Injectable composite bone repair hydrogel as well as preparation method and application thereof

Abstract

The invention discloses injectable composite bone repair hydrogel as well as a preparation method and application thereof. The preparation method of the hydrogel comprises the following steps: firstly, preparing oxidized dextran (ODe), phenylboronic acid modified chitosan (CSPBA), branched polyethyleneimine (PEI) and nano-hydroxyapatite (QCHA) synthesized by taking chitosan quaternary ammonium salt as a template; mixing an ODe solution with QCHA powder, uniformly oscillating, mixing with a CSPBA solution, quickly adding a PEI solution of which the pH value is adjusted, and transiently oscillating and standing to obtain the composite hydrogel. The QCHA is physically blended in the hydrogel network. The composite hydrogel prepared by the invention has fast and controllable gelling time, shows better storage modulus and compressive strength by virtue of the physical enhancement synergistic effect of Schiff base, dynamic reversible boric acid ester bonds and QCHA, and is suitable for being used as an injectable material to be applied to the field of minimally invasive bone defect repair.

Description

Technical Field

[0001] This invention relates to an injectable composite bone repair hydrogel, its preparation method and application, belonging to the field of biomedical polymer materials technology. Background Technology

[0002] Bone defects caused by trauma, tumors, or congenital factors severely impact patients' limb function and quality of life, representing a significant and ongoing clinical concern in orthopedics. Injectable hydrogels have garnered significant attention due to their ability to fill irregular defects minimally invasively, their high biocompatibility with surrounding tissues, and their ability to accelerate tissue repair. An ideal bone repair hydrogel requires an appropriate gelation time for ease of manipulation and provides mechanical support that matches that of natural bone. Currently, many injectable hydrogels face challenges such as slow gelation rates, reliance on external conditions for gelation, or difficulty in achieving an effective balance and synergy between gelation rate and mechanical properties. Therefore, the development of an injectable composite hydrogel that gels rapidly and possesses good mechanical support properties is essential. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides an injectable composite bone repair hydrogel, its preparation method, and its applications. This invention achieves the composite hydrogel through the synergistic preparation of multiple polymer networks and inorganic nanoparticles. The hydrogel prepared by this invention exhibits rapid and controllable gelation time and good mechanical properties, allowing for direct in-situ injection into bone defects for minimally invasive filling and support.

[0004] This invention is achieved through the following technical solution: The first objective of this invention is to provide a method for preparing an injectable composite bone repair hydrogel, comprising the following steps: S1. Mix the oxidized dextran solution with the hydroxyapatite powder and shake until homogeneous; S2. Then add phenylboronic acid modified chitosan solution and branched polyethyleneimine solution, shake rapidly to homogenize, and let stand to obtain the injectable composite bone repair hydrogel. Among them, by adjusting the ratio of oxidized dextran to branched polyethyleneimine, the total molar ratio of amino and aldehyde groups in the hydrogel system was controlled to be 1.0-1.5:1; the grafting rate of phenylboronic acid in phenylboronic acid modified chitosan was 50%-60%.

[0005] In one embodiment of the present invention, the hydroxyapatite powder is synthesized using chitosan quaternary ammonium salt as a template.

[0006] In one embodiment of the present invention, the hydroxyapatite powder accounts for 1%-5% of the mass fraction of the hydrogel, calculated by solid mass.

[0007] In one embodiment of the present invention, the hydroxyapatite powder is specifically prepared by the following method: Chitosan quaternary ammonium salt and Na2PO4 were dissolved in water and stirred until homogeneous. The mixture was then heated to 80-100 °C and 0.4-0.6 M CaCl2 solution was slowly added dropwise under mechanical stirring. The pH of the reaction system was adjusted to 9-11 with NaOH solution. After the reaction, the mixture was centrifuged to obtain a white precipitate. The precipitate was washed and dried to obtain the hydroxyapatite powder.

[0008] In one embodiment of the present invention, the mass fraction of oxidized dextran in the oxidized dextran solution is 5%-10%.

[0009] In one embodiment of the present invention, the degree of oxidation of the oxidized dextran is 20%-40%.

[0010] In one embodiment of the present invention, the oxidized dextran is prepared by the following method: Sodium periodate solution was added to dextran solution, and the reaction was carried out in a dark environment. Ethylene glycol was added to terminate the reaction. The reaction solution was dialyzed and freeze-dried to obtain oxidized dextran with an oxidation degree of 20%-40%.

