Homogeneous gel composition for dermis filling, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a homogeneous gel composition for dermis filling, and a preparation method therefor and the use thereof. The homogeneous gel composition comprises: (Y1) second biocompatible solid particles; and (Y2) a gel material. The gel material comprises the following components: (Z1) first biocompatible solid particles; (Z2) hyaluronic acid; and (Z3) a cellulose-based polysaccharide polymer, wherein the gel material is in a solid powder or gel form. The homogeneous gel composition prepared in the present invention comprises high- and low-association-degree biocompatible solid particles, such that the biocompatible solid particles are gradually released in a matrix, and the biocompatible solid particles can stably exist in a composite system for a long time.

Description

Homogeneous gel composition for dermal filling and its preparation method and application Technical Field

[0001] The present invention relates to the field of medical cosmetic technology, and in particular provides a homogeneous gel composition for dermal filling, a preparation method thereof, and an application thereof. Background Art

[0002] Nowadays, people, especially women, frequently seek correction or surgery to address changes in their skin caused by aging, illness, trauma, and other factors. Dermal fillers and botulinum toxin wrinkle reduction are two of the most popular options. Dermal fillers effectively eliminate wrinkles and deep lines, filling and smoothing facial contours. Dermal fillers have been used for over 40 years, and throughout history, people have tried various methods to enhance facial aesthetics and promote a more youthful appearance.

[0003] Many dermal fillers have been introduced, and their clinical effects vary. For example, soft tissue fillers can be divided into temporary fillers (autologous fat, collagen, hyaluronic acid, etc.), semi-permanent fillers (composite materials loaded with calcium phosphate particles or polylactic acid (PLA)), and permanent fillers (silicone, polymethylmethacrylate (PMMA), polytetrafluoroetylene (PTFE), etc.). However, the effects of existing dermal fillers are far from satisfactory, and they have various disadvantages, such as poor injectability, low biocompatibility, low stability, and difficulty in loading high levels of solid particles such as hydroxyapatite.

[0004] Therefore, there is an urgent need in the art to provide a gel composition that is highly injectable, biocompatible, and stable and capable of loading a high content of solid particles.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a gel composition with high injectability, high biocompatibility and high stability capable of loading a high content of solid particles, as well as its preparation method and use (such as an implant composition for dermal filling or bone sculpture).

[0007] In a first aspect of the present invention, a gel material is provided, which contains the following components: (Z1) first biocompatible solid particles; (Z2) hyaluronic acid (HA); and (Z3) cellulose-based polysaccharide polymer; wherein the gel material is in a solid powder or gel state.

[0008] In another preferred embodiment, the solid powdered gel material is formed by drying and crushing a gel-like gel material.

[0009] In another preferred embodiment, the gel-like gel material is a solid powdered gel material that is reconstituted into a gel-like gel material by adding water or an aqueous buffer solution.

[0010] In another preferred embodiment, the gel-like gel material has physical and chemical properties selected from the following group:

[0011] (a) the gel-like gel material comprises highly associative biocompatible solid particles;

[0012] (b) the pH of the gelatinous gel material is 6-8;

[0013] (c) The water content of the gel-like gel material is 75% to 95%.

[0014] In another preferred embodiment, the hyaluronic acid in the gel material forms a mixture with a cellulose-based polysaccharide polymer, and the hyaluronic acid is cross-linked to form a gel composite support skeleton.

[0015] In another preferred embodiment, the first biocompatible solid particles of the component (Z1) and the gel composite support skeleton form a composite structure.

[0016] In another preferred embodiment, the weight ratio of hyaluronic acid to cellulose polysaccharide polymer is 1:0.5 to 1:5, preferably 1:1 to 1:4, and more preferably 1:1.5 to 1:2.5.

[0017] In another preferred embodiment, the weight ratio of hyaluronic acid to the first biocompatible solid particles is 1:1 to 1:4, preferably 1:2 to 1:3.

[0018] In another preferred embodiment, the molecular weight of the hyaluronic acid is 80-200 wDa.

[0019] In another preferred embodiment, the components Z1, Z2 and Z3 account for 60% to 100% of the dry weight of the gel material, preferably 70% to 100%, and more preferably 80% to 100%.

[0020] In another preferred embodiment, the first biocompatible solid particles are selected from the group consisting of calcium phosphate particles, silicate particles, calcium sulfate particles, ceramic particles, biological bone matrix particles, organic solid particles, or a combination thereof.

[0021] In another preferred embodiment, the calcium phosphate particles are selected from the group consisting of hydroxyapatite (HAP), β-tricalcium phosphate (β-TCP), α-tricalcium phosphate (α-TCP), tetracalcium phosphate (TTCP), or a combination thereof.

[0022] In another preferred embodiment, the silicate particles are selected from the group consisting of bioglass, calcium silicate, sodium silicate, or a combination thereof.

[0023] In another preferred embodiment, the calcium sulfate salt particles are selected from hydrated calcium sulfate.

[0024] In another preferred embodiment, the organic solid particles are selected from the group consisting of PMMA, PLA, poly(ε-caprolactone), PCL, poly(lactic-co-glycolic acid), PLGA, or a combination thereof.

[0025] In another preferred embodiment, the first biocompatible solid particles are hydroxyapatite.

[0026] In another preferred embodiment, the first biocompatible solid particles are hydroxyapatite hollow microspheres.

[0027] In another preferred embodiment, the medium hydroxyapatite hollow microspheres are nanocluster hydroxyapatite hollow microspheres.

[0028] In another preferred embodiment, the particle size of the first biocompatible solid particles is ≤500 μm; preferably, the particle size is 10-500 μm, more preferably, the particle size is 25-250 μm, and most preferably, the particle size is 20-150 μm.

[0029] In another preferred embodiment, the particle size of the first biocompatible solid particles is 20-50 μm.

