CN117547656A - Hydrogel litholytic stent and preparation method and application thereof - Google Patents
Hydrogel litholytic stent and preparation method and application thereof Download PDFInfo
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- CN117547656A CN117547656A CN202311532248.8A CN202311532248A CN117547656A CN 117547656 A CN117547656 A CN 117547656A CN 202311532248 A CN202311532248 A CN 202311532248A CN 117547656 A CN117547656 A CN 117547656A
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- hydrogel
- litholytic
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- pancreatic duct
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 123
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
- C08G73/0666—Polycondensates containing five-membered rings, condensed with other rings, with nitrogen atoms as the only ring hetero atoms
- C08G73/0672—Polycondensates containing five-membered rings, condensed with other rings, with nitrogen atoms as the only ring hetero atoms with only one nitrogen atom in the ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- A61L2420/04—Coatings containing a composite material such as inorganic/organic, i.e. material comprising different phases
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- A61L2420/00—Materials or methods for coatings medical devices
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Abstract
The invention provides a hydrogel litholytic stent, and a preparation method and application thereof. The stent is formed by coating gamma-polyglutamic acid/polyethyleneimine hydrogel containing litholytic medicine citric acid after modifying polydopamine on the outer surface of a pancreatic duct bare stent. The hydrogel litholytic scaffold prepared by the invention has good surface viscoelasticity, soft texture, strong water absorption and good biocompatibility, and can slowly release citric acid after gradually swelling in pancreatic duct, thereby finally achieving the purpose of litholysis. In order to prevent the hydrogel from falling off, the dopamine is firstly oxidized and self-polymerized in a Tris-HCl solution to oxidize catechol into catecholquinone, so that the pancreatic duct stent is subjected to surface modification, and the hydrogel and the stent can be firmly attached by covalent bonding of benzoquinone groups and amino groups and the like in the gamma-polyglutamic acid/polyethyleneimine hydrogel. Meanwhile, the support has good compression resistance and considerable in-vitro litholysis effect.
Description
Technical Field
The invention belongs to the biomedical field and the high polymer material field, relates to a high polymer gel compound, and in particular relates to preparation and application of a hydrogel and soluble stone bracket.
Background
According to clinical medical statistics, pancreatic duct stones have high incidence rate, the traditional treatment method mainly adopts surgical operation treatment, but the wounds are large, the complications are more and the recurrence rate is high; in addition, many patients are not able to tolerate surgical treatment due to their old and weak constitution or concomitant with other diseases. In recent years, with the development of endoscope technology, the technology of taking out stones by inserting pancreatic bile duct under the endoscope (ERCP technology) gradually becomes a main treatment means of pancreatic duct stones, and good treatment effects are obtained. However, for some pancreatic duct stones (such as multiple, huge, hard or site-specific pancreatic duct stones) which are difficult to remove, or patients which are difficult to tolerate long-term endoscopic procedures, only a plastic stent directly placed into the pancreatic duct can be adopted to ensure the smoothness of the pancreatic duct. However, the pancreatic duct plastic stent has no therapeutic effect on the stent itself, restenosis is likely to occur, and the stent needs to be replaced multiple times. Meanwhile, the plastic bare pancreatic duct stent has poor drug-loading effect and low biocompatibility. Thus, there is a strong need in clinical practice for an effective litholytic pancreatic duct stent with good biocompatibility that can load a litholytic drug into a pancreatic duct bare stent, release the drug locally after placement in the pancreatic duct, and form a durable litholytic effect.
The polymerized dopamine is used as melanin, has good biocompatibility and degradability, and the degraded product is nontoxic and harmless. It has very strong adhesion as adhesion material with very multifunctional radical and other properties including reducing, chemical and photoelectric properties. In the stent thrombus taking technology, because of the biocompatibility of the polymerized dopamine, the polymerized dopamine does not cause secondary injury to blood vessels when implanted into a body, and does not generate rejection reaction in clinical treatment, so that the dopamine is a better adhesive material in the stent thrombus taking technology.