[0011] In one embodiment of the present invention, the mass fraction of phenylboronic acid-modified chitosan in the phenylboronic acid-modified chitosan solution is 2%-3%.

[0012] In one embodiment of the present invention, the phenylboronic acid-modified chitosan is prepared by the following method: Chitosan was dissolved in acetic acid to prepare a chitosan solution. 3-Carboxyphenylboronic acid and NHS were dissolved in methanol and stirred. Then, EDC-HCl was added to dissolve the mixture and added to the chitosan solution. After stirring and reacting, the reaction solution was dialyzed and freeze-dried to obtain phenylboronic acid-modified chitosan with a grafting rate of 50%-60%.

[0013] In one embodiment of the present invention, the branched polyethyleneimine solution has a mass fraction of 10%-20% and a pH of 8.0-9.0.

[0014] In one embodiment of the present invention, the mass fraction of oxidized dextran in the hydrogel is 2%-3% by solid mass, the mass fraction of phenylboronic acid modified chitosan in the hydrogel is 0.1%-1% by solid mass, and the mass fraction of branched polyethyleneimine in the hydrogel is 6%-8% by solid mass.

[0015] A second objective of this invention is to provide an injectable composite bone repair hydrogel prepared by the aforementioned preparation method.

[0016] A third objective of this invention is to provide the application of the injectable composite bone repair hydrogel in the preparation of bone repair filler materials.

[0017] The beneficial effects of this invention are: This invention involves mixing ODe solution with QCHA powder, agitating to achieve homogeneity, then mixing with CSPBA solution, followed by rapid addition of a pH-adjusted PEI solution, and brief agitation followed by standing to obtain a composite hydrogel. The composite hydrogel prepared by this invention exhibits rapid and controllable gelation time. Relying on the synergistic effect of Schiff bases, dynamically reversible borate ester bonds, and the physical reinforcing properties of QCHA, it demonstrates good storage modulus and compressive strength, making it suitable as an injectable material for minimally invasive bone defect repair. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 The diagram shows the rheological storage modulus test results of hydrogels with different components according to the present invention. Figure 2 The diagram shows the compressive stress of different components of the hydrogel of this invention under 80% compressive strain.

[0020] Figure 3 This is a gel time diagram of different component hydrogels of the present invention, determined by the inverted bottle method. Detailed Implementation

[0021] The present invention will be further illustrated below with specific examples. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0022] Source of raw materials Sources of raw materials used in the examples: The dextran was purchased from Shanghai Myriel Biochemical Technology Co., Ltd. Chitosan was purchased from Shanghai Biede Pharmaceutical Technology Co., Ltd. Chitosan quaternary ammonium salt (QCS) was purchased from Shanghai Mairui Biochemical Technology Co., Ltd. Polyethyleneimine (PEI) was purchased from Shanghai Titan Technology Co., Ltd. Hydrochloric acid was purchased from Sinopharm Technology Co., Ltd. Acetic acid was purchased from Sinopharm Technology Co., Ltd. 3-Carboxyphenylboronic acid was purchased from Leyan Technology Co., Ltd. Ethylene glycol was purchased from Shanghai Mairui Biochemical Technology Co., Ltd. Anhydrous disodium hydrogen phosphate was purchased from Shanghai Mairui Biochemical Technology Co., Ltd. Calcium chloride solution was purchased from Shanghai Mairui Biochemical Technology Co., Ltd. Phosphate buffer was purchased from Shanghai Mairui Biochemical Technology Co., Ltd. N-hydroxysuccinimide (NHS) was purchased from Shanghai Mairui Biochemical Technology Co., Ltd. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) was purchased from Beijing Innocare Technology Co., Ltd. The preparation methods of ODe, CSPBA1, CSPBA1.5, and QCHA powders used in this invention are as follows: (1) Synthesis of ODE from oxidized dextran: 5 g of dextran was dissolved in 80 mL of deionized water, and 2.37 g of sodium periodate was dissolved in 40 mL of deionized water and then added to the dextran solution. The reaction was carried out in the dark for 4 h, and then 0.6 mL of ethylene glycol was added to terminate the reaction for 30 min. The reaction solution was dialyzed for 3 days and freeze-dried to obtain ODE with a degree of substitution of about 26%.

