Modulus-controllable gel as well as preparation method and application thereof

Abstract

The invention discloses gel with controllable modulus as well as a preparation method and application of the gel. The structure of the gel is as follows: R1-X-R2, wherein R1 and R2 are both amino-containing macromolecules, and the amino-containing macromolecules are at least one of an amino-containing natural macromolecular compound and an amino-containing synthetic polymer; the energy storage modulus of the gel is 100 to 4000 Pa. In the invention, the gel is formed by cross-linking an amino-containing polymer and a carbonyl-containing X linking group through an amido bond, the structure of X is derived from a homodifunctional N-hydroxysuccinimide ester cross-linking agent, and the chain length of the X can be accurately regulated and controlled by selecting diacids with different carbon atom numbers or polyethylene glycol with different molecular weights. The influence of cross-linking agents with different chain lengths on the gel modulus is systematically researched, so that the energy storage modulus of the gel is adjustable in a range of 100-4000 Pa, and a gel scheme with accurately matched energy storage modulus is provided for different clinical application scenes.

Description

Technical Field

[0001] This invention relates to the field of gel preparation technology, specifically to a gel with controllable modulus, its preparation method, and its applications. Background Technology

[0002] Injectable gels, as tissue fillers, have wide applications in medical aesthetics and soft tissue repair. Their core performance indicator—storage modulus (G')—directly determines the gel's support capacity, shaping effect, and mechanical compatibility with surrounding tissues within the body. Different clinical applications place varying demands on gel modulus: for example, filling superficial wrinkles requires soft gels with low modulus (approximately 150-500 Pa) to achieve a natural feel; while deep tissue support or volume filling requires strong gels with high modulus (approximately 1000 Pa or higher) to provide lasting mechanical support.

[0003] In existing technologies, commercially available filling gels mostly use hyaluronic acid (HA) as a matrix and are cross-linked using chemical cross-linking agents (such as BDDE). Their modulus adjustment range is narrow, mostly limited to the hundreds of Pa level, making it difficult to simultaneously cover the wide range of needs for both shallow filling and deep support. Chinese patent document CN114621465A discloses a collagen gel prepared through self-assembly, but the adjustable range of its storage modulus is only 0.3~1 kPa, still unable to meet the differentiated needs of various applications. Chinese patent document CN119632911A discloses a drug-loaded silk fibroin gel, which, although its storage modulus can be adjusted to over 10 kPa, carries the risk of toxic residues from the butylene glycol glycidyl ether cross-linking agent used, and the high cross-linking density often leads to gel embrittlement, sacrificing the material's flexibility.

[0004] In recent years, homologous bifunctional N-hydroxysuccinimide ester (NHS-ester) crosslinking agents have attracted attention due to their mild reaction conditions and excellent biocompatibility. For example, Chinese patent document CN121371310A discloses a polyethylene glycol derivative-collagen injectable cartilage repair gel, which uses polyethylene glycol disuccinimide succinate (SS-PEG-SS) as a crosslinking agent, combined with collagen and polydeoxyribonucleotides (PDRN) and other components for cartilage repair. However, the inventive point of this technical solution lies in the synergistic repair effect of multiple components. Its gel system contains multiple functional components such as collagen, PDRN, and tannic acid. It has not systematically studied the regulatory law of the crosslinking agent structure itself on the mechanical properties of the gel, nor revealed the intrinsic relationship between the crosslinking agent chain length and the gel modulus, nor established the correspondence between the modulus and different clinical application scenarios.

[0005] In fact, homocysteine ​​bifunctional NHS-ester crosslinking agents possess structural designability; their molecular chain length (i.e., the length of the spacer arm between two NHS-ester groups) can be precisely controlled by selecting diacids with different carbon numbers or polyethylene glycols with different molecular weights. Theoretically, different chain lengths lead to differences in the distance between crosslinking points, thereby affecting the density and macroscopic mechanical properties of the gel network. However, existing technologies have not systematically studied the influence of crosslinking agents with different chain lengths on gel modulus, nor have they established a technical solution based on this strong correlation between "crosslinking agent structure - gel modulus - application scenario".

