CN100478032C - Preparation method of injection type pH and glucose sensitive hydrogel - Google Patents
Preparation method of injection type pH and glucose sensitive hydrogel Download PDFInfo
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- CN100478032C CN100478032C CNB2005101146783A CN200510114678A CN100478032C CN 100478032 C CN100478032 C CN 100478032C CN B2005101146783 A CNB2005101146783 A CN B2005101146783A CN 200510114678 A CN200510114678 A CN 200510114678A CN 100478032 C CN100478032 C CN 100478032C
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Abstract
An injection of aquatic gel sensitive to pH value and glucose for controlling the release of the medicine wrapped by it is prepared through preparing the quaternary ammonium salt of chitosan, dissolving it along with polyethanediol in acid solution, adding the solution of glycerin phosphate, stirring, and gelatinizing.
Description
Technical field
The present invention relates to a kind of preparation method of medicine controlled releasing system, or rather, relate to the preparation method of a kind of injection type pH and glucose-sensitive hydrogels, belong to the field of pharmaceutical preparations of pharmaceutical engineering.
Background technology
The linear polysaccharide that chitosan is different with number by the D-glycosamine residue of β (1 → 4) bonding, the random N-acetyl-glucosamine that distributes is formed.As a kind of natural cation biopolymer, chitosan has wide material sources, nontoxic, tasteless, antithrombotic, antistatic, alkaline-resisting, film property, bioadhesive, biocompatibility and biological degradability, and its catabolite is nontoxic, non-immunogenicity, non-carcinogenesis.The biological medicine carrier that these characteristics become chitosan to have a extensive future.(A.Chenite, C.Chaput, D.Wang in the articles that the people write such as Chenite, C.Combes, M.D.Buschmann, C.D.Hoemann, J.C Leroux, B.L.Atkinson, F.Binette, A.Selmani, Novel injectable neutral solutions of chitosan formbiodegradable gels in situ, Biomaterials, 2000,21:2155-2161) a kind of chitosan system with syringeability of utilizing the glycerophosphate preparation is disclosed.This system keeps solution state down at 4 ℃, forms hydrogel when being heated to 37 ℃.Weak point is that this system need use a large amount of sodium glycerophosphate just can be implemented in solution-gel conversion under the body temperature, and too high ionic strength is unfavorable for the activity of the medicine that wraps and the biocompatibility of dosage form.(Jinjiang Li in the articles that the people write such as Li, Zhenghe Xu, Physicalcharacterization of a chitosan-based hydrogel delivery system, Journal ofPharmaceutical Sciences, 2002,91:1669-1677) method that a kind of method that adds hydroxyethyl-cellulose and a small amount of glycerophosphate prepares injectable type chitosan system is disclosed.Weak point is that required gelation temperature is 47 ℃, is higher than the blood heat far away, be unfavorable for the application at human body, and its drug release rate is very fast, and institute's embedding medicinal discharges substantially and finishes in 10h.European Patent Publication No WO2004/006961, open day on January 22nd, 2004, the name of innovation and creation is called Composition for cytocompatible, injectable, self-gelling chitosan solutions for encapsulating and delivering live cells orbiologically active factors (Abdellatif Chenite, Caroline Hoemann, MichaelBuschamann, et al.Composition for cytocompatible, injectable, self-gelling chitosansolutions for encapsulating and delivering live cells or biologically active factors, WO2004/006961), this application case discloses a kind of employing Biformyl, hydroxyethyl-cellulose prepares the method for injectable type chitosan system as cross-linking agent.This system can issue rubber at 37 ℃ and coagulate, and has certain cytotoxicity but weak point is a Biformyl, even the very low biocompatibility that also can reduce system of concentration.
Polyethylene Glycol [poly (ethylene glycol), PEG] is that structural formula is H[OCH by oxirane and water or ethylene glycol progressively addition polymerization and the lower water soluble polyether of molecule amount that obtains
2CH
2]
nOH.Polyethylene Glycol is a kind of amphipathic nature polyalcohol, and both water soluble dissolved in most organic solvent again, and has excellent biological compatibility, nontoxic, characteristics such as immunogenicity is low, can excrete by kidney, does not have in vivo and accumulates.Polyethylene Glycol has certain chemical inertness in addition, but is easy to again carry out bonding with material such as protein after terminal hydroxy group activation.It can be prolonged by the trim half-life in vivo effectively with medicine or pharmaceutical carrier mixing or after being connected, improve hydrophilic, the activity of protection medicine.(Narayan Bhattarai in the articles that the people write such as Narayan, Hassna R.Ramay, Jonathan Gunn, et al.PEG-grafted chitosanas an injectable thermosensitive hydrogel for sustained protein release, Journal ofControlled Release, 2005,103:609-624) disclose and a kind ofly grafted on the chitosan chain after the PEG activation, prepare the method for injectable type chitosan system.Solution-gel transition can take place down at 37 ℃ in this system, but that weak point is a preparation process is loaded down with trivial details, need activate to carry out cross-linking reaction PEG or chitosan earlier; And need use organic solvent or toxic reagent in the preparation process, need remove by filter or dialysis etc.