[0023] (2) Synthesis of phenylboronic acid modified chitosan CSPBA1 and CSPBA1.5: 0.5 g of chitosan was dissolved in 60 mL of 0.3wt% acetic acid to prepare CS solution. 0.38 g and 0.57 g of 3-carboxyphenylboronic acid and 246 mg of NHS were dissolved in 40 mL of methanol and stirred for 30 min. Then, 332 mg of EDC-HCl was added and dissolved, and then added to the CS solution. After stirring for 24 h, the reaction solution was dialyzed for 3 days and freeze-dried to obtain CSPBA1 with a grafting rate of 42% and CSPBA1.5 with a grafting rate of 57%, respectively.

[0024] (3) Synthesis of nano-hydroxyapatite QCHA powder: 1 g of chitosan quaternary ammonium salt (QCS) and 2.13 g of Na2PO4 were dissolved in 50 mL of deionized water and stirred at room temperature for 30 min. Then the temperature was raised to 90 °C, and 50 mL of 0.5 M CaCl2 solution was slowly added dropwise under mechanical stirring. The pH of the reaction system was adjusted to about 10 with 1 M NaOH solution. After reacting for 2 h, a white precipitate was obtained by centrifugation. The precipitate was washed 3 times and then freeze-dried to obtain QCHA powder.

[0025] The technical solution of the present invention will be described in detail below with reference to specific embodiments. In the following embodiments, unless otherwise specified, the reagents, materials and equipment used can be purchased commercially, prepared by conventional methods, or commonly used in the industry.

[0026] Example 1: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0027] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0028] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0029] (4) Take 1380 μL of ODe solution, add 320 μL of PBS buffer and 40 mg of QCHA powder and shake well. Then add 800 μL of CSPBA1.5 solution and 1500 μL of PEI solution, shake rapidly for 1 s and pour into a mold. Let stand to obtain PEI7.5 / ODe / CSPBA1.5 / QCHA1 composite hydrogel.

[0030] Example 2: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0031] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0032] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0033] (4) Take 1380 μL of ODe solution, add 320 μL of PBS buffer and 120 mg of QCHA powder and shake well. Then add 800 μL of CSPBA1.5 solution and 1500 μL of PEI solution, shake rapidly for 1 s and pour into a mold. Let stand to obtain PEI7.5 / ODe / CSPBA1.5 / QCHA3 composite hydrogel.

[0034] Example 3: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0035] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0036] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0037] (4) Take 1380 μL of ODe solution, add 320 μL of PBS buffer and 200 mg of QCHA powder and shake well. Then add 800 μL of CSPBA1.5 solution and 1500 μL of PEI solution, shake rapidly for 1 s and pour into a mold. Let stand to obtain PEI7.5 / ODe / CSPBA1.5 / QCHA5 composite hydrogel.

[0038] Comparative Example 1: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0039] (2) Weigh 0.25 g of CSPBA1 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1 solution.

[0040] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0041] (4) Take 920 μL of ODe solution, add 1780 μL of PBS buffer and shake well, then add 800 μL of CSPBA1 solution and 500 μL of PEI solution, shake quickly for 1 s and pour into a mold, let stand to obtain PEI2.5 / ODe / CSPBA1 composite hydrogel.

[0042] Comparative Example 2: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0043] (2) Weigh 0.25 g of CSPBA1 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1 solution.

[0044] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0045] (4) Take 1140 μL of ODe solution, add 1060 μL of PBS buffer and shake well, then add 800 μL of CSPBA1 solution and 1000 μL of PEI solution, shake quickly for 1 s and pour into a mold, let stand to obtain PEI5.0 / ODe / CSPBA1 composite hydrogel.

[0046] Comparative Example 3: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0047] (2) Weigh 0.25 g of CSPBA1 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1 solution.

[0048] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0049] (4) Take 1380 μL of ODe solution, add 320 μL of PBS buffer and shake well, then add 800 μL of CSPBA1 solution and 1500 μL of PEI solution, shake rapidly for 1 s and pour into a mold, let stand to obtain PEI7.5 / ODe / CSPBA1 composite hydrogel.

[0050] Comparative Example 4: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0051] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0052] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0053] (4) Take 920 μL of ODe solution, add 1780 μL of PBS buffer and shake well, then add 800 μL of CSPBA1.5 solution and 500 μL of PEI solution, shake quickly for 1 s and pour into a mold, let stand to obtain PEI2.5 / ODe / CSPBA1.5 composite hydrogel.

