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Preparation method and application of injectable hyaluronic acid hydrogel

A technology of hyaluronic acid and hydrogel, which is applied in the field of preparation of injectable hydrogel, which can solve the potential safety hazards of biocompatibility, biodegradability and immunogenicity, low biodegradability efficiency and complex synthesis process and other issues, to achieve the effect of excellent biocompatibility and biodegradability, excellent stability and mechanical properties, and simple synthesis method

Inactive Publication Date: 2014-11-12
BEIJING UNIV OF CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the cross-linking process of most chemical gels requires the addition of additional initiators, which often have high toxicity and specific triggering conditions, and are not suitable for in-situ use in vivo [Todd R. Hoare, Daniel S. Kohane. Hydrogels in drug delivery: Progress and challenges. Polymer. 2008;49:1993-2007.]
On the other hand, most of the current chemical gels are usually composed of synthetic or semi-synthetic polymers. The main problems are that the synthesis process of the materials is complicated, the biocompatibility is poor, the biodegradability is low, and there is a certain immunity. The originality makes it have more limitations and potential safety hazards in the application of biomedicine
Although the above work has solved the problem of in situ chemical crosslinking of chemical gels in vivo, the biocompatibility, biodegradability and immunogenicity of hydrogel materials still make them widely used in biomedicine. limitations and security risks

Method used

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  • Preparation method and application of injectable hyaluronic acid hydrogel
  • Preparation method and application of injectable hyaluronic acid hydrogel
  • Preparation method and application of injectable hyaluronic acid hydrogel

Examples

Experimental program
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Effect test

Embodiment 1

[0045] A method for preparing an injectable hyaluronic acid hydrogel constructed by Michael addition reaction, the specific steps are as follows:

[0046] 1) Preparation of hyaluronic acid-adipate dihydrazide derivative (HA-ADH)

[0047] Put 2g HA (molecular weight 50KDa) solution in 400mL deionized water, then add 20g adipic acid dihydrazide and adjust the pH value of the solution to 5.0-7.4 with hydrochloric acid, then add 4.0g 1-ethyl-(3-dimethylaminopropyl base) carbodiimide (EDC) and reacted overnight. Finally, the product HA-ADH solution is purified by dialysis (molecular weight cut-off 8-10KDa dialysis bag), and then freeze-dried and stored.

[0048] 2) Preparation of acrylate functionalized hyaluronic acid (HA-AC)

[0049] Dissolve 1.9g of HA-ADH prepared in step 1 in 350mL of buffer solution with pH=7.4, and dissolve another 1.33g of N-acryloxysuccinimide (NAS) in 10-20mL of DMSO, and further dilute the NAS solution Add it into the HA-ADH solution, stir overnight a...

Embodiment 2

[0057] A method for preparing an injectable hyaluronic acid hydrogel constructed by Michael addition reaction, the specific steps are as follows:

[0058] 1) Preparation of hyaluronic acid-adipate dihydrazide derivative (HA-ADH)

[0059] Put 2g HA (molecular weight 50KDa) solution in 400mL deionized water, then add 30g adipic acid dihydrazide and adjust the pH value of the solution to 5.0-7.4 with hydrochloric acid, further add 6g 1-ethyl-(3-dimethylaminopropyl ) carbodiimide (EDC), reacted overnight. Finally, the product HA-ADH solution is purified by dialysis (molecular weight cut-off 8-10KDa dialysis bag), and then freeze-dried and stored.

[0060] 2) Preparation of acrylate functionalized hyaluronic acid (HA-AC)

[0061] Dissolve 1.9g of HA-ADH prepared in step 1 in 350mL of buffer solution with pH=7.4, and dissolve another 2.85g of N-acryloxysuccinimide (NAS) in 10-20mL of DMSO, and further dilute the NAS solution Add it into the HA-ADH solution, stir overnight at room...

Embodiment 3

[0067] A method for preparing an injectable hyaluronic acid hydrogel constructed by Michael addition reaction, the specific steps are as follows:

[0068] 1) Preparation of hyaluronic acid-adipate dihydrazide derivative (HA-ADH)

[0069] Put 4g HA (molecular weight 50KDa) solution in 400mL deionized water, then add 40g adipic acid dihydrazide and adjust the pH value of the solution to 5.0-7.4 with hydrochloric acid, then add 4.0g 1-ethyl-(3-dimethylaminopropyl base) carbodiimide (EDC) and reacted overnight. Finally, the product HA-ADH solution is purified by dialysis (molecular weight cut-off 8-10KDa dialysis bag), and then freeze-dried and stored.

[0070] 2) Preparation of acrylate functionalized hyaluronic acid (HA-AC)

[0071] Dissolve 3.85g of HA-ADH prepared in step 1 in 350mL of buffer solution with pH=7.4, and dissolve another 1.92g of N-acryloxysuccinimide (NAS) in 10-20mL of DMSO, and further dissolve NAS The solution was added to the HA-ADH solution, stirred over...

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Abstract

The invention discloses a preparation method of an injectable hyaluronic acid hydrogel. The method comprises the following steps: initiating a condensation reaction of an amino group of adipic dihydrazide and a carboxyl group of the main chain of HA (hyaluronic acid) by 1-ethyl-3-(3-dimethylamino)carbodiimide hydrochloride to obtain a hyaluronic acid-adipic dihydrazide (HA-ADH) derivative with the main chain possessing the amino group, and reacting N-acryloxysuccinimide with the amino group of the HA-ADH to obtain an acrylate functionalized hyaluronic acid derivative; and cross-linking the acrylate functionalized hyaluronic acid derivative with a bismercapto cross-linking agent to form the injectable hyaluronic acid hydrogel. The above acrylate functionalized HA-AC synthesis method is simple and easy, and is suitable for industrial amplified production; the environmental protection, biological inertness and reaction speed controllability of a Michael addition reaction lay a good foundation for the application of the Michael addition reaction in the injectable hyaluronic acid hydrogel; and the HA-AC chemically cross-linked hydrogel has better stability and mechanical performances than physically associated injectable gels.

Description

technical field [0001] The invention relates to a preparation method and application of an injection-type hydrogel, in particular to a preparation method and application of an injection-type hyaluronic acid hydrogel. Background technique [0002] The broad application prospects of injectable hydrogels in long-acting sustained-release drug delivery, tissue repair, and cell transplantation have quickly become one of the most popular research directions in the field of biomaterials [1-8]. As a new type of material, injectable hydrogel can make up for the shortcomings of traditional hydrogel. It can be directly implanted into the tissue through a syringe, avoiding the destruction of body tissue by pioneering surgery, and reducing the difficulty of clinical application[Todd R. Hoare, Daniel S. Kohane. Hydrogels in drug delivery: Progress and challenges. Polymer. 2008;49:1993-2007.]. However, most of the injectable hydrogels currently researched and applied are through physical a...

Claims

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Application Information

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IPC IPC(8): C08J3/075C08J3/24C08L5/08C08K5/37C08B37/08
Inventor 张建军李瑞端张晶晶尼尔·福斯特
Owner BEIJING UNIV OF CHEM TECH
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