[0006] Therefore, how to utilize the structural designability of homologous bifunctional NHS-ester crosslinking agents to achieve precise control of gel modulus over a wide range while ensuring biosafety, and to match it with different clinical application scenarios, is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0007] Existing injectable filler gels generally face the following technical bottlenecks: First, their modulus coverage is narrow, with most existing products limited to the 100 Pa level, making it difficult to simultaneously meet the differentiated clinical needs of superficial filling (requiring low modulus) and deep support (requiring high modulus). Second, there is a lack of systematic research on the relationship between crosslinking agent structure and modulus regulation from the perspective of gel structure design. Existing technologies, such as CN121371310A, disclose composite gels containing multiple components (collagen, PDRN, tannic acid), but their invention focuses on the synergistic repair effect of multiple components, without revealing the influence of crosslinking agent chain length on modulus, nor establishing the correspondence between modulus and different application scenarios. Third, high-modulus gels often rely on toxic crosslinking agents or high-density crosslinking, posing potential biosafety risks. Therefore, there is an urgent need to develop a gel material with a clear structure, a wide and controllable modulus range, and precise matching with clinical application scenarios.

[0008] To solve the above-mentioned technical problems, the present invention provides a gel with controllable modulus, the structure of which is shown in formula (I): R1-X-R2 Equation (I) Where X is , , One of them, n≥0, m≥1, "Indicates a connection site; R1 and R2 are both amino-containing polymers, and the amino-containing polymers are at least one of amino-containing natural polymers and amino-containing synthetic polymers. The storage modulus of the gel is 100~4000 Pa.

[0009] In this invention, the gel is formed by crosslinking amino-containing polymers (R1 and R2) with carbonyl-containing linking groups X via amide bonds. The structure of X is derived from a homobifunctional N-hydroxysuccinimide ester crosslinking agent, and its chain length (i.e., the length of the spacer arm between the two NHS-ester groups) can be precisely controlled by selecting diacids with different carbon atom numbers or polyethylene glycols with different molecular weights. Through systematic research on the influence of crosslinking agents with different chain lengths on the gel modulus, the storage modulus of the gel can be controlled, making the storage modulus adjustable within the range of 100–4000 Pa. This invention establishes a correspondence between "crosslinking agent structure and gel modulus," providing a gel solution with precisely matched storage modulus for different clinical applications.

[0010] Preferably, when X in the gel structure is At that time, the gel modulus was 200~450 Pa; When X is When n≥3, the storage modulus of the gel is 100~3300 Pa; When X is When m≥10, the storage modulus of the gel is 200~400 Pa.

[0011] In this invention, by adjusting the different types and chain lengths of X, gel structures with different energy storage moduli are obtained to adapt to different application scenarios.

[0012] Preferably, the gel has a thixotropic index of 2-8, a cohesive strength of 0.01-2 g, and a normal force of 0.1-5 N. The gel of the present invention also possesses the above-mentioned rheological properties, exhibits excellent injection performance and in vivo support capabilities, and can be used as an injectable gel as a tissue filling material.

[0013] Preferably, the amino-containing natural polymeric compounds include proteins, polysaccharides, and nucleic acids, specifically collagen, silk fibroin, chitosan, carboxymethyl chitosan, polydeoxyribonucleotides, or polynucleotides; the amino-containing synthetic polymer is polylysine.

[0014] The present invention also provides a method for preparing the above-mentioned gel, comprising the following steps: (1) Dissolve the amino-containing polymer in a solvent and adjust the pH to 7-9 to obtain component B; (2) The crosslinking agent of the isotype bifunctional N-hydroxysuccinimide ester is dissolved in solvent A to obtain component A; (3) Mix component A and component B, and then perform a cross-linking reaction to obtain a gel; The crosslinking agent of the homo-bifunctional N-hydroxysuccinimide ester has the structure shown in formula (II).

[0015] Formula (II) Among them, Linker is , , One of them, n≥0, m≥1, " " indicates a connection point.

[0016] In this invention, the linker of the crosslinking agent of the homobifunctional N-hydroxysuccinimide ester corresponds to the X group in the gel structure. By adjusting the type of crosslinking agent and the length of the linker, the storage modulus of the resulting gel can be adjusted. Furthermore, this invention also allows for controllable adjustment of the gel modulus by adjusting the mass ratio of the crosslinking agent to the amino-containing polymer.

[0017] Preferably, the mass ratio of the crosslinking agent of the homodifunctional N-hydroxysuccinimide ester to the amino-containing polymer is 1:1 to 1000.

