Ocular delivery devices and methods of making the same

Abstract

The application discloses an ocular delivery device and a preparation method thereof. The first aspect of the application provides an ocular delivery device, which comprises an electroporation assembly, the electroporation assembly comprises a support part, the support part comprises a first surface and a second surface which are oppositely arranged and curved, the first surface is convex, and the second surface is concave; an electrode pattern, the electrode pattern is located on the second surface, and the electrode pattern contains a liquid metal material. The ocular delivery device simulates a contact lens by the support part, and meanwhile, an electrically conductive circuit is formed on the second surface of the support part by the liquid metal material, mechanical differences are eliminated, conformal contact with the cornea is realized, the function of in-situ electroporation is endowed, and the efficiency of electroporation is effectively improved. Moreover, due to the high conductivity of the liquid metal material, electroporation can be completed at a lower voltage, and electrical damage that may be caused to the eye is avoided, so that safe and efficient in-situ electroporation of the eye in vivo is achieved.

Description

Technical Field

[0001] This application relates to the field of drug delivery technology, and in particular to an ocular delivery device and its preparation method. Background Technology

[0002] The complex barrier structure of the eye (cornea, conjunctiva, blood-aqueous humor, etc.) and clearance system result in bioavailability of ophthalmic drugs typically below 5%. Therefore, new delivery systems are needed to improve therapeutic efficacy. Electroporation is a technique for delivering exogenous substances at the cellular or tissue level. By applying a transient high electric field, cell membrane permeability is increased, promoting the uptake of exogenous molecules from the surrounding medium, thereby enabling intracellular regulation and gene transfection. For many years, electroporation has been widely used in the biomedical field due to its ease of operation, safety, and efficiency. However, current commercially available electrodes exhibit low electroporation and substance delivery efficiency when applied directly to the eye. Furthermore, these electrodes require high voltage for electroporation, and direct contact with the eye can easily cause severe electrical damage, contradicting the intended therapeutic purpose. Therefore, it is necessary to provide an ophthalmic delivery device that achieves safe and efficient delivery. Summary of the Invention

[0003] This application aims to address at least one of the technical problems existing in the prior art. To this end, this application proposes an eye delivery device capable of safe and efficient delivery of substances.

[0004] This application also proposes a method for preparing an eye delivery device.

[0005] A first aspect of this application provides an eye delivery device, the eye delivery device including an electroporation assembly, the electroporation assembly comprising:

[0006] The support portion includes a first surface and a second surface that are oppositely disposed and are curved, the first surface being a convex surface and the second surface being a concave surface;

[0007] Electrode pattern, the electrode pattern is located on the second surface, the electrode pattern contains liquid metal material.

[0008] The eye delivery device according to the embodiments of this application has at least the following beneficial effects:

[0009] The ocular delivery device provided in this application uses a support portion to simulate a contact lens, while incorporating a highly conductive, flexible, and malleable liquid metal material to form a conductive circuit on the second surface of the support portion. This eliminates the significant mechanical differences that may exist between existing rigid electrodes and the cornea, achieving conformal contact with the cornea and endowing it with in-situ electroporation capabilities, effectively improving the efficiency of electroporation. Moreover, due to the high conductivity of the liquid metal material, electroporation can be completed at a lower voltage, avoiding potential electrical damage to the eye, thus achieving safe and efficient in-situ ocular electroporation.

[0010] In some embodiments of this application, the radius of curvature of the second surface is 5-12 mm. Preferably, the radius of curvature of the second surface is 6-10 mm, 7-9 mm, or 7-8 mm. The radius of curvature of the cornea in normal individuals is typically around 7.8 mm, while in myopic or hyperopic individuals, the radius of curvature changes due to abnormalities in the shape, size, or position of the cornea. In this application, controlling the radius of curvature of the second surface within the above-mentioned range allows for better conformal contact when it is applied to the cornea, thereby improving electroporation efficiency and achieving better material delivery.

[0011] In some embodiments of this application, the radius of curvature of the first surface is 4 to 15 mm.

