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Injectable double-crosslinked hyaluronic acid aquagel and preparation method thereof

A technology of hyaluronic acid and double cross-linking, which is applied in the direction of pharmaceutical formulations, medical preparations of non-active ingredients, animal cells, etc., and can solve the problems of limiting the practical application of hyaluronic acid, poor controllability of degradation rate, and difficulty in stability , to achieve the effects of good microstructure uniformity, excellent biocompatibility and good mechanical properties

Active Publication Date: 2015-09-16
WUXI JIANGNAN CABLE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the absorption rate of hyaluronic acid in the body is too fast, it is easy to diffuse in the tissue, the residence time is short, and it is difficult to exist stably, which greatly limits the practical application of hyaluronic acid. Therefore, functional modification of hyaluronic acid is required , expand its scope of application and maximize its value
[0003] Traditional hyaluronic acid hydrogels are formed by chemical crosslinking using small molecule crosslinking agents, which generally have problems such as low mechanical strength, uneven network structure, and poor controllability of degradation rate, especially small molecule crosslinking agents. Cytotoxicity [Zhu B, Ge CL, Gu QS. Gas chromatography analysis of divinylsulfone in cross-linked hyaluronan gels. Progress in Biomedical Engineering, 2008, 29:26-28], limiting the use of hyaluronic acid hydrogel in tissue repair Applications

Method used

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  • Injectable double-crosslinked hyaluronic acid aquagel and preparation method thereof
  • Injectable double-crosslinked hyaluronic acid aquagel and preparation method thereof
  • Injectable double-crosslinked hyaluronic acid aquagel and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Preparation of amino / methacryloyl bifunctional hyaluronic acid:

[0034] 1) Prepare an aqueous solution of hyaluronic acid (molecular weight: 600,000) with a concentration of 1% by mass, and then add N-hydroxysuccinimide, 3,3'-dithiodipropionyl hydrazide and 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, the amount of which is respectively 0.7, 4 and 0.6 times the number of moles of hyaluronic acid repeating units; then, using a NaOH solution with a concentration of 1mol / L and hydrochloric acid to adjust the pH to 5.2, and stirred and reacted at room temperature for 36 hours; ℃ / 4 hours freeze-drying to obtain amino-functionalized hyaluronic acid;

[0035] 2) Prepare an amino-functionalized hyaluronic acid aqueous solution with a concentration of 1% by mass, then add glycidyl methacrylate with 0.2 times the number of repeating units of hyaluronic acid, and adjust the pH to 8.0, react with magnetic stirring at 70°C for 6 hours, and then dialyze with deion...

Embodiment 2

[0046] Preparation of amino / methacryloyl bifunctional hyaluronic acid:

[0047] 1) Prepare an aqueous solution of hyaluronic acid (molecular weight: 1 million) with a mass percentage concentration of 0.2%, and then add N-hydroxysuccinimide, cystamine and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride, its dosage is respectively 0.24, 10 and 0.2 times of the number of moles of hyaluronic acid repeating units; then, the pH is adjusted to 5.0 by using NaOH solution and hydrochloric acid with a concentration of 1mol / L, and at room temperature The reaction was stirred for 24 hours; after the reaction, the reaction system was dialyzed with deionized water for 3 days (the molecular weight cut-off of the dialysis bag was 3500Da, the same below), and the amino functionalized hyaluronic acid;

[0048] 2) Prepare an amino-functionalized hyaluronic acid aqueous solution with a concentration of 0.5% by mass, then add glycidyl methacrylate with 0.15 times the number of repeat...

Embodiment 3

[0054] Preparation of amino / methacryloyl bifunctional hyaluronic acid:

[0055] 1) Prepare an aqueous solution of hyaluronic acid (molecular weight: 800,000) with a mass percentage concentration of 2%, and then add N-hydroxysuccinimide, cystine dimethyl ester and 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride, its dosage is respectively 0.5, 6 and 0.4 times of the number of moles of hyaluronic acid repeating units; then, the pH is adjusted to 5.5, Stir the reaction at room temperature for 60 hours; after the reaction, the reaction system is dialyzed with deionized water for 3 days (the molecular weight cut-off of the dialysis bag is 3500Da, the same below), and freeze-dried at minus 20°C / 72 hours and 20°C / 4 hours Obtain amino functionalized hyaluronic acid;

[0056] 2) Prepare an amino-functionalized hyaluronic acid aqueous solution with a concentration of 1.5% by mass, then add glycidyl methacrylate with 0.4 times the number of repeating units of hyaluronic aci...

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Abstract

The invention discloses an injectable double-crosslinked hyaluronic acid aquagel and a preparation method thereof. The preparation method comprises the following steps: synthesizing formylated hyaluronic acid and amino / methylacryloyl bifunctional hyaluronic acid containing disulfide bond in the side chain, uniformly mixing the formylated hyaluronic acid and amino / methylacryloyl bifunctional hyaluronic acid containing disulfide bond in the side chain with a water-soluble photoinitiator, and carrying out photochemical polymerization to obtain the injectable double-crosslinked hyaluronic acid aquagel. The method has the advantages of accessible raw materials, mild reaction conditions, short reaction time, simple technique and the like. The prepared aquagel is formed by a Schiff base crosslinking mechanism and a photocrosslinking mechanism, and the two crosslinking networks are connected together. The crosslinking network chain of the aquagel contains the disulfide bond and Schiff base, and thus, the aquagel has dual sensitivities for reduction and pH. The hyaluronic acid aquagel has flexible and adjustable mechanical properties, microstructure, degradation property, swelling capacity and the like, is injectable, and has application prospects in the aspects of cell transfer, tissue engineering, three-dimensional cell culture and the like.

Description

technical field [0001] The invention belongs to the field of biomedical materials, and in particular relates to an injectable double-crosslinked hyaluronic acid hydrogel and a preparation method thereof. Background technique [0002] The decline or loss of human tissue and organ function due to congenital malformations, tumors, trauma, and surgery is a problem often encountered in clinical practice. The current situation is that the supply of donors for tissue repair is insufficient, resulting in many patients being unable to receive timely treatment. Tissue engineering technology developed in recent years is playing an increasingly important role in tissue repair and organ function reconstruction. Hyaluronic acid hydrogel has the characteristics of degradability, good biocompatibility, high swelling ratio, and a structure highly similar to extracellular matrix. It is a tissue engineering scaffold material with great development potential and has aroused great interest in th...

Claims

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Application Information

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IPC IPC(8): C08J3/28C08J3/24C08L5/08A61L27/20A61L27/58A61K47/36C12N5/07
Inventor 钱军民胥伟军张雅萍赵娜
Owner WUXI JIANGNAN CABLE
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