A hydrogel dissolvable scaffold and its preparation method and application

Abstract

The application provides a hydrogel stone-dissolving stent and a preparation method and application thereof. The stent is a gamma-polyglutamic acid / polyethyleneimine hydrogel coated with a stone-dissolving drug, citric acid, on the outer surface of a bare stent in a pancreatic duct. The hydrogel stone-dissolving stent prepared by the application has good surface viscoelasticity, soft texture, strong water absorption and good biocompatibility, can gradually swell in the pancreatic duct and slowly release citric acid, and finally achieve the purpose of stone dissolution. In order to prevent the hydrogel from falling off, the dopamine is first oxidized and self-polymerized in a Tris-HCl solution to oxidize catechol to catecholquinone, so as to perform surface modification on the pancreatic duct stent, covalently bond the benzenequinone group with amino groups in the gamma-polyglutamic acid / polyethyleneimine hydrogel, and then the hydrogel and the stent can be more firmly attached. Meanwhile, the stent has good pressure resistance and considerable in-vitro stone-dissolving effect.

Description

Technical Field

[0001] This invention belongs to the fields of biomedicine and polymer materials, and relates to a polymer gel composite, specifically the preparation and application of a hydrogel litholytic scaffold. Background Technology

[0002] According to clinical statistics, pancreatic duct stones have a high incidence rate. Traditional treatment methods mainly involve surgery, but this is highly invasive, has many complications, and a high recurrence rate. Furthermore, many patients cannot tolerate surgery due to old age, frailty, or other coexisting diseases. In recent years, with the development of endoscopic technology, endoscopic pancreaticobiliary stone removal (ERCP) has gradually become the main treatment for pancreatic duct stones, achieving good therapeutic results. However, for some difficult-to-remove pancreatic duct stones (such as multiple, large, hard, or specially located stones), or for patients who cannot tolerate prolonged endoscopic procedures, only direct placement of a plastic stent in the pancreatic duct to ensure patency is possible. However, this plastic stent has no therapeutic effect on the stones themselves and is prone to restenosis, requiring multiple stent replacements. Simultaneously, bare plastic pancreatic duct stents have poor drug loading capacity and low biocompatibility. Therefore, clinical practice urgently needs an effective litholytic pancreatic duct stent with good biocompatibility. This stent could load litholytic drugs into the bare pancreatic duct stent, allowing for local release of the drug after placement in the pancreatic duct, resulting in a long-lasting litholytic effect.

[0003] Polymeric dopamine, as a form of melanin, possesses excellent biocompatibility and biodegradability, with its degradation products being non-toxic and harmless. As a widely used adhesive material, it not only exhibits superior adhesion but also possesses numerous functional groups due to its high molecular weight, granting it many other properties, including reducing properties, chemical reactivity, and photoelectric properties. In stent retrieval technology, due to its biocompatibility, polymeric dopamine does not cause secondary damage to blood vessels during implantation and does not induce rejection reactions during clinical treatment. Therefore, dopamine is a superior adhesive material for stent retrieval.

[0004] γ-Polyglutamic acid (γ-PGA) is a biodegradable polymer produced by various Bacillus strains. It is a naturally occurring homopolymer amide containing D- and L-glutamic acid units linked by amide bonds between α-amino and γ-carboxylic acid groups. γ-PGA possesses excellent properties such as water solubility, biodegradability, biocompatibility, and non-immunogenicity. Due to these advantages, polyglutamic acid derivatives and composites have attracted widespread attention in biomedical applications. In fact, polyglutamic acid composites have been developed as antibacterial complexes, vaccine adjuvants, and cancer therapeutic materials, and are also used in medical devices and tissue engineering scaffolds.

[0005] Polyethyleneimine (PEI) is a cationic polymer with wide applications in textiles, adhesives, food packaging, and cosmetics. Due to its high charge density, it has been widely used for gene delivery. The presence of nucleophilic amino groups makes it an excellent scavenger and can also disrupt the stability of the outer membrane of Gram-negative bacteria. These favorable properties have made PEI a promising candidate for biomedical applications in recent years.