[0030] In another preferred embodiment, the cellulose-based polysaccharide polymer is selected from the following group: hydroxypropyl methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxyethyl hydroxyethyl cellulose, hydroxypropyl hydroxyethyl cellulose, methyl cellulose, methyl hydroxymethyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl methyl cellulose or a combination thereof.

[0031] In another preferred embodiment, the cellulose-based polysaccharide polymer is further selected from the following group: cellulose-based polysaccharide derivatives, modified cellulose-based polysaccharide derivatives or a combination thereof.

[0032] In another preferred embodiment, the cellulose-based polysaccharide polymer is hydroxypropyl methylcellulose.

[0033] In a second aspect of the present invention, a method for preparing the gel material is provided, comprising the following steps:

[0034] (S1) providing a first mixture, wherein the first mixture comprises: hyaluronic acid, cellulose polysaccharide polymer and first biocompatible solid particles;

[0035] (S2) In the presence of a cross-linking agent, the hyaluronic acid in the first mixture is cross-linked with the cellulose-based polysaccharide polymer to form a cross-linked mixture.

[0036] In another preferred embodiment, the preparation method further comprises:

[0037] (S3) adding the mixture dropwise into an acetone solution to wash away the residual cross-linking agent, and then drying to obtain a solid powder of the gel material; taking the solid powder of the gel material and dissolving it in water and / or an aqueous buffer solution to obtain a gel of the re-dissolved gel material.

[0038] In another preferred embodiment, step (S2) further comprises treating the cross-linked mixture as follows:

[0039] (i) adjusting the pH of the cross-linking mixture to acidic to terminate the cross-linking reaction, eluting the cross-linking agent and solidifying,

[0040] (ii) washing and drying to obtain the solid powdery gel material,

[0041] (iii) dissolving the solid powdered gel material in water and / or aqueous buffer to obtain a gel-like gel material.

[0042] In another preferred embodiment, the cross-linking reaction is carried out under alkaline conditions.

[0043] In another preferred embodiment, the alkaline condition is a pH of 11-13.

[0044] In another preferred embodiment, the acidic environment is adjusted to a pH of 4 to 6.8.

[0045] In another preferred embodiment, the cross-linking agent is selected from the following group: 1,4-butanediol diglycidyl ether, poly(ethylene glycol) diglycidyl ether, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, polyglycerol polyglycidyl ether, neopentyl glycol diglycidyl ether, ethylene glycol diglycidyl ether, or a combination thereof.

[0046] In another preferred embodiment, the cross-linking agent is 1,4-butanediol diglycidyl ether (BDDE).

[0047] In a third aspect of the present invention, there is provided an injectable homogeneous gel composition, comprising:

[0048] (Y1) second biocompatible solid particles; and (Y2) the gel material described in the first aspect of the present invention.

[0049] In another preferred embodiment, the second biocompatible solid particles are physically mixed with the gel-like gel material described in the first aspect of the present invention to form a low degree of association, thereby obtaining a homogeneous gel composition containing biocompatible solid particles with high and low degrees of association.

[0050] In another preferred embodiment, (W1+W2) / W0=5:1-20:1; preferably 8:1-15:1; wherein W1 is the weight of the first biocompatible solid particles, W2 is the second biocompatible solid particles, and W0 is the weight of the reconstituted gel material (excluding the biocompatible solid particles).

[0051] In another preferred embodiment, the second biocompatible solid particles are the same as or different from the first biocompatible solid particles.

[0052] In another preferred embodiment, the particle sizes of the second biocompatible solid particles may be the same or different.

[0053] In another preferred embodiment, the homogeneous gel composition has one or more characteristics selected from the following group:

[0054] (a) the homogeneous gel composition comprises biocompatible solid particles with high and low association degrees;

[0055] (b) The biocompatible solid particles in the homogeneous gel composition account for 2%-95% of the dry weight of the homogeneous gel composition, preferably 3%-80%, more preferably 4%-60%, and most preferably 5%-30%.

[0056] (c) the hyaluronic acid content of the homogenous gel composition is 0.5% to 4% w / w (5 to 40 mg / g), based on the weight of the homogenous gel composition excluding the biocompatible solid particles;

[0057] (d) The cellulose-based polysaccharide polymer content of the homogeneous gel composition is 0.2% to 8% w / w (2 to 80 mg / g), based on the weight of the homogeneous gel composition excluding the biocompatible solid particles.

[0058] In a fourth aspect of the present invention, a method for preparing the homogeneous gel composition according to the third aspect of the present invention is provided, comprising the following steps:

[0059] (S3) providing a second mixture, the second mixture comprising: the gel material in a gel state according to the first aspect of the present invention and second biocompatible solid particles, or the gel material in a solid powder state, second biocompatible solid particles, and water or an aqueous buffer solution;

[0060] (S4) The second mixture is mixed to form a homogeneous gel composition.

[0061] In another preferred embodiment, when the gel material used in step (S3) is in solid powder form, a buffer solution needs to be added to re-dissolve the gel material to obtain a gel-like gel material.

[0062] In another preferred embodiment, the gel material is redissolved with PBS buffer.

[0063] In another preferred embodiment, the method further comprises the following steps: degassing, packaging and sterilizing the gel compounded in step (S3) to form a homogeneous gel composition.

[0064] In a fifth aspect of the present invention, a use of the homogeneous gel composition according to the third aspect of the present invention is provided. The uses of the homogeneous gel composition include: dermal filling and bone sculpture.

[0065] In a fourth aspect of the present invention, a kit is provided, comprising the following components: the homogeneous gel material according to the first aspect of the present invention or the homogeneous gel composition according to the third aspect of the present invention.

[0066] In another preferred embodiment, the kit further comprises: a pre-filled syringe, instructions, and a spare injection needle.

[0067] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 shows the solid powder after the gel is freeze-dried;

[0069] Figure 2 shows the injectability results of gels prepared at different ratios of HA to HPMC.