Gamma-polyglutamic acid (gamma-PGA), a biodegradable polymeric material produced by various strains of Bacillus, is a naturally occurring homopolyamide comprising D-and L-glutamic acid units linked by an amide linkage between an alpha-amino group and a gamma-carboxylic acid group. The gamma-polyglutamic acid has excellent characteristics of water solubility, biodegradability, biocompatibility, no immunogenicity and the like. Because of these advantages, polyglutamic acid derivatives and composites have received great attention in biomedical applications. In fact, polyglutamic acid composites have been developed as antibacterial composites, vaccine adjuvants and cancer therapeutic materials, and also for medical devices and tissue engineering scaffolds.
Polyethyleneimine (PEI) is a cationic polymer and has wide application in textile, adhesive, food packaging, cosmetics and other aspects. Because of its high charge density, it has been widely used for gene transfer. The presence of nucleophilic amino groups makes it an excellent scavenger, also damaging the stability of the outer membrane of gram-negative bacteria. The good performance enables PEI to have great application prospect in biomedical aspects in recent years.
Hydrogels are three-dimensional hydrophilic polymer networks, natural or synthetic polymers that can be crosslinked physically or chemically to produce hydrogels. The advantages of extremely high water content, porosity, flexibility, versatility, stimulus responsiveness, etc. compared with other alternative biomaterials make hydrogels multifunctional materials for medical applications. Crosslinked polymer network hydrogels are widely used for extracellular matrix (ECM) analogs due to their high hydration capacity. By changing the types, crosslinking degree and pore size of the polymer substances, the control of the mechanical property, the water absorption property, the drug slow release property and other properties of the gel can be realized. Other biomedical fields in which hydrogels can be used are: tissue or organ replacement, wound dressing (hemostasis and healing of chronic wounds), implant surface coatings, drug delivery, biosensors, cell encapsulation, tissue engineering scaffolds, and the like.
Disclosure of Invention
The invention provides a hydrogel and stone bracket aiming at the defects and shortcomings in the prior art. The device comprises a bare bracket, an adhesion layer and a hydrogel layer, wherein the adhesion layer is positioned on the outer side of the bare bracket, and the hydrogel layer is positioned on the outer side of the adhesion layer. The adhesive layer is polydopamine, and the hydrogel litholytic scaffold further comprises litholytic drugs, wherein the litholytic drugs are positioned in the hydrogel layer. The device can keep the channel of the pancreatic duct unobstructed, solves the problems of low drug-loading efficiency and low biocompatibility of the existing litholytic stent, and simultaneously, the litholytic drug in the device can dissolve the formed calculus.
According to the invention, polydopamine is modified on the surface of the bare stent, and covalent bonding between benzoquinone groups and amino groups and the like in gamma-polyglutamic acid/polyethyleneimine hydrogel is utilized, so that the hydrogel and the stent can be firmly attached. Then, the polyglutamic acid/polyethyleneimine hydrogel loaded with the litholytic medicine citric acid is coated in the hydrogel layer on the surface of the bracket, so that the hydrogel litholytic bracket is obtained.
The invention provides a preparation method of a hydrogel litholytic stent, which comprises the following steps:
step A: tris-HCl is dissolved in a solvent to prepare 20mL of 10-20mM Tris-HCl buffer solution, and then dopamine is added into the buffer solution to prepare 2-5mg/mL dopamine solution. Placing a plastic bare pancreatic duct bracket (with the length of 5-10cm and the diameter of 5 Fr) into a Tris-HCl buffer solution of dopamine, stirring (400 rpm) at room temperature for reacting for 12-48h, taking out the bracket after the reaction is finished, placing the bracket into deionized water, washing for multiple times, and removing unpolymerized dopamine on the pancreatic duct bracket. Drying the cleaned pancreatic duct stent to obtain the polydopamine modified pancreatic duct stent.
And (B) step (B): dissolving gamma-polyglutamic acid in a solvent, stirring to completely dissolve the gamma-polyglutamic acid, wherein the mass fraction of the dissolved gamma-polyglutamic acid is 0.25% -5%; and adding the polyethyleneimine into the solution, and stirring to uniformly mix the polyethyleneimine to obtain a mixed solution. Placing the polydopamine modified pancreatic duct stent into a mixed solution, adding a carboxyl activating agent into the mixed solution, wherein the activating agent is one or two of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide, and obtaining the hydrogel coated pancreatic duct stent after complete reaction.
