CN119569943B - A high oxygen permeability, anti-fibrosis, flexible hydrogel microtube and its preparation method and application - Google Patents
A high oxygen permeability, anti-fibrosis, flexible hydrogel microtube and its preparation method and applicationInfo
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- CN119569943B CN119569943B CN202411674624.1A CN202411674624A CN119569943B CN 119569943 B CN119569943 B CN 119569943B CN 202411674624 A CN202411674624 A CN 202411674624A CN 119569943 B CN119569943 B CN 119569943B
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Abstract
The invention provides a high oxygen permeation anti-fibrosis flexible hydrogel microtube, a preparation method and application thereof, wherein the preparation of the hydrogel microtube comprises the following steps: the three monomers of high-strength hydrogen bond monomer, amphoteric ion monomer and silicon monomer are dissolved in a mixed solvent of deionized water and DMSO, a photoinitiator is added, vortex mixing is carried out, the mixture is rapidly added into a mould, and polymerization reaction is initiated by a free radical initiator, so that the anti-fibrosis flexible hydrogel microtubule is obtained. The hydrogel preparation method is simple, and the hydrogel microtubules with good biocompatibility, anti-fibrosis and flexibility can be obtained by adjusting the proportion of the monomers and the size of the hydrogel microtubules, so that the exchange of oxygen, nutrient substances and metabolites is promoted, and the activity and the function of islet cells are maintained.
Description
Technical Field
The invention relates to the technical fields of biomedical materials, tissue engineering and regenerative medicine, in particular to a high-oxygen-permeability anti-fibrosis flexible hydrogel microtube and a preparation method and application thereof.
Background
Diabetes is a common chronic metabolic disease and has become an important public health problem that severely threatens human health. Persistent hyperglycemia and blood glucose fluctuations can cause multiple complications such as diabetic foot, diabetic nephropathy, cardiovascular disease, retinopathy, etc. For patients with type 1 diabetes and middle and late stage type 2 diabetes, a clinically common method is a subcutaneous injection exogenous insulin method, and although the blood sugar level can be reduced to a certain extent, the dynamic balance adjustment of blood sugar is difficult to realize, and repeated insulin injection brings pain and serious economic burden to the patients. With the progress of islet isolation and purification technology, islet transplantation is becoming a potential treatment for diabetes. However, this approach presents a number of challenges in implementation, immune rejection being a major cause of early damage to islet cells and affecting long-term graft efficacy. Despite the use of immunosuppressive agents, immune rejection is not completely inhibited, and there are serious side effects and islet cell damage problems associated with the use of immunosuppressants throughout the life.
In order to avoid adverse reactions caused by long-term use of immunosuppressants, physical barrier immunoisolation methods are proposed. It was found that foreign body reactions of transplanted islet encapsulating materials and their degradation products can cause fibrosis of surrounding tissues, even formation of fibrous vesicles, which can affect the transport of oxygen, nutrients and metabolites, and that hypoxic necrosis of islet cells can occur, eventually leading to failure of islet grafts. The amphoteric electrolyte can be combined with 7-8 water molecules at most, and generates a strong hydration effect through a solvation effect, so that a firm hydration layer is formed on the surface of the material, thereby endowing the hydrogel microtubule with excellent biological antifouling performance and effectively avoiding the formation of fibrous capsules. Silicone hydrogel contact lenses have high oxygen permeability because of the longer bond length of the siloxane bonds present in the silicone monomers, which allows for greater distances between the siloxane molecules, thereby providing more free space for oxygen molecules, facilitating the passage of oxygen molecules, and providing sufficient oxygen for cell survival.
Disclosure of Invention
The invention overcomes the defects in the prior art, and provides a high-oxygen-permeability anti-fibrosis flexible hydrogel microtube and a preparation method and application thereof, the invention adjusts the proportion of monomers and the size of the hydrogel tube by introducing zwitterionic monomers and silicon monomers, the flexible hydrogel microtubule with good biocompatibility, good permeability, fibrosis resistance and no degradation is constructed, and the exchange of oxygen, nutrient substances and metabolites is promoted so as to maintain the activity and the function of islet cells.
