that the hard sodium hyaluronate gel particles have the effect of stimulating collagen production.

[0045] Please see Figure 8-10 ,like Figure 8-10 As shown, this is the data on the promotion of collagen regeneration in L929 cells by the rigid sodium hyaluronate gel provided in Example 1 of this disclosure. It can be seen that the rigid sodium hyaluronate gel particles have a significant effect on promoting collagen regeneration in cells.

[0046] Please see Figure 11 ,like Figure 11 As shown, the compound preparation was injected into the subcutaneous tissue of rats, and the rat skin was observed at 0 min, 30 min, 24 h, 48 h and 2 weeks after injection. No obvious abnormalities such as redness, swelling, bleeding or necrosis were observed.

[0047] Please see Figure 12 ,like Figure 12 As shown, the data on the promotion of collagen regeneration in mice by traditional sodium hyaluronate gel particles and hard sodium hyaluronate gel provided in Example 1 of this disclosure are shown. It can be seen that hard sodium hyaluronate gel particles have a significant effect on promoting collagen regeneration in mouse skin.

[0048] Example 2, Preparation method of rigid sodium hyaluronate gel and composite gel formulation: S1, Dissolve 4g of sodium hyaluronate powder in 20mL of potassium hydroxide aqueous solution with pH=12; Specifically, the molecular weight of the sodium hyaluronate powder is 500,000 Da; S2, with the carboxyl group in sodium hyaluronate being added to carbodiimide and succinimide in a molar ratio of 1:5:5, and allowed to stand to react, to obtain a hard sodium hyaluronate gel. S3, the hard sodium hyaluronate gel obtained from the reaction is granulated, washed and collected to obtain hard sodium hyaluronate gel particles with an average particle size of 200 μm. S4. Add 0.1% by weight of hard sodium hyaluronate gel particles to the collagen solution and mix evenly to obtain a composite gel formulation.

[0049] Example 3, Preparation method of rigid sodium hyaluronate gel and composite gel formulation: S1, Dissolve 2.3g of sodium hyaluronate powder in 20mL of ammonia aqueous solution with pH=10; Specifically, the molecular weight of the sodium hyaluronate powder is 1,000,000 Da; S2, with the carboxyl group in sodium hyaluronate being added to carbodiimide and succinimide in a molar ratio of 1:2:2, and allowed to stand to react, to obtain a hard sodium hyaluronate gel. S3, the hard sodium hyaluronate gel obtained from the reaction is granulated, washed and collected to obtain hard sodium hyaluronate gel particles with an average particle size of 20 μm.

[0050] S4. Add 60% by weight of hard sodium hyaluronate gel particles to sodium hyaluronate gel and mix evenly to obtain a composite gel formulation.

[0051] Example 4, Preparation method of rigid sodium hyaluronate gel and composite gel formulation: S1, Dissolve 8g of sodium hyaluronate powder in 20mL of sodium hydroxide aqueous solution with pH=14; Specifically, the molecular weight of the sodium hyaluronate powder is 2,000,000 Da; S2, with the molar ratio of carboxyl groups in sodium hyaluronate to carbodiimide and succinimide substances being 1:10:10, EDC and NHS were added, and the mixture was allowed to stand to react, resulting in a hard sodium hyaluronate gel. S3, the hard sodium hyaluronate gel obtained from the reaction is granulated, washed and collected to obtain hard sodium hyaluronate gel particles with an average particle size of 30 μm. S4. Add 10% by weight of rigid sodium hyaluronate gel particles to carboxymethyl chitosan gel and mix evenly to obtain a composite injection.

[0052] Example 5, Preparation method of rigid sodium hyaluronate gel and composite gel formulation: S1, Dissolve 5g of sodium hyaluronate powder in 20mL of sodium hydroxide aqueous solution with pH=13; Specifically, the molecular weight of the sodium hyaluronate powder is 1,000,000 Da; S2, with the carboxyl group in sodium hyaluronate being added to carbodiimide and succinimide in a molar ratio of 1:2:2, and allowed to stand to react, to obtain a hard sodium hyaluronate gel. S3, the hard sodium hyaluronate gel obtained from the reaction is granulated, washed and collected to obtain hard sodium hyaluronate gel particles with an average particle size of 60 μm.

[0053] S4. Add 20% by weight of hard sodium hyaluronate gel particles to sodium hyaluronate gel and mix evenly to obtain a composite gel formulation.

