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CN-120983343-B - Injectable hydrogel for alveolar bone repair and preparation method and application thereof

CN120983343BCN 120983343 BCN120983343 BCN 120983343BCN-120983343-B

Abstract

The invention discloses an injectable hydrogel for alveolar bone repair, which comprises a first component and a second component, wherein the first component comprises 4-carboxyl-3-fluorobenzeneboronic acid modified carboxymethyl chitosan CMCS-FPBA and beta-tricalcium phosphate, and the second component comprises oxidized dextran, PPS-HA nano micelle and curcumin. The invention also discloses a preparation method and application of the injectable hydrogel. The injectable hydrogel provided by the invention has the effects of resisting oxidation, resisting inflammation and promoting bone tissue regeneration, has high biocompatibility, can be customized individually, and can be used for repairing alveolar bones.

Inventors

  • GUO RUI
  • FENG LONGBAO

Assignees

  • 暨南大学

Dates

Publication Date
20260508
Application Date
20250724

Claims (7)

  1. 1. The injectable hydrogel for alveolar bone repair is characterized by comprising a first component and a second component, wherein the first component comprises 4-carboxyl-3-fluorobenzeneboronic acid modified carboxymethyl chitosan CMCS-FPBA and beta-tricalcium phosphate beta-TCP, the second component comprises oxidized dextran ODex, PPS-HA nano-micelle and curcumin Cur, and the PPS-HA nano-micelle and the curcumin Cur are prepared into PPS-HA@Cur nano-micelle; The 4-carboxyl-3-fluorobenzeneboronic acid modified carboxymethyl chitosan is prepared by the following steps: Dissolving carboxymethyl chitosan in PBS to obtain carboxymethyl chitosan solution, dissolving 4-carboxyl-3-fluorobenzeneboronic acid, EDC and NHS in DMSO, stirring to activate carboxyl to obtain 4-carboxyl-3-fluorobenzeneboronic acid solution, adding the carboxymethyl chitosan solution into the 4-carboxyl-3-fluorobenzeneboronic acid solution, regulating pH to 12, stirring for overnight reaction, dialyzing the reacted solution, filtering to obtain supernatant after dialysis, and freeze-drying to obtain the 4-carboxyl-3-fluorobenzeneboronic acid modified carboxymethyl chitosan CMCS-FPBA; the PPS-HA nano micelle is prepared by the following steps: Under ice bath condition, adding 3-mercaptopropionic acid into anhydrous tetrahydrofuran, and magnetically stirring and mixing; the preparation method comprises the steps of continuously adding 1, 8-diazabicyclo [5.4.0] undec-7-ene, stirring the reaction mixture under a nitrogen atmosphere, then dropwise adding propylene sulfide, stirring the reaction mixture overnight, then carrying out quenching reaction by adding H 2 O, precipitating and purifying in cold methanol, evaporating the solvent under reduced pressure to obtain yellow oily PPS, adding PPS in methylene dichloride, carrying out magnetic stirring to dissolve, continuously adding N-hydroxysuccinimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, stirring at room temperature to dissolve, then dropwise adding ethylenediamine into the mixture, stirring at room temperature overnight, then adding dichloromethane to dilute the reaction solution, washing with H 2 O and saturated NaCl in sequence, drying through MgSO 4 , filtering, concentrating the solution under reduced pressure to obtain PPS-NH 2 , drying for later use, dialyzing the sodium hyaluronate in HCl solution, then carrying out freeze-drying to obtain the hyaluronate in the acid form, adding H 2 O and the hyaluronate in the acid form, carrying out magnetic stirring to dissolve, then adding N-hydroxysuccinimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, stirring at room temperature to dissolve at room temperature to obtain the complete solution, stirring at room temperature to remove the complete stirring of the complete reaction system of the HA- 2 , stirring at room temperature, stirring the complete stirring at room temperature to obtain the complete solution, completely dissolving the solution under the conditions of water, stirring, dissolving the solution under the conditions of water, dissolving under the condition HAs been reduced pressure, and dissolving.
  2. 2. The injectable hydrogel according to claim 1, wherein the injectable hydrogel comprises, by mass volume, 0.2-2% of 4-carboxy-3-fluorobenzeneboronic acid modified carboxymethyl chitosan, 0.5-1.5% of beta-tricalcium phosphate, 1-5% of oxidized dextran, 0.2-1% of PPS-HA nano-micelle and 0.1-5% of curcumin.
  3. 3. The injectable hydrogel according to claim 1, wherein the injectable hydrogel comprises, by mass volume, 0.35-1% of 4-carboxy-3-fluorobenzeneboronic acid modified carboxymethyl chitosan, 0.5-1% of beta-tricalcium phosphate, 2-4% of oxidized dextran, 0.5-1% of PPS-HA nano-micelles, and 0.5-1% of curcumin.
  4. 4. The injectable hydrogel of claim 1, wherein the injectable hydrogel comprises, in mass volume percent, 0.7% of 4-carboxy-3-fluorobenzeneboronic acid modified carboxymethyl chitosan, 1% of beta-tricalcium phosphate, 4% of oxidized dextran, 1% of PPS-HA nanomicelle, and 0.5% of curcumin.
  5. 5. The injectable hydrogel according to any one of claims 1 to 4, wherein the oxidized dextran is prepared by: and (3) weighing dextran, dissolving in water, cooling to room temperature after dissolving in water bath, adding sodium periodate, reacting in a dark place, adding ethylene glycol to terminate the reaction, continuing stirring, dialyzing, freeze-drying and collecting.
  6. 6. A method for preparing an injectable hydrogel according to any one of claims 1 to 5, characterized by comprising the steps of: S1, preparing PPS-HA@Cur nano micelle; S2, preparing CMCS-FPBA@beta-TCP/ODex@PPS-HA@Cur hydrogel; The step S1 comprises the steps of dissolving PPS-HA nano-micelle in PBS to obtain a water phase, dissolving curcumin in acetone and ethanol solution to obtain an organic phase, adding the organic phase liquid into the water phase under stirring, steaming for 3-5 min at 40 ℃ and 45 rpm, and carrying out ultrasonic treatment for 5-10 min and passing through a 0.45 mu m microporous filter membrane to obtain PPS-HA@Cur nano-micelle; The step S2 comprises the steps of adding CMCS-FPBA into deionized water to obtain a CMCS-FPBA solution, adding beta-TCP into the CMCS-FPBA solution, uniformly mixing to obtain a solution A, adding oxidized dextran ODex into PPS-HA@Cur nano micelle, uniformly mixing to obtain a solution B, uniformly mixing the solution A and the solution B, and regulating the pH value to 7-8 to obtain the injectable hydrogel.
  7. 7. Use of an injectable hydrogel according to any one of claims 1 to 5 for the preparation of an alveolar bone repair drug.