The aim of the invention is achieved by the following technical scheme.
A high oxygen permeability anti-fibrosis flexible hydrogel microtube and a preparation method thereof are carried out according to the following steps:
Dissolving a raw material high-strength hydrogen bond monomer A, a zwitterionic monomer B and a silicon monomer C in a solvent, adding a photoinitiator, oscillating and uniformly mixing, then rapidly adding the mixture into a die, and initiating carbon-carbon double bonds of the high-strength hydrogen bond monomer A, the zwitterionic monomer B and the silicon monomer C by ultraviolet irradiation to perform free radical polymerization to obtain the anti-fibrosis flexible hydrogel microtubule;
wherein, the structure of the high-strength hydrogen bond monomer A is shown in the following chemical formula 1:
Wherein m is an integer of 0 to 10, R 1 is CH 2 or NH, R 2 is NH or O, R 3 is H or (CH 2)kCH3, k is an integer of 0 to 100;
The structure of the zwitterionic monomer B is shown in the following chemical formula 2 (a) or 2 (B):
wherein m is an integer of 0-10, n is an integer of 0-10, R 1 is H or CH 3;R2 is NH or O;
wherein m is an integer of 0-10, n is an integer of 0-10, R 1 is H or CH 3;R2 is NH or O;
the structure of the silicon monomer C is shown in the following chemical formula:
Wherein m is an integer of 0-10, R 1 is H or CH 3;R2 is NH or O;
Wherein m is an integer of 0-10, R 1 is H or CH 3;R2 is NH or O;
The total monomer concentration of the high-strength hydrogen bond monomer A, the amphoteric ion monomer B and the silicon monomer C is 20-40wt%, wherein the mass ratio of the three monomers A to B to C is (15-30): 0-15): 0-3, the solvent adopts a mixed solution of deionized water and dimethyl sulfoxide (DMSO), the initiator adopts an ultraviolet initiator, the diameter range of the obtained hydrogel microtube cavity is 800-1400 mu m, and the thickness range of the tube wall is 300-500 mu m.
In the structure of the high-strength hydrogen bond monomer A, m is 2-6,k and 2-10.
In the structure of the zwitterionic monomer B, in the chemical formula 2 (a), m is 2-6, n is 2-6, and in the chemical formula 2 (B), m is 2-6, and n is 2-6.
In the structure of the silicon monomer C, m is 2-6 in the chemical formula 3 (a), and m is 2-6 in the chemical formula 3 (b).
The total monomer concentration of the mass of the high-strength hydrogen bond monomer A, the mass of the zwitterionic monomer B and the mass of the silicon monomer C is 30 weight percent, wherein the mass ratio of the three monomers A to B to C is 18:10:2.
The solvent adopts the mixed solution of deionized water and dimethyl sulfoxide (DMSO) with the volume ratio of 1 (2-3), preferably 1:2.5.
The ultraviolet initiator is selected from 2-hydroxy-2-methyl-1-phenyl-1-acetone, 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone and dibenzoyl peroxide, preferably 2-hydroxy-2-methyl-1-phenyl-1-acetone, the concentration of the initiator is 0.5% -2%, preferably 1% of the sum of the molar amount of the three monomers, and the polymerization reaction time is 600-3600s, preferably 1800s.
The specification of the die adopts an outer diameter of 1.4mm, an inner diameter of 0.9mm, an outer diameter of 1.1mm, an inner diameter of 0.8mm or an outer diameter of 1.1mm, an inner diameter of 0.7mm, and a preferable outer diameter of 1.1mm, an inner diameter of 0.8mm.
The invention relates to an application of an anti-fibrosis flexible hydrogel microtubule in the technical field of biomedical materials and in the preparation of biomedical materials for maintaining the activity and the function of islet cells.
The preparation method is simple, and the high-oxygen-permeability anti-fibrosis flexible hydrogel microtube is prepared by regulating the total solid content and the proportion of three monomers in a reaction system.
Drawings
FIG. 1 is a microscopic image of a hydrogel microtube prepared according to the present invention.
FIG. 2 is a graph showing the rheological properties of carboxybetaine acrylamides (CBAA) of different solids content to give hydrogels.