Step C: and (3) placing the prepared hydrogel coated pancreatic duct stent in a high-concentration citric acid solution for soaking for 12-48 hours, and loading a litholytic medicament citric acid in the hydrogel by utilizing the osmotic diffusion effect to obtain the hydrogel litholytic stent.
Further, the solvent in the step a is any one of distilled water, phosphate buffer solution (ph=7.4) and physiological saline.
Further, step A also includes adjusting the pH of the Tris-HCl buffer solution to 8.5 prior to adding dopamine.
Further, the solvent in the step B is any one of distilled water, phosphate buffer solution (ph=7.4) and physiological saline.
Further, in the step B, the mass concentration percentage of the polyethyleneimine and the gamma-polyglutamic acid is 12-30%. Wherein the mass concentration of the polyethyleneimine is 0.03-0.04g/mL, and the mass concentration of the gamma-polyglutamic acid is 0.22-0.24g/mL.
Further, in the step B, the dissolution temperature of the gamma-polyglutamic acid and the polyethyleneimine is 20-30 ℃.
Further, in the step B, the mass fraction of the carboxyl activating agent is 1% -15%, and the mass concentration of the carboxyl activating agent in the final reaction solution is 0.01-0.02g/mL.
Further, in the step B, the reaction temperature is 10-30 ℃.
Further, in step C, the solvent used for the high-concentration citric acid solution is any one of distilled water, phosphate buffer solution (ph=7.4), and physiological saline.
Further, in the step C, the concentration of the high-concentration citric acid solution is 0.5-2g/mL.
Further, the reaction temperature in the step C is 20-30 ℃.
The invention also provides application of the hydrogel litholytic stent prepared by the method in preparing pancreatic duct calculus dissolving equipment, and the hydrogel litholytic stent has excellent effects in safe and efficient drug delivery and pancreatic duct litholytic.
The invention carries out oxidation self-polymerization on dopamine in Tris-HCl solution and carries out surface modification on pancreatic duct brackets. And placing the polydopamine modified pancreatic duct stent into a gamma-polyglutamic acid and polyethyleneimine solution added with a carboxyl activating agent. Taking 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride-N-hydroxysuccinimide (EDC-NHS) as a carboxyl activator as an example, the preparation method of the gel on the surface of the coated stent is provided: dissolving gamma-polyglutamic acid in a solvent, adding polyethyleneimine into the solution, stirring to uniformly mix the mixture to obtain a mixed solution, and then adding EDC-NHS into the mixed solution to form gel. And finally, soaking the pancreatic duct stent coated by the hydrogel in a high-concentration citric acid solution to obtain the hydrogel litholytic stent.
According to the invention, dopamine is oxidized and self-polymerized in Tris-HCl solution, so that catechol is oxidized into catechol quinone, and the hydrogel can be firmly coated on the surface of the bracket through covalent bonding of benzoquinone groups and amino groups and the like in polyglutamic acid/polyethyleneimine hydrogel. Meanwhile, the carboxyl group in the gamma-polyglutamic acid can be activated by utilizing the carboxyl activating agent, so that the carboxyl group can be subjected to crosslinking reaction with the polyethyleneimine, and the preparation method for realizing crosslinking of the gamma-polyglutamic acid and the polyethyleneimine under the activation of EDC-NHS is provided. Finally, the litholytic medicine citric acid is loaded in the hydrogel on the surface of the bracket through osmotic diffusion.
The invention has simple process and short preparation time of the product, and the obtained product has good biocompatibility in-vivo and in-vitro mold experiments. According to the invention, polydopamine is selected to modify the surface of the pancreatic duct stent, gamma-polyglutamic acid and polyethyleneimine are used as matrixes, and EDC-NHS is utilized to activate carboxyl groups in the gamma-polyglutamic acid, so that the gamma-polyglutamic acid can be subjected to crosslinking reaction with polyethyleneimine to prepare the hydrogel-litholytic stent. Experiments show that the stent prepared by the invention has good viscoelasticity, soft texture, strong water absorption and good biocompatibility. The stent can gradually release the citric acid, so that the bioavailability of the drug is improved, the stability and the persistence of the drug are improved, meanwhile, the side effect of the drug is reduced, and the damage influence on normal tissues and organs is reduced.