[0012] In some embodiments of this application, the distance between the first surface and the second surface is 0.01 to 1 mm. Preferably, the distance between the first surface and the second surface is 0.01 to 0.1 mm or 0.01 to 0.07 mm. The distance between the first surface and the second surface can also refer to the thickness of the support portion. When the distance between the two or the thickness of the support portion meets the above conditions, the subject will experience a certain degree of comfort when wearing the electroporation device on the eye. However, the larger the distance, the more intense the discomfort may be for the subject.

[0013] In some embodiments of this application, the electrode pattern includes:

[0014] The first electrode includes a first annular portion with a notch, the first annular portion being located at the outer edge of the second surface;

[0015] The second electrode includes a straight portion extending inward from the notch and a second annular portion connected to the straight portion, the radius of the second annular portion being smaller than the radius of the first annular portion.

[0016] The above-described electrode pattern structure enables electroporation to be performed effectively.

[0017] In some embodiments of this application, the curved surfaces of the first and second surfaces are independently selected from any one of a sphere, an ellipsoid, a continuous curved surface composed of multiple arc surfaces with different radii of curvature, etc. It is understood that the sphere or ellipsoid is not limited to the first or second surface being a complete sphere or ellipsoid; it can also be a curved surface formed by cutting a portion of a complete sphere or ellipsoid, or other approximate cases.

[0018] In some embodiments of this application, the support portion comprises a polymer material.

[0019] In some embodiments of this application, the polymer material is selected from at least one of polymethyl methacrylate, polycellulose acetate butyrate, polysilicate, poly(2-hydroxyethyl methacrylate), polydimethylsiloxane, polyethylene terephthalate, and polyorthoester. These polymer materials exhibit good biocompatibility and are therefore preferably used as the support portion of the electroporation assembly.

[0020] In some embodiments of this application, the liquid metal material includes at least one of gallium, gallium-indium alloy, and gallium-indium-tin alloy.

[0021] In some embodiments of this application, the second surface is loaded with a delivery substance.

[0022] In some embodiments of this application, the eye delivery device further includes an instillation assembly, which includes an instillation chamber for receiving the delivery substance, and the instillation assembly is configured to instill the delivery substance onto the corneal surface or inject it into the cornea.

[0023] Exogenous substances delivered to the eye include various types such as macromolecular drugs, plasmids, proteins, and nucleic acids (e.g., mRNA, siRNA). Considering the properties of the delivery substances themselves, relatively stable substances such as plasmids, proteins, and macromolecular drugs can be loaded onto a second surface in powder form through methods such as lyophilization, and then directly introduced through electroporation when the electroporation component of the ocular delivery device is placed on the cornea. For other delivery substances that may cause contamination when lyophilized or whose concentration decreases due to easy degradation, affecting the efficacy after perforation, delivery can be achieved by directly dripping them onto the corneal surface or injecting them directly into the cornea through an additional instillation component before electroporation.

[0024] A second aspect of this application provides a method for preparing the aforementioned eye delivery device, the method comprising the following steps:

[0025] Provide support;

[0026] Electrode patterns are formed by printing liquid metal ink, and the electrode patterns are directly printed or transferred to the support using an elastic material. After drying, an electroporation assembly is obtained.

[0027] The preparation method provided in this application solves the problem of patterning curved surfaces of liquid metal by printing electrode patterns and then using an elastic material as a flexible substrate to directly print or transfer the electrode patterns onto the curved surface of the second surface of the support.

[0028] In some embodiments of this application, a step of modifying the electrode pattern with an extracellular matrix after drying is also included. Modifying the electrode pattern with an extracellular matrix improves its cell and tissue compatibility while stabilizing the support and electrode pattern of the electroporation assembly.

[0029] In some embodiments of this application, the extracellular matrix includes at least one of collagen, fibronectin, and laminin. Modifying the second surface and the electrode pattern thereon using these protein materials effectively improves its biocompatibility and further avoids toxic or inflammatory reactions when the electrode pattern on the second surface and the electrode pattern thereon comes into contact with the eyeball.

[0030] In some embodiments of this application, the elastic material is silicone.

[0031] In some embodiments of this application, the printing method is at least one of screen printing, inkjet printing, 3D printing, etc.