[0006] Hydrogels are three-dimensional hydrophilic polymer networks. Natural or synthetic polymers can be cross-linked physically or chemically to create hydrogels. Compared to other alternative biomaterials, hydrogels offer advantages such as extremely high water content, porosity, flexibility, multifunctionality, and stimuli-responsiveness, making them versatile materials for medical applications. Cross-linked polymer network hydrogels are widely used in extracellular matrix (ECM) analogues due to their high hydration capacity. By changing the type of polymer, the degree of cross-linking, and the pore size, the mechanical properties, water absorption properties, and drug release properties of the gel can be controlled. Other biomedical applications of hydrogels include: tissue or organ replacement, wound dressings (for hemostasis and chronic wound healing), implant surface coatings, drug delivery, biosensors, cell encapsulation, and tissue engineering scaffolds. Summary of the Invention

[0007] This invention addresses the shortcomings and deficiencies of existing technologies by providing a hydrogel litholytic scaffold. The device comprises a bare scaffold, an adhesive layer, and a hydrogel layer. The adhesive layer is located outside the bare scaffold, and the hydrogel layer is located outside the adhesive layer. The adhesive layer is polydopamine. The hydrogel litholytic scaffold also includes a litholytic drug, which is located within the hydrogel layer. This device maintains pancreatic duct patency, solves the problems of low drug loading efficiency and low biocompatibility in existing litholytic scaffolds, and simultaneously, the litholytic drug in this device can dissolve already formed stones.

[0008] This invention modifies the surface of a bare scaffold with polydopamine, utilizing the covalent bonding of benzoquinone groups with amino groups in the γ-polyglutamic acid / polyethyleneimine hydrogel to achieve a more robust adhesion between the hydrogel and the scaffold. Then, a polyglutamic acid / polyethyleneimine hydrogel loaded with the litholytic drug citric acid is encapsulated within the hydrogel layer on the surface of the scaffold to obtain a hydrogel litholytic scaffold.

[0009] This invention provides a method for preparing a hydrogel-based litholytic scaffold, comprising:

[0010] Step A: Dissolve Tris-HCl in a solvent to prepare 20 mL of a 10-20 mM Tris-HCl buffer solution. Then add dopamine to the buffer solution to prepare a 2-5 mg / mL dopamine solution. Place a bare plastic pancreatic duct stent (5-10 cm in length, 5 Fr in diameter) into the dopamine-Tris-HCl buffer solution and stir at room temperature (400 rpm) for 12-48 h. After the reaction is complete, remove the stent and place it in deionized water for repeated washing to remove unpolymerized dopamine from the pancreatic duct stent. Dry the washed pancreatic duct stent to obtain a polydopamine-modified pancreatic duct stent.

[0011] Step B: Dissolve γ-polyglutamic acid in a solvent and stir until completely dissolved. The mass fraction of the dissolved γ-polyglutamic acid should be 0.25%-5%. Add polyethyleneimine to the above solution and stir until homogeneous to obtain a mixed solution. Place the polydopamine-modified pancreatic duct stent in the mixed solution and add a carboxyl activator to the mixed solution. The activator can be any one or both of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. After the reaction is complete, a hydrogel-coated pancreatic duct stent can be obtained.

[0012] Step C: Coat the pancreatic duct stent with the hydrogel prepared above and immerse it in a high-concentration citric acid solution for 12-48 hours. Utilize the permeation and diffusion effect to load the litholytic drug citric acid into the hydrogel, thus obtaining the hydrogel litholytic stent.

[0013] Furthermore, the solvent in step A is any one of distilled water, phosphate buffer solution (pH=7.4), or physiological saline.

[0014] Furthermore, step A also includes adjusting the pH of the Tris-HCl buffer solution to 8.5 before adding dopamine.

[0015] Furthermore, the solvent in step B is any one of distilled water, phosphate buffer solution (pH=7.4), or physiological saline.

[0016] Further, in step B, the mass concentration percentage of polyethyleneimine and γ-polyglutamic acid is 12%-30%. Specifically, the mass concentration of polyethyleneimine is 0.03-0.04 g / mL, and the mass concentration of γ-polyglutamic acid is 0.22-0.24 g / mL.

[0017] Furthermore, in step B, the dissolution temperature of γ-polyglutamic acid and polyethyleneimine is 20-30℃.

[0018] Furthermore, in step B, the mass fraction of the carboxyl activator is 1%-15%, and the mass concentration of the carboxyl activator in the final reaction solution is 0.01-0.02 g / mL.

