Degradable glaucoma drainage device with stepwise scar control and method for manufacturing same

Abstract

A degradable glaucoma drainage device for gradually controlling scarring and a method for manufacturing the same, the device (1) comprising a long strip-shaped drainage sheet (11) of uniform overall cross-sectional size, the drainage sheet (11) made of a biodegradable material, the surface of the drainage sheet (11) having drainage gaps (12) penetrating two opposing sides of the drainage sheet (11), the outer surface of the drainage sheet (11) coated with a biodegradable surface coating, the surface coating carrying an anti-scarring drug, the anti-scarring drug being gradually released as the surface coating decomposes, and the distribution concentration of the anti-scarring drug within the surface coating changing non-monotonicly.

Description

[Technical Field]

[0001] The present invention relates to the field of medical implants, and more particularly to a degradable glaucoma drainage device with progressive scar control and a method for manufacturing the same.

[0002] This application claims priority to a Chinese patent application filed with the China Patent Office on December 20, 2022, bearing application number CN202211642621.0 and entitled "Biodegradable aqueous humor drainage device for treating glaucoma and its manufacturing method," the entire contents of which are incorporated herein by reference. [Background technology]

[0003] Glaucoma is an optic nerve disease characterized by visual field loss and optic nerve cup-like atrophy. Glaucoma is the second leading cause of blindness worldwide and the leading cause of irreversible blindness. Elevated intraocular pressure is the main risk factor for glaucomatous optic nerve atrophy, and lowering intraocular pressure is currently the only proven effective method for slowing glaucomatous optic nerve damage. When medications cannot control intraocular pressure, surgical diversion of aqueous humor is the primary treatment for glaucoma.

[0004] Conventional external glaucoma drainage devices have a fixed diameter, which can lead to excessive drainage of aqueous humor during the early stages of surgery, resulting in postoperative complications such as a shallow anterior chamber. In the later stages of implantation, prolonged foreign body irritation can cause the drainage device to become encased in scar tissue, reducing aqueous humor discharge and causing a re-rise in intraocular pressure, resulting in surgical failure. At the same time, the tip of conventional glaucoma drainage tubes remains in the anterior chamber for a long time, resulting in continuous friction between the drainage tube and the corneal endothelium, which can lead to corneal endothelial cell loss and corneal decompensation, resulting in corneal opacity and loss of transparency. This can cause patients to experience discomfort, such as a noticeable foreign body sensation and watery eyes, which can require removal of the drainage device, leading to a re-rise in intraocular pressure, surgical failure, and even the need for corneal endothelial transplantation.

[0005] The applicant previously filed a patent application for a biodegradable glaucoma drainage device (patent number 202123353992.0) for draining aqueous humor from the anterior chamber. The device includes a drainage sheet, the insertion end of which is beveled and the surface is provided with a drainage coating with an internal gap, allowing aqueous humor to flow through the internal gap after insertion into the anterior chamber. The drainage device is made of biodegradable materials and can gradually degrade over time after implantation in the eye. This biodegradable drainage device effectively prevents inflammation, scar formation, and scarring caused by foreign body irritation. It also prevents the loss of corneal endothelial cells due to friction and irritation caused by foreign bodies in the anterior chamber over a long period of time. Thus, once the drainage device is fully biodegraded, a natural aqueous humor filtration and drainage pathway (from the anterior chamber to the subconjunctiva) can be formed without foreign body irritation, improving the success rate of glaucoma surgery.

[0006] However, this drainage device has the following problems. 1) The insertion end of this drainage device is designed with a beveled surface, and because the insertion end is relatively sharp, external force may damage intraocular tissues such as the lens and cornea, posing a safety issue. At the same time, the connection with the anterior chamber is narrow, which poses a hidden risk of impeding the drainage of aqueous humor. 2) The internal gaps of the surface coating are used to guide the outflow of aqueous humor, but because the internal gaps of the coating are tortuous and small, there is a hidden risk that the flow of aqueous humor may be impaired in the early stages after implantation, making it impossible to effectively reduce intraocular pressure. 3) Because the drainage sheet is thick (0.3-0.8 mm), the thickness of the coating is strictly limited, being no more than 0.003 mm at most, and it only serves to slow the decomposition rate of pure magnesium in aqueous humor and cannot control fibroblast proliferation. Furthermore, due to the limited coating thickness, the effect of slowing the decomposition rate of pure magnesium in aqueous humor is also very limited, significantly limiting the range of indications for the degradable drainage device. 4) It is impossible to reasonably control the degree of scarring at the implanted site, and it is difficult to ensure that aqueous humor is effectively drained throughout the entire implantation process. 5) In the later stages of decomposition, the protective effect of the coating on the substrate weakens and disappears, accelerating the rate of decomposition of the substrate, intensifying tissue irritation and promoting the scarring reaction. When the material is completely decomposed, excessive scarring may cause blockage of the aqueous humor channels created in the earlier stages.