In addition by above-mentioned glycerophosphate with PEG crosslinking method prepared chitosan hydrogel does not all show glucose-sensitive or this character is not studied as yet.Glucose-sensitive type drug delivery system is in order to imitate the normal insulin secretion pattern of human body, diabetics to be realized the drug delivery system of insulin intelligence pulse release.The glucose-sensitive type administration of being studied at present has three classes, is respectively glucoseoxidase-pH sensitive material system, concanavalin A system, phenylboric acid system.Their weak point is that preceding two kinds of systems need be utilized foreign protein, can cause the immunoreation of human body, need separate with the human body environment with semipermeable membrane or other materials; The phenylboric acid system can not biodegradation, in external shaping, needs implant by operation.
Summary of the invention
The present invention has overcome deficiency of the prior art, and a kind of easy injection type pH and the preparation method of glucose-sensitive hydrogels are provided.This hydrogel at room temperature is the solution form by Polyethylene Glycol that contains a small amount of glycerophosphate and chitosan quaternary ammonium salt formulations prepared from solutions, can enter human body by injection, forms hydrogel under body temperature, has excellent biological compatibility and biodegradable.This hydrogel can pass through hybrid mode embedding medicinal, protein, polypeptide, cell, enzyme, antibody etc. simply at solution state.Owing to have cationic quaternary ammonium group on the chitosan quaternary ammonium salt, therefore can make quaternary ammonium group ionization produce the interchain Coulomb repulsion, thereby cause gel swelling, dissolving by regulating pH value.Polyethylene Glycol and chitosan quaternary ammonium salt mainly form hydrogen bond by amino on hydroxyl on the polyglycol chain and the chitosan quaternary ammonium salt chain or hydroxyl, thereby constitute gel network.Be with an aldehyde radical and a hydroxyl on the glucose, equally can with chitosan quaternary ammonium salt chain formation hydrogen bond.Under the condition that glucose exists, because the part glucose replaces Polyethylene Glycol and glucose response, thereby the partial gel network is dissociated, cause gel swelling, dissolving.Therefore the chitosan quaternary ammonium salt that is cross-linked to form by Polyethylene Glycol can respond pH in the body, concentration of glucose changes generation dissolving or swelling, realizes that controlled delivery of pharmaceutical agents discharges.
The present invention is achieved by following technical proposals:
Its preparation process is as follows:
With molar ratio range is 1: 2-1: 8 chitosan and 2,3-epoxypropyl trimethylammonium chloride ammonium is scattered in water or the isopropyl alcohol, behind reaction 2-12h between 60-90 ℃, with acetone precipitation, washing, drying obtains the chitosan quaternary ammonium salt that the quaternary ammonium group substitution value is 20%-100%; The chitosan quaternary ammonium salt of preparation is dissolved in the chitosan quaternary ammonium saline solution that obtains 1.0-10.0wt.% in the acid solution of pH2.0-6.0; Adding molecular weight ranges in the chitosan quaternary ammonium saline solution is the Polyethylene Glycol of 200-25000, and obtaining Polyethylene Glycol concentration is chitosan quaternary ammonium salt-Polyethylene Glycol mixed solution of 1.0-20.0wt.%; Phosphoglycerol saline solution with 0.5-3.0wt.% between 4-30 ℃ dropwise adds chitosan quaternary ammonium salt-Polyethylene Glycol mixed solution, stirs to obtain the even limpid mixed solution of pH between 6.5-8.0; Mixed solution is poured in container, the model, constant temperature a period of time under gelation temperature, obtained having the homogeneous transparent chitin quarternary ammonium salt aquagel of required form.
The chitosan molecule amount is 5-200 ten thousand.
Deacetylating degree of chitosan is 65%-100%.