Compared with the prior art, the invention has obvious technical progress. The hydrogel litholytic stent prepared by the invention has simple process, easily obtained product, good viscoelasticity and water absorption performance, can keep the channel of the pancreatic duct smooth, and solves the problems of low drug-loading efficiency and low biocompatibility of the existing litholytic stent. The litholytic medicine in the bracket can dissolve formed stones, is hopeful to be applied to the fields of cholangiopancreatic litholytic medicine delivery, medicine slow release and the like, and has excellent clinical application value. The hydrogel litholytic stent of the invention is not only used for pancreas ducts, but also can be used for litholytic applications of organs such as bile ducts, bladder ducts, kidney ducts and the like.
Drawings
Fig. 1a is an SEM image of a gamma-polyglutamic acid/polyethyleneimine hydrogel.
Figure 1b SEM image of gamma-polyglutamic acid/polyethyleneimine hydrogel loaded with the litholytic agent citric acid.
FIG. 2a is a compressive strain-stress curve of a gamma-polyglutamic acid/polyethyleneimine hydrogel.
FIG. 2b is the compressive modulus of a gamma-polyglutamic acid/polyethyleneimine hydrogel.
Fig. 2c shows the compressive strength of gamma-polyglutamic acid/polyethyleneimine hydrogels.
FIG. 3a shows the results of a hemolysis test of gamma-polyglutamic acid/polyethyleneimine hydrogel.
FIG. 3b shows the L929 cell viability after co-culture with gamma-polyglutamic acid/polyethyleneimine hydrogel.
FIG. 3c shows DEAD/LIVE staining results of L929 cells: untreated material and treated with gamma-polyglutamic acid/polyethyleneimine hydrogels of varying concentrations (2.5 mg/mL;5mg/mL;10 mg/mL).
Fig. 4a is the swelling kinetics of gamma-polyglutamic acid/polyethyleneimine hydrogels in distilled water, PBS (ph=7.4), and physiological saline.
Figure 4b is the maximum swelling ratio of gamma-polyglutamic acid/polyethyleneimine hydrogel after 24h swelling balance in distilled water, PBS (ph=7.4),
fig. 5 is an in vitro degradation curve of hydrogels in different solutions: deionized water, phosphate buffer solution (ph=7.4).
FIG. 6 shows the drug loading rate in gamma-polyglutamic acid/polyethyleneimine hydrogel-stone scaffolds.
FIG. 7 shows the results of in vitro release analysis of gamma-polyglutamic acid/polyethyleneimine hydrogel-lysine scaffold: in vitro release rate of citric acid for 48 h.
Fig. 8a is an in vitro litholytic result of a gamma-polyglutamic acid/polyethyleneimine hydrogel litholytic scaffold: egg shell dissolution curves (48 h) under different concentrations of citric acid-soaked hydrogel.
Fig. 8b is an in vitro litholytic result of a gamma-polyglutamic acid/polyethyleneimine hydrogel litholytic scaffold: pancreatic duct calculus dissolution curve (24 h) after 1g/mL citric acid solution soaked hydrogel; experimental group: hydrogel+calculus after 1g/mL citric acid solution is soaked; control group: hydrogel without drug + stone; blank group: distilled water + stones.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the teachings of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
Example 1
Preparing 10mM Tris-HCl buffer solution: 1mL of 1.5M Tris-HCl was taken and 150mL of deionized water was added.
Preparing 2mg/mL dopamine solution: 0.1600g of dopamine powder is weighed and 80mL of Tris-HCl buffer solution is added; and placing the bare pancreatic duct stent in the solution to obtain the polydopamine modified pancreatic duct stent.
Example 2
Dissolving 0.5g of gamma-polyglutamic acid in 1.5mL of deionized water, adding 250 mu L of polyethyleneimine into the solution, and uniformly stirring at 30 ℃ to obtain a gamma-polyglutamic acid-polyethyleneimine mixed solution. The polydopamine-modified pancreatic duct stent obtained in example 1 was placed in a mixed solution. Then, 300 mu L of EDC-NHS mixed solution (with the concentration of 0.1 g/mL) is added into the gamma-polyglutamic acid-polyethyleneimine mixed solution, and the mixture is stirred uniformly, thus obtaining the hydrogel coated pancreatic duct stent.