[0007] To address the issue of aqueous humor drainage channel fusion due to scarring after glaucoma surgery, the conventional approach is to briefly apply an anti-scarring drug patch under the conjunctiva during surgery (rinsing with saline after 2–4 minutes). This approach has several drawbacks. First, the anti-scarring drug has a limited residence time under the conjunctiva and is completely lost when rinsed with saline. This can lead to scar fusion on the wound surface and surgical failure during the mid- and late postoperative periods. Second, the high concentrations of anti-scarring drugs currently used in surgery are highly toxic and irritating, causing discomfort to patients and potentially serious ocular side effects such as ocular atrophy, leading to surgical failure. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention addresses the above-mentioned problems and provides a degradable glaucoma drainage device that gradually controls scarring, and a method for manufacturing such a drainage device, in order to solve the problems of conventional drainage devices, such as low safety during use, poor drainage, inability to rationally adjust the degree of scarring at the implanted site, inability to effectively reduce intraocular pressure, and reduced therapeutic efficacy. [Means for solving the problem]

[0009] The present invention provides a degradable glaucoma drainage device that provides stepwise scar control, comprising: The drainage sheet includes a long strip-shaped drainage sheet having a uniform overall cross-sectional size, the drainage sheet is made of a biodegradable material, the surface of the drainage sheet is provided with drainage gaps that penetrate opposing sides of the drainage sheet, the outer surface of the drainage sheet is coated with a biodegradable surface coating, the surface coating is loaded with a scarring inhibitor, the scarring inhibitor is gradually released as the surface coating decomposes, and the distribution concentration of the scarring inhibitor within the surface coating changes non-monotonicly.

[0010] A method for manufacturing the degradable glaucoma drainage device for gradually controlling scarring, comprising: 1) providing a drainage sheet; 2) preparing a surface coating solution using a liquid deposition method; 3) providing the prepared anti-scarring drug; 4) The method includes a step of placing the drainage sheet in a surface coating solution, and intermittently adding a scarring inhibitor during the process of forming a surface coating on the drainage sheet, thereby forming a surface coating on the surface of the drainage sheet whose distribution concentration changes non-monotonically. [Brief explanation of the drawings]

[0011] In order to more clearly describe the embodiments of the present invention or the technical solutions in the prior art, the drawings that need to be used in describing the embodiments or the prior art are briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention, and those skilled in the art can obtain drawings of other embodiments based on these drawings without creative efforts.

[0012] [Figure 1] 1 is a top view of a drainage device provided by the present invention implanted in an eye. FIG. [Figure 2] 1 is a side view of a drainage device provided by the present invention being implanted in an eye. FIG. [Figure 3] 1 is a schematic diagram of the overall structure of the drainage device provided by the present invention; [Figure 4] 1 is a schematic diagram of a side structure of a drainage device provided by the present invention; [Figure 5] 1 illustrates the effect on scar formation of a drainage device provided by the present invention. [Figure 6] 1 illustrates the degradation of the drainage device provided by the present invention after it has been implanted in the eye. [Figure 7] 1 shows HE staining after the drainage device provided by the present invention is implanted into the eyeball. [Figure 8] 1 shows intraocular pressure fluctuations after a drainage device provided by the present invention is implanted in the eye. [Figure 9] 1 shows corneal endothelial cells after a drainage device provided by the present invention has been implanted in the eye. [Figure 10] 1 shows corneal endothelial cells after a drainage device provided by the present invention has been implanted in the eye. [Figure 11] 1 shows the drainage of aqueous humor when the drainage device provided by the present invention is implanted in the eyeball. [Figure 12] 1 shows the drainage of aqueous humor when the drainage device provided by the present invention is implanted in the eyeball. [Figure 13] FIG. 1 is a schematic diagram of the release rate of mitomycin-C in the drainage device provided by the present invention. [Figure 14] FIG. 1 is a schematic diagram of the weekly release concentration of mitomycin-C in the drainage device provided by the present invention. [Figure 15] 1 is a schematic diagram of the release rate of 5-fluorouracil in the drainage device provided by the present invention. [Figure 16] 1 is a schematic diagram of the weekly drug release concentration of 5-fluorouracil in the drainage device provided by the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] The following detailed description is given of the embodiments of the technical solution of the present invention in conjunction with the accompanying drawings. The following embodiments are only used to more clearly explain the technical solution of the present invention, and are therefore only used as examples, and are not intended to limit the protection scope of the present invention.

[0014] It should be noted that unless otherwise specified, technical or scientific terms used in this application have the common meaning as understood by a person skilled in the art to which this invention belongs. Unless otherwise specified, raw materials, equipment, devices, etc. used in this application are assumed to be available through commercial channels.

[0015] In the description of this application, it should be understood that the term "drainage device" refers to a special medical product that connects the anterior chamber and the subconjunctival gap and guides the outflow of aqueous humor from the anterior chamber to reduce intraocular pressure and treat glaucoma; the term "drainage sheet" refers to a degradable magnesium alloy sheet that is the base part of the drainage device; the term "drainage gap" refers to an aqueous humor bypass path formed on the surface of the drainage sheet by mechanical processing or chemical etching methods and is an important structural unit of the drainage device; and the term "surface coating" refers to an additional coating layer applied to the surface of the drainage sheet and is a component that further improves the usage effect and range of indications of the drainage device.

[0016] The degradable glaucoma drainage device for gradual scar control provided by the present invention, as shown in Figures 1, 2, 3, and 4, is used to connect the anterior chamber and the subconjunctival gap to drain aqueous humor from the anterior chamber. It includes a long, strip-shaped drainage sheet 11 with a uniform overall cross-sectional size, and drainage gaps 12 are formed on the surface of the drainage sheet 11, penetrating two opposing sides of the drainage sheet 11. The drainage sheet 11 is made of a biodegradable material. In specific implementation, one drainage gap 12 may be provided, or one drainage gap 12 may be provided on each opposing side, i.e., two drainage gaps 12 may be provided. The edges of the drainage sheet 11 also need to be blunted.

[0017] In order to slow down the degradation rate of the magnesium alloy drainage device, improve its effect of inhibiting fibroblast proliferation, and expand the range of indications for the drainage device, a biodegradable coating is applied to the outer surface of the drainage sheet 11, and the thickness of the surface coating 13 is set to 0.02 mm or less, as shown in Figure 4. Furthermore, the component of the surface coating 13 is one or a mixture of two or more selected from hydroxyapatite, tricalcium phosphate, and calcium hydrogen phosphate.

