Novel 4D printing drug sustained-release glaucoma drainage device and preparation method thereof

Abstract

The invention provides a novel 4D printing drug sustained release glaucoma drainage device and a preparation method thereof, and relates to the technical field of eye medical devices.The preparation method comprises the steps that S1, MMC and F127DA micelles are mixed with an organic solvent, dissolved and evaporated, then added into deionized water and filtered, and an MMC drug-loaded micelle solution is obtained; s2, mixing the MMC drug-loaded micelle solution with a temperature-sensitive hydrogel and a photosensitive hydrogel, magnetically stirring uniformly, and adding a photoinitiator to obtain F127 micelle cross-linked dual-network drug-loaded hydrogel; s3, the 3D model of the drainage disc is guided into a DLP printer, the filtered F127 micelle cross-linked dual-network drug-loaded hydrogel is added into an ink tank, the drainage disc is printed layer by layer through the digital light projection technology, then the drainage disc is connected with a drainage pipe and a drainage valve, and the novel 4D printing drug sustained release glaucoma drainage device is obtained. Accelerated release and slow release of the medicine can be realized under temperature stimulation.

Description

Technical Field

[0001] The present invention relates to the technical field of ocular medical devices, and in particular to a novel 4D printed drug sustained-release glaucoma drainage device and a preparation method thereof. Background Art

[0002] Glaucoma is currently the world's leading irreversible blinding eye disease. With the growth and aging of the population, the number of glaucoma patients has increased accordingly. For refractory glaucoma, lowering intraocular pressure has been proven to be an effective means of treating glaucoma, and the preferred treatment is glaucoma drainage valve implantation (AGV). At present, the drainage valve usually consists of three parts: a silicone drainage disc, a drainage tube, and a valve structure. After implantation, the aqueous humor is drained through the drainage tube to the subconjunctival space to form a filtering bubble for diffuse absorption, thereby achieving the goal of reducing intraocular pressure. However, as a foreign body, the drainage valve often causes a characteristic wound healing reaction, resulting in scarring of the subconjunctival tissue of the drainage valve body, thereby inhibiting the outflow of aqueous humor, causing intraocular pressure to rise again, and reducing the success rate of the operation. In order to improve the success rate of surgery, anti-metabolites are usually used, among which mitomycin C (MMC) is a commonly used anti-metabolite in glaucoma surgery. It inhibits scarring of the filtration area after glaucoma drainage valve implantation by inhibiting the proliferation period of wound healing. Therefore, MMC is often used in combination with AGV surgery during and after surgery. However, the one-time instantaneous high-concentration drug application during surgery is prone to tissue toxicity and has a limited duration of action. Therefore, some experts combine multiple subconjunctival injections of MMC after surgery to inhibit scar formation, but multiple injections are invasive operations and are prone to infection, bleb leakage and other complications. Summary of the invention

[0003] The problem solved by the present invention is how to reduce the instantaneous concentration of antimetabolites, prolong the action time of the drugs, and maximize the inhibitory effect of the antimetabolites.

[0004] In order to solve the above problems, the present invention provides a method for preparing a novel 4D printed drug sustained-release glaucoma drainage device, comprising the following steps: Step S1: Mixing MMC and F127DA micelles with an organic solvent, evaporating after fully dissolving to obtain a solid powder; adding the solid powder into deionized water and filtering to obtain an MMC drug-loaded micelle solution; Step S2: mixing the MMC drug-loaded micelle solution with the temperature-sensitive hydrogel and the photosensitive hydrogel, stirring them evenly with a magnetic stirrer, and then adding a photoinitiator to obtain a F127 micelle cross-linked double-network drug-loaded hydrogel; Step S3: Import the 3D model of the drainage disc into the DLP printer, add the filtered F127 micellar cross-linked double-network drug-loaded hydrogel into the ink tank of the DLP printer, print the drainage disc layer by layer using digital light projection technology, connect the printed drainage disc with the drainage tube and the drainage valve, and obtain a 4D printed drug sustained-release novel glaucoma drainage device.

[0005] Furthermore, in step S1, the organic solvent includes dichloromethane, chloroform, and carbon tetrachloride.

[0006] Furthermore, in step S1, the filtration is performed through a filter membrane, and the pore diameter of the filter membrane is 0.22 μm.

[0007] Furthermore, in step S2, the temperature-sensitive hydrogel includes poly (N-isopropylacrylamide), polyethylene glycol, and poly (lactic acid-glycolic acid copolymer).