The acid solution of dissolving chitosan quaternary ammonium salt comprises acetic acid, hydrochloric acid, lactic acid, citric acid, ascorbic acid, formic acid.
The molecular weight polyethylene glycol scope is 500-10000.
Polyethylene Glycol comprises hydroxyl end groups Polyethylene Glycol, mono methoxy polyethylene glycol, carboxyl end groups Polyethylene Glycol, aldehyde radical polyethyleneglycol of end group and other functional polyethylene glycol derivants.
Also can add cross-linking agent such as sodium tripolyphosphate, sodium alginate, polyvinyl alcohol in chitosan quaternary ammonium salt-Polyethylene Glycol mixed solution after adding glycerophosphate.
Before or after adding, Polyethylene Glycol, glycerophosphate all can in the chitosan quaternary ammonium saline solution, add the solid particle, water solublity additive, medicine, polypeptide, protein, enzyme, cell, antibody of need embedding etc.
The gelation temperature scope is 30-60 ℃, and optimum is 37-38 ℃.
The gained chitin quarternary ammonium salt aquagel can change generation swelling, dissolving in response to pH and concentration of glucose.
Owing to adopt technique scheme, the preparation method that the present invention adopts has as follows compared with prior art
Beneficial effect:
1. needn't be in advance to Polyethylene Glycol or chitosan quaternary ammonium salt activation, preparation method is simple and convenient, can effectively keep the activity of biologically active drug;
2. needn't be with an organic solvent or toxic reagent, the system good biocompatibility, biodegradable;
3. prepared system can the variation by ambient temperature realize solution-gel conversion, at room temperature is injected in the body with the solution form, and gelling on the throne under body temperature can adapt to the difformity in in-vivo tissue or space, can be used for that drug disposition discharges, tissue repair.
4. prepared system has pH sensitivity and glucose-sensitive simultaneously, can be used as pH sensitivity or glucose-sensitive delivery system, realizes drug controllable release.
Description of drawings
The infrared spectrum of chitosan and made chitosan quaternary ammonium salt among Fig. 1 embodiment 1.
The a line is the infrared spectrum of chitosan among the figure, and the b line is the infrared spectrum of the chitosan quaternary ammonium salt after quaternized.
The drug release curve of medicine carrying chitin quarternary ammonium salt aquagel in the phosphate buffer solution of different pH of Fig. 2 embodiment 7 preparations
The drug release curve of medicine carrying chitin quarternary ammonium salt aquagel in the phosphate buffer solution of different pH of Fig. 3 embodiment 8 preparations
The drug release curve of medicine carrying chitin quarternary ammonium salt aquagel in the phosphate buffer solution (pH7.4) of different concentration of glucose of Fig. 4 embodiment 7 preparations
The drug release curve of medicine carrying chitin quarternary ammonium salt aquagel in the phosphate buffer solution (pH7.4) of different concentration of glucose of Fig. 5 embodiment 8 preparations
The specific embodiment
The invention will be further described below in conjunction with drawings and Examples.
The concrete grammar and the step of chitin quarternary ammonium salt aquagel preparation are described as follows:
(1) preparation of chitosan quaternary ammonium salt
With molar ratio range is 1: 2-1: 8 chitosan and 2,3-epoxypropyl trimethylammonium chloride ammonium is scattered in water or the isopropyl alcohol, is heated to 60-90 ℃ reaction temperature, reaction 2-12h.Pour reactant liquor into precipitation in the acetone, washing, oven dry obtains chitosan quaternary ammonium salt.
The molecular weight ranges of chitosan is 5-200 ten thousand, and deacetylation is 65%-100%.
(2) preparation of Polyethylene Glycol cross-linked chitosan quarternary ammonium salt aquagel
The chitosan quaternary ammonium salt of above-mentioned steps (1) gained is dissolved in the chitosan quaternary ammonium saline solution that obtains 1.0-10.0wt.% in the acid solution of pH2.0-6.0, acid solution comprises acetic acid, hydrochloric acid, lactic acid, citric acid, ascorbic acid, formic acid.Adding molecular weight ranges in the chitosan quaternary ammonium saline solution is the Polyethylene Glycol of 200-25000, obtaining Polyethylene Glycol concentration is chitosan quaternary ammonium salt-Polyethylene Glycol mixed solution of 1.0-20.0wt.%, the optimum weight scope of Polyethylene Glycol is 500-10000, and Polyethylene Glycol comprises hydroxyl end groups Polyethylene Glycol, mono methoxy polyethylene glycol, carboxyl end groups Polyethylene Glycol, aldehyde radical polyethyleneglycol of end group and other functional polyethylene glycol derivants.Phosphoglycerol saline solution with 0.5-3.0wt.% between 4-30 ℃ dropwise adds chitosan quaternary ammonium salt-Polyethylene Glycol mixed solution, stirring obtains the even limpid mixed solution of pH between 6.5-8.0, also can add cross-linking agent such as sodium tripolyphosphate, sodium alginate, polyvinyl alcohol in the mixed solution.Mixed solution is poured in container, the model, constant temperature a period of time under gelation temperature, can be obtained having the homogeneous transparent chitin quarternary ammonium salt aquagel of required form.