[0018] Furthermore, to rationally control the degree of scarring at the implantation site, the surface coating is loaded with a scarring inhibitor, which is gradually released as the surface coating degrades, and the distribution concentration of the scarring inhibitor within the surface coating varies non-monotonically.

[0019] In actual use, one end of the drainage device 1 is inserted into the anterior chamber through an incision in the limbus 4, and the other end is placed under the conjunctiva 3, connecting the anterior chamber with the subconjunctiva, allowing aqueous humor to be effectively drained through the drainage gap 12 on the surface of the drainage device 1, thereby reducing intraocular pressure.

[0020] The biodegradable material is pure magnesium or a magnesium alloy, preferably a medical-grade magnesium alloy. The biodegradable material exhibits a degradation rate of 0.01-0.1 mm / month in sodium lactate Ringer's solution (immersed at 37°C ± 0.5°C for 30 days with daily artificial replacement of aqueous humor) in vitro, and the tensile strength of the magnesium alloy is 200 MPa or greater. The degradable biomaterial used in the aqueous humor drainage device of the present invention effectively connects the anterior chamber and the subconjunctival gap, creating a physiological aqueous humor drainage pathway and preventing its blockage. Therefore, when the aqueous humor drainage device of the present invention is fully biodegraded, a natural aqueous humor drainage pathway (from the anterior chamber to the subconjunctival space or from the anterior chamber to the suprachoroidal space) can be formed without foreign body irritation, improving the success rate of glaucoma surgery. It should also be understood that the drainage device gradually degrades over time, effectively preventing postoperative corneal endothelial cell loss. At the same time, it can also be understood that the drainage device will gradually decompose over time, the drainage passage will gradually expand, the aqueous humor discharge will slowly increase, and after the drainage device is completely decomposed, a stable flow rate will be reached, thereby achieving the purpose of regulating the aqueous humor discharge.

[0021] Pure magnesium is 99.99% or more by mass of magnesium. Magnesium alloys contain 0.01-2.0% by mass of Zn, 0.0-0.5% by mass of Ca, and 0.0-0.5% by mass of Sr, with the remainder being magnesium and unavoidable impurities. It should be noted that the total content of impurities must be controlled to 0.01% or less.

[0022] The present invention uses a long, strip-shaped drainage sheet with a uniform cross-sectional size and a stronger magnesium alloy, eliminating weak spots in the drainage device and improving its strength. Therefore, instead of creating a special scleral tunnel during surgery, the drainage device can be inserted into the eye simply by making an incision in the sclera with a tunnel knife, thereby connecting the anterior chamber with the subconjunctival gap, allowing aqueous humor to drain from the eye and controlling intraocular pressure. Figures 1 and 2 show the use of the implanted aqueous humor drainage device. The surgical procedure takes significantly less time, typically 5 to 10 minutes, 0.5 to 1 times faster than conventional glaucoma external device implantation procedures, significantly improving surgical efficiency. In other words, the aqueous humor drainage device of the present invention significantly reduces the risk of aqueous humor leakage due to poor fit between the scleral tunnel and the implant, resulting in complications such as hypotony, significantly shortens surgery time, and reduces the risk of intraoperative anesthesia failure. More importantly, the drainage device is more firmly fixed in the scleral tunnel, reducing the risk of aqueous humor leakage due to poor fit between the scleral tunnel and the drainage device, resulting in complications such as hypotony, shallow anterior chamber, and choroidal detachment. It also significantly reduces the use of viscoelastic materials during surgery, effectively improving surgical safety and efficacy. Furthermore, the alloying elements Zn, Ca, and Sr selected in the present invention all have excellent biocompatibility, and by appropriately controlling their content, the strength of the aqueous humor drainage device can be improved without compromising its safety. At the same time, the dissolution and release of these alloying elements during the degradation process can also play a supporting role in controlling fibroblast proliferation. However, if the content of magnesium alloy elements is too high, the decomposition rate of the magnesium alloy drainage device will be significantly increased, shortening the effective support time of the aqueous humor drainage device in the body and making it difficult to achieve good therapeutic effects.

[0023] During the drainage process, as the drainage sheet gradually decomposes within the eye, the inner diameter of the drainage passage connecting the anterior chamber and the suprachoroidal space gradually increases, gradually increasing the amount of aqueous humor drained. This effectively avoids the disadvantages of conventional external drainage devices for glaucoma implantation, which can lead to postoperative complications such as low intraocular pressure and a shallow anterior chamber in the early stages, as well as late postoperative complications related to filtering blebs.

[0024] Furthermore, in the initial stage of implantation, the drug is gradually released as the surface coating decomposes, and the surface coating 13 controls the release of the drug, changing the amount of drug released over time in a non-monotonic curve, thereby appropriately controlling the degree of scarring at the implantation site. This allows aqueous humor to be effectively drained throughout the entire implantation process, and no passageway blockage due to excessive scarring occurs after the material has completely decomposed.

[0025] Referring to Figures 3 and 4, the drainage gap 12 can be formed by machining or chemically etching the surface of the drainage device, and further, the drainage gap 12 is a groove formed through the length of the drainage sheet, parallel to the length, and having a depth of 0.01 to 0.1 mm and a width of 0.05 to 0.2 mm.