[0054] Comparative Example 5: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0055] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0056] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0057] (4) Take 1140 μL of ODe solution, add 1060 μL of PBS buffer and shake well, then add 800 μL of CSPBA1.5 solution and 500 μL of PEI solution, shake rapidly for 1 s and pour into a mold, let stand to obtain PEI5.0 / ODe / CSPBA1.5 composite hydrogel.

[0058] Comparative Example 6: Compared with Examples 1-3, Comparative Example 6, without the addition of QCHA nanoparticles, includes the following steps in its preparation method of injectable composite bone repair hydrogel: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0059] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0060] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0061] (4) Take 1380 μL of ODe solution, add 320 μL of PBS buffer and shake well, then add 800 μL of CSPBA1.5 solution and 1500 μL of PEI solution, shake rapidly for 1 s and pour into a mold, let stand to obtain PEI7.5 / ODe / CSPBA1.5 composite hydrogel.

[0062] As shown in Table 1, the gelation time of Comparative Example 6 was the same as that of Examples 1-3, but the strength of the prepared gel was weak, indicating that QCHA nanoparticles played a certain role in enhancing the hydrogel matrix network.

[0063] Depend on Figure 1 It can be seen that comparing Comparative Examples 1, 2, and 3 with Comparative Examples 4, 5, and 6 respectively, it can be found that when other variables remain unchanged, using CSPBA1.5 with a higher degree of PBA substitution can increase the storage modulus of the hydrogel by 0.6-2 kPa; and the increasing modulus trend shown in Comparative Examples 1, 2, 3 and Comparative Examples 4, 5, and 6 shows that the strength of the hydrogel also increases with the increase of PEI concentration.

[0064] Comparative Example 7: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0065] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0066] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0067] (4) Take 1140 μL of ODe solution, add 1060 μL of PBS buffer and 40 mg of QCHA powder and shake well. Then add 800 μL of CSPBA1.5 solution and 1000 μL of PEI solution, shake rapidly for 1 s and pour into a mold. Let stand to obtain PEI5.0 / ODe / CSPBA1.5 / QCHA1 composite hydrogel.

[0068] Comparative Example 8: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0069] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0070] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0071] (4) Take 1140 μL of ODe solution, add 1060 μL of PBS buffer and 120 mg of QCHA powder and shake well. Then add 800 μL of CSPBA1.5 solution and 1000 μL of PEI solution, shake rapidly for 1 s and pour into a mold. Let stand to obtain PEI5.0 / ODe / CSPBA1.5 / QCHA3 composite hydrogel.

[0072] Comparative Example 9: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0073] (2) Weigh 0.25 g of CSPBA1.5 and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain a 2.5% CSPBA1.5 solution.

[0074] (3) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0075] (4) Take 1140 μL of ODe solution, add 1060 μL of PBS buffer and 200 mg of QCHA powder and shake well. Then add 800 μL of CSPBA1.5 solution and 1000 μL of PEI solution, shake rapidly for 1 s and pour into a mold. Let stand to obtain PEI5.0 / ODe / CSPBA1.5 / QCHA5 composite hydrogel.

[0076] Figure 2 The figures show the compressive stress diagrams of hydrogels with different components in Examples 1-3 and Comparative Examples 7-9 at 80% compressive strain. As can be seen from the figures, under the same QCHA addition amount, when the ratio of amino to aldehyde groups in the hydrogel system is controlled at about 1.2:1, the compressive strength of Examples 1, 2, and 3 is improved compared with Comparative Examples 7, 8, and 9. This indicates that the mechanical properties of the hydrogel can be improved by using a higher 7.5% PEI concentration. At the same time, when the PEI concentration is fixed, the increasing trend shown in Comparative Examples 7, 8, and 9 and Examples 1, 2, and 3 shows that the mechanical strength of the hydrogel also increases with the increase of QCHA addition amount.

[0077] Comparative Example 10: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0078] (2) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0079] (4) Take 2000 μL of ODe solution, add 1000 μL of PBS buffer and shake well, then add 1000 μL of PEI solution, shake quickly for 1 s and pour into a mold, let stand to obtain PEI / ODe hydrogel.

[0080] Comparative Example 11: An injectable composite bone repair hydrogel, the preparation method of which includes the following steps: (1) Weigh 0.8 g of ODe and dissolve it in 10 mL of pH 8.5 PBS buffer to obtain an 8% ODe solution.