[0032] In summary, most commercially available electroporation devices currently use rigid metal electrodes. These electrodes have significant mechanical differences from cells and tissues and cannot achieve conformal contact with the cornea, resulting in low efficiency of ocular electroporation. Furthermore, these electrodes require high voltage for electroporation, which can cause severe electrical damage. The ocular delivery device provided in this application utilizes the strong conductivity and malleability of liquid metal. By endowing a support portion similar to a contact lens with electroporation functionality, it introduces exogenous macromolecular drugs, genes, or proteins to regulate ocular tissues, thereby treating ophthalmic diseases. Additionally, the materials used in this application are soft and conductive, enabling conformal contact with the cornea and achieving efficient electroporation delivery of exogenous substances, thus achieving the goal of highly effective treatment of ophthalmic diseases.

[0033] Furthermore, conventional techniques typically pattern materials on a flat surface, which is significantly different from patterning on a curved surface. It is difficult to pattern liquid metal onto a curved surface, presenting a great technical challenge. However, the embodiments of this application solve the above problems by patterning liquid metal onto a curved surface using methods such as screen printing and transfer technology.

[0034] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0035] Figure 1This is a cross-sectional side view of the electroporation assembly of an eye delivery device in one embodiment of this application.

[0036] Figure 2 This is a top view of the electroporation assembly of an eye delivery device in one embodiment of this application.

[0037] Figure 3 These are photographs of the electroporation assembly of the eye delivery device in Embodiment 1 of this application, where a is a top view (first surface) and b is a bottom view (second surface).

[0038] Figure 4 This is a fluorescence photograph of the delivery result of doxorubicin by the ocular delivery device in Embodiment 2 of this application.

[0039] Figure 5 This is a fluorescence photograph of the siRNA delivery results by the eye delivery device in Example 2 of this application.

[0040] Figure 6 This is a fluorescence photograph of the mRNA delivery results of the eye delivery device in Embodiment 2 of this application.

[0041] Figure 7 This is a fluorescence photograph of the plasmid delivery result by the eye delivery device in Embodiment 2 of this application.

[0042] Figure 8 These are fluorescence and bright-field photographs of the plasmid delivered to the cornea (a) and conjunctiva (b) by the ocular delivery device in Embodiment 3 of this application.

[0043] Figure 9 These are the results of plasmid delivery efficiency of the eye delivery device with different electrode spacing in Embodiment 6 of this application. a is a fluorescence image of the large-spacing electrode and b is a fluorescence image of the small-spacing electrode.

[0044] Reference numerals: support portion 100, first surface 110, second surface 120, electrode pattern 200, first annular portion 210, straight portion 221, second annular portion 222. Detailed Implementation

[0045] The following will clearly and completely describe the concept and technical effects of this application in conjunction with embodiments, so as to fully understand the purpose, features and effects of this application. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are all within the scope of protection of this application.

[0046] The embodiments of this application are described in detail below. The described embodiments are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0047] In the description of this application, "several" means one or more, "multiple" means two or more, "greater than," "less than," and "exceeding" are understood to exclude the stated number, while "above," "below," and "within" are understood to include the stated number. The use of "first" and "second" in the description is merely for distinguishing technical features and should not be construed as indicating or implying relative importance, or implicitly indicating the number of indicated technical features, or implicitly indicating the order of the indicated technical features.

[0048] In the description of this application, the terms "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0049] refer to Figure 1 and Figure 2 This illustration shows an eye delivery device according to an embodiment of the present application. The eye delivery device includes an electroporation assembly, which includes a support portion 100 and an electrode pattern 200. The support portion 100 includes opposing first surfaces 110 and second surfaces 120, both of which are curved surfaces, with the first surface 110 being convex and the second surface 120 being concave. The electrode pattern 200 is located on the second surface 120 and contains a liquid metal material used as a raw material. In the eye delivery device of the embodiment of the present application, the curved support portion 100 is used as a base. This curved surface configuration allows it to make conformal contact with the contacting cornea during use, resulting in a closer fit compared to existing electrodes, thereby improving the efficiency of subsequent electroporation. Furthermore, due to the high conductivity of the liquid metal material, electroporation can be performed at a lower voltage, thereby avoiding potential electrical damage to the eye and enabling safe and efficient in-situ electroporation of the eye.