[0008] Furthermore, in step S2, the photosensitive hydrogel includes methacrylated hydrogel, acrylated sodium alginate, and acrylated chitosan.

[0009] Furthermore, the photoinitiator includes phenyl-2,4,6-trimethylbenzoyl lithium phosphite and 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropionylphenone.

[0010] The advantage of the preparation method of the novel 4D printed drug sustained-release glaucoma drainage device described in the present invention over the prior art is that the present invention introduces MMC, F127DA, temperature-sensitive hydrogel, photosensitive hydrogel and photoinitiator into the drainage disc, and combines 4D printing technology to deform and adjust the mesh structure of the drainage disc under temperature stimulation, thereby achieving accelerated and slow release of drugs, thereby reducing scarring of the filtration area after glaucoma drainage surgery and improving the success rate of surgery. The material has good biocompatibility and is biodegradable.

[0011] The present invention also provides a 4D printed drug sustained-release novel glaucoma drainage device, which is made according to the preparation method of the 4D printed drug sustained-release novel glaucoma drainage device.

[0012] Furthermore, it comprises a drainage tray, a drainage tube and a drainage valve, wherein the mass ratio of MMC, F127DA, temperature-sensitive hydrogel, photosensitive hydrogel and photoinitiator in the drainage tray is (0.05-0.5): (1-10): (10-30): (1-10): (0.1-0.5).

[0013] Furthermore, the drainage plate includes a first surface and a second surface that are opposite to each other, and a drainage groove is provided on the first surface.

[0014] Furthermore, the drainage groove comprises an inflow tube groove, a liquid storage cavity and an outflow tube groove which are connected, and the inflow tube groove matches the connection end of the drainage tube so as to allow aqueous humor to flow into the liquid storage cavity and out through the outflow tube groove.

[0015] The advantages of the 4D printed drug sustained-release novel glaucoma drainage device described in the present invention over the prior art are the same as the advantages of the preparation method of the 4D printed drug sustained-release novel glaucoma drainage device described in the present invention over the prior art, and will not be repeated here. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is a flow chart of the preparation method of the novel glaucoma drainage device with 4D printing and sustained drug release in Example 1 of the present invention; Figure 2 This is the preparation ratio of the temperature-responsive hydrogel that can be printed by 4D printing in the comparative example of the present invention; Figure 3 The 3D model of the glaucoma drainage tray in Example 1 of the present invention; Figure 4 This is an electron micrograph of a temperature-responsive hydrogel that can be printed by 4D printing in a comparative example of the present invention; Figure 5 This is a stress-strain curve of the F127 micellar cross-linked double network drug-loaded hydrogel at 25° C. in Example 1 of the present invention; Figure 6 This is a graph showing the changes in the in vitro cumulative drug release of the F127 micellar cross-linked double network drug-loaded hydrogel in Example 1 of the present invention; Figure 7 This is a graph showing the changes in the in vitro cumulative drug release of the F127 micellar cross-linked double network drug-loaded hydrogel at different temperatures in Example 1 of the present invention; Figure 8 This is a biocompatibility diagram of the F127 micelle cross-linked double network hydrogel in Example 1 of the present invention; Fig. 9 This is a graph of cell survival rate of F127 micelle cross-linked double network hydrogel in Example 1 of the present invention; Fig.10 This is a graph showing the inhibition of cell proliferation by the F127 micellar cross-linked double network drug-loaded hydrogel in Example 1 of the present invention; Fig.11 This is a graph showing cell survival rate of the F127 micelle cross-linked double network drug-loaded hydrogel in Example 1 of the present invention; Fig.12 This is a graph showing changes in intraocular pressure corresponding to different substances at different times after implantation of the drug sustained-release glaucoma drainage device in Example 1 of the present invention; Fig.13 Comparison of scar thickness in the filtration area after implantation of different glaucoma drainage devices in Example 1 of the present invention Figure 1 ; Fig.14 Comparison of scar thickness in the filtration area after implantation of different glaucoma drainage devices in Example 1 of the present invention Figure 2 .