Description

Injectable hydrogel for alveolar bone repair and preparation method and application thereof Technical Field The invention belongs to the field of bone regeneration bioremediation, and particularly relates to an injectable hydrogel for alveolar bone repair, and a preparation method and application thereof. Background Alveolar bone (Alveolar bone) is a skeletal part to which the root of a tooth is attached, and is located in the upper jaw and the lower jaw in the oral cavity, which is an important structure for supporting and fixing the tooth. The main function of the alveolar bone is to support the teeth and provide sufficient stability so that the teeth can perform chewing and the like. Alveolar bone defect refers to the loss or absence of alveolar bone due to various causes (e.g., periodontal disease, trauma, tooth extraction, infection, etc.). Alveolar bone defects not only affect the stability of teeth, but also may cause loosening and falling of teeth, and a decrease in oral function. Current treatments for alveolar bone defects include medicine and oral care, bone grafting, guided Bone Regeneration (GBR), dental implants, biomaterials, and the like. In periodontal basic therapy, although infection can be controlled, the effect on serious bone defects is limited. Traditional methods of drug modulation of bone metabolism, such as bisphosphonates, while helping to inhibit bone resorption, may trigger the risk of jawbone necrosis and, in addition, autologous bone grafting is considered to be the gold standard for periodontal bone repair, but clinical application is greatly limited due to donor site morbidity, limited bone resources, and surgical complexity. Although allogeneic or xenogeneic bone may be substituted, they may be at risk of immune rejection or disease transmission and have high absorption rates. In GBR technology (guided bone regeneration technology), the barrier membrane may shift or be exposed, resulting in infection or surgical failure. Bone tissue engineering is taken as an emerging therapeutic means, and has a better repairing prospect by combining the synergistic effect of biological materials, cells and growth factors. However, the high cost of growth factors and the limitations of low cell viability have affected their wide application. Accordingly, researchers are working on developing alternative biomaterials, particularly hydrogels based on natural components. Hydrogels, because of their excellent biocompatibility and ability to mimic the properties of extracellular matrix, have great potential in bone tissue regeneration. However, conventional hydrogels have difficulty completely filling irregular periodontal defects, which can lead to tissue damage and prolonged procedure time. In contrast, injectable hydrogels are becoming potential materials to solve this problem due to their good flexibility and ease of handling, and are becoming a research hotspot in the area of alveolar bone repair. Disclosure of Invention The invention aims to solve the following technical problems: (1) The complexity and adaptability of the operation are poor, the traditional bone grafting needs open operation, the wound is large, and the preformed bracket is difficult to attach to the complex defect. The CMCS-FPBA/ODex dynamic network allows the gel to be injected through a needle and self-healing molded in vivo, adapting to irregular bone defects. (2) The degradation rate is not matched with bone regeneration, and the degradation of a single material (such as pure beta-TCP) is too fast, or the degradation of a synthetic polymer is too slow, which is asynchronous with bone growth. Multistage response degradation, wherein beta-TCP provides early calcium phosphate release, promoting mineralization. PPS-HA is oxidized and responsive degraded through thioether bonds, and the requirement of post-inflammatory repair is matched. ODex, adapt to the change of the microenvironment of the oral cavity, and realize time sequence degradation. (3) Traditional materials have insufficient mechanical properties, and traditional beta-TCP has high brittleness and is easy to crack (such as failure under biting force). The CMCS-FPBA and ODex form a dynamic cross-linked network, wrap beta-TCP particles, disperse stress, improve compressive strength, avoid the brittleness defect of pure beta-TCP, and have toughness and strength. (4) Insufficient bioactivity and osseointegration efficiency of the alveolar, short half-life of free Cur and insufficient local concentration, and the traditional stent only provides passive support and lacks signals for actively inducing bone regeneration. The targeting slow release of Cur is realized and the curative effect is prolonged by utilizing the oxidation responsiveness (ROS increase at the inflammation part) of PPS and the enzyme responsiveness (hyaluronidase enrichment) of HA. (5) Infection and inflammation control, namely complex oral flora, easy infection caused by exposed implants and eas