[0070] Figure 3 shows the stability of homogenous compositions with and without HPMC;

[0071] FIG4 shows a flow chart for the preparation of a homogeneous gel composition.

[0072] Figure 5 shows the hydroxyapatite sedimentation of Examples 1-5, wherein A in Figure 5 is the hydroxyapatite sedimentation of Example 1, B in Figure 5 is the hydroxyapatite sedimentation of Example 2, C in Figure 5 is the hydroxyapatite sedimentation of Example 3, D in Figure 5 is the hydroxyapatite sedimentation of Example 4, and E in Figure 5 is the hydroxyapatite sedimentation of Example 5. DETAILED DESCRIPTION

[0073] The present inventors have conducted extensive and in-depth research and, through extensive screening, unexpectedly developed for the first time a gel material and a corresponding injectable homogeneous gel composition using cross-linked hyaluronic acid and a cellulose-based polysaccharide polymer as a gel carrier (or gel support skeleton) and a composite of highly loaded biocompatible solid particles. The gel material and injectable homogeneous gel composition of the present invention contain a composite structure composed of specific components, wherein the component (Z2) hyaluronic acid is cross-linked in the presence of the component (Z1) first biocompatible solid particles and the component (Z3) cellulose-based polysaccharide polymer, so that the first biocompatible solid particles have a high degree of association and a high load. In the injectable homogeneous gel composition of the present invention, the gel material of the present invention and the second biocompatible solid particles are adsorbed and physically mixed so that the second biocompatible solid particles have a low degree of association, thereby ultimately forming a homogeneous gel composition having high and low association properties. Tests have shown that the homogeneous gel composition of the present invention contains at least two biocompatible solid particles with different degrees of association, allowing the biocompatible solid particles to be gradually released from the matrix and to remain stably in the composite system for a long period of time. This invention was completed on this basis.

[0074] Terminology

[0075] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0076] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0077] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0078] As used herein, the terms "HAP" and "hydroxyapatite," "nu-HAP," and "nanoclustered hydroxyapatite hollow microspheres" are used interchangeably.

[0079] As used herein, the terms "BDDE," "1,4-butanediol diglycidyl ether," and "1,4-butanediol diglycidyl ether" are used interchangeably.

[0080] The terms "tightly associated" or "highly associated" and "loosely associated" or "lowly associated" as used herein with respect to the binding of a gel to hydroxyapatite should be interpreted as relating to regions in the gel having different degrees of association (high and low, respectively) between the biocompatible solid particles and the gel.

[0081] Homogeneous gel composition

[0082] In the present invention, the terms "homogeneous gel composition", "homogeneous gel", "homogeneous hydroxyapatite-hyaluronic acid gel", "homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel", "homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel with different degrees of association" or similar terms have the same meaning with emphasis on homogeneity.

[0083] Hyaluronic acid

[0084] Hyaluronic acid, also known as hyaluronic acid (HA), is an acidic mucopolysaccharide that is a common component of injectable fillers and is used in several cosmetic procedures, particularly for wrinkle filling. However, due to rapid enzymatic degradation and hydrolysis, natural HA has poor in vivo stability and is insufficient to maintain the long-term stability of hydroxyapatite particles.

[0085] In the present invention, suitable hyaluronic acid is hyaluronic acid with a molecular weight of 50-200 wDa. It should be understood that hyaluronic acid suitable for the present invention includes unmodified and modified hyaluronic acid. For example, representative modifications include (but are not limited to): chemical cross-linking, ion modification, esterification, etc.

[0086] The research of the present invention shows that when single cross-linked hyaluronic acid is used as a carrier, its injectability is significantly affected.

[0087] Cellulose-based polysaccharide polymers

[0088] Cellulose-based polysaccharide polymers possess excellent biocompatibility, biodegradability, and mechanical stability, making them widely used in biomedical applications such as sustained drug release, wound healing, and tissue engineering scaffolds. Cellulose-based polysaccharide polymers possess a sufficiently large pore structure and three-dimensional space, allowing for strong water absorption and retention, providing a space for cells in the body to survive and store nutrients. Furthermore, due to their unique structure and properties, they are a preferred material for injectable formulations used to fill tissue defects.

[0089] In the present invention, the cellulose-based polysaccharide polymer includes natural cellulose or modified cellulose. Representative cellulose-based polysaccharide polymers include (but are not limited to): hydroxypropyl methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxyethyl hydroxyethyl cellulose, hydroxypropyl hydroxyethyl cellulose, methylcellulose, methyl hydroxymethyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl methyl cellulose or a combination thereof.

[0090] Particularly preferred cellulose-based polysaccharide polymers include hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, or a combination thereof.

[0091] Biocompatible solid particles

[0092] The "biocompatible solid particles" in the present invention refer to active solid particles that can play a role in certain biological processes or solid particles with good biocompatibility.

[0093] Preferably, the biocompatible solid particles are selected from the group consisting of calcium phosphate particles, silicate particles, acid calcium salt particles, ceramic particles, biological bone matrix particles, organic solid particles, or a combination thereof.

[0094] Preferably, the calcium phosphate particles are selected from the group consisting of HAP, β-TCP, α-TCP, TTCP, or a combination thereof.

[0095] Preferably, the silicate particles are selected from the group consisting of bioglass, calcium silicate, sodium silicate, or a combination thereof.

[0096] Preferably, the calcium sulfate salt particles are selected from hydrated calcium sulfate.

[0097] Preferably, the organic solid particles are selected from the group consisting of PMMA, PCL, PLA, PLGA, or a combination thereof.

[0098] Preferably, the biocompatible solid particles are hydroxyapatite.

[0099] Preferably, the biocompatible solid particles are hydroxyapatite hollow microspheres.