[0017] Description of reference numerals: 1-first surface; 2-second surface; 11-drainage groove. DETAILED DESCRIPTION

[0018] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, specific embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0019] like Figure 1 As shown, an embodiment of the present invention provides a method for preparing a novel 4D printed drug sustained-release glaucoma drainage device, comprising the following steps: Step S1: Mixing MMC and F127DA micelles with an organic solvent, evaporating after fully dissolving to obtain a solid powder; adding the solid powder to deionized water and filtering to obtain an MMC drug-loaded micelle solution; Step S2: Mix the MMC drug-loaded micelle solution with the temperature-sensitive hydrogel and the photosensitive hydrogel, stir them evenly with a magnetic stirrer, and then add a photoinitiator to obtain the F127 micelle cross-linked double-network drug-loaded hydrogel; Step S3: Import the 3D model of the drainage disc into the DLP printer, add the filtered F127 micellar cross-linked double-network drug-loaded hydrogel into the ink tank of the DLP printer, print the drainage disc layer by layer using digital light projection technology, connect the printed drainage disc with the drainage tube and drainage valve, and obtain a 4D printed drug sustained-release new glaucoma drainage device.

[0020] The embodiment of the present invention introduces MMC, F127DA, temperature-sensitive hydrogel, photosensitive hydrogel and photoinitiator into the drainage disc, and combines 4D printing technology to adjust the mesh structure of the drainage disc under temperature stimulation, thereby achieving accelerated and slow release of drugs, thereby reducing scarring of the filtration area after glaucoma drainage surgery and improving the success rate of surgery. The material has good biocompatibility and is biodegradable.

[0021] Specifically, MMC, also known as mitomycin C, is an antimetabolite drug that can inhibit scarring of the filtration area after glaucoma drainage valve implantation by inhibiting the proliferation phase of wound healing. The embodiment of the present invention combines MMC with a temperature-sensitive hydrogel, and uses a 4D printer, a photosensitive hydrogel, and a photoinitiator to achieve structural construction of a combination containing MMC and a temperature-sensitive hydrogel. Under the premise of having excellent biocompatibility, the structure is arbitrarily optimized to optimize the drug release process. At the same time, through the temperature change within an appropriate range, the instantaneous amount and release time of the drug release are further adjusted, thereby avoiding the instantaneous high concentration of the antimetabolite drug, and being able to prolong the action time of the drug, maximizing the inhibitory effect of the antimetabolite drug, and improving the success rate of glaucoma surgery.

[0022] Specifically, in step S1, the F127DA micelles are obtained by grafting and modifying the hydroxyl groups of the F127 molecular chains to introduce acryloyl groups. In step S1, MMC and F127DA micelles are dissolved in an organic solvent, and after being fully dissolved, the organic solvent is removed by rotary evaporation to obtain a purple solid powder, which is then dissolved in deionized water and filtered with a filter membrane with a fixed pore diameter to obtain an MMC drug-loaded micelle solution.

[0023] The DLP printer in step S3 can print and solidify the F127 micelle cross-linked double network drug-loaded hydrogel through digital light projection technology to achieve printing and molding of the drainage disk. In some preferred embodiments, the structure of the drainage disk can be as follows: Figure 3 shown.

[0024] In some specific embodiments, in step S1, the organic solvent includes dichloromethane, chloroform, or carbon tetrachloride, so that the solute is fully dissolved and easily removed by evaporation.

[0025] In some specific embodiments, in step S1, the filtration is performed by filtering through a filter membrane, and the filter pore diameter of the filter membrane is 0.22 μm. Thus, the printing efficiency of the DLP printer and the molding stability of the drainage disk are improved.

[0026] In some specific embodiments, in step S2, the temperature-sensitive hydrogel includes poly (N-isopropylacrylamide), polyethylene glycol, and poly (lactic acid-co-glycolic acid). Therefore, the material has good biocompatibility, and the temperature control range is suitable for the eye, reducing damage to eye tissue.

[0027] In some specific embodiments, in step S2, the photosensitive hydrogel includes methacrylated hydrogel, acrylated sodium alginate, and acrylated chitosan. Thus, in combination with the digital light projection printing technology, the drainage tray structure is successfully established.

[0028] In some specific embodiments, the photoinitiator includes phenyl-2,4,6-trimethylbenzoyl lithium phosphite, 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropionophenone.

[0029] In some specific embodiments, in step S3, the connection method of the drainage tray with the drainage tube and the drainage valve includes: gluing the drainage tube and the drainage valve with biological glue. Thus, the connection method is simple and has good biological adaptability.

[0030] Combination Figures 2 to 3 As shown, an embodiment of the present invention further provides a 4D printed drug sustained-release novel glaucoma drainage device, which is manufactured according to the preparation method of the 4D printed drug sustained-release novel glaucoma drainage device.