(3) preparation of medicine carrying chitin quarternary ammonium salt aquagel
The chitosan quaternary ammonium salt of above-mentioned steps (1) gained is dissolved in obtains the chitosan quaternary ammonium saline solution in the acid solution.In the chitosan quaternary ammonium saline solution, add Polyethylene Glycol, obtain chitosan quaternary ammonium salt-Polyethylene Glycol mixed solution.Between 4-30 ℃, the phosphoglycerol saline solution is dropwise added chitosan quaternary ammonium salt-Polyethylene Glycol mixed solution, stir and obtain even limpid mixed solution, also can add cross-linking agent such as sodium tripolyphosphate, sodium alginate, polyvinyl alcohol in the mixed solution.The medicine of required embedding, protein, polypeptide, cell, enzyme or antibody can add before or after Polyethylene Glycol, glycerophosphate add.Gained medicine carrying mixed solution is poured in container, the model, constant temperature a period of time under gelation temperature, obtained the medicine carrying chitin quarternary ammonium salt aquagel.
Said method will further describe by following example, but the example that provides can not be as the restriction to the method.
Embodiment 1
The 3.0g chitosan is scattered in the 20mL water, stirs 1h down at 80 ℃.With 16.94g 2,3-epoxypropyl trimethylammonium chloride ammonium is dissolved in the 40mL water, adds in the chitosan dispersion liquid.Behind 80 ℃ of following stirring reaction 10h, reactant liquor poured in the acetone precipitate, the agitator treating back oven dry of spending the night obtains the white loose product in refrigerator.By infrared spectrum characterization, see accompanying drawing 1, quaternized back 1597cm
-1The amino stretching vibration peak at place disappears, at 1481cm
-1Appearance-CH
3The strong absworption peak of C-H bending vibration, prove on the chitosan chain that quaternary ammonium group takes place to be replaced, and generates chitosan quaternary ammonium salt.
Made chitosan quaternary ammonium salt 0.50g and 0.72gPEG8000 among the embodiment 1 are dissolved in the lactic acid solution of 8mL0.1mol/L, stir the sodium solution 2mL that dropwise adds 0.125g/mL down, fully stir and make its mix homogeneously.Gained solution pH value is 7.4.This mixed solution is heated to 37 ℃ and be incubated 60min and make this system gelling abundant.This system can be stablized preservation under 4 ℃.
Made chitosan quaternary ammonium salt 0.50g and 0.72gPEG500 among the embodiment 1 are dissolved in the lactic acid solution of 8mL0.1mol/L, stir the sodium solution 2mL that dropwise adds 0.125g/mL down, fully stir and make its mix homogeneously.Gained solution pH value is 7.4.This mixed solution is heated to 37 ℃ and be incubated 60min and make this system gelling abundant.This system can be stablized preservation under 4 ℃.
Made chitosan quaternary ammonium salt 0.50g among the embodiment 1 and 0.72g mono methoxy PEG2000 are dissolved in the lactic acid solution of 8mL0.1mol/L, stir the sodium solution 2mL that dropwise adds 0.125g/mL down, fully stir and make its mix homogeneously.Gained solution pH value is 7.4.This mixed solution is heated to 37 ℃ and be incubated 60min and make this system gelling abundant.This system can be stablized preservation under 4 ℃.
Made chitosan quaternary ammonium salt 0.50g and 0.72gPEG8000 among the embodiment 1 are dissolved in the acetum of 8mL 0.1mol/L, stir the sodium solution 2mL that dropwise adds 0.125g/mL down, fully stir and make its mix homogeneously.Gained solution pH value is 7.4.This mixed solution is heated to 37 ℃ and be incubated 60min and make this system gelling abundant.This system can be stablized preservation under 4 ℃.