[0050] To ensure a closer conformal contact between the support and the cornea during use, the radius of curvature of the second surface of the support needs to be close to the radius of curvature of the human cornea. In some embodiments, the radius of curvature of the second surface is 5-12 mm, for example, 5.0 mm, 5.5 mm, 6.0 mm, 6.5 mm, 7.0 mm, 7.5 mm, 8.0 mm, 8.5 mm, 9.0 mm, 9.5 mm, 10.0 mm, 10.5 mm, 11.0 mm, 11.5 mm, or 12.0 mm. Preferably, the radius of curvature of the second surface is 6-10 mm, 7-9 mm, or 7-8 mm. The radius of curvature of a normal person's cornea is typically around 7.8 mm, but considering that the cornea changes in people with myopia or hyperopia, the radius of curvature of the second surface is limited to a slightly larger range so that the eye delivery device can achieve better conformal contact when facing different groups of people. Similarly, to avoid excessive thickness of the support portion due to an excessively large or small radius of curvature of the first surface, which could cause comfort issues during wear, the radius of curvature of the first surface is close to that of the second surface. In some specific embodiments, the radius of curvature of the first surface is 4-15 mm, preferably 5-12 mm, 6-10 mm, or 7-9 mm. It should be noted that the radii of curvature of the first and second surfaces mentioned above refer to the absolute values ​​of the radii of curvature. "Close" means that their absolute values ​​are close, and does not directly indicate whether the surface is convex or concave based on the sign of the radius of curvature. The radius of curvature can be the radius of curvature of a single curved surface, or it can be the radius of curvature of at least one of the arc surfaces in a continuous curved surface composed of multiple arc surfaces with different radii of curvature.

[0051] In some embodiments, the surfaces of the first surface 110 and the second surface 120 are each independently selected from any one of a sphere, an ellipsoid, or a continuous surface composed of multiple arc surfaces with different radii of curvature. It is understood that the sphere or ellipsoid is not limited to the first surface or the second surface being a complete sphere or ellipsoid; it can also be a surface formed by cutting a portion of a complete sphere or ellipsoid, or other approximate spheres or ellipsoids.

[0052] In some embodiments, the distance h between the first surface 110 and the second surface 120 is 0.01~1 mm, specifically 0.01 mm, 0.02 mm, 0.03 mm, 0.04 mm, 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.1 mm, 0.15 mm, 0.2 mm, 0.3 mm, 0.5 mm, or 1 mm. Preferably, the distance h is 0.01~0.1 mm, 0.01~0.08 mm, or 0.01~0.07 mm. The distance h may also refer to the center thickness of the first surface 110 and the second surface 120.

[0053] The electrode pattern 200 can be designed in any way, as long as it can form a certain electric field near the second surface 120 and change its permeability to complete perforation and delivery after the electric field is applied to the cell. For example, it can be an optional regular or irregular array or non-array pattern.

[0054] In some specific embodiments, the electrode pattern 200 includes a first electrode 210 and a second electrode 220. The first electrode 210 includes a first annular portion with a notch located at the outer edge of the second surface 120. The second electrode 220 includes a straight portion 221 extending from the notch toward the interior of the first electrode 210 and a second annular portion 222 connected to the straight portion 221, wherein the radius r2 of the second annular portion 222 is smaller than the radius r1 of the first annular portion. With this electrode pattern configuration, the electric field formed in the electroporation assembly is more uniform, and the degree of change in permeability of cells at different locations is more similar, thus enabling more uniform delivery of exogenous substances into the cells. It is understood that, in order to achieve differentiated delivery to cells at different locations, factors such as the electrode pattern configuration (e.g., adjacent spacing, pattern structure) and voltage at different locations can be modified to achieve a more precise delivery effect.

[0055] In some embodiments, the support portion is composed of a polymer material. Since this delivery device is primarily used in the eye, the polymer material must meet basic safety requirements, such as biocompatibility. In some specific embodiments, the polymer material includes, but is not limited to, at least one of polymethyl methacrylate, polycellulose acetate butyrate, polysilicate, poly-2-hydroxyethyl methacrylate, polydimethylsiloxane, polyethylene terephthalate, and polyorthoester. These polymer materials have good biocompatibility and are therefore preferred for use as the support portion of the electroporation assembly. Furthermore, to ensure the mechanical and biological properties of the support portion, further modified or altered polymer materials can be selected. Meanwhile, the liquid metal material used for the electrode pattern includes gallium, gallium-indium alloy, gallium-indium-tin alloy, etc.