[0026] The present invention uses mechanical processing or chemical etching to create drainage gaps on the surface of the drainage sheet, ensuring good drainage even at the early stage of implantation. When the drainage device is first implanted in the eye, it adheres directly to the sclera, and aqueous humor drainage relies solely on the internal gaps on the coating surface, resulting in poor drainage and making it difficult to effectively reduce intraocular pressure and relieve pain for the patient. The specially designed drainage gaps of the present invention fundamentally solve this problem. The drainage gaps run the entire length of the drainage device, directly connecting the anterior chamber and the subconjunctival gap. Therefore, once the drainage device is implanted, aqueous humor can smoothly drain through the drainage gaps, effectively reducing intraocular pressure and relieving pain for the patient. The drainage gap should be 0.01 to 0.1 mm deep and 0.05 to 0.2 mm wide. If it is too shallow or narrow, effective drainage is difficult. If it is too deep or wide, the aqueous humor will flow out too quickly in the early stages (usually around 2 weeks), which can lead to a decrease in intraocular pressure and an increase in postoperative complications. The strength of the drainage device will also be significantly reduced.

[0027] The present invention applies a biodegradable coating to the surface of the magnesium alloy material, which not only reduces the degradation rate of the magnesium alloy drainage device but also promotes the formation of a natural scleral aqueous humor drainage channel. The drainage device is surgically placed between the scleral layers, and the upper and lower surfaces of the magnesium alloy drainage device come into contact with the interlaminar tissue. The coating, the magnesium alloy substrate, and its degradation products inhibit fibroblast proliferation, forming very thin fibrous proliferative membranes between the upper and lower layers of the scleral drainage channel. Once the drainage device is completely degraded, the proliferation and scarring of the two layers of fibrous proliferative membranes stops, preventing further scar healing between the upper and lower fibrous membranes and forming a natural aqueous humor drainage channel. This effectively prevents the scleral drainage channel from being blocked by scarring and significantly improves the long-term efficacy of external drainage surgery for glaucoma.

[0028] In the present invention, the maximum thickness of the surface coating can reach 0.02 mm, allowing the thickness of the surface coating to be adjusted over a wide range, effectively reducing the degradation rate of the drainage device and achieving the goals of controlling fibroblast proliferation. Furthermore, the present invention introduces several beneficial alloying elements, eliminating the need for coating (i.e., the coating thickness is zero), greatly increasing the range of patients suitable for the aqueous humor drainage device of the present invention.

[0029] The drainage device has a length of 1 to 6 mm, a width of 0.5 to 4.0 mm, and a thickness of 0.1 to 0.5 mm.

[0030] The improved strength of magnesium alloy materials allows drainage devices to be made thinner and smaller, allowing them to be used in more types of glaucoma, such as angle-closure glaucoma. This also further reduces the risk of corneal endothelial loss due to continuous friction between the tip of the drainage device (inside the anterior chamber) and the corneal endothelial cells, effectively improving the long-term safety of external drainage surgery for glaucoma.

[0031] Specifically, the concentration of the anti-scarring drug within the surface coating is distributed in a curve that gradually decreases from a high point along the depth direction, then gradually increases, reaching a maximum at the bottom of the surface coating. In specific implementation, the concentration of the anti-scarring drug can decrease from the outside to the inside at 1 / 3 to 1 / 2 of the coating thickness, and then gradually increase to a maximum at the bottom of the coating (i.e., the position in contact with the surface of the substrate).

[0032] During use, the decomposition process of the drainage device begins with the surface coating 13, and once the surface coating 13 has decomposed to a certain extent, the substrate begins to decompose, but the remaining surface coating 13 can still protect the substrate.

[0033] In the early stages after the drainage device is implanted, the body's stress response leads to rapid scar formation and growth, and the scar tissue comes into direct contact with the surface of the material. In severe cases, this may result in blockage of the passageway. In such cases, a strong inhibitory effect on the scar reaction is required. Therefore, the surface concentration of the scar inhibitor on the surface coating 13 is relatively high, and the amount released at this time is also large, which can delay scar formation and maintain smooth drainage.

[0034] As time passes after implantation, a scar gradually grows, forming a certain barrier between the material and normal ocular tissue. Furthermore, the body also adapts to the material to a certain extent, and the scar-inhibiting effect may gradually weaken, and the concentration of the scar-inhibiting drug may be appropriately reduced, so that the amount released may also be reduced accordingly.

[0035] During the middle and late stages of surface coating 13 decomposition (starting about one-third to one-half of the way through), the protective effect of surface coating 13 on the substrate weakens, significantly accelerating the decomposition of the magnesium or magnesium alloy in the substrate. This releases large amounts of magnesium ions and alloy element ions, potentially stimulating and inducing a strong chronic inflammatory response and leading to further scar growth. Therefore, the concentration of the anti-scarring agent must be increased, which increases the release of the anti-scarring agent and achieves a stronger anti-scarring effect. Similarly, after surface coating 13 is completely decomposed, the decomposition of the substrate accelerates significantly, leading to a strong scarring response. At this time, a large amount of anti-scarring drug is required to inhibit scarring, and after the coating decomposes and disappears, the anti-scarring drug is no longer continuously released, so the amount of anti-scarring drug must be increased again at the bottom of the coating.As a result, even after the coating is completely decomposed, a large amount of anti-scarring drug remains in the surrounding tissue, maintaining the anti-scarring effect for a certain period of time until the base material decomposes.Even after the drainage device is completely decomposed, scar tissue no longer develops, and stable scar tissue surrounds effective aqueous humor drainage channels.

[0036] As manufactured, the anti-scarring drug consists of either one or a mixture of the two of mitomycin-C and 5-fluorouracil.