[0019] Furthermore, in step B, the reaction temperature is 10-30℃.

[0020] Furthermore, 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), or physiological saline.

[0021] Furthermore, in step C, the concentration of the high-concentration citric acid solution is 0.5-2 g / mL.

[0022] Furthermore, the reaction temperature in step C is 20-30℃.

[0023] The present invention also provides the application of the hydrogel litholytic scaffold prepared by the above method in the preparation of pancreatic duct stone dissolution devices, which has excellent effects as a safe and efficient drug delivery and pancreatic duct stone dissolution.

[0024] This invention modifies the surface of a pancreatic duct stent by oxidizing and self-polymerizing dopamine in Tris-HCl solution. The polydopamine-modified pancreatic duct stent is then placed in a solution of γ-polyglutamic acid and polyethyleneimine containing a carboxyl activator. Using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-N-hydroxysuccinimide (EDC-NHS) as an example of the carboxyl activator, a method for preparing a hydrogel-coated stent surface is provided: γ-polyglutamic acid is dissolved in a solvent, polyethyleneimine is added to the solution, and the mixture is stirred until homogeneous to obtain a mixed solution. Then, EDC-NHS is added to the mixed solution to form a gel. Finally, the hydrogel-coated pancreatic duct stent is immersed in a high-concentration citric acid solution to obtain a hydrogel-coated litholytic stent.

[0025] This invention utilizes the oxidative self-polymerization of dopamine in Tris-HCl solution to oxidize catechol to catechol quinone. The benzoquinone group then covalently bonds with the amino groups in the polyglutamic acid / polyethyleneimine hydrogel, allowing the hydrogel to firmly coat the scaffold surface. Simultaneously, leveraging the property of carboxyl activators to activate the carboxyl groups in γ-polyglutamic acid, enabling it to undergo a cross-linking reaction with polyethyleneimine, a method for preparing a cross-linked gel of γ-polyglutamic acid and polyethyleneimine under the activation of EDC-NHS is provided. Finally, the litholytic drug citric acid is loaded into the hydrogel on the scaffold surface via permeation diffusion.

[0026] This invention features a simple process, short product preparation time, and the resulting product exhibits good biocompatibility in both in vitro and in vivo simulation experiments. This invention selects polydopamine to modify the surface of a pancreatic duct scaffold, using γ-polyglutamic acid and polyethyleneimine as the matrix. EDC-NHS is used to activate the carboxyl groups in γ-polyglutamic acid, enabling it to cross-link with polyethyleneimine to prepare a hydrogel litholytic scaffold. Experiments show that the scaffold prepared by this invention has good viscoelasticity, a soft texture, strong water absorption, and good biocompatibility. The scaffold can gradually release citric acid, improving drug bioavailability, increasing drug stability and persistence, while reducing drug side effects and minimizing damage to normal tissues and organs.

[0027] Compared with existing technologies, the present invention represents a significant technological advancement. The hydrogel litholytic scaffold prepared by this invention features a simple process, readily available product, and excellent viscoelasticity and water absorption properties. It maintains the patency of the pancreatic duct and solves the problems of low drug loading efficiency and low biocompatibility in existing litholytic scaffolds. The litholytic drug in this scaffold can dissolve already formed stones, and it holds promise for applications in pancreaticobiliary litholytic drug delivery and sustained-release, demonstrating excellent clinical application value. This hydrogel litholytic scaffold is not only applicable to the pancreatic duct but can also be used for stone dissolution in organs such as the bile duct, bladder, and renal duct. Attached Figure Description

[0028] Figure 1 Image a is a SEM image of the γ-polyglutamic acid / polyethyleneimine hydrogel.

[0029] Figure 1 SEM image of bγ-polyglutamic acid / polyethyleneimine hydrogel loaded with the litholytic drug citric acid.

[0030] Figure 2 a represents the compressive strain-stress curve of the γ-polyglutamic acid / polyethyleneimine hydrogel.

[0031] Figure 2 b represents the compressive modulus of the γ-polyglutamic acid / polyethyleneimine hydrogel.

[0032] Figure 2 c represents the compressive strength of the γ-polyglutamic acid / polyethyleneimine hydrogel.

[0033] Figure 3 a represents the hemolysis test results of the γ-polyglutamic acid / polyethyleneimine hydrogel.

