Preclinical ocular research requires non-invasive, repeatable imaging that can detect meaningful changes in the living eye. Two imaging tools, color fundus photography (FP) and optical coherence tomography (OCT), have become central to that effort, providing complementary views of retinal structure that together cover what neither can accomplish alone. Their value is best realized in the context of a well-validated disease model: The nonhuman primate (NHP) laser model of choroidal neovascularization (CNV), which uses laser-induced retinal lesions to reproduce the abnormal subretinal vessel growth seen in wet age-related macular degeneration (AMD). Together, FP and OCT serve as two of the primary tools for establishing, monitoring, and quantifying the lesions this model produces, from baseline through intervention to outcome.
Color Fundus Imaging: The Broad View
FP uses a camera to photograph the retina by projecting light into the eye and capturing the reflected image. It is the most direct way to see what a clinician would see with an ophthalmoscope, with the added advantages of permanent digital recording and the ability to cover a wide area of the retina in a single image. That last point matters more than it might seem; many of the structural changes relevant to toxicology studies, including vascular alterations, retinal swelling, and optic nerve abnormalities, are best appreciated in broad context, not at the high magnification that specialized imaging systems, such as OCT or adaptive optics, provide.
FP can capture true color that faithfully matches what the ophthalmologist sees when examining the retina. It supports stereoscopic imaging, which uses two slightly offset images to add depth information, which is useful for assessing swelling of the optic nerve or retina. It can also reach the outer edges of the retina, a region that other imaging tools do not cover well. Rapid image acquisition means that a complete photographic record of the back of the eye can be obtained without prolonged anesthesia in animal subjects, and the images provide a permanent, reviewable record that is not available from real-time ophthalmoscopy alone (Nork et al., Ocular Toxicity in Laboratory Animals, 2012).
One point worth emphasizing is that FP provides information that neither OCT nor scanning laser ophthalmoscopy (a related technique that uses a laser to scan the retina) can supply. These technologies are complementary rather than interchangeable. A complete imaging strategy in a preclinical ocular study uses them together, with each assigned to the questions it is best equipped to answer.
Optical Coherence Tomography: Histology Without the Tissue
OCT uses reflected light to generate cross-sectional images of the retina with a resolution approaching what can be seen on tissue sections examined under a microscope, but in the living animal, without removing tissue. This makes it one of the most powerful tools available in preclinical ocular research, both for following individual animals over time and for reducing the number of animals required in a study.
OCT can detect and localize structural changes with considerable sensitivity. Thinning of the retina consistent with cell loss, thickening consistent with swelling or fluid buildup, and disruption of individual retinal layers, including the photoreceptors (the light-sensing cells) and the ganglion cell layer (the cells that transmit visual signals from the eye to the brain), can all be identified and measured quantitatively (Nork et al., Archives of Ophthalmology, 2012; Nork et al., Documenta Ophthalmologica, 2023; Lavery et al., Current Eye Research, 2025). Software that automatically measures the thickness of individual retinal layers can assign those measurements to specific regions, turning qualitative observations into measurable data points that can be tracked over time.
The sensitivity of OCT is high enough that it can sometimes detect abnormal changes that are otherwise visible only on electron microscopy. In one study, OCT identified reduced reflectivity at the junction between photoreceptor inner and outer segments at three months following subretinal injection, a finding that corresponded directly to abnormal outer segment disk spacing seen on electron microscopy in the same tissue (Nork et al., Archives of Ophthalmology, 2012). That level of sensitivity, achieved non-invasively in a living animal, is what makes OCT so valuable as a tool for tracking animals over time. Rather than sacrificing animals at multiple timepoints to assess disease progression, OCT allows the same animals to be imaged repeatedly, generating a richer dataset with fewer subjects.
OCT is particularly well suited to studies examining how drugs or treatments affect retinal tissue, including gene therapy, where detecting subtle structural changes early and tracking their course over time is essential for understanding the relationship between a treatment and its effect (Ye et al., Human Gene Therapy Clinical Development, 2016; Bantseev et al., Journal of Ocular Pharmacology and Therapeutics, 2019).
The NHP Laser Model of Choroidal Neovascularization: A Translational Platform for AMD Research
While FP and OCT are two of the primary imaging tools in preclinical retinal research, their utility depends on having a disease model that generates measurable, reproducible pathology. The NHP laser model of CNV serves that role: it uses a focused laser to induce retinal lesions that closely replicate the abnormal subretinal vessel growth characteristic of wet AMD, providing the biological target tissue that FP in particular, through the mechanism of fluorescein angiography (FA), is used to monitor. It has a stronger record of predicting human clinical outcomes than most other preclinical retinal disease models.
Choroidal neovascularization is the hallmark of wet AMD, in which abnormal blood vessels grow from the choroid into the retina, leaking fluid and causing progressive vision loss. The NHP laser model induces CNV by applying a focused laser to specific retinal locations, creating localized damage that triggers the same abnormal vessel growth seen in human disease. The model is rapid, producing measurable CNV (as determined by vascular leakage on FA) within days to weeks, which makes it practical from a study design perspective as does the fact that the fundus images obtained can be read quickly by an independent observer.
It is also reproducible, and critically, it is a preclinical model of wet AMD with a well-documented record of translating to human clinical outcomes (Nork et al., Archives of Ophthalmology, 2011; Oliner et al., Investigative Ophthalmology and Visual Science, 2012; Adamson et al., Journal of Controlled Release, 2016).
The clinical impact of that predictive reliability is substantial. Anti-VEGF therapies (treatments that block a protein driving abnormal vessel growth) developed and validated in part using this model are now used to treat wet AMD in patients worldwide. Worldwide, over 20 million patients annually receive anti-VEGF therapy for wet AMD, with a substantial proportion experiencing meaningful vision preservation. That scale of benefit reflects not just the prevalence of AMD as a disease but the degree to which reliable preclinical modeling can accelerate the path from laboratory to clinic. Aflibercept (Eylea) is a direct example of this translational pathway: our group’s preclinical work using the NHP laser CNV model showed that a single intravitreous injection reduced choroidal neovascularization leakage, contributing to the evidence base that supported the drug’s regulatory approval and its current use as a standard-of-care anti-VEGF therapy for wet AMD (Nork et al., Archives of Ophthalmology, 2011).
For researchers working on new treatments for retinal vascular disease, the NHP CNV model remains the benchmark. The combination of a well-characterized disease lesion, established imaging endpoints using FP and FA, and a demonstrated record of predicting clinical outcomes makes it a uniquely credible platform for early-stage efficacy testing and dose-finding studies. In this model, OCT may also add information related to toxicity and fibrosis formation but is not necessary for determining pharmaceutical efficacy.
A Layered Approach
The case for pairing FP and OCT within the NHP CNV model rests on how the pieces fit together. FP provides the broad structural overview needed to locate and characterize laser-induced lesions across the retinal surface. OCT delivers layer-by-layer, quantitative detail that may be useful for tracking how those lesions evolve over time and how they respond to treatment. The NHP CNV model, in turn, provides the biologically meaningful context: a well-validated platform that reproduces the pathology of wet AMD and has been shown to predict clinical outcomes. Applied together, FP and OCT within this disease model may yield a preclinical framework more informative than any single approach, and more likely to generate findings that translate to the clinic.
References
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