Example 3
2.5 g, 5g and 7.5g of citric acid are respectively dissolved in 5mL of deionized water to obtain high-concentration citric acid solution. 3 pieces of the hydrogel coated pancreatic duct stent in example 2 are respectively put into the three citric acid solutions for soaking for 24 hours, and taken out for air drying, so as to obtain the hydrogel-coated pancreatic duct stent.
Example 4
The hydrogels of example 2 and example 3 were freeze-dried and analyzed for morphology. Samples were analyzed on a ZEISS Sigma 300 field emission scanning electron microscope.
As can be seen from the electron microscopy images, the pores are visible on the surface of the hydrogel without citric acid (fig. 1 a), whereas the pores on the surface of the hydrogel with citric acid are filled with citric acid and become flat (fig. 1 b).
Example 5
Mechanical evaluation was performed on a Zwick Roell Z2.5 TH universal material tester using a 2.5kN sensor. The hydrogel compression properties obtained in example 2 were studied using a modified American society for testing and materials method. In the compression test, the hydrogel was molded in a cylinder having a diameter of 10mm and a thickness of 3mm, and the compression strain rate was 1mm/min. The compressive modulus was recorded by a linear fit of the stress-strain curve over a strain range of 20-30% (fig. 2 b). The maximum compressive strength and the compressive modulus of the hydrogel prepared in example 2 are 980.1+/-71.7 kPa and 127.9+/-6.6 kPa (figures 2b and 2 c), respectively, and the hydrogel is coated on the surface of the bracket to provide strong compressive property for the bracket, so that the problem that the bracket is easy to deform is solved.
Example 6
The blood compatibility of the hydrogel of example 2 was investigated. Red blood cells were obtained after centrifugation (3000 rpm,5 minutes) of 0.5mL whole blood and three washes with phosphate buffer solution. The resulting red blood cells were stored in 50mL of phosphate buffer to prepare 2% diluted blood for further use. In the hemolysis test, 0.6mL of the above-mentioned mouse erythrocytes were placed in a 5.0mL centrifuge tube and incubated with 2.4mL of phosphate buffer solution (negative control), 2.4mL of deionized water (positive control) and hydrogels prepared in example 2 of different qualities (5, 15, 30, 50mg/mL in 2.4mL of phosphate buffer solution) in a constant temperature incubator at 37℃for 2 hours. The supernatant was collected, the absorbance at 541nm was measured using an ultraviolet spectrophotometer, and the hemolysis rate of erythrocytes was calculated. As shown in FIG. 3a, the calculated hemolysis rates of the hydrogels were all less than 5%. From the supernatant photographs, it can be seen that the red cell supernatant incubated with the hydrogel and phosphate buffer solution is transparent. However, blood treated with deionized water appears significantly red due to hemolysis positivity. The results show that the hydrogel has good blood compatibility.
Example 7
L929 cells were seeded in 96-well plates and cultured overnight with 100. Mu.L of cell culture medium. The above medium was discarded, and the hydrogels (2.5, 5, 10 mg/mL) obtained in example 2 and 100. Mu.L of new cell culture medium were added in different weights, and the control group was added with 100. Mu.L of cell culture medium alone (survival rate was set to 100%). Placing the above cells in CO 2 Incubation was performed for 24 hours in a constant temperature incubator, and the survival of the cells was quantitatively and qualitatively detected using CCK-8 and LIVE/DEAD cell Activity detection kit. As shown in fig. 3b, the hydrogel did not affect cell survival. Similar to the control, hydrogel-treated cells could be stained green with LIVE/DEAD reagent (LIVE cells were stained green) and almost no cells were stained red (DEAD cells were stained red) (fig. 3 c). The results of CCK-8 and LIVE/DEAD cell staining indicate that the prepared hydrogels have good cell compatibility.
Example 8
To investigate the effect of different solutions on the swelling of the hydrogels obtained in example 2, the hydrogels obtained in example 2 were added to deionized water, PBS solution, physiological saline, respectively, and immersed at 37 ℃ for 24 hours. The hydrogel was removed at a preset time point and then gently rubbed to remove surface moisture and weighed to draw a corresponding swelling kinetics curve as shown in fig. 4 a. In addition, the maximum swelling ratio of the hydrogel reached after 24h swelling balance was studied (fig. 4 b), and it is revealed from the graph that the swelling ratio of the hydrogel in water was 1806.7 + -122.9 g/g, and the swelling ratio in PBS and physiological saline was reduced to 430.5+ -5.8% and 551.8 + -26.8%, respectively, and the results showed that the hydrogel can effectively absorb excessive tissue fluid and maintain a relatively moist in vivo environment, avoiding compression and damage to tissues.