[0031] The advantages of the 4D printed drug sustained-release novel glaucoma drainage device described in the present invention over the prior art are the same as the advantages of the preparation method of the 4D printed drug sustained-release novel glaucoma drainage device described in the present invention over the prior art, and will not be repeated here.

[0032] In some specific embodiments, a drainage plate, a drainage tube and a drainage valve are included, and the mass ratio of MMC, F127DA, temperature-sensitive hydrogel, photosensitive hydrogel and photoinitiator in the drainage plate is (0.05-0.5): (1-10): (10-30): (1-10): (0.1-0.5).

[0033] In some specific embodiments, the drainage plate includes a first surface 1 and a second surface 2 that are opposite to each other, and a drainage groove 11 is provided on the first surface 1. Figure 3 As shown, a certain thickness is provided between the first surface 1 and the second surface 2 of the drainage tray, which is suitable for the drainage tray to be positioned on the scleral surface or the subscleral cavity of the eye. Preferably, the edges of the first surface 1 and the second surface 2 of the drainage tray are provided with alternating straight line parts and curved line parts, which is more conducive to less damage to the relevant parts of the eye. The drainage groove 11 opened on the first surface 1 of the drainage tray is also covered with a sealing layer, which is suitable for storing aqueous humor.

[0034] In some specific embodiments, the drainage groove includes an inlet tube groove, a liquid storage cavity and an outlet tube groove that are connected. The inlet tube groove matches the connection end of the drainage tube to allow aqueous humor to flow into the liquid storage cavity and out through the outlet tube groove.

[0035] Specifically, Figure 3 As shown, the liquid storage cavity is arranged in the middle of the first surface 1, and the shape can be trapezoidal, which is conducive to storing aqueous humor. The structure of the outflow pipe groove can be V-shaped to adjust the flow rate of aqueous humor out of the liquid storage cavity.

[0036] Comparative Example Preparation of temperature-responsive hydrogels that can be printed by 4D: 0.127 g of F127DA was mixed with 1.1215 g of N-isopropylacrylamide and 0.5 g of methacrylated hydrogel, and the reaction system was fixed to 10 g with deionized water. After magnetic stirring, high-purity nitrogen was introduced for 10 minutes to remove residual oxygen in the system, and 0.05 g of photoinitiator LAP, i.e., phenyl-2,4,6-trimethylbenzoyl lithium phosphite, was added to obtain a F127DA micelle cross-linked double network hydrogel precursor solution numbered N1F1. The preparation methods of the other two hydrogels numbered N1F2 and N1F4 were the same, for example Figure 2 As shown, it is then filtered through a filter membrane with a pore diameter of 0.22 μm and transferred to the DLP printer ink tank for use.

[0037] Example 1 This embodiment is to prepare a glaucoma drainage device by a preparation method of a novel glaucoma drainage device with sustained drug release using 4D printing, comprising the following steps: Step S1: 5 mg of MMC and 0.1 g of F127DA micelles were dissolved in 5 mL of dichloromethane. After fully dissolved, the organic solvent was removed by rotary evaporation at 25°C and -0.1 MPa. The obtained purple solid powder was dissolved in 5 ml of deionized water and filtered with a filter membrane with a pore diameter of 0.22 μm to obtain a 1 mg / mL MMC drug-loaded micelle solution. Step S2: Mix the MMC drug-loaded micelle solution with N-isopropylacrylamide and methacrylated hydrogel in a ratio of 1.05:10:1, stir evenly with a magnetic stirrer, and then add the photoinitiator LAP to obtain the F127 micelle cross-linked double network drug-loaded hydrogel; Step S3: Import the 3D model of the drainage disc into the DLP printer, add the filtered F127 micellar cross-linked double-network drug-loaded hydrogel into the ink tank of the DLP printer, print the drainage disc layer by layer using digital light projection technology, connect the printed drainage disc with the drainage tube and drainage valve, and obtain a 4D printed drug sustained-release new glaucoma drainage device.