[0018] Preferably, the gel has a pushing force of 1~60 N, which allows for smooth injection under a 27G needle and provides good needle penetration; the swelling rate is 100%~500%, and the volume stability after implantation is good; the residual amount of cross-linking agent in the gel is less than 1 ppm, and the biocompatibility is excellent.

[0019] This invention also provides the application of the above-mentioned gel in the preparation of injectable filler materials or wound dressings. Preferably, the injectable filler material includes a low-modulus gel for filling superficial wrinkles and a high-modulus gel for supporting deep tissues, wherein the storage modulus of the low-modulus gel is 100~300 Pa and the storage modulus of the high-modulus gel is 1000~4000 Pa.

[0020] Compared with the prior art, the present invention has the following beneficial effects: (1) Establish a strong correlation between “crosslinker structure-gel modulus-application scenario”. This invention systematically studies the influence of crosslinkers of different chain lengths of isomorphous bifunctional N-hydroxysuccinimide esters on gel modulus, reveals the intrinsic correlation between crosslinker chain length and energy storage modulus, and accurately matches different modulus ranges with specific clinical application scenarios (shallow filling, deep support).

[0021] (2) Wide range of precisely controllable modulus. By selecting crosslinking agents of different chain lengths (from short-chain DSC to long-chain NHS-PEG-NHS) and / or adjusting the mass ratio of the crosslinking agent to the amino-containing polymer, this invention achieves continuous adjustment of the gel storage modulus within the range of 100~4000 Pa, covering clinical needs from shallow filling (100~300 Pa) to deep support (1000~4000 Pa). Compared with existing commercial products (whose modulus is mostly limited to the hundred Pa level), the modulus control range of this invention is wider and the matching is better.

[0022] (3) Excellent biocompatibility. This invention uses a homodifunctional NHS-ester crosslinking agent, which reacts with amino-containing polymers under mild conditions of pH 7-9 to form stable amide bonds. The only byproduct is non-toxic N-hydroxysuccinimide (NHS), which is easy to wash away. The measured residual amount of crosslinking agent is less than 1 ppm, which is far lower than the residual levels of traditional crosslinking agents such as glutaraldehyde and BDDE, meeting the biocompatibility requirements for implantable materials.

[0023] (4) Both injection performance and in vivo stability are taken into account. The gel of the present invention has a suitable thixotropic index (2~8), extrusion force (1~60 N) and swelling rate (100%~500%), which not only ensures the needle penetration of clinical injection, but also provides lasting mechanical support after implantation, avoiding volume loss caused by excessive swelling or rapid degradation.

[0024] (5) Simple composition and controllable process. The gel of the present invention consists of only two necessary components: an amino-containing polymer and a cross-linking agent. The composition is simple, the quality is easy to control, and the preparation process is green and easy to scale up for production. Attached Figure Description

[0025] Figure 1 This is a state diagram of the syringe injection process in Example 1.

[0026] Figure 2 This is a state diagram of the syringe injection process in Example 3.

[0027] Figure 3 This is a microscopic morphology diagram of Example 1.

[0028] Figure 4 This is a microscopic morphology diagram of Example 4.

[0029] Figure 5 This is a microscopic morphology diagram of Example 12.

[0030] Figure 6 This is a rheological curve diagram of Example 3.

[0031] Figure 7 This is a rheological curve for Comparative Example 2.

[0032] Figure 8 The figures show the pushing force curves for Examples 1-3.

[0033] Figure 9 This is a graph showing the pushing force curve of Example 6.

[0034] Figure 10 This is a graph showing the pushing force curve of Example 14. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0036] All raw materials used in this invention are commercially available.

[0037] Example 1 (1) Dissolve bis(succinimide) octanoate (DSS, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., product number: D596968-1g) in DMSO to obtain a 0.2 g / mL DSS solution, i.e. component A; (2) Collagen (COL, purchased from Hangzhou Meiliu Biotechnology Co., Ltd., collagen type is recombinant type III humanized collagen) was dissolved in PBS and adjusted to pH 8 to obtain component B, i.e. 20% COL solution; (3) Mix component A solution and component B at a ratio of 1:10 and crosslink at 37 °C. Quench unreacted crosslinking agent with Tris-HCl solution at pH 7.5 (Sangon Biotech (Shanghai) Co., Ltd.), and dialyze with pure water and PBS. The DSS@COL-high crosslinked gel is obtained by sieving.

[0038] Examples 2-15 The preparation methods of Examples 2-15 are the same as those of Example 1, with the differences shown in Table 1.