[0100] Preferably, the hydroxyapatite hollow microspheres are nanocluster hydroxyapatite hollow microspheres.

[0101] Hydroxyapatite (HAP)

[0102] Hydroxyapatite (HAP), molecular formula: (Ca 10(PO4)6(OH)2) is the primary inorganic component of human bone. Natural HAP in the human body manifests itself as needle-rod-shaped nanocrystals. HAP exhibits bidirectional biological regulatory functions. HAP can form chemical bonds with adsorbates or undergo metal ion replacement, resulting in a strong adsorption capacity for various protein growth factors. This promotes the local accumulation of endogenous growth factors, promoting tissue repair and regeneration, and exhibits excellent biocompatibility and bioactivity. HAP degradation products are calcium, phosphate ions, and water. During adsorption, the released calcium and phosphate ions exert other physiological functions.

[0103] Nanoclustered Hydroxyapatite Hollow Microspheres (nu-HAP)

[0104] Nanoclustered hydroxyapatite hollow microspheres (nu-HAP) are based on nanoscale needle-like hydroxyapatite, constructed into clustered stacks and then fabricated into hollow microspheres. Their larger surface area provides more attachment points for proteins and bioactive factors, while their larger particle size enhances dermal filling. This allows hydroxyapatite hollow microspheres to fully leverage the bidirectional regulatory effects of HAP while meeting clinical requirements.

[0105] Organic solid particles-PMMA microspheres

[0106] Polymethyl methacrylate (PMMA) microspheres continuously stimulate the growth of subcutaneous collagen and other subcutaneous tissue. After being injected into the dermis, collagen products containing PMMA microspheres are slowly absorbed by the body over several months. The PMMA microspheres continuously stimulate collagen regeneration, and after 1-3 months, the body's own collagen replaces the original collagen. As long as the amount of collagen beneath the skin remains stable, wrinkles can be kept free of wrinkles for a long time, providing facial wrinkle filling and anti-aging benefits.

[0107] Bioactive glass

[0108] Bioactive glass (BAG) is a type of material that can repair, replace, and regenerate tissues, forming bonds between tissues and materials. It is composed of SiO2, Na2O, CaO, and P2O5, among other components. The degradation products of bioactive glass can promote the production of growth factors, stimulate cell proliferation, enhance gene expression in osteoblasts, and promote bone tissue growth, making it widely used in bone sculpture and plastic surgery.

[0109] Gel material of the present invention

[0110] The gel material of the present invention comprises the following components: (Z1) first biocompatible solid particles; (Z2) hyaluronic acid; and (Z3) cellulose-based polysaccharide polymer; wherein the gel material is in solid powder or gel form.

[0111] In another preferred embodiment, the solid powdered gel material is formed by drying and crushing a gel-like gel material.

[0112] In another preferred embodiment, the solid powdered gel material is reconstituted into a gel-like gel material by adding water or an aqueous buffer solution.

[0113] In another preferred embodiment, the gel-like gel material has physical and chemical properties selected from the following group:

[0114] (a) the gel-like gel material comprises highly associative biocompatible solid particles;

[0115] (b) the pH of the gelatinous gel material is 6-8;

[0116] (c) The water content of the gel-like gel material is 75% to 95%.

[0117] In another preferred embodiment, the cross-linked mixture of the component (Z2) hyaluronic acid and the component (Z3) cellulose-based polysaccharide polymer serves as the gel support skeleton of the component (Z1) first biocompatible solid particles.

[0118] In another preferred embodiment, the first biocompatible solid particles of the component (Z1) and the gel support skeleton form a composite structure.

[0119] In another preferred embodiment, the weight ratio of hyaluronic acid to cellulose polysaccharide polymer is 1:0.5 to 1:5, preferably 1:1 to 1:4, and more preferably 1:1.5 to 1:2.5.

[0120] In another preferred embodiment, the weight ratio of hyaluronic acid to the first biocompatible solid particles is 1:1 to 1:4, preferably 1:2 to 1:3.

[0121] In another preferred embodiment, the molecular weight of the hyaluronic acid is 80-200 wDa.

[0122] In another preferred embodiment, the components Z1, Z2 and Z3 account for 60% to 100% of the dry weight of the gel material, preferably 70% to 100%, and more preferably 80% to 100%.

[0123] Preparation of the gel material of the present invention

[0124] The preparation method of the gel material comprises the following steps:

[0125] (S1) providing a first mixture, wherein the first mixture comprises: hyaluronic acid, cellulose polysaccharide polymer and first biocompatible solid particles;

[0126] (S2) In the presence of a cross-linking agent, cross-linking the hyaluronic acid in the first mixture to form a cross-linked mixture.

[0127] In another preferred embodiment, step (S2) further comprises treating the cross-linked mixture as follows:

[0128] (i) adjusting the pH of the cross-linking mixture to acidic to terminate the cross-linking reaction, eluting the cross-linking agent and solidifying,

[0129] (ii) washing and drying to obtain the solid powdery gel material.

[0130] (iii) dissolving the solid powdered gel material in water and / or aqueous buffer to obtain a gel-like gel material.

[0131] In another preferred embodiment, the cross-linking reaction is carried out under alkaline conditions.

[0132] In another preferred embodiment, the alkaline condition is a pH of 11-13.

[0133] In another preferred embodiment, the acidic environment is adjusted to a pH of 4 to 6.8.

[0134] In another preferred embodiment, the cross-linking agent is selected from the following group: 1,4-butanediol diglycidyl ether, poly(ethylene glycol) diglycidyl ether, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, polyglycerol polyglycidyl ether, neopentyl glycol diglycidyl ether, ethylene glycol diglycidyl ether, or a combination thereof.

[0135] In another preferred embodiment, the cross-linking agent is 1,4-butanediol diglycidyl ether (BDDE).