FIG. 3 shows the oxygen permeability of hydrogels obtained from different solids contents of (3-methacryloxy-2-hydroxypropoxy) propylbis (trimethylsiloxy) methylsilane (SIGMA).
FIG. 4 shows contact angles of hydrogels obtained from different solids contents of (3-methacryloxy-2-hydroxypropoxy) propylbis (trimethylsiloxy) methylsilane (SIGMA).
FIG. 5 is a graph showing the change in blood glucose after transplantation of hydrogel microtubule-encapsulated islet cells of example 4 into the abdominal cavity of a mouse.
Detailed Description
The technical scheme of the invention is further described by specific examples.
And observing the lumen and wall thickness of the hydrogel microtube by adopting an inverted microscope. Rheological properties were determined using a rheometer (Anton Paar, MCR 302). The microscopic morphology of the hydrogel microtubes was observed using a scanning electron microscope (Japan, S4800). The oxygen permeability was measured using a contact lens oxygen permeability meter (Model 201T Permeometer TM).
Example 1
Step 1, 0.28g of acryloylglycinamide (NAGA) and 0.02g of carboxybetaine acrylamide (CBAA) were dissolved in 0.7mL of a mixed solvent of H 2 O: dmso=1:2.5. The molecular formulas of NAGA and CBAA are shown in chemical formula 4 and chemical formula 5, respectively:
and 2, adding a photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-propanone with a molar quantity of 1% into the solution, oscillating and vortex, then rapidly adding the solution into a mold with the specification of 1.4mm in outer diameter, 0.9mm in inner diameter, 1.1mm in outer diameter, 0.8mm in inner diameter and 1.1mm in outer diameter and 0.7mm in inner diameter, and irradiating for 1800 seconds in an ultraviolet cross-linking box to obtain the P (NAGA-CBAA) hydrogel microtube of a non-knocked-out mold.
And 3, knocking out a die outside the P (NAGA-CBAA) hydrogel microtube, soaking in a PBS buffer solution at 37 ℃ for 5 days, demolding, swelling and balancing, replacing the PBS buffer solution for 3 times each day, and cutting the hydrogel microtube with the length of 3cm by using a cutter.
The resulting hydrogel microtubes were observed under a microscope for lumen diameter and wall thickness. The image under the microscope is shown in fig. 1. The diameter range of the hydrogel microtube lumen obtained by using the mould with the specification is 800-1400 mu m, and the thickness range of the tube wall is 300-500 mu m, so that the diameter and the wall thickness of the lumen can be adjusted by adjusting the specification of the mould.
Example 2
Step 1, NAGA 0.2g, (3-methacryloxy-2-hydroxypropoxy) propylbis (trimethylsiloxy) methylsilane (SIGMA) 0.1g, SIGMA 0.1g and 0.01g CBAA;0.18g NAGA, SIGMA 0.1g and 0.02g CBAA;0.17g NAGA, SIGMA 0.1g and 0.03. 0.03g CBAA were dissolved in 0.7mL of a mixed solvent of H 2 O DMSO=1:2.5, respectively. The molecular formula of SIGMA is shown in the following chemical formula 6, respectively:
and 2, respectively adding a photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-propanone with the molar weight of 1 percent into the solution, oscillating and vortex, then rapidly adding the solution into a die with the specification of 1.1mm in outer diameter and 0.8mm in inner diameter, and irradiating 1800 seconds in an ultraviolet cross box to obtain the hydrogel microtube without the die knocked out.
And 3, knocking out a die outside the hydrogel microtube, soaking in a PBS buffer solution at 37 ℃ for 5 days, demolding, swelling and balancing, replacing the PBS buffer solution 3 times each day, and cutting the hydrogel microtube with the length of 3cm by using a cutter.
Hydrogel discs with a diameter of 2.5cm were prepared using the monomer ratios described above and were subjected to rheological testing, FIG. 2 under conditions of a fixed temperature of 25℃and a time sweep of 0-300s, strain of 1%, frequency 1Hz. As can be seen from FIG. 2, the hydrogel microtube prepared by the invention has good rheological property, thus proving that the hydrogel prepared by the invention has microcosmic stability, and the mechanical property of the prepared hydrogel microtube can be adjusted by the monomer proportion.