Made chitosan quaternary ammonium salt 0.50g and 0.72gPEG8000 among the embodiment 1 are dissolved in the lactic acid solution of 8mL0.1mol/L, dropwise add the sodium solution 1mL of 0.25g/mL and the sodium tripolyphosphate solution 1mL of 10mg/mL under stirring, fully stir and make its mix homogeneously.Gained solution pH value is 7.4.This mixed solution is heated to 37 ℃ and be incubated 60min and make this system gelling abundant.This system can be stablized preservation under 4 ℃.
Embodiment 7
Made chitosan quaternary ammonium salt 0.50g and 0.72gPEG8000 among the embodiment 1 are dissolved in the lactic acid solution of 8mL 0.1mol/L, stir the sodium solution 2mL that dropwise adds 0.125g/mL down, fully stir and make its mix homogeneously.In mixed solution, add 10mg doxorubicin hydrochloride (model drug), and mix homogeneously.The mixed solution that will contain doxorubicin hydrochloride is heated to 37 ℃ and be incubated 60min and make this system gelling abundant.
Embodiment 8
Made chitosan quaternary ammonium salt 0.50g and 0.72gPEG8000 among the embodiment 1 are dissolved in the lactic acid solution of 8mL 0.1mol/L, dropwise add the sodium solution 1mL of 0.25g/mL and the sodium tripolyphosphate solution 1mL of 10mg/mL under stirring, fully stir and make its mix homogeneously.In mixed solution, add 10mg doxorubicin hydrochloride (model drug), and mix homogeneously.The mixed solution that will contain doxorubicin hydrochloride is heated to 37 ℃ and be incubated 60min and make this system gelling abundant.This mixed solution is heated to 37 ℃ and be incubated 60min and make this system gelling abundant.
Embodiment 9
Made medicine carrying mixed solution in embodiment 7 or 8 is respectively got 1.0g place the 10mL teat glass, be incubated 60min down at 37 ℃ and make solution gel abundant.The phosphate buffer solution that adds the different pH value of 4mL again in each test tube respectively is 37 ℃ of vibrations down.Regularly take out the 1mL supernatant, survey absorbance at the 484nm place, and additional 1mL is with the buffer solution of pH value.With the standard doxorubicin hydrochloride solution of the phosphate buffer solution of different pH value preparation variable concentrations,, and draw standard curve at 484nm place survey absorbance.Determine the doxorubicin hydrochloride release value according to standard curve, and draw accumulative total burst size-time graph.The drug release curve of medicine carrying chitin quarternary ammonium salt aquagel in different pH buffer solution of embodiment 7 or 8 preparations seen accompanying drawing 2,3 respectively.
Made medicine carrying mixed solution in embodiment 7 or 8 is respectively got 1.0g place the 10mL teat glass, be incubated 60min down at 37 ℃ and make solution gel abundant.The phosphate buffer solution (pH7.4) that adds the different concentration of glucose of 4mL again in each test tube respectively is 37 ℃ of vibrations down.Regularly take out the 1mL supernatant, survey absorbance at the 484nm place, and additional 1mL is with the buffer solution of concentration of glucose.With the standard doxorubicin hydrochloride solution of the phosphate buffer solution (pH7.4) of different concentration of glucose preparation variable concentrations,, and draw standard curve at 484nm place survey absorbance.Determine the doxorubicin hydrochloride release value according to standard curve, and draw accumulative total burst size-time graph.The drug release curve of medicine carrying chitin quarternary ammonium salt aquagel in the phosphate buffer solution (pH7.4) of different concentration of glucose of embodiment 7 or 8 preparations seen accompanying drawing 4,5 respectively.