[0056] In some specific embodiments, the second surface 120 is loaded with a delivery substance. In other embodiments, the ocular delivery device also provides an instillation assembly for containing the delivery substance, such as having an instillation chamber for containing the delivery substance, from which the delivery substance is delivered when electroporation is required, such as by instilling it onto the patient's corneal surface and then covering the electroporation assembly so that it is positioned between the second surface and the cornea, or by directly injecting it into the patient's cornea. Then, the delivery substance is delivered into the cell by electroporation through the application of voltage by the electroporation assembly. The reason for providing multiple delivery methods in this ocular delivery device is that there are many types of ocular delivery substances, including not only conventional plasmids, proteins, or macromolecular drugs, but also small nucleic acid drugs such as siRNA. However, these drugs are unstable and easily degraded. If they are directly loaded onto the electrode pattern by lyophilization, not only is the preparation process of the lyophilized powder time-consuming, but it may also cause enzyme contamination, thereby causing siRNA degradation and affecting the delivery effect. However, using the ocular delivery device provided in the embodiments of this application, an appropriate method can be selected according to the physicochemical properties of different delivery substances, thereby maximizing the activity of the delivery substance. The specific components of the drip assembly can be, for example, a syringe or similar structure.

[0057] This application also relates to a method for preparing the above-mentioned eye delivery device, the method comprising the following steps:

[0058] Provide support;

[0059] Electrode patterns are formed by printing liquid metal ink, and then the electrode patterns are transferred to the support using silicone. After drying, an electroporation assembly is obtained.

[0060] In some embodiments, the support portion can be made in-house or purchased directly from finished materials. The support portion can be prepared in any manner known in the art, such as by molding. Specifically, the raw materials for preparing the support portion can be added to the first half mold, and then the second half mold is used to combine with the first half mold to close the mold, causing the raw materials in the closed mold cavity to polymerize. After the polymerization is complete, the support portion is peeled out.

[0061] In some embodiments, the liquid metallic ink is formed by mixing a liquid metallic material with a solvent. For example, the liquid metallic material is placed in a solvent and ultrasonically mixed to obtain the liquid metallic ink. The solvent can be any volatile liquid solvent, such as a volatile liquid organic solvent, including but not limited to at least one of n-decyl alcohol, anhydrous ethanol, terpineol, N,N-dimethylformamide, and acetone. The ultrasonic mixing time can be 1–10 min, specifically 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, etc.

[0062] In some embodiments, the printing method is at least one of screen printing, inkjet printing, 3D printing, etc. An electrode pattern is first formed using these methods, and then directly printed or transferred onto the second surface of the support using an elastic material. The elastic material can be any material that can be directly or indirectly modified to conform to the curved surface of the support, thereby printing or transferring the electrode pattern onto the curved surface, specifically including but not limited to silicone materials.

[0063] The present application will be described below with reference to specific embodiments.

[0064] Example 1

[0065] This embodiment provides an eye delivery device, which includes an electroporation assembly. The fabrication process of the electroporation assembly is as follows:

[0066] (1) Design of conductive patterns for ocular electroporation

[0067] refer to Figure 2 Using AutoCAD, arc-shaped electrode patterns suitable for different corneal sizes were designed and constructed. This electrode pattern was then fabricated into a 1:1 screen printing mask, wherein the first electrode includes a first annular portion with a notch, and the width of the first electrode and the second electrode are 1 mm, with a spacing of 2 mm, for subsequent transfer of liquid metallic ink.

[0068] (2) Preparation of the support

[0069] refer to Figure 1 and Figure 2 The structure is selected by using a punch and a die as half molds. A flexible polymer solution (polydimethylsiloxane is used in this embodiment) is added to the die half mold and then combined with the punch half mold to close the mold. After the polymer solution is cured, it is peeled off from the mold to obtain the support part.

[0070] (3) Printing of electrode patterns

[0071] Take 5 g of gallium-indium alloy and mix it with 1 mL of n-decanol. After sonication for 4 min, liquid metal particle ink is prepared. The prepared liquid metal particle ink is used to draw electrode patterns by screen printing. Then, the electrode patterns are directly printed or transferred onto the second surface of the support prepared in step 2 using silicone. After the transfer is completed, the sample is placed at room temperature to dry for 6-12 h or at 80 ℃ for 10-30 min.