[0037] The drug loading in the surface coating 13 is carried out by a simultaneous drug loading method during coating, that is, the drug is loaded while the coating is being produced. First, a phosphate coating solution for producing the surface coating is prepared, to which 0.1 to 1 mg / ml of mitomycin-C and 10 to 100 mg / ml of 5-fluorouracil, which are anti-scarring drugs, are added and stirred uniformly. After that, the drainage sheet 11 is placed in the solution and the coating process is carried out. During the coating process, the anti-scarring drug is added at regular intervals, the amount added being first reduced each time compared to the previous time, and after reaching one-third to one-half of the specified coating process time, the amount of the anti-scarring drug added is increased each time compared to the previous time until the coating process is completed. Finally, the device is washed, dried, and sterilized to obtain a drainage device having the anti-scarring drug in its coating. [Example]

[0038] Manufacturing of drainage devices made of magnesium alloy materials In this embodiment, a magnesium alloy (Mg-2Zn-0.1Ca (i.e., containing 2% by weight of Zn and 0.1% by weight of Ca, the same applies below), with a tensile strength of 220 MPa and a decomposition rate of 0.03 mm / month) is used as an example to manufacture a drainage device using the alloy, and the following method may be used. a. Hot extruded magnesium alloy b. The material was processed into long strips of device material measuring 3 mm in length, 2 mm in width, and 0.3 mm in thickness. c. A drainage gap with a width of 0.3 mm and a depth of 0.1 mm was machined along the entire length on each of the top and bottom surfaces. If two gaps were machined, the gaps on the two surfaces must be misaligned by at least 0.2 mm. d. The surface of the device material was polished to a gloss using 400#, 600#, 800#, and 1200# sandpaper. e. Ultrasonic cleaning in acetone. f. The drainage device made of magnesium alloy material was obtained by air-drying. [Example]

[0039] Magnesium alloy / HA coating composite material Based on Example 1, a magnesium alloy drainage device processed in steps a-f was used as the substrate. The drainage sheet of the device was placed in the solution at a temperature of 40°C or higher but lower than 100°C. An anti-scarring drug was added to the solution using simultaneous drug loading (coating) to form an anti-scarring drug-loaded hydroxyapatite (HA) coating by electrochemical deposition. The electrolyte was an aqueous solution of 0.042 mol / L Ca(NO3)2 and 0.025 mol / L NH4H2PO4, with a Ca / P ratio of 1.68, pH 5.0, and a current density of 10 mA / cm2. The deposition was performed at room temperature for 2 hours. During the deposition process, the anti-scarring drug was initially added at 1 mg / mL mitomycin-C, which was then added once every 10 minutes, with each addition decreasing by 10%. From the 50th minute onward, the amount added each time increased by 15%. The resulting drug-loaded coating was 0.004 mm thick and was ultrasonically cleaned. The degradation rate of the fabricated drainage device was 0.06 mm / month. [Example]

[0040] Magnesium alloy / tricalcium phosphate coated aqueous humor drainage device In this embodiment, magnesium alloy (Mg-5Zn-0.5Sr, tensile strength is 280 MPa, decomposition rate is 0.03 mm / month) is used as an example to manufacture a drainage device, and the following method may be used. a. Hot extruded magnesium alloy b. The material was processed into long strips of device material measuring 1 mm in length, 0.5 mm in width, and 0.1 mm in thickness. c. A drainage gap of 0.1 mm width and 0.05 mm depth was machined along the entire length on each of the top and bottom surfaces. The drainage gaps on the two surfaces must be misaligned by at least 0.2 mm. d. The surface of the device material was polished to a gloss using 400#, 600#, 800#, and 1200# sandpaper. e. Ultrasonic cleaning in acetone. f. The drainage device made of magnesium alloy material was obtained by air-drying. g. Using the magnesium alloy drainage device processed in the above step as the substrate, the drainage sheet of this device was placed in the solution at a temperature of 40°C or higher but lower than 100°C, and a scarring inhibitor was added to the solution using the simultaneous drug loading method, and a tricalcium phosphate coating was formed by chemical deposition. The tricalcium phosphate coating was fabricated as follows. The magnesium alloy drainage device fabricated in steps a-f was used as the substrate. A tricalcium phosphate (TCP) coating was formed by chemical deposition. The deposition solution was an aqueous solution of 0.075 mol / L Ca(NO3)2 and 0.05 mol / L Na2HPO4, with a Ca / P molar ratio of 1.5. The deposition was performed at 60°C for 24 hours. During the deposition process, the anti-scarring drug, 100 mg / mL 5-fluorouracil, was added first, followed by one addition every 30 minutes, with each addition decreasing by 5%. From the 720th minute onward, the amount added each time increased by 10%. The resulting drug-loaded coating had a thickness of 0.02 mm. i. Ultrasonic cleaning. [Example]

[0041] Magnesium alloy / calcium hydrogen phosphate coated aqueous humor drainage device In this embodiment, magnesium alloy (Mg-4Zn-0.5Ca, tensile strength is 260 MPa, decomposition rate is 0.075 mm / month) is used as an example to manufacture a drainage device, and the following method may be used. a. Hot extruded magnesium alloy b. The material was processed into long strips of device material measuring 3 mm in length, 1.5 mm in width, and 0.2 mm in thickness. c. A drainage gap measuring 0.2 mm wide and 0.05 mm deep was machined along the entire length of the upper and lower surfaces. The drainage gaps on the two surfaces must be misaligned by at least 0.2 mm. d. The surface of the device material was polished to a gloss using 400#, 600#, 800#, and 1200# sandpaper. e. Ultrasonic cleaning in acetone. f. The drainage device made of magnesium alloy material was obtained by air-drying. g. Using the magnesium alloy drainage device processed in the above step as the substrate, the drainage sheet of this device was placed in the solution at a temperature of 40°C or higher but lower than 100°C, and a scar prevention drug was added to the solution using the simultaneous coating and drug loading method, and a calcium hydrogen phosphate coating was formed by chemical deposition. The calcium hydrogen phosphate coating was fabricated as follows. The magnesium alloy drainage device fabricated in steps a-f was used as the substrate. A calcium hydrogen phosphate (DCP) coating was formed by electrochemical deposition. The deposition solution was an aqueous solution of 0.032 mol / L Ca(NO3)2 and 0.022 mol / L Na2HPO4, with a Ca / P molar ratio of 1.45. The deposition was performed at 50°C for 10 hours. The anti-scarring drugs added during the deposition process were 0.1 mg / ml mitomycin-C and 80 mg / ml 5-fluorouracil. Subsequently, additional doses were added every 20 minutes, decreasing each dose by 5%. From the 240th minute onward, the amount added each time increased by 10%. The resulting drug-loaded coating had a thickness of 0.01 mm. i. Ultrasonic cleaning. [Example]