[0034] Figure 3 b represents the survival rate of L929 cells after co-culturing with γ-polyglutamic acid / polyethyleneimine hydrogel.

[0035] Figure 3c shows the DEAD / LIVE staining results of L929 cells: untreated and treated with different concentrations of γ-polyglutamic acid / polyethyleneimine hydrogel (2.5 mg / mL; 5 mg / mL; 10 mg / mL).

[0036] Figure 4 a represents the swelling kinetics of γ-polyglutamic acid / polyethyleneimine hydrogel in distilled water, PBS (pH=7.4), and physiological saline.

[0037] Figure 4 b represents the maximum swelling ratio of the γ-polyglutamic acid / polyethyleneimine hydrogel after 24 hours of swelling equilibrium in distilled water, PBS (pH=7.4), and physiological saline.

[0038] Figure 5 The in vitro degradation curves of the hydrogel in different solutions are shown: deionized water and phosphate buffer solution (pH=7.4).

[0039] Figure 6 The drug loading rate in the γ-polyglutamic acid / polyethyleneimine hydrogel litholytic scaffold.

[0040] Figure 7 In vitro release analysis results of γ-polyglutamic acid / polyethyleneimine hydrogel litholytic scaffold: in vitro release rate of citric acid at 48 h.

[0041] Figure 8 a) Results of in vitro litholysis of γ-polyglutamic acid / polyethyleneimine hydrogel litholysis scaffold: Dissolution curves of eggshells under hydrogel soaked in different concentrations of citric acid (48h).

[0042] Figure 8 b shows the in vitro litholytic results of the γ-polyglutamic acid / polyethyleneimine hydrogel litholytic scaffold: the dissolution curve of pancreatic duct stones after soaking the hydrogel in 1 g / mL citric acid solution (24 h); experimental group: hydrogel soaked in 1 g / mL citric acid solution + stones; control group: hydrogel without drug loading + stones; blank group: distilled water + stones. Detailed Implementation

[0043] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0044] Example 1

[0045] To prepare a 10 mM Tris-HCl buffer solution: take 1 mL of 1.5 M Tris-HCl and add 150 mL of deionized water.

[0046] Prepare a 2 mg / mL dopamine solution: Weigh 0.1600 g of dopamine powder and add 80 mL of Tris-HCl buffer solution; place the bare pancreatic duct stent in the above solution to obtain a polydopamine-modified pancreatic duct stent.

[0047] Example 2

[0048] Dissolve 0.5 g of γ-polyglutamic acid in 1.5 mL of deionized water, and add 250 μL of polyethyleneimine to the solution. Stir well at 30 °C to obtain a γ-polyglutamic acid-polyethyleneimine mixed solution. Place the polydopamine-modified pancreatic duct stent obtained in Example 1 into the mixed solution. Then, add 300 μL of EDC-NHS mixed solution (concentration 0.1 g / mL) to the γ-polyglutamic acid-polyethyleneimine mixed solution and stir well to obtain the hydrogel-coated pancreatic duct stent.

[0049] Example 3

[0050] Dissolve 2.5, 5, and 7.5 g of citric acid in 5 mL of deionized water to obtain high-concentration citric acid solutions. Immerse three pancreatic duct stents coated with the hydrogel from Example 2 in the three citric acid solutions for 24 hours each, then remove and air-dry to obtain hydrogel litholytic stents.

[0051] Example 4

[0052] The hydrogels from Examples 2 and 3 were freeze-dried, and their morphology was analyzed. The samples were analyzed using a ZEISS Sigma 300 field emission scanning electron microscope.

[0053] As can be seen from the electron microscopy images, pores are visible on the surface of the hydrogel without citric acid loading. Figure 1 a) However, the pores on the surface of the citric acid-loaded hydrogel are filled by the citric acid, making it smooth. Figure 1 b).

[0054] Example 5

[0055] Mechanical evaluation was performed using a 2.5 kN sensor on a Zwick Roell Z2.5 TH universal testing machine. The compressibility of the hydrogel obtained in Example 2 was investigated using a modified American Society for Testing and Materials (ASTM) method. In the compression test, the hydrogel was molded in a cylinder with a diameter of 10 mm and a thickness of 3 mm, and the compression strain rate was 1 mm / min. The compressive modulus was recorded by linear fitting of the stress-strain curve within a strain range of 20-30%. Figure 2b). The maximum compressive strength and compressive modulus of the hydrogel prepared in Example 2 were 980.1 ± 71.7 kPa and 127.9 ± 6.6 kPa, respectively. Figure 2 (b, 2c) Coating the surface of the scaffold with the hydrogel provides the scaffold with strong compressive strength and solves the problem of the scaffold being easily deformed.

