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Imitated extracellular matrix injectable in-situ hydrogel and preparation method and application thereof

A technology of hydrogel and extracellular matrix, which is applied in the field of in situ hydrogel which imitates extracellular matrix and can be injected and its preparation and application, can solve the problem of single release rate, complicated steps, no controllable degradation, controllable Issues such as release and/or regulation of cell behavior, to achieve controllable release and/or regulation of cell behavior, to meet the requirements of different release rates, and to have broad clinical application prospects.

Active Publication Date: 2015-01-28
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0005] Chinese patent CN101864178A discloses an injectable protein / polypeptide in situ hydrogel for drug sustained release and cell culture, but the hydrogel is made of natural or synthetic protein / polypeptide with cross-linkable phenolic hydroxyl groups Composed of peptides, horseradish peroxidase and hydrogen peroxide, chemically cross-linked hydrogels are rapidly formed under physiological conditions, and the hydrogels prepared by this method do not have controlled degradation, controlled release and / or regulation of cell behavior function, and cross-linking with hydrogen peroxide can cause oxidative toxicity to cells
[0006] Chinese patent CN102718991A discloses a Michael addition reaction between the double bond of polyethylene glycol diacrylate (PEGDA) and the sulfhydryl group on the mercaptolated natural polymer, and simultaneously uses polyethylene glycol and polycaprolactone (PEG- PCL-PEG) triblock copolymer nanoparticles are hydrogels formed as reinforcing agents. Chinese patent CN103665397A discloses a hydrogel and a preparation method thereof, using high molecular weight polyethylene glycol and hyaluronic acid as Raw materials, so that the hydrogel has strong flexibility and certain mechanical strength, both of which use Michael addition reaction to prepare in-situ hydrogel, but the prepared hydrogel does not have controllable degradation and controllable release and / or functions that regulate cellular behavior
Chinese patent CN103467755A discloses a drug sustained-release hydrogel and its preparation method and application. The high-voltage electrostatic droplet method is used to prepare monodisperse drug-containing calcium alginate microspheres, and the drug-loaded calcium alginate microspheres are placed in the hydrogel In the glue network structure, the steps of this method are complicated, and it does not have the functions of controlled degradation, controlled release and / or regulation of cell behavior
[0008] Existing hydrogel carrier materials usually only have a single release rate, which is often limited in practical applications. When the required release rate changes, it is necessary to re-select the appropriate carrier material type and dosage, the type of carrier material and The dosage may change, resulting in the need to spend time, energy and cost on carrier materials when facing active ingredients with different release rate requirements

Method used

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  • Imitated extracellular matrix injectable in-situ hydrogel and preparation method and application thereof
  • Imitated extracellular matrix injectable in-situ hydrogel and preparation method and application thereof
  • Imitated extracellular matrix injectable in-situ hydrogel and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0072] Example 1 Preparation of injectable in situ hydrogel imitating extracellular matrix

[0073] (1) Preparation of thiolated gelatin

[0074] Add 1 g of gelatin into 100 ml of ultrapure water, heat to 40°C, stir to dissolve, and then cool to room temperature. Cystamine dihydrochloride, EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiethylene amine hydrochloride) and NHS (N-hydroxysuccinimide), adjust the pH of the reaction solution to 4.75, start dialysis after 4 hours of reaction at room temperature, change the dialysate every 24 hours, add 0.5gDTT (dithiothreose) after 3 days of dialysis Alcohol), adjust the pH of the reaction solution to 8.5, adjust the pH to 4.0 after 2 hours of reaction, dialyze under nitrogen protection for 3 days, and change the dialysate once a day. After the dialysis is completed, filter sterilization and freeze-dry to obtain thiolated gelatin. The schematic diagram of its preparation is as follows: figure 1 .

[0075] The thiol content was deter...

Embodiment 2

[0084] Example 2: Preparation of injectable in situ hydrogel imitating extracellular matrix

[0085] (1) Preparation of thiolated gelatin

[0086] Add 1 g of gelatin into 100 ml of ultrapure water, heat to 40°C, stir to dissolve, and then cool to room temperature. Add cystamine dihydrochloride, EDC and NHS according to the molar ratio of 1:1:2:2 (the molar ratio of carboxyl groups in gelatin is 1), adjust the pH of the reaction solution to 4.75, and start dialysis after 4 hours of reaction at room temperature, every 24 hours Change the dialysate once, add 0.5g DTT after 3 days of dialysis, adjust the pH of the reaction solution to 8.5, react for 2 hours, adjust the pH to 4.0, dialyze for 3 days under nitrogen protection, and change the dialysate once a day. After the dialysis is completed, filter sterilization and freeze-drying to obtain thiolated gelatin.

[0087]The mercapto group content was determined to be 0.42 mmol / g by the Ellman method.

[0088] (2) Preparation of t...

Embodiment 3

[0096] Example 3: Preparation of injectable in situ hydrogel imitating extracellular matrix

[0097] (1) Preparation of thiolated gelatin

[0098] Add 1 g of gelatin into 100 ml of ultrapure water, heat to 40°C, stir to dissolve, and then cool to room temperature. Add cystamine dihydrochloride, EDC and NHS according to the molar ratio of 1:3:3:3 (the carboxyl molar ratio in gelatin is 1), adjust the pH of the reaction solution to 4.75, and start dialysis after 4 hours of reaction at room temperature, every 24 hours Change the dialysate once, add 0.5g DTT after 3 days of dialysis, adjust the pH of the reaction solution to 8.5, react for 2 hours, adjust the pH to 4.0, dialyze for 3 days under nitrogen protection, and change the dialysate once a day. After the dialysis is completed, filter sterilization and freeze-drying to obtain thiolated gelatin.

[0099] The mercapto group content was determined to be 0.6 mmol / g by the Ellman method.

[0100] (2) Preparation of mercaptohep...

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Abstract

The invention discloses imitated extracellular matrix injectable in-situ hydrogel and a preparation method and application thereof. The hydrogel is prepared by carrying out a cross-linking reaction between sulfhydrylation gelatin, sulfhydrylation polysaccharides or RGD-containing cell adhesion peptides and polyethylene glycol diacrylate. The composition of the hydrogel is similar to that of the extracellular matrix, so that the hydrogel has high biocompatibility, has the effects of controlled degradation, controlled release and / or cell behavior regulation in performance and can conveniently meet the requirements on different release rates of growth factors or medicines. Meanwhile, the clinical injectable and in-situ forming operation requirements can be met, and the hydrogel has good application prospects in tissue repair and regeneration.

Description

technical field [0001] The invention relates to an injectable in-situ hydrogel imitating extracellular matrix, a preparation method and application thereof. Background technique [0002] For a long time, human beings have been exploring the repair and regeneration of body tissues. In recent years, with the development of biomaterials, tissue engineering and stem cell technology, breakthroughs have been made in the field of tissue repair and regeneration. Current research mainly focuses on two aspects: one is to induce endogenous cells to perform tissue reconstruction in the diseased site by administering drug treatment such as growth factors; the other is to implant cells to play a therapeutic role in the diseased site. In both strategies, the design and development of carrier materials undoubtedly plays an increasingly important role. [0003] First, the degradation of the carrier material should match the tissue growth. Secondly, the carrier used for drug delivery must ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61L27/52A61L27/26A61L27/54A61K47/42A61K47/36A61K47/34A61K38/18A61K9/08C12N5/07A61L27/38A61K35/12
CPCA61L27/26A61L27/52A61L27/54A61L2300/252A61L2300/412A61L2430/02C08L5/04C08L5/08C08L5/10C08L89/00
Inventor 田猛游潮
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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