CN111214706A - Temperature-sensitive composite gel emulsion and application thereof - Google Patents
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Abstract
本发明涉及一种温敏复合凝胶乳液，其制备过程为：(1)制备壳聚糖溶液，在零下4至4摄氏度及搅拌条件下将β‑甘油磷酸钠溶液逐滴加入到壳聚糖溶液中，制备得到壳聚糖温敏凝胶成胶溶液；(2)将含有生长因子的明胶微球加入上述低温的壳聚糖温敏凝胶成胶溶液；(3)将细胞加入含有明胶微球的低温壳聚糖温敏凝胶成胶溶液，从而得到温敏复合凝胶乳液。该温敏复合凝胶乳液在处于36‑40℃条件时可快速转变为凝胶态，可作为生长因子及细胞的注射型体内传递载体，通过注射到达体内受损部位，原位快速形成细胞‑生长因子‑凝胶复合物，起到修复、治疗的作用。The invention relates to a temperature-sensitive composite gel emulsion, the preparation process of which is as follows: (1) preparing a chitosan solution, adding β-sodium glycerophosphate solution dropwise to the chitosan at minus 4 to 4 degrees Celsius and under stirring conditions In the solution, a chitosan thermosensitive gel gelation solution is prepared; (2) the gelatin microspheres containing growth factors are added to the above-mentioned low-temperature chitosan thermosensitive gel gelation solution; (3) the cells are added to the low temperature containing gelatin microspheres. The chitosan temperature-sensitive gel forms a gel solution, thereby obtaining a temperature-sensitive composite gel emulsion. The temperature-sensitive composite gel emulsion can rapidly transform into a gel state at 36-40°C, and can be used as an injectable in vivo delivery carrier for growth factors and cells. It can reach the damaged part of the body through injection, and rapidly form cells-in situ. Growth factor-gel complex, which plays the role of repair and treatment.
Description
Technical Field
The invention relates to the field of regenerative medicine, in particular to a temperature-sensitive composite gel emulsion and application thereof.
Background
the injection type temperature-sensitive gel is liquid at low temperature, is converted into hydrogel at 37 ℃, is suitable for being used as a transfer carrier for in vivo injection treatment, and effectively avoids secondary damage of organisms, so the injection type temperature-sensitive gel has a wide clinical application prospect.
In order to overcome the defects of poor capability of slowly releasing growth factors and unsatisfactory repairing effect of the conventional chitosan temperature-sensitive gel, the invention discloses a temperature-sensitive composite gel emulsion, which is characterized in that gelatin microspheres and cells containing the growth factors are added into a gelling solution of the chitosan temperature-sensitive gel, so that the slow release of the growth factors and the promotion of tissue repair can be realized, and the temperature-sensitive composite gel emulsion has very important application prospect.
Disclosure of Invention
the invention discloses a temperature-sensitive composite gel emulsion which is prepared by the steps of (1) preparing a chitosan solution, dropwise adding β -sodium glycerophosphate solution into the chitosan solution at the temperature of minus 4-4 ℃ under the stirring condition to prepare a chitosan temperature-sensitive gel forming solution, (2) adding gelatin microspheres containing growth factors into the low-temperature chitosan temperature-sensitive gel forming solution, and (3) adding cells into the low-temperature chitosan temperature-sensitive gel forming solution containing the gelatin microspheres to obtain the temperature-sensitive composite gel emulsion.
The deacetylation degree of the chitosan is 95% or more;
the molecular weight of the chitosan is 10000-300000Da, preferably 200000 Da;
the concentration of the chitosan solution is 1-3% (w/v, g/ml), preferably 2% (w/v, g/ml);
the concentration of the β -sodium glycerophosphate solution is 40-56% (w/v, g/ml);
the volume ratio of the chitosan solution to the sodium beta-glycerophosphate solution is 35:1-5:1, preferably 14: 1.
the growth factor is one or more of basic fibroblast growth factor (bFGF), Vascular Endothelial Growth Factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), Nerve Growth Factor (NGF), acidic fibroblast growth factor (aFGF), Epidermal Growth Factor (EGF), Bone Morphogenetic Protein (BMP), Stem Cell Factor (SCF), Hepatocyte Growth Factor (HGF), Erythropoietin (EPO) and interleukin-1 α (IL-1 α), the mass content of the growth factor in the gelatin microsphere is 0.02-2% (w/w), preferably 0.2% (w/w), and the particle size of the gelatin microsphere is 10-200 microns.
The concentration of the gelatin microspheres in the chitosan temperature-sensitive gel forming solution is 1-10mg/ml, preferably 5 mg/ml.
The density of the cells in the low-temperature chitosan temperature-sensitive gel forming solution containing the gelatin microspheres is 105-107Per ml, preferably 106/ml。
The cells are one or more than two of stem cells (iPS cells, embryonic stem cells and mesenchymal stem cells), mature cells (primary cells separated from tissues and cells obtained by inducing and differentiating stem cells) and transgenic cells.