[0056] Example 6

[0057] The blood compatibility of the hydrogel in Example 2 was investigated. Red blood cells were obtained by centrifuging 0.5 mL of whole blood (3000 rpm, 5 min) and washing three times with phosphate buffer. The obtained red blood cells were stored in 50 mL of phosphate buffer to prepare a 2% blood dilution for further use. In the hemolysis test, 0.6 mL of the above mouse red blood cells were placed in a 5.0 mL centrifuge tube and incubated for 2 hours with 2.4 mL of phosphate buffer (negative control), 2.4 mL of deionized water (positive control), and different masses of the hydrogel prepared in Example 2 (5, 15, 30, 50 mg / mL, in 2.4 mL of phosphate buffer). The incubation was carried out at 37°C for 2 hours. The supernatant was collected, and the absorbance at 541 nm was measured using a UV spectrophotometer to calculate the hemolysis rate of the red blood cells. Figure 3 As shown in Figure a, the calculated hemolysis rates of the hydrogels were all less than 5%. The supernatant images show that the red blood cell supernatant incubated with the hydrogel and phosphate buffer solution was transparent. However, the blood treated with deionized water appeared distinctly red due to positive hemolysis. These results indicate that the hydrogel has good blood compatibility.

[0058] Example 7

[0059] L929 cells were seeded in 96-well plates and cultured overnight with 100 μL of cell culture medium. The culture medium was then discarded, and different weights of the hydrogel obtained in Example 2 (2.5, 5, 10 mg / mL) and 100 μL of fresh cell culture medium were added. The control group received only 100 μL of cell culture medium (viability set at 100%). The cells were incubated in a CO2 incubator for 24 hours, and cell viability was quantitatively and qualitatively assessed using the CCK-8 and LIVE / DEAD cell viability assay kits. Figure 3 As shown in b, the hydrogel did not affect cell survival. Similar to the control group, all cells treated with the hydrogel were stained green by the LIVE / DEAD reagent (live cells were stained green), and almost no cells were stained red (dead cells were stained red). Figure 3 c). The results of CCK-8 and LIVE / DEAD cell staining showed that the prepared hydrogels all had good cell compatibility.

[0060] Example 8

[0061] To investigate the effect of different solutions on the swelling of the hydrogel obtained in Example 2, the hydrogel obtained in Example 2 was added to deionized water, PBS solution, and physiological saline, respectively, and soaked at 37°C for 24 hours. The hydrogel was removed at preset time points, and then gently wiped to remove surface moisture. The hydrogel was then weighed and the corresponding swelling kinetic curves were plotted. Figure 4 As shown in figure a. Furthermore, the maximum swelling ratio reached by the hydrogel after 24 hours of swelling equilibrium was investigated. Figure 4 b) As shown in the figure, the swelling rate of the hydrogel in water is 1806.7±122.9 g / g. The swelling rate in PBS and physiological saline is reduced to 430.5±5.8% and 551.8±26.8%, respectively. The results indicate that the hydrogel can effectively absorb excess tissue fluid and maintain a relatively moist in vivo environment, avoiding compression and damage to tissues.

[0062] Example 9

[0063] Lysozyme was dissolved in deionized water and phosphate buffer solution, respectively, at a concentration of 1×10⁻⁶. 4 U / mL. Then, weigh the lyophilized hydrogel obtained in Example 2 and incubate it with 10 mL of deionized water or phosphate buffer containing lysozyme at 37°C for 21 consecutive days. The culture 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 buffer, and lyophilized. The mass of the lyophilized hydrogel was weighed to calculate the degradation rate. The study found that after 21 days of degradation in distilled water containing lysozyme, the hydrogel was approximately 57.9 ± 7.4% degraded (U / mL). Figure 5 In contrast, the hydrogel degraded slightly slower in phosphate buffer solution containing lysozyme, losing approximately 40.2 ± 3.4% of its original mass after 21 days. Figure 5 The results show that the hydrogel prepared in Example 2 can continue to function in vivo and will not rapidly degrade or fail.