[0136] Injectable homogeneous gel composition of the present invention

[0137] The homogeneous gel composition comprises: (Y1) second biocompatible solid particles; and (Y2) the gel material.

[0138] In another preferred embodiment, the second biocompatible solid particles and the gel-like gel material are adsorbed and physically mixed to form a homogeneous gel composition comprising biocompatible solid particles with high and low association degrees.

[0139] In another preferred embodiment, (W1+W2) / W0=5:1-20:1; preferably 8:1-15:1; wherein W1 is the weight of the first biocompatible solid particles, W2 is the second biocompatible solid particles, and W0 is the weight of the reconstituted gel material (excluding the biocompatible solid particles).

[0140] In another preferred embodiment, the second biocompatible solid particles are the same as or different from the first biocompatible solid particles.

[0141] In another preferred embodiment, the particle sizes of the second biocompatible solid particles may be the same or different.

[0142] In another preferred embodiment, the homogeneous gel composition has one or more characteristics selected from the following group:

[0143] (a) the homogeneous gel composition comprises biocompatible solid particles with high and low association degrees;

[0144] (b) The biocompatible solid particles in the homogeneous gel composition account for 2%-95% of the dry weight of the homogeneous gel composition, preferably 3%-80%, more preferably 4%-60%, and most preferably 5%-30%.

[0145] (c) the hyaluronic acid content of the homogenous gel composition is 0.5% to 4% w / w (5 to 40 mg / g), based on the weight of the homogenous gel composition excluding the biocompatible solid particles;

[0146] (d) The cellulose-based polysaccharide polymer content of the homogeneous gel composition is 0.2% to 8% w / w (2 to 80 mg / g), based on the weight of the homogeneous gel composition excluding the biocompatible solid particles.

[0147] Preparation of the homogeneous gel composition of the present invention

[0148] The preparation method of the homogeneous gel composition comprises the following steps:

[0149] (S3) providing a second mixture, wherein the second mixture comprises: the gel material in a gel state and second biocompatible solid particles, or the gel material in a solid powder state, second biocompatible solid particles, and water or an aqueous buffer solution;

[0150] (S4) The second mixture is mixed to form a homogeneous gel composition.

[0151] In another preferred embodiment, when the gel material used in step (S3) is in solid powder form, a buffer solution needs to be added to re-dissolve the gel material to obtain a gel-like gel material.

[0152] In another preferred embodiment, the gel material is redissolved with PBS buffer.

[0153] In another preferred embodiment, the following steps are further included: degassing, packaging and sterilizing the gel compounded in step (S3) to form a homogeneous gel composition. The preparation flow chart is shown in FIG4 .

[0154] Use of homogeneous gel composition

[0155] The uses of the homogeneous gel composition include: dermal filling and bone sculpture and plastic surgery.

[0156] Reagent test kit

[0157] The kit comprises the following components: the homogeneous gel material or the homogeneous gel composition.

[0158] In another preferred embodiment, the kit further comprises: a pre-filled syringe, instructions, and a spare injection needle.

[0159] Compared with the prior art, the present invention has the following beneficial effects:

[0160] (a) The present invention uses cross-linked hyaluronic acid and cellulose-based polysaccharide polymers as carriers of biocompatible solid particles, utilizing the properties of cross-linked hyaluronic acid and the stability of cellulose-based polysaccharide polymers to provide long-term stable support for the solid particles.

[0161] (b) The present invention obtains a homogeneous gel containing biocompatible solid particles with different degrees of association by adding biocompatible solid particles before and after the cross-linking reaction, thereby allowing the biocompatible solid particles to be gradually released in the matrix and to exist stably in the composite system for a long time.

[0162] (c) The hydroxypropyl methylcellulose used in this method is readily available, safe, and a commonly used pharmaceutical excipient. The reaction has the advantages of mild reaction conditions and simple operation steps.

[0163] (d) In this method, the hyaluronic acid cross-linking agent BDDE is easy to obtain and remove, and the cross-linking reaction conditions are mild, making it easy to regulate the cross-linking degree of hyaluronic acid.

[0164] (e) The nanoclustered hydroxyapatite hollow microspheres prepared by this method have a higher specific surface area, providing more attachment sites for active proteins and effectively promoting the adsorption and regeneration of collagen.

[0165] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0166] Example 1: Preparation of Tightly Associated Biocompatible Solid Particle Gel

[0167] 2g of hyaluronic acid and 1g of hydroxypropyl methylcellulose were added to 27g of water and mixed at 500 rpm at room temperature until homogeneous. 1g of sodium hydroxide solution (1M) was then added to the mixture to a pH > 12, and the mixture was further mixed at 500 rpm for 30 minutes. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20-50μm were added to the mixture and mixed again at 300 rpm for 30 minutes. 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was then added, and the mixture was homogenized at 300 rpm for 30 minutes. The homogenized mixture was placed in an oven at 45°C for 3 hours and then at 25°C for an additional 12 hours. 5g of hydrochloric acid (0.5M) was then added, and the pH was adjusted to < 7 to terminate the cross-linking reaction. The mixture was mixed at 300 rpm for 10 minutes to obtain a gel-like, slightly acidic composite gel containing hydroxyapatite hollow microspheres, which was between solid and liquid states.

[0168] The resulting gel was washed dropwise with 300 mL of acetone to elute the BDDE while the gel solidified. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 8 g of a solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel, as shown in Figure 1.

[0169] 1 g of solid powder was redissolved in 11.5 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0170] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0171] Example 2: Preparation of biocompatible solid particle gels with different association degrees (HA:HPMC=2:1)

[0172] 2g of hyaluronic acid and 1g of hydroxypropyl methylcellulose were added to 27g of water and mixed at 500rpm at room temperature until uniform. Subsequently, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH>12, and further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20-50μm were added to the mixture and mixed again at 300rpm for 30min. Subsequently, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in a 45°C oven for 3h and then at 25°C for another 12h. Then 5g of hydrochloric acid (0.5M) was added and the pH was adjusted to <7 to terminate the cross-linking reaction. The mixture was mixed at 300rpm for 10min to obtain a gel-like acidic composite gel between solid and liquid states containing hydroxyapatite hollow microspheres.