[0038] Example 2 This embodiment is to prepare a glaucoma drainage device by a preparation method of a novel glaucoma drainage device with sustained drug release using 4D printing, comprising the following steps: Step S1: 5 mg of MMC and 0.1 g of F127DA micelles were dissolved in 5 mL of dichloromethane. After fully dissolved, the organic solvent was removed by rotary evaporation at 25°C and -0.1 MPa. The obtained purple solid powder was dissolved in 5 ml of deionized water and filtered with a filter membrane with a pore diameter of 0.22 μm to obtain a 1 mg / mL MMC drug-loaded micelle solution. Step S2: Mix the MMC drug-loaded micelle solution with N-isopropylacrylamide and methacrylated hydrogel in a ratio of 5:15:5, stir evenly with a magnetic stirrer, and then add the photoinitiator LAP to obtain the F127 micelle cross-linked double network drug-loaded hydrogel; Step S3: Import the 3D model of the drainage disc into the DLP printer, add the filtered F127 micellar cross-linked double-network drug-loaded hydrogel into the ink tank of the DLP printer, print the drainage disc layer by layer using digital light projection technology, connect the printed drainage disc with the drainage tube and drainage valve, and obtain a 4D printed drug sustained-release new glaucoma drainage device.

[0039] Example 3 This embodiment is to prepare a glaucoma drainage device by a preparation method of a novel glaucoma drainage device with sustained drug release using 4D printing, comprising the following steps: Step S1: 5 mg of MMC and 0.1 g of F127DA micelles were dissolved in 5 mL of dichloromethane. After fully dissolved, the organic solvent was removed by rotary evaporation at 25°C and -0.1 MPa. The obtained purple solid powder was dissolved in 5 ml of deionized water and filtered with a filter membrane with a pore diameter of 0.22 μm to obtain a 1 mg / mL MMC drug-loaded micelle solution. Step S2: Mix the MMC drug-loaded micelle solution with N-isopropylacrylamide and methacrylated hydrogel in a ratio of 10.5:30:10, stir evenly with a magnetic stirrer, and then add the photoinitiator LAP to obtain the F127 micelle cross-linked double network drug-loaded hydrogel; Step S3: Import the 3D model of the drainage disc into the DLP printer, add the filtered F127 micellar cross-linked double-network drug-loaded hydrogel into the ink tank of the DLP printer, print the drainage disc layer by layer using digital light projection technology, connect the printed drainage disc with the drainage tube and drainage valve, and obtain a 4D printed drug sustained-release new glaucoma drainage device.

[0040] Electron microscope test The hydrogel sample of the comparative example was freeze-dried, and its surface morphology was observed at 200 times and 500 times after gold was sprayed on the surface. Figure 4 As shown, the higher the F127DA content, the denser the hydrogel network, the smaller the pore size, and the easier it is to hinder the release of drugs. The experimental results show that the larger the pore size of N1F1, the more conducive to the release of drugs.

[0041] Mechanical properties test The hydrogel in the comparative example was subjected to uniaxial tensile tests at 25°C and 42°C, respectively, to obtain tensile stress-strain curves, and the slope was calculated to obtain the elastic modulus, such as Figure 5 As shown, the higher the F127DA content, the greater the hydrogel cross-linking density and the higher the mechanical strength. The experimental results show that N1F4 has the highest strength.

[0042] In vitro drug release assay A syringe filter was used to simulate the aqueous humor outflow environment in the filtration bleb after AGV surgery to test the drug release process of the hydrogel in the comparative example. The two ends of the extension tube were connected to a 50 mL syringe and a 450 mm 2 At the inlet end of the syringe filter, start the microinfusion pump to pre-fill the entire device with PBS (pH=7.4) to exhaust all the air. Take the hydrogel in Example 1 and place it in the filter. Connect the outlet end of the filter to an empty 50mL centrifuge tube. Pay attention to operate in a dark environment at room temperature. Collect the filtrate at a fixed time point every day, measure the absorbance of MMC in the filtrate with a UV spectrophotometer, calculate the MMC concentration in the supernatant according to the standard curve, and draw the MMC in vitro release curve with the detection time as the horizontal axis and the cumulative release amount as the vertical axis. Figure 6 As shown, the drug release curve of the drug-loaded hydrogel shows that MMC is slowly released for about 30 days as time goes by, and the cumulative drug release on the 30th day is about 80%. In vitro drug release process of the hydrogel after temperature stimulation in Detection Example 2: The hydrogel in Detection Example 1 was placed in 2mL PBS (pH=7.4). The hydrogel was divided into two groups, one group was treated with 42°C temperature for about 1 minute at the beginning of the experiment, and the other group was used as a control at room temperature. 500μL of the release solution was taken at the same time point and supplemented with an equal volume of PBS solution. The cumulative release of MMC was calculated, and the in vitro release curve of MMC was drawn, as shown in FIG. Figure 7 As shown, the in vitro drug release of thermally driven hydrogels was significantly accelerated under 42°C temperature stimulation. After 30 minutes of thermal drive, the drug release in the thermally driven group was significantly higher than that in the non-thermal driven group. This property of thermally driven hydrogels can be used to prepare temperature-responsive drug controlled release carriers.