[0064] Example 10

[0065] The amount of citric acid loaded in the hydrogel-coated litholytic scaffold obtained in Example 3 was determined using acid-base titration. The principle is that citric acid reacts with an alkaline solution to produce the corresponding salt and water; the citric acid content can be calculated based on the chemical equation of the reaction. First, the hydrogel litholytic scaffold obtained in Example 3 (immersed in a 1 g / mL citric acid solution) was removed at a predetermined time point. 1 mL of the remaining solution was taken, diluted to 20 mL with distilled water, and 3 drops of 1% phenolphthalein indicator were added. Titration was then performed with a 1 mol / L sodium hydroxide standard solution until a faint pink endpoint was reached. Finally, the concentration of citric acid in the solution was calculated by the volume of sodium hydroxide standard solution consumed in the titration, yielding the total citric acid content in the remaining solution. The citric acid content loaded in the hydrogel was then calculated. Figure 6 ).

[0066] Example 11

[0067] The amount of citric acid released from the hydrogel scaffold obtained in Example 3 at a preset time point was determined by acid-base titration. The principle is that citric acid reacts with an alkaline solution to generate corresponding salt and water, and the content of citric acid can be calculated based on the chemical equation of the reaction.

[0068] To assess the drug release, 180 mg of the hydrogel-soluble stone support used in Example 3, which had been soaked in a 1 g / mL high-concentration citric acid solution for 24 h, was placed into a dialysis bag with a cutoff molecular weight of 3500 kDa. The dialysis bag was then placed into a 15 mL centrifuge tube containing 10 mL of deionized water. The centrifuge tube was then incubated in a 37°C steam bath shaker. At each specific time point, 1 mL of deionized water was taken, and 1 mL of fresh deionized water was added. The 1 mL of deionized water was then diluted to 20 mL with distilled water, and 3 drops of 1% phenolphthalein indicator were added. The solution was titrated with 1 mol / L sodium hydroxide standard solution until a faint pink endpoint was reached. Finally, the citric acid concentration in the solution was calculated based on the volume of sodium hydroxide standard solution consumed during titration, thus determining the amount of citric acid released at that time point.

[0069] like Figure 7 As shown, the hydrogel litholytic scaffold exhibited significant sustained release in both deionized water and phosphate buffer solutions. Subsequently, the release tended to stabilize, indicating that the prepared hydrogel litholytic scaffold has good application potential in drug sustained release.

[0070] Example 12

[0071] To verify the in vitro litholytic effect of the hydrogel litholytic scaffold, an eggshell dissolution experiment was first conducted. The hydrogel litholytic scaffold, after being soaked in citric acid solutions of different concentrations obtained in Example 3, was incubated with 40 mg of eggshell in 2 mL of deionized water for 12 h, 24 h, and 48 h. At these time points, the eggshell was removed, the surface liquid was absorbed with filter paper, and the eggshell was weighed to obtain the remaining weight ratio (…). Figure 8 a). The results show that the high-concentration citric acid solution loads citric acid into the hydrogel through osmosis, endowing the pancreatic duct stent with litholytic properties. Taking the litholytic stent obtained in Example 3, which is soaked in a 1 g / mL high-concentration citric acid solution, as an example, 25 mg of stones were incubated in 2 mL of deionized water. The stones were removed at preset time points, the surface liquid was absorbed with filter paper, and the stones were weighed to obtain the remaining weight ratio ( Figure 8 b). The results show that the hydrogel litholytic scaffold prepared in Example 3 has a significant litholytic effect, dissolving approximately 93.2% of the stones within 24 hours.

[0072] The above descriptions are merely some embodiments of the present invention. Those skilled in the art can make various modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the scope of protection of the present invention.