[0173] The resulting gel was washed dropwise with 300 mL of acetone to elute the BDDE while the gel solidified. The solidified product was collected by filtration and washed with anhydrous ethanol, followed by freeze-drying to obtain approximately 8 g of a solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0174] 1 g of solid powder was redissolved in 11.5 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0175] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0176] Then, 3.32 g of hydroxyapatite hollow microspheres with a particle size of 20 to 50 μm were added to the gel and homogenized at 300 rpm for 30 min to obtain hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite with different degrees of association (the concentration of hollow microspheres was 25 w / w%).

[0177] Example 3: Preparation of biocompatible solid particle gels with different association degrees (HA:HPMC=1:1)

[0178] 2g of hyaluronic acid and 2g of hydroxypropyl methylcellulose were added to 36g of water and mixed at 500rpm at room temperature until uniform. Subsequently, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH>12, and further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20-50μm were added to the mixture and mixed again at 300rpm for 30min. Subsequently, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in a 45°C oven for 3h and then placed at 25°C for another 12h. Then 5g of hydrochloric acid (0.5M) was added and the pH was adjusted to <7 to terminate the cross-linking reaction. The mixture was mixed at 300rpm for 10min to obtain a gel-like acidic composite gel between solid and liquid states containing hydroxyapatite hollow microspheres.

[0179] The resulting gel was washed dropwise with 300 mL of acetone to elute the BDDE while the gel solidified. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 9 g of a solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0180] 1 g of solid powder was redissolved in 10.1 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0181] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0182] Then, 2.94 g of hydroxyapatite hollow microspheres with a particle size of 20 to 50 μm were added to the gel and homogenized at 300 rpm for 30 min to obtain hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite with different degrees of association (the concentration of hollow microspheres was 25 w / w%).

[0183] Example 4: Preparation of biocompatible solid particle gels with different association degrees (HA:HPMC=1:2)

[0184] 2g of hyaluronic acid and 4g of hydroxypropyl methylcellulose were added to 44g of water and mixed at 500rpm at room temperature until uniform. Subsequently, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH>12, and further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20-50μm were added to the mixture and mixed again at 300rpm for 30min. Subsequently, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in a 45°C oven for 3h and then placed at 25°C for another 12h. Then 5g of hydrochloric acid (0.5M) was added and the pH was adjusted to <7 to terminate the cross-linking reaction. The mixture was mixed at 300rpm for 10min to obtain a gel-like acidic composite gel between solid and liquid states containing hydroxyapatite hollow microspheres.

[0185] The resulting gel was washed dropwise with 300 mL of acetone to elute the BDDE while the gel solidified. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 11 g of a solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0186] 1 g of solid powder was redissolved in 9.1 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0187] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0188] Then, 2.74 g of hydroxyapatite hollow microspheres with a particle size of 20 to 50 μm were added to the gel and homogenized at 300 rpm for 30 min to obtain hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite with different degrees of association (the concentration of hollow microspheres was 25 w / w%).

[0189] Example 5: Preparation of biocompatible solid particle gels with different association degrees (HA:HPMC=1:3)

[0190] 2g of hyaluronic acid and 6g of hydroxypropyl methylcellulose were added to 44g of water and mixed at 500rpm at room temperature until uniform. 1g of sodium hydroxide (1M) solution was then added to the mixture to make the pH>12, and further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20-50μm were added to the mixture and mixed again at 300rpm for 30min. 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was then added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in an oven at 45°C for 3h and at 25°C for another 12h. 5g of hydrochloric acid (0.5M) was then added and the pH was adjusted to <7 to terminate the cross-linking reaction. The mixture was mixed at 300rpm for 10min to obtain a gel-like, slightly acidic composite gel between solid and liquid states containing hydroxyapatite hollow microspheres.

[0191] The resulting gel was washed dropwise with 300 mL of acetone to elute the BDDE while the gel solidified. The solidified product was collected by filtration and washed with anhydrous ethanol, followed by freeze-drying to obtain approximately 13 g of a solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0192] 1 g of solid powder was redissolved in 6.1 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0193] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0194] Then, 1.84 g of hydroxyapatite hollow microspheres with a particle size of 20 to 50 μm were added to the gel and homogenized at 300 rpm for 30 min to obtain hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite with different degrees of association (the concentration of hollow microspheres was 25 w / w%).

[0195] Comparative Example C1: Comparison of the association strength of hydroxyapatite hollow microspheres added at different steps

[0196] Sample C1 (product prepared in Example 1): The experimental method is the same as that in Example 4, except that 5.26 g of hydroxyapatite hollow microspheres are added only before the cross-linking reaction.

[0197] Comparative Example C2: Comparison of the association strength of hydroxyapatite hollow microspheres added at different steps

[0198] Sample C2: The experimental method is the same as that of Example 4, except that no hydroxyapatite hollow microspheres are added before the cross-linking reaction, and 5.26 g of hydroxyapatite hollow microspheres are added only after re-dissolution.

[0199] Comparison of the association strength of hydroxyapatite hollow microspheres in different samples.

[0200] Comparative Example C3: Preparation of gel without cellulose polysaccharide polymer

[0201] 2g of hyaluronic acid was added to 18g of water and mixed at 500rpm at room temperature until uniform. 1g of sodium hydroxide (1M) solution was then added to the mixture so that the pH was greater than 12, and further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20-50μm were added to the mixture and mixed again at 300rpm for 30min. 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was then added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in a 45°C oven for 3h and then at 25°C for another 12h. 5g of hydrochloric acid (0.5M) was then added, and the pH was adjusted to <7 to terminate the cross-linking reaction. The mixture was mixed at 300rpm for 10min to obtain a gel-like acidic hyaluronic acid gel between solid and liquid states containing hydroxyapatite hollow microspheres.