Example 3
Step 1, NAGA and 0.05g SIGMA;0.2g NAGA in a ratio of 0.25g and 0.1g SIGMA;0.15g NAGA and 0.15g SIGMA, respectively, were dissolved in 0.7mL of a mixed solvent of H 2 O: DMSO=1:2.5.
And 2, respectively adding a photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-propanone with the molar weight of 1 percent into the solution, oscillating and vortex, then rapidly adding the solution into a die with the specification of 1.1mm in outer diameter and 0.8mm in inner diameter, and irradiating 1800 seconds in an ultraviolet cross box to obtain the hydrogel microtube without the die knocked out.
And 3, knocking out a die outside the hydrogel microtube, soaking in a PBS buffer solution at 37 ℃ for 5 days, demolding, swelling and balancing, replacing the PBS buffer solution 3 times each day, and cutting the hydrogel microtube with the length of 3cm by using a cutter.
Oxygen permeability test to evaluate the oxygen permeability of the hydrogel of example 3, an experiment was conducted using a contact lens oxygen permeability meter (Model 201T Permeometer TM). Specifically, the hydrogels are placed in normal saline for soaking for 48 hours, and the oxygen permeability of each group of hydrogels is measured under the simulated physiological condition of human body with the relative humidity of 98% at 37 ℃ by adopting the standard of national standard GB/T11417.3-2012. Each group of samples was tested three times and the average value was calculated as the basis for the evaluation of the final oxygen permeation performance. As can be seen from fig. 3, the hydrogel prepared by the present invention has good oxygen permeability, and the ratio of the introduced silicon monomer is adjusted to improve the oxygen permeability, thereby improving the survival rate of islet cells.
Hydrogel sheets were prepared using the monomer ratios described above and contact angle measurements were performed. As can be seen from fig. 4, the hydrogel microtubule prepared by the method has good surface wettability, the surface wettability can be adjusted by adjusting the proportion of SIGMA, the adhesion of protein and cells in vivo can be reduced, and the formation of fibrous capsules can be avoided.
Example 4
Step 1, 0.18g NAGA, 0.1g SIGMA and 0.02g CBAA were dissolved in 0.7mL H 2 O: DMSO=1:2.5.
And 2, adding a photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-propanone with a molar quantity of 1% into the solution, oscillating and vortex, then rapidly adding the solution into a die with a specification of 1.1mm in outer diameter and 0.8mm in inner diameter, and irradiating for 1800 seconds in an ultraviolet cross-over box to obtain the hydrogel microtube without the die knocked out.
And 3, knocking out a die outside the hydrogel microtube, soaking in a PBS buffer solution at 37 ℃ for 5 days, demolding, swelling and balancing, replacing the PBS buffer solution 3 times each day, and cutting the hydrogel microtube with the length of 3cm by using a cutter.
And sterilizing the hydrogel microtubule prepared by the monomer proportion, packaging islet cells, transplanting the islet cells into the abdominal cavity of a mouse, and monitoring blood sugar. As can be seen from fig. 5 (the icons are basically consistent with fig. 2), the hydrogel microtubule prepared by the method has good biological antifouling performance and oxygen permeability, and can well maintain the activity and function of islet cells.
According to the invention, the preparation of the hydrogel microtube can be realized by adjusting the technological parameters, and the hydrogel microtube shows the performance basically consistent with the invention through test. The foregoing has described exemplary embodiments of the invention, it being understood that any simple variations, modifications, or other equivalent arrangements which would not unduly obscure the invention may be made by those skilled in the art without departing from the spirit of the invention.