[0072] After all the solvent in the liquid metal particles has evaporated, a pattern composed of liquid metal particles is formed on the second surface of the support.

[0073] (4) Fibronectin modification

[0074] Fibronectin was dissolved in Tris buffer to obtain a fibronectin solution (100 μg / mL, pH 7.4). The electroporation assembly prepared in step 3 was then immersed in the solution at 37°C for 6 hours to complete the modification, thereby stabilizing the structure of the electroporation assembly and improving its cell and tissue compatibility.

[0075] refer to Figure 3 These are photographs of the eye delivery device prepared in this embodiment. The left image is a top view (i.e., a view of the first surface), and the right image is a bottom view (i.e., a view of the second surface). Reference Figure 3 and combined Figure 1 and Figure 2 The ocular delivery device includes an electroporation assembly, which comprises a support portion and an electrode pattern. The support portion has a first surface and a second surface that are oppositely disposed and curved. The first surface is convex, and the second surface is concave. The absolute value of the radii of curvature of the first and second surfaces is approximately 7.5 mm. The electrode pattern is located on the second surface and includes a first electrode and a second electrode located on the second surface. The first electrode is located at the outer edge of the second surface and includes a first annular portion with a notch. The second electrode includes a straight portion extending inward from the notch and a second annular portion connected to the straight portion. The radius of the second annular portion is smaller than the radius of the first annular portion.

[0076] Example 2

[0077] Electroporation delivery of cells

[0078] 2×10 7 Cells were dispersed in 100 μL of electroporation buffer, and doxorubicin, Cy5-labeled siRNA, green fluorescent protein mRNA, and fluorescently labeled plasmid were added, respectively. After mixing, the mixture was added to the groove formed by placing the second surface upwards in the ocular delivery device prepared in Example 1. The first and second electrodes were respectively connected to an electroporator via extended electrode wires for electroporation experiments. The results were then observed using a fluorescence microscope, and the results are shown below. Figures 4-7As shown, obvious red or green fluorescence appears in all cases, indicating that the eye delivery device provided in Example 1 can deliver macromolecular drugs, proteins, plasmids, nucleic acids, etc.

[0079] Example 3

[0080] Electroporation delivery of corneal / conjunctival experiments

[0081] Ex vivo corneas and conjunctiva were obtained by dissecting New Zealand rabbits. The corneas and conjunctiva were co-incubated with fluorescently labeled plasmids, and then placed in the ocular delivery device prepared in Example 1 according to the method provided in Example 2 for electroporation experiments. Afterwards, they were incubated in culture medium for 48 h and observed using a fluorescence microscope. Results are as follows: Figure 8 As shown, a is a corneal photograph under a fluorescence microscope and a bright field microscope, and b is a conjunctival photograph under a fluorescence microscope and a bright field microscope. It can be seen from the figures that there is obvious green fluorescence in both the cornea and conjunctiva, indicating that the ocular delivery device provided in Example 1 can deliver the substance to be delivered to the cornea or conjunctiva.

[0082] Example 4

[0083] This embodiment provides an eye delivery device, which differs from Embodiment 1 in that the surface of the electrode pattern is loaded with plasmids to be delivered, and its preparation process is as follows:

[0084] The electroporation assembly prepared in Example 1 was sterilized by irradiation, and then 2 mL of 60 μg / mL plasmid solution was added to the surface of the electrode pattern. The assembly was then frozen at -20°C and subsequently freeze-dried in a freeze dryer to obtain an electroporation assembly loaded with plasmid. The first and second electrodes of the electroporation assembly were used to connect to an electroporator.

[0085] When using this ocular delivery device to deliver plasmids, the electroporation component can be directly attached to the cornea with its second surface covering the subject's eye, and then the electroporation instrument can be turned on to perform electroporation, thereby delivering the plasmid into the subject's cornea.

[0086] Example 5

[0087] This embodiment provides an eye delivery device, which differs from Embodiment 1 in that it further includes an infusion assembly having an infusion chamber for containing the delivery substance.