[0054] Example 6, Preparation method of rigid sodium hyaluronate gel and composite gel formulation: S1, Dissolve 3g of sodium hyaluronate powder in 20mL of sodium hydroxide aqueous solution with pH=14; Specifically, the molecular weight of the sodium hyaluronate powder is 3,000,000 Da; S2, with the carboxyl group in sodium hyaluronate being added to carbodiimide and succinimide in a molar ratio of 1:3:3, and allowed to stand to react, to obtain a hard sodium hyaluronate gel. S3, the hard sodium hyaluronate gel obtained from the reaction is granulated, washed and collected to obtain hard sodium hyaluronate gel particles with an average particle size of 100 μm.

[0055] S4. Add 40% by weight of hard sodium hyaluronate gel particles to the sodium hyaluronate solution and mix evenly to obtain a composite gel formulation.

[0056] Specifically, the performance of the composite gel formulations obtained in Examples 1-6 was tested, and the results are shown in Table 1 below.

[0057] Table 1 Performance data of compound gel formulation

[0058] In Table 1, the more "+" signs in the regeneration effect, the better the effect; and the more "+" signs in the decomposition rate, the faster the degradation.

[0059] In summary, this rigid sodium hyaluronate gel particle and its preparation method utilize a highly alkaline bulk reaction system of high-concentration sodium hyaluronate, combined with a large excess of condensing agent to offset hydrolysis losses, forming a high-density cross-linked network within / between molecules. The resulting gel particles, under an EDC / NHS activation system, can wash away the condensing agent, reducing adverse reactions. The resulting rigid sodium hyaluronate gel particles not only have superior collagen regeneration promotion capabilities but also a lower swelling rate, avoiding the risk of postoperative swelling after injection. Their mechanical properties are superior to traditional hyaluronic acid hydrogels, with a slower degradation rate and a longer duration of in vivo maintenance.

[0060] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for preparing rigid sodium hyaluronate gel particles, characterized in that, Includes the following steps: S1, Dissolve sodium hyaluronate or its salt in an alkaline aqueous phase to obtain a high-concentration sodium hyaluronate or its salt solution; S2, a condensing agent is added to the high-concentration sodium hyaluronate or its salt solution to react and generate a hard sodium hyaluronate gel; S3, granulate and wash the hard sodium hyaluronate gel to obtain hard sodium hyaluronate gel particles; The mass percentage concentration of the high-concentration sodium hyaluronate or its salt solution is 10% to 40%. The pH value of the alkaline aqueous phase is 10-14.

2. The method for preparing rigid sodium hyaluronate gel particles as described in claim 1, characterized in that, The condensing agent is a carbodiimide or succinimide. The molar ratio of the carboxyl group to the carbodiimide and succinimide substances in the sodium hyaluronate or its salt is 1:x:y, where x = y, x ranges from 2 to 10, and y ranges from 2 to 10.

3. The method for preparing rigid sodium hyaluronate gel particles as described in claim 2, characterized in that, The carbodiimide class includes at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and its salts; The succinimide compounds include at least one of N-hydroxysuccinimide and N-hydroxythiosuccinimide.

4. The method for preparing rigid sodium hyaluronate gel particles as described in claim 1, characterized in that, The alkaline aqueous phase is any one of sodium hydroxide, potassium hydroxide, or ammonia.

5. The method for preparing rigid sodium hyaluronate gel particles as described in claim 1, characterized in that, The molecular weight of the sodium hyaluronate or its salt is 50 to 3,000,000 Da.

6. A type of rigid sodium hyaluronate gel particle, characterized in that, Prepared by the method described in any one of claims 1-5 The rigid sodium hyaluronate gel particles have a particle size of 20–200 μm and a swelling degree ranging from 1 to 20.

7. A composite gel formulation, characterized in that, include: The rigid sodium hyaluronate gel particles and matrix as described in claim 6, The matrix includes at least one of a solution matrix and a gel matrix; The mass concentration of the rigid sodium hyaluronate gel particles in the matrix is ​​0.1% to 60%.

8. The composite gel formulation as described in claim 7, characterized in that, The solution matrix includes at least one of the following: sodium hyaluronate solution, collagen solution, silk fibroin solution, cellulose and its derivatives solution, chitosan and its derivatives solution, polyethylene glycol solution, sodium alginate solution, polyvinyl alcohol solution, gelatin solution, and salt solutions of the above solutions; The gel matrix includes at least one of sodium hyaluronate gel, collagen gel, silk fibroin gel, cellulose and its derivatives gel, chitosan and its derivatives gel, polyethylene glycol gel, sodium alginate gel, polyvinyl alcohol gel, gelatin gel, and salt solutions of the above solutions.

9. The application of the rigid sodium hyaluronate gel particles as described in any one of claims 1-5 in the field of stimulating collagen regeneration.

10. The application of a composite gel formulation as described in claim 7 or 8 in the field of medical aesthetic collagen regeneration.

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