Claims (10)
1. The preparation method of the high oxygen permeation anti-fibrosis flexible hydrogel microtube is characterized by comprising the following steps:
Dissolving a raw material high-strength hydrogen bond monomer A, a zwitterionic monomer B and a silicon monomer C in a solvent, adding a photoinitiator, oscillating and uniformly mixing, then rapidly adding the mixture into a die, and initiating carbon-carbon double bonds of the high-strength hydrogen bond monomer A, the zwitterionic monomer B and the silicon monomer C by ultraviolet irradiation to perform free radical polymerization to obtain the anti-fibrosis flexible hydrogel microtubule;
wherein, the structure of the high-strength hydrogen bond monomer A is shown in the following chemical formula 1:
Wherein m is an integer of 0 to 10, R 1 is CH 2 or NH, R 2 is NH or O, R 3 is H or (CH 2)kCH3, k is an integer of 0 to 100;
The structure of the zwitterionic monomer B is shown in the following chemical formula 2 (a) or 2 (B):
wherein m is an integer of 0-10, n is an integer of 0-10, R 1 is H or CH 3;R2 is NH or O;
wherein m is an integer of 0-10, n is an integer of 0-10, R 1 is H or CH 3;R2 is NH or O;
the structure of the silicon monomer C is shown in the following chemical formula:
Wherein m is an integer of 0-10, R 1 is H or CH 3;R2 is NH or O;
Wherein m is an integer of 0-10, R 1 is H or CH 3;R2 is NH or O;
The total monomer concentration of the high-strength hydrogen bond monomer A, the amphoteric ion monomer B and the silicon monomer C is 20-40wt%, wherein the mass ratio of the three monomers A to B to C is 19:1:10, or 18:2:10, or 17:3:10, the solvent adopts a mixed solution of deionized water and dimethyl sulfoxide, and the initiator adopts an ultraviolet initiator.
2. The method for preparing a highly oxygen permeable anti-fibrosis flexible hydrogel microtube as claimed in claim 1, wherein m is 2-6,k and m is 2-10 in the structure of the high strength hydrogen bond monomer A.
3. The method for preparing a highly oxygen permeable anti-fibrosis flexible hydrogel microtube as claimed in claim 1, wherein in the structure of the zwitterionic monomer B, m is 2-6 and n is 2-6 in chemical formula 2 (a), and m is 2-6 and n is 2-6 in chemical formula 2 (B).
4. The method for preparing a highly oxygen permeable anti-fibrosis flexible hydrogel microtube as claimed in claim 1, wherein in the silicon monomer C structure, m is 2-6 in chemical formula 3 (a), and m is 2-6 in chemical formula 3 (b).
5. The method for preparing the high-oxygen-permeability anti-fibrosis flexible hydrogel microtubes as claimed in claim 1, wherein the total monomer concentration of the high-strength hydrogen bond monomer A, the zwitterionic monomer B and the silicon monomer C is 30wt%.
6. The method for preparing the high-oxygen-permeability anti-fibrosis flexible hydrogel microtube according to claim 1, wherein the solvent is a mixed solution of deionized water and dimethyl sulfoxide in a volume ratio of 1 (2-3).
7. The method for preparing the high oxygen permeability anti-fibrosis flexible hydrogel microtube according to claim 1, wherein the ultraviolet initiator is selected from 2-hydroxy-2-methyl-1-phenyl-1-acetone, 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone or dibenzoyl peroxide, the concentration of the initiator is 0.5% -2% of the sum of the molar amounts of the three monomers, and the polymerization reaction time is 600-3600 s.
8. The method for preparing the high oxygen permeation and anti-fibrosis flexible hydrogel microtube as claimed in claim 1, wherein the mold is 1.4mm in outer diameter, 0.9mm in inner diameter, 1.1mm in outer diameter, 0.8mm in inner diameter or 0.7mm in outer diameter, 1.1mm in inner diameter.
9. A highly oxygen-permeable anti-fibrosis flexible hydrogel microtube prepared by the method of any one of claims 1 to 8, wherein the diameter of the lumen of the obtained hydrogel microtube is 800-1400 μm and the thickness of the tube wall is 300-500 μm.
10. The use of a highly oxygen permeable anti-fibrotic flexible hydrogel microtubule as claimed in claim 9 in the preparation of biomedical materials for maintaining islet cell activity and function.
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| CN110857326A (en) * | 2018-08-22 | 2020-03-03 | 天津大学 | Supermolecule polymer hydrogel with injectability and rapid recovery performance as well as preparation method and application thereof |
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