Claims

1. A hydrogel-based stone-dissolving scaffold, characterized in that, The hydrogel-based scaffold comprises a bare scaffold, an adhesive layer, and a hydrogel layer, wherein the adhesive layer is located outside the bare scaffold, and the hydrogel layer is located outside the adhesive layer. The method for preparing the hydrogel-based scaffold includes: Step A: Dissolve Tris-HCl in a solvent to prepare a 10-20 mM Tris-HCl buffer solution. Then add dopamine to the Tris-HCl buffer solution at a concentration of 2-5 mg / mL. Place the bare plastic pancreatic duct stent into the dopamine Tris-HCl buffer solution and stir the reaction at room temperature for 12-48 h. After the reaction is complete, remove the stent and place it in deionized water for repeated washing to remove unpolymerized dopamine from the pancreatic duct stent. Dry the washed pancreatic duct stent to obtain a polydopamine-modified pancreatic duct stent. Step B: Dissolve γ-polyglutamic acid in a solvent and stir until completely dissolved. The mass fraction of the dissolved γ-polyglutamic acid is 0.25% - 5%. Add polyethyleneimine to the γ-polyglutamic acid solution and stir until homogeneous to obtain a mixed solution. Place the polydopamine-modified pancreatic duct stent in the mixed solution and add a carboxyl activator to the mixed solution. The carboxyl activator is any one or two of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. After the reaction is complete, a hydrogel-coated pancreatic duct stent is obtained. Step C: Coat the pancreatic duct stent with the hydrogel prepared in step B and soak it in citric acid solution for 12-48 h. Load the hydrogel with the litholytic drug citric acid to obtain the hydrogel litholytic stent.

2. The hydrogel-based scaffold according to claim 1, characterized in that, The adhesion layer is polydopamine, and the hydrogel litholytic scaffold further includes a litholytic drug located in the hydrogel layer.

3. The method for preparing the hydrogel lithotomy scaffold as described in claim 1 or 2, characterized in that, The method includes: Step A: Dissolve Tris-HCl in a solvent to prepare a 10-20 mM Tris-HCl buffer solution. Then add dopamine to the Tris-HCl buffer solution at a concentration of 2-5 mg / mL. Place the bare plastic pancreatic duct stent into the dopamine Tris-HCl buffer solution and stir the reaction at room temperature for 12-48 h. After the reaction is complete, remove the stent and place it in deionized water for repeated washing to remove unpolymerized dopamine from the pancreatic duct stent. Dry the washed pancreatic duct stent to obtain a polydopamine-modified pancreatic duct stent. Step B: Dissolve γ-polyglutamic acid in a solvent and stir until completely dissolved. The mass fraction of the dissolved γ-polyglutamic acid is 0.25% - 5%. Add polyethyleneimine to the γ-polyglutamic acid solution and stir until homogeneous to obtain a mixed solution. Place the polydopamine-modified pancreatic duct stent in the mixed solution and add a carboxyl activator to the mixed solution. The carboxyl activator is any one or two of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. After the reaction is complete, a hydrogel-coated pancreatic duct stent is obtained. Step C: Coat the pancreatic duct stent with the hydrogel prepared in step B and soak it in citric acid solution for 12-48 h. Load the hydrogel with the litholytic drug citric acid to obtain the hydrogel litholytic stent.

4. The method for preparing the hydrogel lithotomy scaffold according to claim 3, characterized in that, Step A further includes adjusting the pH of the Tris-HCl buffer solution to 8.5 before adding dopamine; The solvent in step A and / or step B is any one of distilled water, phosphate buffer solution, or physiological saline; the solvent used for the citric acid solution in step C is any one of distilled water, phosphate buffer solution, or physiological saline; the pH of the phosphate buffer solution is 7.

4.

5. The method for preparing the hydrogel lithotomy scaffold according to claim 3, characterized in that, In step B, the mass fraction of polyethyleneimine and γ-polyglutamic acid is 12%-30%.

6. The method for preparing the hydrogel lithotomy scaffold according to claim 3, characterized in that, In step B, the mass concentration of polyethyleneimine is 0.03 - 0.04 g / mL, and the mass concentration of γ-polyglutamic acid is 0.22 - 0.24 g / mL.

7. The method for preparing the hydrogel lithotomy scaffold according to claim 3, characterized in that, In step B, the mass concentration of the carboxyl activator in the final reaction solution is 0.01 - 0.02 g / mL.

8. The method for preparing the hydrogel lithotomy scaffold according to claim 3, characterized in that, In step C, the concentration of the citric acid solution is 0.5 - 2 g / mL.

9. The method for preparing the hydrogel lithotomy scaffold according to claim 3, characterized in that, The reaction temperature for steps A, B, and C is 10-30°C. o C.

10. The application of the hydrogel stone-dissolving scaffold as described in claim 1 or 2 in the preparation of stone-dissolving equipment.

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