Example 9
Dissolving lysozyme in deionized water and phosphate buffer solution respectively at a concentration of 1×10 4 U/mL. The lyophilized product obtained in example 2 was then weighedThe hydrogel was incubated with 10mL of lysozyme-containing deionized water or phosphate buffer solution and incubated continuously at 37℃for 21 days. The medium was changed every other day. At each time point, the hydrogel was removed from the culture medium, gently rinsed with deionized water or phosphate buffered saline, and lyophilized. The mass of the lyophilized hydrogel was weighed to calculate the degradation rate. It was found that after 21 days of degradation of the hydrogel in distilled water containing lysozyme, the hydrogel was degraded by about 57.9.+ -. 7.4% (FIG. 5). In contrast, the hydrogel degraded slightly slower in phosphate buffer containing lysozyme, about 40.2±3.4% of the original mass after 21 days of degradation (fig. 5). From the results, the hydrogel prepared in example 2 can continuously act in vivo without rapid degradation and failure.
Example 10
The amount of citric acid loaded in the hydrogel coated litholytic scaffold obtained in example 3 was measured by acid-base titration, the principle being that citric acid and an alkali solution were reacted to form the corresponding salt and water, and the amount of citric acid was calculated from the chemical equation of the reaction. Firstly, taking out the hydrogel fluorite scaffold obtained in the example 3 (soaked in 1g/mL citric acid solution) at a preset time point, taking 1mL of the residual solution, adding distilled water to dilute to 20mL, dripping 3 drops of 1% phenolphthalein indicator, and titrating to reddish color with 1mol/L sodium hydroxide standard solution. Finally, the concentration of citric acid in the solution is calculated by titrating the volume of the consumed sodium hydroxide standard solution to obtain the total content of citric acid in the residual solution, and further the content of citric acid loaded in the hydrogel is calculated (figure 6).
Example 11
The amount of citric acid released at a predetermined time point in the hydrogel-coated stone scaffold obtained in example 3 was measured using an acid-base titration method, and the principle was that citric acid and an alkali solution were reacted to generate corresponding salts and water, and the content of citric acid was calculated according to a chemical equation of the reaction.
To evaluate drug release, 180mg of the hydrogel-coated stent of example 3 immersed in 1g/mL high-strength citric acid solution for 24 hours was placed in a dialysis bag having a cutoff molecular weight of 3500kDa, and then the dialysis bag was placed in a 15mL centrifuge tube containing 10mL deionized water. Subsequently, the centrifuge tube was incubated in a steam bath shaker at 37 ℃. At each particular time point, 1mL of deionized water was taken and 1mL of fresh deionized water was added. Next, 1mL of the deionized water thus removed was diluted to 20mL with distilled water, 3 drops of 1% phenolphthalein indicator were added dropwise, and titration was carried out with 1mol/L sodium hydroxide standard solution until reddish color was reached as an end point. Finally, the concentration of citric acid in the solution is calculated by titrating the volume of the consumed sodium hydroxide standard solution, and the amount of citric acid released at the time point is obtained.
As shown in fig. 7, both hydrogel-coated and phosphate buffered saline cases exhibited a more pronounced sustained release. Then, the release tends to be in a stable state, which shows that the prepared hydrogel-litholytic scaffold has good application potential in the aspect of drug slow release.