The temperature-sensitive composite gel emulsion is applied as an injection type in-vivo transfer carrier of growth factors and cells.
The low-temperature-sensitive composite gel emulsion can be quickly converted into a gel state at the temperature of 36-40 ℃.
THE ADVANTAGES OF THE PRESENT INVENTION
1. According to the invention, the gelatin microspheres containing the growth factors are added into the chitosan temperature-sensitive gel system, so that the slow release of the growth factors is realized;
2. the invention integrates the cells and the temperature-sensitive gel forming solution, improves the biological activity of the compound and has great in vivo treatment potential.
Detailed Description
Example 1:
preparing 200ml of 0.1mol/L hydrochloric acid solution, slowly adding 2g of chitosan (deacetylation degree is 95%, molecular weight is 10000Da) under the stirring condition (400rpm), stirring at room temperature to obtain 1% (w/v, g/ml) chitosan solution, preparing 40% (w/v, g/ml) β -sodium glycerophosphate solution, dropwise adding the β -sodium glycerophosphate solution into the chitosan solution under the ice bath and stirring conditions (the volume ratio of the chitosan solution to the β -sodium glycerophosphate solution is 35:1), preparing to obtain the chitosan temperature-sensitive gel forming solution, then adding gelatin microspheres containing bFGF and VEGF (the mass contents of bFGF and VEGF in the gelatin microspheres are both 0.02% (w/w), the diameter of the gelatin microspheres is 10 microns) into the low-temperature chitosan temperature-sensitive gel forming solution, wherein the concentration of the gelatin microspheres is 1mg/ml, and then adding human mesenchymal cells into the low-temperature chitosan gel forming solution containing the gelatin microspheres, wherein the cell density is 10 microns5And/ml, thereby obtaining the temperature-sensitive composite gel forming solution. The low-temperature-sensitive composite gel forming solution is injected into a rat myocardial ischemia model, and the myocardial infarction area is evaluated after four weeks. The PBS injection group, the gelatin-free microsphere injection group and the cell-free group were used as control groups, and the other conditions were the same. After four weeks of injection, it was found that the infarct size of the group injected with the complex temperature-sensitive gel containing microspheres and cells was the smallest (2.7 cm)2) Followed by injection of gelatin-free microsphere sets (3.9 cm)2) Followed by injection of a cell-free group (4.1 cm)2) While the group injected with PBS had the largest infarct size (4.5 cm)2) The results show that the temperature-sensitive composite gel injection can accelerate the in-vivo tissue repair, and the gelatin microspheres containing positive charge growth factors and cells have the best combined use effect.
Example 2:
200ml of 0.1mol/L hydrochloric acid solution was prepared, and 6g of chitosan (degree of deacetylation 97%; 400rpm) was added under stirring300000Da) is slowly added, and the mixture is stirred at room temperature to obtain 3% (w/v, g/ml) of chitosan solution, 56% (w/v, g/ml) of β -sodium glycerophosphate solution is prepared, the β -sodium glycerophosphate solution is dropwise added into the chitosan solution under the conditions of ice bath and stirring (the volume ratio of the chitosan solution to the β -sodium glycerophosphate solution is 5:1) to prepare the chitosan temperature-sensitive gel forming solution, gelatin microspheres containing bFGF and BMP (the mass contents of the bFGF and the BMP in the gelatin microspheres are both 2% (w/w), the diameter of the gelatin microspheres is 200 microns) are added into the low-temperature chitosan temperature-sensitive gel forming solution, the concentration of the gelatin microspheres is 10mg/ml, and then human primary cardiomyocytes are also added into the low-temperature chitosan temperature-sensitive gel forming solution containing the gelatin microspheres, and the cell density is 107And/ml, thereby obtaining the temperature-sensitive composite gel forming solution. The low-temperature-sensitive composite gel forming solution is injected into a rat myocardial ischemia model, and the myocardial infarction area is evaluated after four weeks. The PBS group was injected as a control group, and the other conditions were the same. After four weeks of injection, the infarct size of the group injected with the temperature-sensitive complex gel was found to be minimal (2.5 cm)2) While the group injected with PBS had the largest infarct size (4.7 cm)2) These results indicate that temperature-sensitive complex gel injection can accelerate tissue repair in vivo.