[0081] (2) Weigh out a 20% aqueous solution of PEI and adjust the pH to 8.5 with dilute hydrochloric acid.

[0082] (4) Take 2000 μL of ODe solution, add 1000 μL of PBS buffer and 200 mg of QCHA powder, shake well, then add 1000 μL of PEI solution, shake rapidly for 1 s, pour into a mold, and let stand to obtain PEI / ODe / QCHA5 composite hydrogel.

[0083] Comparing Comparative Example 10 and Comparative Example 11, it can be seen that the modulus of PEI / ODe hydrogel can be improved to some extent after adding 5% QCHA. However, its modulus is still low. Without the addition of CSPBA, although the hydrogel can meet the appropriate gelation time, its modulus is less than 1 kPa, which cannot provide the mechanical strength required for bone repair.

[0084] Test example: The gelation time, storage modulus (G'), loss modulus (G''), and compressive strength of the hydrogels prepared in the test examples and comparative examples are determined using the following specific test methods: The storage modulus and loss modulus of the hydrogel were tested using a rotational rheometer. The test range was 0.1 rad / s to 100 rad / s.

[0085] The compressibility of hydrogels was tested using a universal testing machine. The hydrogels were made into cylinders of uniform size and compressed to 80% strain at a rate of 2 mm / min. The compressive stress at this strain was recorded.

[0086] The gelation time of the hydrogel was tested using the inverted bottle method. Specifically, the solutions of each component were mixed in the sample bottle, and the mixing time was recorded as the initial time. The sample bottle was then gently shaken up and down until the liquid inside no longer flowed when the bottle was inverted; this time was recorded as the gelation time. The results are shown in Table 1.

[0087] Table 1

[0088] As shown in Table 1, the storage modulus of the composite hydrogel prepared in the embodiments of the present invention is higher than that of the comparative example, indicating that QCHA nanoparticles play a certain reinforcing role in the hydrogel matrix network. Meanwhile, in the embodiments, with the increase of PEI concentration or CSPBA substitution degree, the gelation time of the composite hydrogel is correspondingly shortened, and the storage modulus and compressive stress of the composite hydrogel are correspondingly increased. This indicates that by controlling the components, it is possible to improve the strength of the hydrogel to a certain extent while controlling the gelation time, thus achieving results that are both convenient for clinical operation and meet the basic requirements of practical applications.

[0089] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.

Claims

1. A method for preparing an injectable composite bone repair hydrogel, characterized in that, Includes the following steps: S1. Mix the oxidized dextran solution with the hydroxyapatite powder and shake until homogeneous; S2. Then add phenylboronic acid modified chitosan solution and branched polyethyleneimine solution, shake rapidly to homogenize, and let stand to obtain the injectable composite bone repair hydrogel. Among them, by adjusting the ratio of oxidized dextran to branched polyethyleneimine, the total molar ratio of amino and aldehyde groups in the hydrogel system was controlled to be 1.0-1.5:1; the grafting rate of phenylboronic acid in phenylboronic acid modified chitosan was 50%-60%.

2. The preparation method according to claim 1, characterized in that, The hydroxyapatite powder was synthesized using chitosan quaternary ammonium salt as a template.

3. The preparation method according to claim 1 or 2, characterized in that, The hydroxyapatite powder accounts for 1%-5% of the mass of the hydrogel, based on solid mass.

4. The preparation method according to claim 1, characterized in that, The mass fraction of oxidized dextran in the oxidized dextran solution is 5%-10%.

5. The preparation method according to claim 1 or 4, characterized in that, The degree of oxidation of the oxidized dextran is 20%-40%.

6. The preparation method according to claim 1, characterized in that, The mass fraction of phenylboronic acid-modified chitosan in the phenylboronic acid-modified chitosan solution is 2%-3%.

7. The preparation method according to claim 1, characterized in that, The branched polyethyleneimine solution has a branched polyethyleneimine mass fraction of 10%-20% and a pH of 8.0-9.

0.

8. The preparation method according to claim 1, characterized in that, Based on solid mass, oxidized dextran accounts for 2%-3% of the hydrogel, phenylboronic acid-modified chitosan accounts for 0.1%-1% of the hydrogel, and branched polyethyleneimine accounts for 6%-8% of the hydrogel.

9. An injectable composite bone repair hydrogel prepared by the preparation method according to any one of claims 1-8.

10. The application of the injectable composite bone repair hydrogel according to claim 9 in the preparation of bone repair filling materials.

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