Example 12
In order to verify the in vitro litholytic effect of the hydrogel litholytic scaffold, firstly a dissolution experiment of eggshells is utilized for verification. The hydrogel-coated scaffold obtained in example 3 was incubated with 40mg of eggshells in 2mL of deionized water for 12h, 24h, 48h after soaking in citric acid solutions of different concentrations, the eggshells were removed at the above time points, surface liquid was sucked with filter paper, and the eggshells were weighed to obtain the remaining weight ratio (fig. 8 a). From the results, it was found that the citric acid was loaded into the hydrogel by permeation with the high-concentration citric acid solution, and the pancreatic duct stent litholytic performance was imparted. Taking the 1g/mL high-concentration citric acid solution hydrogel lithotripter obtained in example 3 as an example, 25mg of the calculus was incubated in 2mL deionized water, the calculus was taken out at a preset time point, the surface liquid was sucked by filter paper, and the calculus was weighed to obtain the remaining weight ratio (FIG. 8 b). From the results, the hydrogel litholytic scaffold prepared in example 3 has a remarkable litholytic effect, and the litholytic effect is about 93.2% after 24 hours.
What has been described above is merely some embodiments of the present invention. It will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the spirit of the invention.
Claims (10)
1. The hydrogel litholytic support is characterized by comprising a bare support, an adhesion layer and a hydrogel layer, wherein the adhesion layer is positioned on the outer side of the bare support, and the hydrogel layer is positioned on the outer side of the adhesion layer.
2. The hydrogel litholytic stent of claim 1, wherein the adhesive layer is polydopamine, the hydrogel litholytic stent further comprising a litholytic drug located in the hydrogel layer.
3. A method of preparing a hydrogel fluorite scaffold according to claim 1 or 2, said method comprising:
step A, dissolving Tris-HCl in a solvent to prepare a Tris-HCl buffer solution with the concentration of 10-20mM, adding dopamine into the Tris-HCl buffer solution, wherein the concentration of the dopamine is 2-5mg/mL, putting a plastic bare pancreatic duct stent into the Tris-HCl buffer solution of the dopamine, and stirring and reacting for 12-48 hours at room temperature; taking out the stent after the reaction is finished, placing the stent in deionized water, washing for multiple times, and removing unpolymerized dopamine on the pancreatic duct stent; drying the cleaned pancreatic duct stent to obtain a polydopamine modified pancreatic duct stent;
step B, dissolving gamma-polyglutamic acid in a solvent, and stirring to completely dissolve the gamma-polyglutamic acid, wherein the mass fraction of the dissolved gamma-polyglutamic acid is 0.25% -5%; adding polyethyleneimine into gamma-polyglutamic acid solution, and stirring to uniformly mix the polyethyleneimine and the gamma-polyglutamic acid solution to obtain mixed solution; placing the polydopamine modified pancreatic duct stent in the mixed solution, adding a carboxyl activating agent into the mixed solution, wherein the carboxyl activating agent is any one or two of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide, and obtaining the hydrogel coated pancreatic duct stent after complete reaction;
and C, placing the hydrogel coated pancreatic duct stent prepared in the step B into citric acid solution for soaking for 12-48 hours, and loading litholytic medicine citric acid into the hydrogel to obtain the hydrogel litholytic stent.
4. A method of preparing a hydrogel litholytic scaffold according to claim 3, wherein step a further comprises adjusting the pH of the Tris-HCl buffer solution to 8.5 prior to adding dopamine;
the solvent in the step A and/or the step B is any one of distilled water, phosphate buffer solution and physiological saline; the solvent used in the citric acid solution in the step C is any one of distilled water, phosphate buffer solution and physiological saline; the pH of the phosphate buffer solution was 7.4.
5. A method of preparing a hydrogel litholytic scaffold according to claim 3, wherein in step B the mass fraction of polyethylenimine to gamma-polyglutamic acid is 12% -30%.
6. A method of preparing a hydrogel litholytic scaffold according to claim 3, wherein in step B the mass concentration of polyethylenimine is between 0.03 and 0.04g/mL and the mass concentration of gamma-polyglutamic acid is between 0.22 and 0.24g/mL.
7. A method of preparing a hydrogel litholytic scaffold according to claim 3, wherein in step B the mass concentration of the carboxy activator in the final reaction solution is 0.01-0.02g/mL.
8. A method of preparing a hydrogel litholytic scaffold according to claim 3, wherein in step C the concentration of citric acid solution is 0.5-2g/mL.
9. A method of preparing a hydrogel litholytic scaffold according to claim 3, wherein the reaction temperatures of step a, step B and step C are all 10-30 ℃.
10. Use of a hydrogel litholytic scaffold according to claim 1 or 2 for the preparation of a litholytic apparatus.
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