Example 3:
preparing 200ml of 0.1mol/L hydrochloric acid solution, slowly adding 4g of chitosan (deacetylation degree is 98%, molecular weight is 200000Da) under stirring conditions (400rpm), stirring at room temperature to obtain 2% (w/v, g/ml) of chitosan solution, preparing 56% (w/v, g/ml) of sodium β -glycerophosphate solution, dropwise adding the sodium β -glycerophosphate solution into the chitosan solution under ice bath conditions and stirring conditions (the volume ratio of the chitosan solution to the sodium β -glycerophosphate solution is 14:1), preparing to obtain a chitosan temperature-sensitive gel forming solution, then adding gelatin microspheres containing VEGF and HGF (the mass contents of VEGF and HGF in the gelatin microspheres are both 0.2% (w/w), the diameter of the gelatin microspheres is 100 micrometers) into the low-temperature chitosan temperature-sensitive gel forming solution, wherein the concentration of the gelatin microspheres is 5mg/ml, differentiating, and then adding myocardial cells obtained by inducing human iPS cells into the low-temperature chitosan solution containing gelatin microspheres, wherein the density of the gelatin microspheres is the low-temperature chitosan gel106And/ml, thereby obtaining the temperature-sensitive composite gel forming solution. The low-temperature-sensitive composite gel forming solution is injected into a rat myocardial ischemia model, and the myocardial infarction area is evaluated after four weeks. The PBS group was injected as a control group, and the other conditions were the same. After four weeks of injection, the infarct size of the group injected with the temperature-sensitive complex gel was found to be minimal (1.8 cm)2) While the group injected with PBS had the largest infarct size (4.6 cm)2) These results indicate that temperature-sensitive complex gel injection can accelerate tissue repair in vivo.
Claims (8)
1. A temperature-sensitive composite gel emulsion is characterized by comprising the preparation processes of (1) preparing a chitosan solution, dropwise adding β -sodium glycerophosphate solution into the chitosan solution at the temperature of minus 4-4 ℃ under stirring to prepare a chitosan temperature-sensitive gel forming solution, (2) adding gelatin microspheres containing growth factors into the low-temperature chitosan temperature-sensitive gel forming solution, and (3) adding cells into the low-temperature chitosan temperature-sensitive gel forming solution containing the gelatin microspheres to obtain the temperature-sensitive composite gel emulsion.
2. A gel emulsion according to claim 1, wherein:
the deacetylation degree of the chitosan is 95% or more;
the molecular weight of the chitosan is 10000-300000Da, preferably 200000 Da;
the concentration of the chitosan solution is 1-3% (w/v, g/ml), preferably 2% (w/v, g/ml);
the concentration of the β -sodium glycerophosphate solution is 40-56% (w/v, g/ml);
the volume ratio of the chitosan solution to the sodium beta-glycerophosphate solution is 35:1-5:1, preferably 14: 1.
3. A gel emulsion according to claim 1, wherein:
the growth factor is one or more of basic fibroblast growth factor (bFGF), Vascular Endothelial Growth Factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), Nerve Growth Factor (NGF), acidic fibroblast growth factor (aFGF), Epidermal Growth Factor (EGF), Bone Morphogenetic Protein (BMP), Stem Cell Factor (SCF), Hepatocyte Growth Factor (HGF), Erythropoietin (EPO) and interleukin-1 α (IL-1 α), the mass content of the growth factor in the gelatin microsphere is 0.02-2% (w/w), preferably 0.2% (w/w), and the particle size of the gelatin microsphere is 10-200 microns.
4. A gel emulsion according to claim 1 or 3, characterized in that:
the concentration of the gelatin microspheres in the chitosan temperature-sensitive gel forming solution is 1-10mg/ml, preferably 5 mg/ml.
5. A gel emulsion according to claim 1, wherein:
the density of the cells in the low-temperature chitosan temperature-sensitive gel forming solution containing the gelatin microspheres is 105-107Per ml, preferably 106/ml。
6. A gel emulsion according to claim 1 or 5, wherein: the cells are one or more than two of stem cells (iPS cells, embryonic stem cells and mesenchymal stem cells), mature cells (primary cells separated from tissues and cells obtained by inducing and differentiating stem cells) and transgenic cells.
7. 1-6 application of the temperature-sensitive composite gel emulsion as an injection type in-vivo delivery carrier of growth factors and cells.
8. The emulsion of low temperature-sensitive composite gel according to claim 7, which can be rapidly transformed into gel state at 36-40 ℃.
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| CN116712609A (en) * | 2023-07-26 | 2023-09-08 | 鑫华微(厦门)生物科技有限公司 | An injectable temperature-sensitive composite hydrogel and its application in preparing filling materials for shaping and/or repairing |
| CN118873635A (en) * | 2024-07-24 | 2024-11-01 | 广东壹加再生医学研究院有限公司 | A composition, composite cytokine hydrogel and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115317665A (en) * | 2022-08-12 | 2022-11-11 | 济南格莱威医疗科技有限公司 | Polyester particle composite temperature-sensitive in-situ gel subcutaneous implant |
| CN115317665B (en) * | 2022-08-12 | 2023-08-18 | 济南格莱威医疗科技有限公司 | Polyester particle composite temperature-sensitive instant gel subcutaneous implant |
| CN116712609A (en) * | 2023-07-26 | 2023-09-08 | 鑫华微(厦门)生物科技有限公司 | An injectable temperature-sensitive composite hydrogel and its application in preparing filling materials for shaping and/or repairing |
| CN118873635A (en) * | 2024-07-24 | 2024-11-01 | 广东壹加再生医学研究院有限公司 | A composition, composite cytokine hydrogel and preparation method and application thereof |
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