[0043] Biocompatibility assay The cytotoxicity of the hydrogel in the control example was tested using the CCK-8 method and the live / dead staining method. The cells were divided into three groups: hydrogel group, silicone sheet group, and blank group. The HTFs cell suspension was adjusted to a cell density of 1×105 / mL, 1 mL was taken and added to a 24-well plate, and a Transwell (8 μm) was placed in each well after the cells adhered to the wall. The hydrogel and blank silicone sheet were placed in the upper chamber respectively, and a blank control was set up at the same time. After culturing in the incubator for 24 hours, the culture medium was aspirated, the cell state was observed under a light microscope, and the OD value of each well was measured at a wavelength of 450nm using an enzyme marker. The experiment was repeated three times to calculate the relative cell survival rate, and the cell activity was observed under a microscope. Figure 8 and 9As shown in the figure, Gel is the hydrogel group, Silico is the blank silica gel sheet, and Control is the blank control. In the silica gel sheet and the hydrogel group, the living cells stained green are closely arranged, and no obvious cell damage occurs. The CCK-8 test results show that there is no significant statistical difference in the survival rate of fibroblasts in the hydrogel group compared with the silica gel group.

[0044] In vitro inhibition of cell proliferation assay The CCK-8 method and live / dead cell staining method were used to determine the inhibition of cell proliferation in vitro by the hydrogel in Example 1. The cells were divided into four groups: drug-loaded hydrogel group, hydrogel group, silicone sheet group, and blank group. The cell density of the HTFs cell suspension was adjusted and planted in a 24-well plate (1×104 cells / well). 1 mL of cell culture medium was added to each well and placed in an incubator. After the cells adhered to the wall, a Transwell (8 μm) was placed in each well, and the drug-loaded hydrogel, hydrogel and blank silicone sheet were placed in the upper chamber, respectively. A blank control was also set up. After culturing for 24 hours, the cell status was observed under an optical microscope, and CCK-8 detection and live / dead cell staining were performed, as shown in FIG. Fig.10 and 11 As shown in the figure, Control is the blank group, Silico is the silica gel group, Gel is the hydrogel group, and Gel-MMC is the drug-loaded hydrogel group. Live / dead staining showed that the number of surviving cells in the drug-loaded group was significantly reduced. CCK-8 test results showed that the cell survival rate of HTFs in the drug-loaded group was significantly reduced.

[0045] Determination of intraocular pressure after glaucoma drainage valve implantation in each group A Tono-pen tonometer was used to measure the intraocular pressure after the drainage device implantation in Example 1. The experimental animals were healthy New Zealand white rabbits weighing approximately 2.5-3 kg, with a total of 30 rabbits of both sexes, and they were randomly divided into the following groups: Group A: (6 rabbits) implanted with AGV; Group B: (6 rabbits) implanted with AGV, and infiltrated with MMC cotton pads during the operation; Group C: (6 rabbits) implanted with a new glaucoma drainage valve (not loaded with drugs); Group D: (6 rabbits) implanted with a new glaucoma drainage valve (drug loading without deformation); Group E: (6 rabbits) implanted with a new glaucoma drainage valve (drug loading + heat-driven deformation). After the drainage device was implanted into the eye, the intraocular pressure was measured using a Tono-pen tonometer on the 30th, 60th, and 90th days after the operation. Fig.12 As shown in the figure, the five groups from top to bottom represent animal experiment A, B, C, D and E groups respectively. The average baseline intraocular pressure of each group before surgery was 15.1 ± 0.87 mmHg. The intraocular pressure was significantly reduced on the first day after surgery. At 1 month after surgery, the intraocular pressure of groups D and E was significantly lower than that of groups A and B.