[0039] Comparative Example 1 (1) Dissolve bis(succinimide) octanoate (DSS, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., product number: D596968-1g) in DMSO to obtain a 0.2g / mL DSS solution, i.e. component A; (2) Dissolve hyaluronic acid in PBS and adjust the pH to 8 to obtain component B, i.e., 20% HA solution; (3) When component A solution and component B are mixed at a ratio of 1:10 and allowed to stand at 37 °C for 3 h for cross-linking, the solution does not gel.

[0040] Comparative Example 2 (1) Collagen (COL, purchased from Hangzhou Meiliu Biotechnology Co., Ltd., collagen type is recombinant type III humanized collagen) was dissolved in PBS and adjusted to pH 5.5 to obtain a 20% COL solution; (2) Add EDC and NHS to the above 1 mL COL solution at a ratio of 2:1. The mass ratio of crosslinking agent to COL is 1:4. After activation for 30 min, adjust the pH to 7.5, stir thoroughly, and let it stand at 37 °C for 3 h for crosslinking. Dialyze with pure water and PBS, and sieve to obtain EDC / NHS@COL gel.

[0041] Comparative Example 3 (1) Add collagen (COL) to PBS, stir to dissolve completely, and adjust to pH 8 to obtain a 20% COL solution; (2) Prepare a 0.5% glutaraldehyde solution and add it to the above 1 mL COL solution. The mass ratio of crosslinking agent to COL is 1:500. Stir thoroughly and let stand at 37 °C for 3 h for crosslinking. Dialyze with pure water and PBS and sieve to obtain GA@COL gel.

[0042] Table 1: Differences between Examples 1-15 and Comparative Examples 1-3

[0043] Sample testing I. Degree of cross-linking The absorbance of collagen before and after cross-linking was determined using the ninhydrin colorimetric method, and the degree of cross-linking was calculated using the following formula:

[0044] The crosslinking degree of Example 1, calculated using the formula for crosslinking degree (%), is 96%. Figure 1 It can be seen that when the crosslinking degree reaches 96%, the gel exhibits excellent shear-thinning behavior, forming a uniform and continuous filamentous gel during syringe injection, without droplet formation or flow interruption, and achieving "shear-self-healing" characteristics. Based on the crosslinking degree (%) formula, the crosslinking degree of Example 3 is calculated to be 40%. Figure 2 As shown, when the degree of crosslinking reaches 40%, the cohesive force of the gel is low, and it is extruded in the form of discontinuous droplets when passing through a syringe.

[0045] II. Microscopic Morphology The cross-section of the lyophilized gel was observed using a scanning electron microscope (Regulus 8230). Figure 3 The image shows the microstructure of the DSS@COL gel prepared in Example 1. It has a honeycomb structure with uniformly distributed pores. Figure 4The image shows the microstructure of the NHS-PEG8000-NHS@COL gel prepared in Example 4. The pores are of varying sizes and the cross-section is uneven. Figure 5 The image shows the microstructure of the DSS@CS gel prepared in Example 12, which exhibits a layered structure with narrow and elongated pores.

[0046] III. Thixotropic Index Viscosities at shear rates of 0.1 rad / s and 1 rad / s were determined using a rotational rheometer (TA, Discovery HR-2). The thixotropic index was obtained using the following formula. Each sample was measured three times, and the average value was used for calculation. Method: Flow-Peak hold mode, 20 mm plate clamp, sample volume 0.3 mL, scan time 120 s, gap value 500 μm, temperature 25 ℃.

[0047]

[0048] Table 2 shows the thixotropic index of Examples 1-3.

[0049] As shown in Table 2, by measuring the gel viscosity at high shear rates (1 rad / s) and low shear rates (0.1 rad / s), the results indicate that the material possesses both "solid" (at rest) and "liquid" (under shear) behaviors, objectively reflecting the degree of gel shear thinning behavior and its recovery ability after deformation. A higher thixotropic index indicates that the material can immediately recover to a gel state after injection into the target site, providing mechanical support.

[0050] IV. Cohesion After cleaning and sieving the gel (100 mesh), the gel was loaded into a 1 mL syringe and extruded at a constant speed of 7.5 mm / min in a tensile testing machine (CMT 5205, MTES Industrial Systems Co., Ltd.). The range was unlimited. The sample in the syringe was pushed out through a 27G needle. After the extrusion force curve stabilized, ten drops of gel were weighed. The gel weight was used to characterize the gel cohesive force.