[0042] Pure magnesium / (hydroxyapatite) coated drainage device In this embodiment, pure magnesium (99.99% Mg, decomposition rate is 0.02 mm / month) is taken as an example, and the following method may be used to manufacture a glaucoma drainage device using it. a. Pure magnesium in the recrystallized annealed state after cold extrusion b. The material was processed into long strips of device material measuring 2.8 mm in length, 1.5 mm in width, and 0.4 mm in thickness. c. A drainage gap measuring 0.2 mm wide and 0.08 mm deep was machined along the entire length of the upper and lower surfaces. The drainage gaps on the two surfaces must be misaligned by at least 0.2 mm. d. The surface of the device material was polished to a gloss using 400#, 600#, 800#, and 1200# sandpaper. e. Ultrasonic cleaning in acetone. f. The drainage device was made of pure magnesium material after air-drying. g. Using the pure magnesium drainage device processed in the above step as the substrate, the drainage sheet of this device was placed in the solution at a temperature of 40°C or higher but lower than 100°C, and using the simultaneous coating and drug loading method, a scarring inhibitor was added to the solution, and a hydroxyapatite coating was formed by chemical deposition. The manufacturing method of hydroxyapatite coating is as follows. The magnesium alloy material drainage device processed in steps a to f is used as a substrate, and a coating is formed by chemical deposition. The deposition liquid is 0.35 mol / L (C 10 H 12The coating was a mixture of CaN2Na2O8·2H2O (EDTA-Ca) and 0.45 mol / L KH2PO4, adjusted to pH 7.3 with NaOH solution, and deposited for 15 hours at 95°C. During the deposition process, the anti-scarring drugs added initially were 0.5 mg / ml mitomycin-C and 40 mg / ml 5-fluorouracil. Subsequently, additional doses were added every 25 minutes, each time decreasing by 10%. From the 400th minute, each dose was increased by 15% until coating was complete. The resulting drug-loaded coating had a thickness of 0.008 mm. i. Ultrasonic cleaning was performed. Test Example 1

[0043] Aqueous humor concentration two months after the drainage device was implanted The applicant simultaneously introduced comparative values ​​(conventional trabeculectomy, medical titanium alloy) for the above examples (1, 2, 3, and 4) and measured the aqueous humor concentration two months after implantation using a fully automated biochemical analyzer. The results are shown in Table 1.

[0044] Table 1. Comparison of aqueous humor ion concentrations 2 months after surgery TIFF2026507384000002.tif9678

[0045] As can be seen from the data in Table 1, after the aqueous humor drainage devices prepared in Examples 1 to 4 were implanted in the eye, there was no significant difference in the aqueous humor components compared to the simple trabeculectomy and titanium alloy implantation groups. This indicates that the aqueous humor drainage devices designed according to the present invention, when biodegraded in the eye, do not produce any significant effects on the changes in ion concentration in the anterior chamber.

[0046] Effect of Mg-2Zn-0.1Ca / HA drainage device on scar formation The applicant tested the effect of the aqueous humor drainage device manufactured in Example 2 on scar formation. The sample manufacturing and testing steps are as follows: (1) Protein extraction and Western blot (2) Protein extraction (3) Protein concentration detection (4) Preparation of electrophoresis gel (5) Electrophoresis (6) Chemical conversion coating (7) Fixation and antibody incubation (8) Light-emitting identification (9)Result analysis

[0047] The results are shown in Figure 5. The decomposition products of Mg-2Zn-0.1Ca / HA inhibited the expression of α-SMA in Tenon's fibroblasts by mediating the TGFβ / Smad signaling pathway.

[0048] Degradation status of drainage device at different times In this test example, the aqueous humor drainage device prepared in Example 5 was used as an example to test the state of degradation in vivo. The specific method was as follows. (1) One month after surgery, the communication between the anterior chamber and the subconjunctival gap and the degradation of the drainage device were measured using an ultrasound biomicroscope. Figure 6 shows the communication between the anterior chamber and the subconjunctival gap (New Zealand white rabbit) using the UBM drainage device one month after surgery. As can be seen from Figure 6, the drainage device is firmly fixed in the scleral tunnel, with one end located in the anterior chamber and the other end located in the subconjunctival gap, causing the filtering bleb to protrude. (2) HE staining of ocular tissue sections from the site where the drainage device was implanted 6 months after surgery Figure 7 shows HE staining of an ocular tissue section (New Zealand white rabbit) 6 months after surgery. As can be seen from Figure 7, the drainage device was completely degraded, a linear aqueous humor drainage channel was present, the filtering bleb was elevated, small cystic loose tissue was formed, and anterior iris adhesions were observed. No obvious inflammatory cell infiltration was observed in any tissue. The arrows in the figure represent the drainage channel, the red circle represents the anterior iris adhesion, and the blue rectangle represents the elevated, small cystic filtering bleb. Test Example 4

[0049] Effect of drainage devices on intraocular pressure New Zealand white rabbits underwent surgery to implant the aqueous humor drainage device (Mg Plate) prepared in Example 1 of the present application and trabeculectomy, and the eyes that did not undergo surgery (Control) served as a blank control group.

