Abstract
Several critical ocular diseases that can lead to blindness are due to retinal disorders. Subretinal drug delivery has been developed recently for the treatment of retinal disorders such as hemorrhage because of the specific ocular structure, namely, the blood retinal barrier (BRB). In the present study, we developed an Arched Micro-injector (ARCMI) for subretinal drug delivery with minimal retinal tissue damage. ARCMIs were fabricated using three major techniques: reverse drawing lithography, controlled air flow, and electroplating. In order to achieve minimal retinal tissue damage, ARCMIs were fabricated with specific features such as a 0.15 mm−1 curvature, 45° tip bevel, 5 mm length, inner diameter of 40 µm, and an outer diameter of 100 µm. These specific features were optimized via in-vitro experiments in artificial ocular hemispherical structures and subretinal injection of indocyanine green in porcine eye ex-vivo. We confirmed that the ARCMI was capable of delivering ocular drugs by subretinal injection without unusual subretinal tissue damage, including hemorrhage.
Highlights
The linear form of this plastic cannula, is not sufficient to reduce the risk of unintended accidental punctures, which can cause retinal and choroidal hemorrhages during needle insertion in the subretinal region, which is located at the posterior region in the 70% spherical section of the eye and has a thickness of only several hundred micrometers
Metallic shooter instruments have been developed for subretinal cell delivery, including a 20 gauge flattened 7 mm long metal tube bent at 25 degrees in consideration of the ocular structure, the size of this flattened tip was not able to penetrate the retina without causing retinal hemorrhage.[11]
To achieve innocuous subretinal injection, we developed the Arched Micro-injector (ARCMI), which was optimized for specific characteristics including a length of 5 mm, curvature of 0.15 mm21, an outer diameter of approximately 100 microns, and a 45u beveled tip for minimal tissue damage during subretinal injection
Summary
Irreversible visual loss can be caused by disruption of optic nerves in the retina resulting from retinal disorders such as retinal detachment, retinal vessel occlusion, and macular degeneration.[1,2,3] Due to the complex ocular structure, especially the blood retinal barrier (BRB), the subretinal space has become a target of interest for retinal treatment and has been used as an insertion site for drugs or stem cells in many medical procedures including transscleral injection,[4,5] subretinal implant,[6,7] and subretinal injection with vitrectomy.[8,9] All of these procedures require surgical intervention that can cause damage to the ocular tissue, and direct injection with a hypodermic needle having a small outer diameter is preferred over trans-scleral or subretinal injections.[4,5,6,7,8,9].Flexible micro-cannula (39 gauge; 39 G) with an outer diameter of 120 mm have been introduced as subretinal injectors to reduce retinal tissue damage.[10]. The flexibility of such micro-cannula devices is an inconvenience for injection into the soft subretinal space.[10] metallic shooter instruments have been developed for subretinal cell delivery, including a 20 gauge flattened 7 mm long metal tube bent at 25 degrees in consideration of the ocular structure, the size of this flattened tip was not able to penetrate the retina without causing retinal hemorrhage.[11] Recently, the tower microneedle (TM), a metallic hollow microneedle with a beveled tip, was developed for innocuous intravitreal drug delivery, and is one such application of hollow microneedles in the ocular research field.[12,13] Because TMs are designed to deliver drug into the intravitreal space through the sclera, they have enough strength to penetrate the outer ocular barrier of the sclera and even the conjunctiva. Various subretinal injectors have been developed to minimize tissue damage, there is as of yet no single, ideal subretinal injector that satisfies the necessary criteria such as small tip diameter for minimal tissue damage, curved shape for delivering the drug into the ocular curve, and sufficient stiffness to minimize inconvenience during subretinal injection
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