[0051] Table 3 shows the cohesive strength of Examples 1-3 and Comparative Examples 2-3.

[0052] The cohesive forces of Examples 1-3 are shown in Table 3. The higher the mass ratio of crosslinking agent to collagen, the higher the degree of crosslinking, the lower the toughness, and the weaker the adhesion between molecules, which shows a decrease in cohesive force. This can be controlled by adding linear polymers.

[0053] V. Normal Force The normal force at a gap of 1100 μm was determined using a rotational rheometer (TA, Discovery HR-2). Method: Other-Axial mode was used, with Compression selected, Distance set to 500 μm, and gap speed set to 1.0 μm / s. A 25 mm-2° cone plate was used as the fixture, with a sample volume of 1 mL, a gap of 1500 μm, and a temperature of 25 °C. The normal force at a gap of 1100 μm was recorded, and the test was performed in triplicate.

[0054] Table 4 shows the normal forces in Examples 1-3 and Comparative Examples 2-3.

[0055] According to the results in Table 4, the normal force in Examples 1-3 is greater than 2N, which is suitable for the natural modulus of the tissue, provides sufficient mechanical support, and is not easily deformed or displaced. The normal force in the comparative example is less than 0.1N, which is easily dispersed and causes displacement during subcutaneous filling, resulting in insufficient shaping.

[0056] VI. Modulus The storage modulus G' and loss modulus G” at a frequency of 1 Hz were determined using a rotational rheometer (TA, Discovery HR-2). Methods: Frequency mode, 20 mm plate clamp, 0.3 mL sample volume, frequency range 0.1–100 Hz, strain 1%, gap 500 μm, temperature 25 ℃.

[0057] according to Figure 6 As shown, in Example 3, the energy storage modulus is 392.9 Pa and the loss modulus is 52.2 Pa at a frequency of 1 Hz. According to... Figure 7 As shown, the EDC / NHS@COL gel prepared in Comparative Example 2 has a storage modulus of 93.1 Pa at a frequency of 1 Hz, which is about 300 Pa lower than that of the DSS@COL-low crosslinked gel in Example 3.

[0058] Table 5 compares the energy storage modulus and loss modulus of the examples and comparative examples at a frequency of 1 Hz.

[0059]

[0060] VII. Pushing force The cleaned and sieved gel (100 mesh) was loaded into a 1 mL syringe and extruded at a constant speed of 32.34 mm / min on a tensile testing machine (CMT 5205, METS Industrial Systems Co., Ltd.). The range was 10 mm. The sample in the syringe was pushed out through a 27G needle, and the extrusion force curve was obtained.

[0061] Figure 8 The graphs show the pushing force curves for Examples 1-3. Example 1 has the highest degree of crosslinking, with a pushing force of around 55N when passing through a 27G needle. By reducing the mass ratio of crosslinking agent to collagen, the pushing forces of Examples 2 and 3 decreased to 25N and 15N, respectively. Figure 9 The graph shows the extrusion force curve of the DSG@COL gel prepared in Example 6. The extrusion force of the DSG@COL gel stabilizes at around 4 N when passing through a 27G needle. Figure 10 The extrusion force curve of the DSS@PDRN gel prepared in Example 14 shows that the extrusion force of the DSS@PDRN gel stabilizes at around 2.5 N when passing through a 27 G needle, which meets the requirements for shallow injection.

[0062] VIII. Swelling Properties Swelling performance tests were conducted on Examples 13-15. The gels were freeze-dried and weighed, with the dry weight recorded as W0. The gels were then completely immersed in 50 mL of 1X PBS buffer and allowed to stand at room temperature. At different time points, the gels were removed, and the surface moisture was wiped dry with filter paper, with the wet weight recorded as W1, until swelling equilibrium was reached. The swelling ratio was calculated using the following formula.

[0063]

[0064] Table 6 shows the swelling rates of Examples 1-3.

[0065] As shown in Table 6, all samples swelled rapidly within the first 60 minutes, then gradually slowed down to equilibrium. Example 3, with the lowest crosslinking agent content, had a loose gel network, strong water absorption capacity, and the highest swelling rate. Example 1, with the highest crosslinking agent content, formed a dense gel network, limiting swelling and resulting in the lowest swelling rate.