[0046] Determination of scar thickness in the filtration zone after glaucoma drainage surgery in vivo The animals were killed 3 months after the operation after the intraocular pressure measurement, and the eyeballs were removed and fixed in 4% paraformaldehyde for 1 week. The tissue was trimmed to retain the conjunctiva in the surgical area and the scleral tissue at the corresponding position of the bleb. The bleb was cut open from the middle of the drainage tray along the direction of the drainage tube, and the drainage valve was removed. The scar tissue in the filtration area was dehydrated, paraffin-embedded, sliced, HE-stained, and Masson-stained. Image J software was used to measure the thickness of the collagen layer on the upper and lower walls of the bleb after Masson staining. Fig.13 and Fig.14 As shown in the figure, HE staining of the bleb wall tissues in each group one month after surgery showed no obvious inflammatory cells, and Masson staining showed that dense collagen tissue was formed around the drainage valve. One month after surgery, the thickness of the collagen layer on the upper and lower walls of the bleb in groups C, D, and E was significantly lower than that in groups A and B.

[0047] Although the present invention is disclosed as above, the protection scope of the present invention is not limited thereto. Those skilled in the art may make various changes and modifications without departing from the spirit and scope of the present invention, and these changes and modifications will fall within the protection scope of the present invention.

Claims

1. A method for preparing a novel 4D printed drug sustained-release glaucoma drainage device, characterized in that: The following steps are involved: Step S1: Mixing MMC and F127DA micelles with an organic solvent, evaporating after fully dissolving to obtain a solid powder; adding the solid powder into deionized water and filtering to obtain an MMC drug-loaded micelle solution; Step S2: mixing the MMC drug-loaded micelle solution with the temperature-sensitive hydrogel and the photosensitive hydrogel, stirring them evenly with a magnetic stirrer, and then adding a photoinitiator to obtain a F127 micelle cross-linked double-network drug-loaded hydrogel; Step S3: Import the 3D model of the drainage disc into the DLP printer, add the filtered F127 micellar cross-linked double-network drug-loaded hydrogel into the ink tank of the DLP printer, print the drainage disc layer by layer using digital light projection technology, connect the printed drainage disc with the drainage tube and the drainage valve, and obtain a 4D printed drug sustained-release novel glaucoma drainage device.

2. The method for preparing the novel 4D printed drug sustained-release glaucoma drainage device according to claim 1, characterized in that: In step S1, the organic solvent includes dichloromethane, chloroform, and carbon tetrachloride.

3. The method for preparing the novel 4D printed drug sustained-release glaucoma drainage device according to claim 1, characterized in that: In step S1, the filtration is performed by filtering through a filter membrane, and the filter pore diameter of the filter membrane is 0.22 μm.

4. The method for preparing the novel 4D printed drug sustained-release glaucoma drainage device according to claim 1, characterized in that: In step S2, the temperature-sensitive hydrogel includes poly (N-isopropylacrylamide), polyethylene glycol, and poly (lactic acid-glycolic acid copolymer).

5. The method for preparing the novel 4D printed drug sustained-release glaucoma drainage device according to claim 1, characterized in that: In step S2, the photosensitive hydrogel includes methacrylated hydrogel, acrylated sodium alginate, and acrylated chitosan.

6. The method for preparing the novel 4D printed drug sustained-release glaucoma drainage device according to claim 1, characterized in that: The photoinitiator includes phenyl-2,4,6-trimethylbenzoyl lithium phosphite and 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropionylphenone.

7. A 4D printed drug sustained-release novel glaucoma drainage device, characterized in that: The 4D printed drug sustained-release novel glaucoma drainage device is made according to the preparation method of any one of claims 1-6.

8. The 4D printed drug sustained-release novel glaucoma drainage device according to claim 7, characterized in that: It comprises a drainage plate, a drainage tube and a drainage valve. The mass ratio of MMC, F127DA, temperature-sensitive hydrogel, photosensitive hydrogel and photoinitiator in the drainage plate is (0.05-0.5): (1-10): (10-30): (1-10): (0.1-0.5).

9. The 4D printed drug sustained-release novel glaucoma drainage device according to claim 7, characterized in that: The drainage plate comprises a first surface (1) and a second surface (2) which are arranged opposite to each other, and a drainage groove (11) is provided on the first surface (1).

10. The 4D printed drug sustained-release novel glaucoma drainage device according to claim 9, characterized in that: The drainage groove (11) comprises an inflow tube groove, a liquid storage cavity and an outflow tube groove which are connected to each other. The inflow tube groove matches the connection end of the drainage tube so as to allow aqueous humor to flow into the liquid storage cavity and flow out through the outflow tube groove.

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