[0050] Intraocular pressure was measured weekly using a Tonopen tonometer, and the average of three IOP values ​​was recorded. The results are shown in Figure 8. As shown in Figure 8, during IOP monitoring five months after surgery, IOP values ​​in both the Mg Plate group and the trabeculectomy group were lower than those in the control group during the first month. Subsequently, IOP in the trabeculectomy group returned to the control group level, indicating complete adhesion of the drainage channels. IOP in the Mg Plate group was significantly lower than those in the trabeculectomy and control groups and further decreased from three to five months after surgery. This indicates that as the drainage device biodegrades, the physiological drainage channels gradually expand, aqueous humor outflow gradually increases, and a scleral aqueous humor drainage channel is formed and maintained.

[0051] New Zealand white rabbits underwent surgery to implant the aqueous humor drainage device (MgPlate) prepared in Example 5 of the present application and trabeculectomy, and the eyes that did not undergo surgery (Control) served as a blank control group.

[0052] One week before the experiment, the intraocular pressure of New Zealand White rabbits was measured daily using a Tonopen tonometer. Preoperative baseline intraocular pressure varied between 12 and 15 mmHg, with a binocular intraocular pressure difference of <5 mmHg. After surgery, intraocular pressure was measured weekly for 21 weeks. The results are shown in Table 2. A one-way analysis of variance (ANOVA) was performed to examine the changes in intraocular pressure in the three groups. A statistically significant difference (p<0.05) was observed in the changes in intraocular pressure at different time points among the three groups. Five weeks after surgery, intraocular pressure values ​​in both the Mg Plate and Trabeculectomy groups were lower than those in the control group. From week 6 onward, intraocular pressure in the Trabeculectomy group essentially returned to the level of the control group. After surgery, intraocular pressure in the Mg Plate group was lower than those in the Trabeculectomy and Control groups, and intraocular pressure further decreased from week 15 to week 16 after surgery.

[0053] Table 2. Postoperative intraocular pressure monitoring results and analysis TIFF2026507384000003.tif10465Test Example 5

[0054] Effect of drainage devices on the compensatory properties of corneal endothelial cells Using the aqueous humor drainage device prepared in Example 1 of the present application as an example, the effect of the device on the compensatory performance of corneal endothelial cells after implantation was tested. In this test example, no surgical treatment was performed on the left eyes of Rabbit 14 and Rabbit 2. The right eye of Rabbit 14 underwent drainage device surgery, and the right eye of Rabbit 2 underwent trabeculectomy. Five months after surgery, corneal endothelial cells were measured using a corneal endothelial cell counter (EM-3000, TOMEY, Japan). The results are shown in Figure 9. As can be seen from the figure, there was no significant difference in the number, density, or morphology of corneal endothelial cells between the right and left eyes of the two rabbits.

[0055] Using the aqueous humor drainage device prepared in Example 5 of the present application as an example, the effect on the compensatory performance of corneal endothelial cells after implantation was tested. Corneal endothelial cells were measured 5 months after surgery. The results are shown in Figure 10. As can be seen from the figure, when comparing the aqueous humor drainage device implantation group with the contralateral non-operated group, the corneal endothelial cell density and morphology were similar, and when a paired-samples T test (P=0.857) was performed on the number of corneal endothelial cells between the two groups, no statistically significant difference was observed (N=5). Test Example 6

[0056] Effect of drainage devices on aqueous humor drainage Using the aqueous humor drainage device prepared in Example 1 of the present application as an example, the influence on aqueous humor drainage was tested, specifically as follows.

[0057] An anterior capsule dye (trypan blue) was injected into the anterior chamber of the experimental animals at 1, 2, 3, 4, and 5 months after surgery, and the area of ​​the effective drainage zone was determined by observing whether the dye was discharged under the conjunctiva and the extent of its diffusion.

[0058] The status of dye discharge is shown in Figure 11. A and B are diagrams of the state after the drainage device was implanted. C shows the status of aqueous humor discharge one month after surgery. D shows the status of aqueous humor discharge five months after surgery. E shows the status of aqueous humor discharge after simple trabeculectomy one month after surgery. F shows the status of aqueous humor discharge using a conventional drainage tube five months after surgery.

[0059] As can be seen in Figure 11, trypan blue was injected into the anterior chamber one month after surgery. In the drainage device group, the blue dye was clearly seen to be drained under the conjunctiva, while in the trabeculectomy group (Group E), no blue dye was observed, indicating complete adhesion of the aqueous humor drainage channel. Five months after surgery, trypan blue was injected into the anterior chamber. In the drainage device group, the blue dye was still visible under the conjunctiva, and the diffusion area was significantly larger than that one month after drainage device surgery and five months after conventional drainage tube surgery. As the drainage device degraded, the area of ​​the scleral aqueous humor drainage channel gradually increased. Because the channel did not become scarred, the drainage channel remained intact.

[0060] Using the aqueous humor drainage device prepared in Example 5 of the present application as an example, the influence on aqueous humor drainage was tested, specifically as follows.