[0202] The resulting gel was washed dropwise into 300 mL of acetone, during which the BDDE was eluted and the gel solidified. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 7 g of hydroxyapatite-hyaluronic acid gel as a solid powder.

[0203] 1 g of solid powder was redissolved in 13.25 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid gel.

[0204] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0205] As shown in Table 1, the addition of the first biocompatible solid particles and the second biocompatible solid particles in the comparative example is shown.

[0206] Table 1 Biocompatible solid particles added in Comparative Examples C1-C3

[0207] Test 1 - Injectability Assay

[0208] The syringe push rod was pushed at a constant speed (30 mm / min) with a 27G needle installed during the experiment to simulate actual injection conditions. The push rod was pushed at a constant speed, forcing the sample in the syringe through the needle, generating a force curve. This force curve illustrates the variation in force during sample extrusion: low force facilitates sample extrusion; high force reduces sample extrusion; and large fluctuations in force indicate uneven sample dispersion or concentrated sample.

[0209] As shown in FIG2 , the results show that none of the five groups of samples in Examples 1, 2, 3, 4, and 5 exhibited uneven dispersion or aggregation and concentration. In addition, as the specific gravity of HPMC increased, the samples became increasingly difficult to extrude.

[0210] Testing the association strength of 2-hydroxyapatite

[0211] Method 1

[0212] Use an electronic balance to weigh 30 g of the re-dissolved gel and place it in a test tube. Leave it at room temperature for one week or even longer to observe the sedimentation of hydroxyapatite.

[0213] The products obtained in Example 1 and C3 were used to evaluate the carrying capacity of different gels for hydroxyapatite using the above method. As shown in FIG3 , it was found that the nanoclustered hydroxyapatite hollow microspheres in C3 had obvious sedimentation.

[0214] The results showed that the incorporation of HPMC could enhance the gel's carrying capacity for hydroxyapatite hollow microspheres.

[0215] Method 2

[0216] 1.5g of the re-dissolved gel was accurately weighed using an electronic balance and placed in a 2mL Eppendorf tube. The gel was symmetrically placed on an Eppendorf centrifuge and centrifuged at 3000rpm for 10min at 735g. After centrifugation, two phases were observed. The bottom portion of the centrifuge tube contained the hydroxyapatite particles separated from the gel, and the top portion contained a residual gel portion that had particles still attached to the gel. The two phases were separated, and hyaluronidase was used to digest the gel in the top phase. The hydroxyapatite particles were then washed with water and dried before weighing. The hydroxyapatite particles in the bottom phase were dried before weighing. The percentage of hydroxyapatite in each phase was then calculated to reflect the association strength of hydroxyapatite.

[0217] Table 2 Percentage of hydroxyapatite in homogeneous gels prepared with different ratios of HA to HPMC

[0218] The centrifugation results are shown in Table 2. The slight deviations of the hydroxyapatite hollow microsphere loading in Examples 2 to 5 from the theoretical 25 w / w% hydroxyapatite hollow microsphere loading, as well as the slight deviations of the hydroxyapatite hollow microsphere loading in Samples C1 and C2 from the theoretical 5 w / w% hydroxyapatite hollow microsphere loading, can be attributed to weighing errors.

[0219] The results showed that after centrifugation of the homogenous gel compositions of Examples 2, 3, and 4, the HAP in the upper phase still accounted for 69.96%, 83.53%, and 88.66% of the total HAP dry weight in the homogenous gel compositions. In contrast, after centrifugation of Samples C1 and C2, the HAP in the upper phase only accounted for 35.24% and 0.97% of the total HAP dry weight in the homogenous gel compositions. In Sample C2, nearly all particles (>99%) separated from the gel after centrifugation. In Example 4, the HA:HPMC ratio of 1:2 achieved the best association strength for the hydroxyapatite hollow microspheres.

[0220] The samples obtained in Example 1, Example 2, Example 3, Example 4 and Example 5 were filled and sterilized, and an accelerated stability test was carried out. The accelerated test storage conditions were: temperature 50°C ± 2°C, humidity 75% ± 5%.

[0221] Test 3 - Average Pushing Force Test

[0222] The syringe push rod was pushed at a constant speed (30 mm / min) and a 27G needle was attached to simulate actual injection conditions. The push rod was pushed at a constant speed, forcing the sample in the syringe through the needle. The force curve was generated and the average force value in the plateau region was recorded.

[0223] The average pushing force results are shown in Table 3. The results show that after the accelerated stability test was carried out for 3 months, the average pushing force of the samples did not change significantly.

[0224] Table 3 Average pushing force record of accelerated stability test samples

[0225] Testing the sedimentation of 4-hydroxyapatite

[0226] Methods: The samples were placed under accelerated test conditions and the hydroxyapatite sedimentation was observed regularly.

[0227] The sedimentation of hydroxyapatite is shown in Table 4 and the actual photos are shown in Figure 5. The results show that after 3 months of accelerated stability test, there is no obvious sedimentation of hydroxyapatite in the sample.

