The researchers built their study around a well-characterized rabbit model of aqueous-deficient dry eye. They injected concanavalin A, an immune-stimulating plant protein, directly into the lacrimal glands of New Zealand white rabbits under ultrasound guidance, damaging the tear-producing glands and triggering the hallmark features of the disease. Within five days, tear break-up time collapsed by roughly 81 percent, Schirmer tear test values fell by about 51 percent, and tear osmolarity rose significantly, confirming that the animals had developed a genuine dry eye phenotype. Notably, the rabbits’ corneas also became markedly less sensitive to touch, requiring much stronger stimulation to provoke a protective blink.

Measuring that sensitivity required a device with a long pedigree. The team used a Cochet-Bonnet esthesiometer, an instrument descended from a design first described in 1894, which touches the central cornea with a fine nylon filament. By shortening the filament in five-millimeter steps, the examiner increases the force delivered until the animal blinks and retracts its eye; the filament length at which this occurs provides an index of corneal touch threshold. Dry eye rabbits responded only when the filament was shortened to about 3.8 centimeters, compared with 5.7 centimeters in healthy controls, mirroring the reduced corneal sensitivity documented in human patients with the disease.

Against this baseline, the effect of phosphosulindac was striking. A single 25-microliter eye drop of the compound, formulated at 0.2 percent in a Carbopol-based hydrogel, restored corneal sensitivity to normal levels within five minutes, the first time point tested. The normalization persisted for roughly 26 to 27 hours before gradually dissipating, an unusually stable response that raises the possibility of once-daily dosing. Intriguingly, a higher concentration of 0.6 percent produced a shorter effect lasting only about two and a half hours, hinting at a dose-response relationship that is far from linear.

The choice of formulation proved critical. Cyclodextrin-based solutions, in which the hydrophobic phosphosulindac molecule is shuttled inside the cup-shaped interior of cyclic glucose oligomers, and an oil-in-water emulsion also restored sensitivity in dry eyes, but their effects lasted under an hour. Polymer nanoparticles, by contrast, were ineffective. The team also uncovered a sharp pharmacological threshold: in solution, 0.05 and 0.1 percent phosphosulindac did nothing, while 0.2 percent was fully active, and an eightfold higher dose of 1.6 percent added no further benefit. In cyclodextrin formulations, activity peaked at pH 6.2, consistent with pH-dependent shifts in the stability of the drug-cyclodextrin inclusion complex.

What distinguishes phosphosulindac is the company it failed to keep. None of six structurally related compounds, including sulindac itself, aspirin derivatives and an ibuprofen derivative, reproduced the effect. Neither did cyclosporine and lifitegrast, the two pillar immunomodulatory drugs approved for dry eye, nor a commercial artificial tear. Ketorolac and bromfenac, two non-steroidal anti-inflammatory eye drops, actually further depressed corneal sensitivity in the dry eye animals, as did the anesthetics proparacaine and benoxinate, which abolished responses almost immediately. Phosphosulindac, uniquely among everything tested, pushed sensitivity in the opposite direction.

In healthy eyes, the story inverted. Applied to normal rabbit corneas, phosphosulindac suppressed sensitivity, producing a peak reduction of nearly 56 percent at 50 minutes that resolved by about 140 minutes, a slower and longer-lasting effect than lidocaine, which numbed more powerfully but faded within 30 minutes. The authors speculate that in a normal cornea, densely populated with sensory endings, the drug may depolarize or overwhelm mechanosensory and polymodal nociceptors beyond the threshold needed to propagate a blink reflex, whereas in a dry eye, where nerve endings have been lost, the same action sensitizes the surviving receptors enough to restore measurable responses.

Several features of the data argue that the effect is direct and non-anesthetic. It appeared within minutes, was fully reversible within hours, and outlasted the measurable residence of the drug in the cornea reported in earlier pharmacokinetic work, pointing to downstream changes in nerve function rather than simple tissue numbing. Crucially, phosphosulindac is not itself a classical NSAID and does not suppress prostaglandin production in the cornea; unlike ketorolac and bromfenac, which have been linked to the devastating complication of corneal melt, it inhibits matrix metalloproteinases instead. The team also confirmed the findings in pigmented Dutch-belted rabbits, ruling out melanin sequestration as a confounder.

The therapeutic implications are twofold. For dry eye disease, where nearly all symptoms are mediated through the nerves of the ocular surface, a drug that both treats the underlying inflammation, as the team’s earlier rabbit work demonstrated by normalizing tear break-up time, osmolarity and lactoferrin, and rapidly restores sensory function could address both signs and symptoms in a way current medications, whose benefits often take weeks to appear, do not. For normal eyes, the numbing effect suggests a potential role in managing acute ocular pain, for example after cataract surgery, though the authors stress that any anesthetic-like use would demand careful safety evaluation.

Important caveats remain. The work was conducted in rabbits with an induced, aqueous-deficient form of the disease, whereas most human dry eye is evaporative in origin, and whether the striking dichotomy between normal and dry corneas translates to patients is unknown. Confirming the proposed mechanism, a direct action on mechanosensory and polymodal corneal nociceptors, will require electrophysiological, immunohistochemical and molecular studies. Still, with dry eye affecting a substantial share of the adult population and its neuropathic pain increasingly recognized as under-treated, a small molecule that can flip corneal sensitivity back on within minutes, safely and reversibly, is a result that both neuroscientists and ophthalmologists will be watching closely.

Subject of Research: Restoration of corneal sensitivity in dry eye disease by topical phosphosulindac in a rabbit model

Article Title: Phosphosulindac (OXT-328) restores the suppressed corneal sensitivity in rabbits with dry eye disease: therapeutic implications

Article References: Huang, W., Wen, Z., Tourmouzis, K., Huang, L., Goldstein, S. M., Natke, E., Honkanen, R., & Rigas, B. (2026). Phosphosulindac (OXT-328) restores the suppressed corneal sensitivity in rabbits with dry eye disease: therapeutic implications. Frontiers in Drug Delivery, 6, Article 1778440. https://doi.org/10.3389/fddev.2026.1778440

Image Credits: AI Generated

DOI: 10.3389/fddev.2026.1778440

Keywords: dry eye disease, phosphosulindac, OXT-328, corneal sensitivity, corneal nerves, rabbit model, ophthalmic drug delivery, cyclodextrin, hydrogel, NSAIDs, esthesiometry, ocular pain