[0061] As shown in Figure 12A, (A) is a diagram of the state after the drainage device was implanted. In the trabeculectomy group, trypan blue was injected into the anterior chamber one month after surgery, and no blue dye was observed to leak from under the conjunctiva (B). Furthermore, a patency test of the passage was performed on all New Zealand white rabbits in the trabeculectomy group one month after surgery, but no dye was observed to be discharged under the conjunctiva. In the drainage device implantation group, one month after surgery, both ends of the drainage sheet were observed to be located in the anterior chamber and under the conjunctiva, respectively, and when trypan blue was injected into the anterior chamber, the blue dye was observed to be discharged under the conjunctiva (C). Five months after surgery, the drainage device was completely decomposed and absorbed, and when trypan blue was injected into the anterior chamber, the blue dye was still visible under the conjunctival bleb (D). Test Example 7

[0062] Effect of drainage devices on aqueous humor drainage Using the aqueous humor drainage device prepared in Example 2 of the present application as an example, the cumulative release rate and weekly released drug concentration of mitomycin-C (abbreviated as MMC) were tested, as follows:

[0063] The mitomycin-C-loaded coated material was removed, clamped with dialysis clips, and placed in 2 mL of PBS buffer (pH 7.4). The material was immersed continuously for 24 hours at 37°C, shaking at 100 rpm in an air bath shaker. The exudate was removed by suction. The dialysis bag and test tube were rinsed three times with PBS every 2–3 days, and the PBS solution was replaced. The exudate was removed weekly and stored at 4°C. Standard PBS solution served as a control. The exudate samples were measured at each time point using a UV-visible spectrophotometer. The drug concentration of each sample was calculated using a standard curve.

[0064] The cumulative release rate and weekly released drug concentration of mitomycin-C were tested. The results showed that the release rate of mitomycin-C was rapid during the first week, with a rapid increase in drug concentration and cumulative release rate. Subsequently, the drug release decreased and the curve plateaued, resulting in a slowdown in the cumulative release rate. From the ninth week onward, the release rate of mitomycin-C increased again, a second peak appeared, and the drug concentration further increased, resulting in a further increase in the cumulative release rate. This was due to the complete degradation of the coating, resulting in the release of a large amount of mitomycin-C. The release rate of mitomycin-C (abbreviated as MMC) is shown in Figure 13, and the weekly released concentration of mitomycin-C (abbreviated as MMC) is shown in Figure 14.

[0065] Using the same method, the cumulative release rate of 5-fluorouracil (5-FU) measured is shown in FIG. 15, and the released drug concentration per week is shown in FIG.

[0066] The above examples are only used to illustrate the technical solutions of the present invention, and are not intended to limit the same. Although the present invention has been described in detail with reference to the above examples, those skilled in the art should understand that it is still possible to modify the technical solutions described in the above examples, or to replace some or all of the technical features with equivalents, and these modifications or substitutions do not cause the essence of the corresponding technical solutions to depart from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the claims and description of the present invention. [Explanation of symbols]

[0067] 1. Drainage device 2 Pupils 3 Conjunctiva 4 limbus 11 Drainage Sheet 12 Drainage gap 13 Surface Coating

Claims

1. 1. A degradable glaucoma drainage device that provides gradual scar control, comprising: It includes a long strip of drainage sheet with a uniform cross-sectional size throughout, The drainage sheet is made of a biodegradable material, the surface of the drainage sheet is provided with drainage gaps penetrating two opposing sides of the drainage sheet, the outer surface of the drainage sheet is coated with a biodegradable surface coating, the surface coating carries a scarring inhibitor, the scarring inhibitor is gradually released as the surface coating decomposes, and the distribution concentration of the scarring inhibitor within the surface coating changes non-monotonicly. A degradable glaucoma drainage device that gradually controls scarring, characterized by:

2. the concentration of the anti-scarring drug in the surface coating is distributed in a curve that gradually decreases from a high point along the depth direction, then gradually increases, and reaches a maximum at the bottom of the surface coating; 2. The degradable glaucoma drainage device for gradual scar control according to claim 1.

3. The anti-scarring drug is composed of either one of mitomycin-C and 5-fluorouracil, or a mixture of the two.

3. The degradable glaucoma drainage device for gradual scar control according to claim 2.

4. The decomposition rate of the drainage sheet in extracorporeal sodium lactate Ringer's solution is 0.01 to 0.1 mm / month.

2. The degradable glaucoma drainage device for gradual scar control according to claim 1.

5. The biodegradable material is pure magnesium, and the magnesium content of the pure magnesium is 99.99% or more.

5. The degradable glaucoma drainage device for gradual scar control according to claim 4.

6. The biodegradable material is a magnesium alloy, the magnesium alloy containing 2.0 to 5.0 mass% Zn, 0.0 to 0.5 mass% Ca, and 0.0 to 0.5 mass% Sr, with the remainder being magnesium and unavoidable impurities, and the magnesium alloy having a tensile strength of 200 MPa or more.

6. The degradable glaucoma drainage device for gradual scar control according to claim 5.

7. The thickness of the surface coating is 0.02 mm or less.

2. The degradable glaucoma drainage device for gradual scar control according to claim 1.

8. The surface coating component is one or a mixture of two or more selected from hydroxyapatite, tricalcium phosphate, and calcium hydrogen phosphate.

8. The degradable glaucoma drainage device for gradual scar control according to claim 7.

9. 1) providing a drainage sheet; 2) preparing a surface coating solution using a liquid deposition method; 3) providing the prepared anti-scarring drug; 4) placing the drainage sheet in a surface coating solution, and intermittently adding an anti-scarring drug during the process of forming a surface coating on the drainage sheet, thereby forming a surface coating on the surface of the drainage sheet whose distribution concentration changes non-monotonically; A method for manufacturing a degradable glaucoma drainage device for stepwise scar control according to any one of claims 1 to 8.

10. The method of intermittently adding the anti-scarring drug involves adding a certain amount of drug every 10 to 30 minutes, calculating the amount according to the actual concentration in the solution, adding the largest amount initially, then gradually decreasing it, and gradually increasing the amount added when the deposition time is half to two-thirds of the way through until the deposition is complete.

10. A method for manufacturing a degradable scar-controlling glaucoma drainage device according to claim 9.

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