Claims (7)
1, the preparation method of a kind of injection type pH and glucose-sensitive hydrogels is characterized in that, it comprises the following steps:
(1) be 1 with molar ratio range: 2-1: 8 chitosan and 2,3-epoxypropyl trimethylammonium chloride ammonium is scattered in water or the isopropyl alcohol, behind reaction 2-12h between 60-90 ℃, with acetone precipitation, washing, drying obtains the chitosan quaternary ammonium salt that the quaternary ammonium group substitution value is 20%-100%, wherein the molecular weight ranges of chitosan is 5-200 ten thousand, and the deacetylation scope is 65%-100%;
(2) chitosan quaternary ammonium salt with preparation is dissolved in the chitosan quaternary ammonium saline solution that obtains 1.0-10.0wt.% in the acid solution of pH2.0-6.0;
(3) adding molecular weight ranges in the chitosan quaternary ammonium saline solution is Polyethylene Glycol or the Polyethylene Glycol analog derivative of 200-25000, obtain chitosan quaternary ammonium salt-Polyethylene Glycol or Polyethylene Glycol analog derivative mixed solution that Polyethylene Glycol or polyethylene glycols derivatives concentration are 1.0-20.0wt.%, described Polyethylene Glycol or Polyethylene Glycol analog derivative are hydroxyl end groups Polyethylene Glycol, mono methoxy polyethylene glycol, carboxyl end groups Polyethylene Glycol, aldehyde radical polyethyleneglycol of end group;
(4) between 4-30 ℃, the phosphoglycerol saline solution of 0.5-3.0wt.% is dropwise added the mixed solution of chitosan quaternary ammonium salt-Polyethylene Glycol or Polyethylene Glycol analog derivative, stir and obtain the even limpid mixed solution of pH between 6.5-8.0;
(5) mixed solution is poured in container, the model, elevated temperature is to gelation temperature, and constant temperature a period of time, obtains having the homogeneous transparent chitin quarternary ammonium salt aquagel of required form.
2, preparation method according to claim 1, acid solution is acetic acid, hydrochloric acid, lactic acid, citric acid, ascorbic acid, formic acid described in the step (2).
3, preparation method according to claim 1, Polyethylene Glycol described in the step (3) or polyethylene glycols derivative molecular weight range are 500-10000.
4, preparation method is according to claim 1 added sodium tripolyphosphate, polyvinyl alcohol crosslinked dose in mixed solution described in the step (4).
5, preparation method according to claim 1 adds solid particle, water solublity additive in each the described solution in step (2) to (5).
6, preparation method according to claim 1, the gelation temperature scope in step (5) is 30-60 ℃.
7, as preparation method as described in the claim 6, described gelation temperature scope is 37-38 ℃.
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| CN100560136C (en) * | 2008-03-27 | 2009-11-18 | 山东大学 | A kind of ferrite/bacillus calmette-guerin vaccine/thermosensitive hydrogel composite material and preparation method thereof |
| CN101935364B (en) * | 2009-09-15 | 2012-05-02 | 上海交通大学医学院附属第九人民医院 | Quaternary ammonium salt of chitosan and application thereof |
| CN102068700B (en) * | 2009-12-28 | 2012-11-21 | 中国人民解放军总医院 | Phenylboronic acid polyethylene glycol gel and application thereof serving as glucose-sensitive material |
| CN102370612B (en) * | 2010-08-24 | 2013-04-03 | 吴志宏 | Chitosan-monomethoxy polyethylene glycol gel delivery system and preparation method thereof |
| CN102652833B (en) * | 2011-03-02 | 2013-07-31 | 中国科学院过程工程研究所 | Gastric targeted drug carrier and preparation method thereof |
| CN103169978B (en) * | 2013-04-03 | 2014-10-22 | 江苏省农业科学院 | Temperature control slow release injection for bird immune globulin as well as preparation method and application thereof |
| CN104119577A (en) * | 2013-04-28 | 2014-10-29 | 江苏兴通生物科技有限公司 | Irradiation degradation-resistant and pH-adjustable chitosan gel and preparation method thereof |
| CN103694479B (en) * | 2013-11-21 | 2016-04-20 | 中国科学院长春应用化学研究所 | Polymkeric substance, glucose-sensitive nanogel, glucose-sensitive medicament-carried nano gel and preparation method thereof |
| CN103690993B (en) * | 2013-11-26 | 2015-06-10 | 四川大学 | Scaffold material capable of blood sugar induced controlled-release of drugs and used for periodontal treatment and preparation method thereof |
| CN105802916B (en) * | 2016-04-06 | 2020-05-29 | 北京化工大学 | Preparation and application methods of chitosan hydrogel three-dimensional cell culture medium |
| CN107855080B (en) * | 2017-10-30 | 2020-09-08 | 中国科学院过程工程研究所 | Polymer gel particle, preparation method thereof, composite gel particle containing polymer gel particle and application |
| CN112773930A (en) * | 2021-02-02 | 2021-05-11 | 福州大学 | Injectable temperature-controllable antibacterial hydrogel |
| CN117258048B (en) * | 2023-11-23 | 2024-01-30 | 旭和（天津）医药科技有限公司 | Nerve repair biological material carrying exosomes and preparation method thereof |
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