[0088] When delivering the substance, the device first drips or injects the solution in the instillation chamber onto the corneal surface or into the cornea / conjunctiva or other ocular structures. Then, the electroporation assembly is attached to the cornea with its second surface covering the subject's eye. Subsequently, the electroporator is turned on to perform electroporation, thereby delivering the substance to be delivered to the cornea or other ocular structures.

[0089] The advantage of this ocular delivery device lies in its ability to address the issue of unstable and easily degraded substances like plasmids and proteins, such as siRNA. If the lyophilized material is directly loaded onto the electrode pattern using the method described in Example 4, the preparation process is not only time-consuming but also prone to enzyme contamination, leading to siRNA degradation and a significantly lower loading amount than expected, thus affecting delivery and treatment efficacy. Therefore, the material to be delivered can be specifically instilled directly into the eye or injected into the cornea or other delivery sites, followed by the electroporation assembly being worn in the eye for ocular electroporation to complete the delivery.

[0090] Example 6

[0091] Comparative experiment on electroporation effects with different electrode pattern spacing

[0092] An ocular delivery device was prepared according to the method described in Example 1, with r1-r2 values ​​(i.e., electrode spacing) of 2 mm and 2.5 mm, respectively. Plasmid delivery was performed according to the method described in Example 3, and the results are as follows: Figure 9 As shown, the left side displays fluorescence images of the ocular delivery device when the electrode spacing is 2.5 mm, and the right side displays fluorescence images of the ocular delivery device when the electrode spacing is 2 mm. It can be seen from the images that the fluorescence quantity on the right side is significantly higher than that on the left, indicating that the delivery efficiency on the right side is significantly higher than that on the left. Therefore, the efficiency of electroporation delivery can be controlled by adjusting the electrode spacing; within a certain range, the smaller the electrode spacing, the higher the electroporation delivery efficiency.

[0093] The present application has been described in detail above with reference to the embodiments. However, the present application is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present application. Furthermore, unless otherwise specified, the embodiments and features in the embodiments of the present application can be combined with each other.

Claims

1. An eye delivery device, characterized in that, Includes an electroporation assembly, the electroporation assembly comprising: The support portion includes a first surface and a second surface that are oppositely disposed and are curved, wherein the first surface is a convex surface and the second surface is a concave surface; An electrode pattern located on the second surface, the electrode pattern comprising a liquid metal material; The electrode pattern includes: A first electrode, the first electrode including a first annular portion having a notch, the first annular portion being located at the outer edge of the second surface; The second electrode includes a straight portion extending inward from the notch and a second annular portion connected to the straight portion, the radius of the second annular portion being smaller than the radius of the first annular portion.

2. The eye delivery device according to claim 1, characterized in that, The radius of curvature of the second surface is 5~12mm.

3. The eye delivery device according to claim 1, characterized in that, The support portion comprises a polymer material.

4. The eye delivery device according to claim 3, characterized in that, The polymer material is selected from at least one of polymethyl methacrylate, polycellulose acetate butyrate, polysilicate, poly(2-hydroxyethyl methacrylate), polydimethylsiloxane, polyethylene terephthalate, and polyorthoester.

5. The eye delivery device according to claim 1, characterized in that, The liquid metal material includes at least one of gallium, gallium-indium alloy, and gallium-indium-tin alloy.

6. The eye delivery device according to claim 1, characterized in that, The eye delivery device further includes an instillation assembly having an instillation chamber for receiving the delivery substance, the instillation assembly being configured to instill the delivery substance onto the corneal surface or inject it into the cornea.

7. The eye delivery device according to claim 1, characterized in that, The second surface is loaded with a delivery substance.

8. A method for preparing the eye delivery device according to any one of claims 1 to 7, characterized in that, Includes the following steps: Provide support; Electrode patterns are formed by printing liquid metal ink, and the electrode patterns are directly printed or transferred onto the support using an elastic material. After drying, the electroporation assembly is obtained. The elastic material is a material that can be directly or indirectly changed into a shape that conforms to the curved surface of the support, thereby printing or transferring the electrode patterns onto the curved surface.

9. The preparation method according to claim 8, characterized in that, It also includes a step of modifying the electrode pattern with an extracellular matrix after drying.

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