Delivering a drug to the retina is a technically demanding problem. The eye is a small, enclosed space with multiple tissue layers, each with its own properties and barriers. Getting a drug or therapy to the right layer, in sufficient quantity, without damaging the tissue in the process, requires both the right tools and a detailed understanding of ocular anatomy. Two routes that are increasingly important in preclinical research are the suprachoroidal space and the subretinal space. Each has distinct advantages, distinct technical demands, and a growing body of practical knowledge around how to use them effectively in animal models.
Subretinal Injections: A Well-Characterized Route for Precision Delivery
The technical and biological consequences of subretinal injection in nonhuman primates were systematically characterized in a study that established what investigators can reasonably expect from the procedure itself, independent of any test compound, and that continues to inform study design today (Nork et al., Archives of Ophthalmology, 2012). The subretinal space is a potential space that lies between the photoreceptors and the retinal pigment epithelium (RPE), the cell layer just beneath the photoreceptors that keeps them healthy. Many gene therapy approaches targeting inherited retinal diseases aim to reach this space directly, placing therapeutic material as close as possible to the cells it needs to act on. In nonhuman primates, achieving this reliably requires careful attention to technique at every step.
Visualization of the ocular fundus (the interior surface of the back of the eye) during injection is essential. Specialized contact lenses placed on the cornea provide a clear view of the retina under an operating microscope, allowing precise needle placement. The approach does not require a full vitrectomy (surgical removal of the eye’s gel-like interior). Instead, access is gained through small transscleral ports, (meaning incisions through the white outer wall of the eye), which reduces procedural complexity. A fiber optic light source introduced through a separate port illuminates the retina from within, giving the surgeon a direct view of the injection site.
Injector selection has a meaningful effect on ease of use and the quality of the result, and the options available have evolved considerably since the foundational work in this area. Based on accumulated laboratory experience, the DORC injector, while usable, carries approximately 200 microliters of dead space (fluid trapped in the device before it reaches the tissue) and requires a surgical assistant. The MedOne system, powered via the silicone oil injection port of the Constellation surgical platform (a standard ophthalmic surgical system), addresses both limitations: dead space is reduced to 10 microliters or less, and the surgeon maintains complete independent control of the injection speed and volume. This matters not only for procedural efficiency but for reproducibility across animals and studies.
After a successful subretinal injection, a bleb (a small fluid-filled pocket) forms where the injected material separates the photoreceptors from the RPE. OCT imaging confirms that the retina reattaches within two days. By 90 days post-injection, retinal function as measured by electroretinography (which measures the retina’s electrical response to light) had recovered to nearly baseline levels, though some residual changes at the photoreceptor outer segments (the specialized tips of the light-sensing cells) remained detectable on electron microscopy at three months (Nork et al., Archives of Ophthalmology, 2012). This recovery pattern is important for study design: it establishes that functional endpoints can be used to assess the pharmacological effect of a test compound independently of the procedural effect of the injection itself, provided sufficient recovery time is allowed.
The Suprachoroidal Route: A New Path to the Back of the Eye
The suprachoroidal space is a potential space that sits between the choroid (the vascular layer behind the retina) and the sclera (the white outer wall of the eye). Until recently it was largely inaccessible as a delivery route. That has changed with the development of specialized injectors capable of depositing material into this narrow space without damaging the retina. Several competing delivery systems are now available commercially, although most require contractual arrangements with manufacturers. An important practical finding is that injectors for suprachoroidal delivery can also be fabricated in the laboratory, making the route accessible to research groups that lack commercial supply agreements (Nork et al., Journal of Ocular Pharmacology and Therapeutics, 2025).
Two questions matter most when evaluating any new delivery route: where does the injected material go, and what factors control its spread? Work in rabbits has shown that distributing two injections 180 degrees apart, rather than delivering a single injection at one site, improves the spread of material through the suprachoroidal space (Nork et al., Journal of Ocular Pharmacology and Therapeutics, 2025). More surprisingly, distribution is not appreciably affected by the pressure inside the eye (intraocular pressure) at the time of injection. This is a practically important finding: it means that suprachoroidal delivery does not need to be timed around intraocular pressure fluctuations, simplifying study design.
The suprachoroidal route is particularly attractive for reaching the outer retina and choroid without the risks associated with entering through the vitreous and perforating the retina. As gene therapies and slow-release drug formulations for retinal disease continue to advance, understanding how to control distribution in this space will become increasingly important for translating preclinical results to clinical use.
Choosing the Right Route
Suprachoroidal and subretinal delivery are not interchangeable. The choice between them depends on what tissue needs to be targeted, what the test article is, and what the study is designed to measure. Suprachoroidal delivery reaches the choroid and outer retina broadly, making it well suited for drugs targeting the blood vessels of the choroid or the RPE over a wide area. Subretinal delivery is more spatially precise and places material directly adjacent to the photoreceptors, making it the preferred route for gene therapies targeting photoreceptor or RPE disorders.
Both routes share a common requirement: the technical execution must be consistent enough that variability in delivery does not obscure the biological signal being measured. The practical lessons accumulated across studies in rabbits and nonhuman primates, from injector selection to injection placement and pattern to post-procedure monitoring, form an increasingly solid foundation for designing reliable preclinical delivery studies.
References
Nork TM, Katz AW, Rasmussen CA, et al. Custom-made injector for suprachoroidal ocular delivery: effect of intraocular pressure, volume, and location on the distribution of aqueous solutions in rabbits. J Ocul Pharmacol Ther. 2025;41(9):544-553. doi: 10.1177/10807683251366799.
Nork TM, Murphy CJ, Kim CB, et al. Functional and anatomic consequences of subretinal dosing in the cynomolgus macaque. Arch Ophthalmol. 2012;130(1):65-75. doi: 10.1001/archophthalmol.2011.295.