[0228] Table 4 Accelerated test sample hydroxyapatite association strength record

[0229] discuss

[0230] The craniofacial skeleton is fundamental to the aesthetic features of the human face, and therefore, facial bone sculpture may be a potential cosmetic procedure. Hydroxyapatite (HAP), as the primary mineral component of bone tissue, possesses excellent biocompatibility and osteoconductive properties and has been widely used as a bone substitute for many years. Furthermore, Youngmin H et al. added 0.5–1 w / w% HAP to a fructan-based hydrogel as a long-lasting dermal filler to enhance collagen production in vivo, thereby enhancing the filler's wrinkle-reducing effect. Experimental results also demonstrated that the addition of HAP promoted the proliferation of human dermal fibroblasts, improved the filler's in vivo stability, and promoted collagen production. While HAP can support the dermis and promote local collagen regeneration, its effect is slow to onset, resulting in imperfect early collagen production at the filler site. This can easily lead to secondary migration of HAP particles, resulting in poor clinical efficacy and the need for multiple revisions. Currently, researchers have developed a variety of polymer / HAP composite systems, including polymer binders such as collagen, sodium alginate, chitosan, carboxymethyl chitin, carboxymethyl cellulose, polyhydroxybutyrate, and hyaluronic acid. However, it is still difficult to solve the problem of secondary release of HAP particles in the composite system.

[0231] The gel material and injectable homogeneous gel composition of the present invention contain a composite structure composed of specific components, wherein hyaluronic acid, cellulose polysaccharide polymer and first biocompatible solid particles form a first mixture; in the presence of a cross-linking agent, the hyaluronic acid in the first mixture is cross-linked to form a cross-linked mixture. The mixture of the cross-linked component (Z2) hyaluronic acid and the component (Z3) cellulose-based polysaccharide polymer serves as a gel support skeleton for the first biocompatible solid particles of component (Z1), so that the first biocompatible solid particles have a high degree of association and a high load. In the injectable homogeneous gel composition of the present invention, the gel material of the present invention and the second biocompatible solid particles are adsorbed and physically mixed so that the second biocompatible solid particles have a low degree of association, thereby ultimately forming a homogeneous gel composition with high degree of association and low degree of association characteristics. Tests show that the homogeneous gel composition of the present invention contains at least two biocompatible solid particles with different degrees of association, so that the biocompatible solid particles are gradually released in the matrix, so that the biocompatible solid particles can be stably present in the composite system for a long time.

[0232] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A gel material, characterized in that: The gel material contains the following components: (Z1) first biocompatible solid particles; (Z2) hyaluronic acid; and (Z3) cellulose-based polysaccharide polymers; Wherein, the gel material is in solid powder or gel form.

2. The gel material according to claim 1, wherein The gel-like gel material has physical and chemical properties selected from the group consisting of: (a) the gel-like gel material comprises highly associative biocompatible solid particles; (b) the pH of the gelatinous gel material is 6-8; (c) The water content of the gel-like gel material is 75% to 95%.

3. The gel material according to claim 1, wherein The solid powdered gel material is formed by drying and crushing a gel-like gel material.

4. The gel material according to claim 1, wherein The hyaluronic acid in the gel material forms a mixture with the cellulose-based polysaccharide polymer, and the hyaluronic acid is cross-linked to form a gel composite support skeleton.

5. The gel material according to claim 1, wherein The first biocompatible solid particles of the component (Z1) and the gel composite support skeleton form a composite structure.

6. The gel material according to claim 1, wherein The first biocompatible solid particles are selected from the group consisting of calcium phosphate particles, silicate particles, calcium sulfate particles, ceramic particles, biological bone matrix particles, organic solid particles, or a combination thereof.

7. The gel material according to claim 1, wherein The cellulose-based polysaccharide polymer is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxyethyl hydroxyethyl cellulose, hydroxypropyl hydroxyethyl cellulose, methyl cellulose, methyl hydroxymethyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl methyl cellulose, or a combination thereof.

8. A method for preparing the gel material according to claim 1, characterized in that: The following steps are involved: (S1) providing a first mixture, wherein the first mixture comprises: hyaluronic acid, cellulose polysaccharide polymer and first biocompatible solid particles; (S2) in the presence of a cross-linking agent, causing the hyaluronic acid in the first mixture to undergo a cross-linking reaction, thereby forming to form a cross-linked mixture.

9. The preparation method according to claim 8, wherein The crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether, poly(ethylene glycol) diglycidyl ether, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, polyglycerol polyglycidyl ether, neopentyl glycol diglycidyl ether, ethylene glycol diglycidyl ether, or a combination thereof.

10. An injectable homogeneous gel composition, characterized in that The homogeneous gel composition comprises: (Y1) second biocompatible solid particles; and (Y2) The gel material according to claim 1.

11. The homogeneous gel composition according to claim 10, wherein (W1+W2) / W0=5:1-20:1; preferably 8:1-15:1; wherein W1 is the weight of the first biocompatible solid particles, W2 is the second biocompatible solid particles, and W0 is the weight of the reconstituted gel material (excluding the biocompatible solid particles).

12. The homogeneous gel composition according to claim 10, wherein The homogeneous gel composition has one or more characteristics selected from the following group: (a) the homogeneous gel composition comprises biocompatible solid particles with high and low association degrees; (b) the biocompatible solid particles in the homogeneous gel composition account for 2% to 95% of the dry weight of the homogeneous gel composition; (c) the hyaluronic acid content in the homogeneous gel composition is 5-40 mg / g, based on the weight of the homogeneous gel composition excluding the biocompatible solid particles; (d) The content of the cellulose-based polysaccharide polymer in the homogeneous gel composition is 2-80 mg / g, based on the weight of the homogeneous gel composition excluding the biocompatible solid particles.

13. A method for preparing the homogeneous gel composition according to claim 10, characterized in that: The following steps are involved: (S3) providing a second mixture, the second mixture comprising: the gel material in a gel state of claim 1 and second biocompatible solid particles, or the gel material in a solid powder state, second biocompatible solid particles, and water or an aqueous buffer solution; (S4) The second mixture is mixed to form a homogeneous gel composition.

14. Use of the homogeneous gel composition according to claim 10, characterized in that: The uses of the homogeneous gel composition include: dermal filling and bone sculpture and plastic surgery.

15. A kit, characterized in that The kit comprises the following components: the homogeneous gel material according to claim 1 or the homogeneous gel composition according to claim 10.

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