[0066] IX. Crosslinking agent residue test The residual amounts of DSS crosslinking agent and its byproduct NHS in Examples 1-3 were detected by time-of-flight mass spectrometry. The specific methods are as follows: 1. Preparation of standard solutions DSS and NHS standard solutions were prepared using acetonitrile at concentrations of 1 μg / mL, 2.5 μg / mL, 5 μg / mL, 10 μg / mL, and 25 μg / mL, respectively.

[0067] 2. Sample solution preparation Weigh 1 g of the washed gel, add 10 mg of collagenase (200 U / mg), and 1 mL of 1X PBS. Incubate at 37 °C with shaking for 12 h. Add 2 volumes of acetonitrile to precipitate, vortex thoroughly, and then centrifuge at 12000 rpm for 15 minutes. Pivot 1 mL of the supernatant, filter through a 22 μm filter membrane, and transfer to a sample vial.

[0068] 3. Time-of-flight mass spectrometry (LC-Q-TOF) detection DSS and NHS residues were detected by mass spectrometry according to General Chapter 0431 of Part IV of the 2015 edition of the Pharmacopoeia of the People's Republic of China, with DSS detected in positive ion mode and NHS detected in negative ion mode.

[0069] Table 7 shows the DSS and NHS residues in Examples 1-3.

[0070] As shown in Table 7, no DSS cross-linking agent residue was detected, and the residual amount of the byproduct NHS was less than 1 ppm. This is because the NHS esters at both ends of the DSS cross-linking agent undergo a highly efficient nucleophilic reaction with the primary amines on the collagen surface, forming stable amide bonds and releasing NHS. During the cross-linking reaction, the formation of amide bonds makes the collagen network structure more compact, resulting in a large number of small NHS molecules generated during the reaction being physically captured in the pores of the collagen gel. Theoretically, increasing the number of water changes or extending the washing time can completely remove DSS and NHS.

[0071] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A gel with controllable modulus, characterized in that, The structure of the gel is shown in formula (Ⅰ): R1-X-R2 Equation (I) Where X is , , One of them, n≥0, m≥1, "Indicates a connection site; R1 and R2 are both amino-containing polymers, and the amino-containing polymers are at least one of amino-containing natural polymers and amino-containing synthetic polymers. The storage modulus of the gel is 100~4000 Pa.

2. The modulus-controllable gel according to claim 1, characterized in that, When X in the gel structure is At that time, the gel modulus was 200~450 Pa; When X is When n≥3, the storage modulus of the gel is 100~3300 Pa; When X is When m≥10, the storage modulus of the gel is 200~400 Pa.

3. The gel according to claim 1, characterized in that, The gel has a thixotropic index of 2 to 8, a cohesive force of 0.01 to 2 g, and a normal force of 0.1 to 5 N.

4. The gel according to claim 1, characterized in that, The amino-containing natural polymers are protein polymers, polysaccharide polymers, and nucleic acid polymers; the amino-containing synthetic polymer is polylysine.

5. The method for preparing the gel according to any one of claims 1 to 4, characterized in that, Includes the following steps: (1) Dissolve the amino-containing polymer in a solvent and adjust the pH to 7-9 to obtain component B; (2) The crosslinking agent of the isotype bifunctional N-hydroxysuccinimide ester is dissolved in solvent A to obtain component A; (3) Mix component A and component B, and then perform a cross-linking reaction to obtain a gel; The crosslinking agent of the homo-bifunctional N-hydroxysuccinimide ester has the structure shown in formula (II). Formula (II) Among them, Linker is , , One of them, n≥0, m≥1, " " indicates a connection point.

6. The method for preparing the gel according to claim 5, characterized in that, The mass ratio of the crosslinking agent to the amino-containing polymer in the homo-bifunctional N-hydroxysuccinimide ester is 1:1 to 1000.

7. The method for preparing the gel according to claim 5, characterized in that, The extrusion force of the gel is 1~60N; the swelling rate is 100%~500%.

8. The method for preparing the gel according to claim 5, characterized in that, The residual amount of crosslinking agent in the gel is less than 1 ppm.

9. The use of the gel according to any one of claims 1 to 4 in the preparation of injectable filler materials or wound dressings.

10. The application according to claim 9, characterized in that, The injectable filler material includes a low-modulus gel for filling superficial wrinkles and a high-modulus gel for supporting deep tissues, wherein the storage modulus of the low-modulus gel is 100~300 Pa and the storage modulus of the high-modulus gel is 1000~4000 Pa.

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