# Ultrasound-enhanced corneal drug delivery

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $396,250

## Abstract

Project Summary/Abstract
Medical treatment of corneal disease depends upon effective penetration of topical agents into the cornea. In
many instances the corneal epithelium serves as a barrier to diffusion, while in cases with epithelial defects
drug penetration through the stroma can be unreliable or inadequate. This study proposes to evaluate
ultrasound technology to enhance the permeability of the cornea and promote corneal uptake of selected
topical medications – riboflavin, vancomycin, and voriconazole. Riboflavin is used in corneal cross-linking, a
treatment for diseases of corneal weakening that stiffens the tissue through the interaction of riboflavin with
ultraviolet energy. Since the epithelium is generally removed to achieve adequate riboflavin penetration in the
cornea, subjecting patients to pain and the risk of infection, there is a need for an innovation that can increase
stromal riboflavin uptake while avoiding epithelial removal. Since riboflavin is autofluorescent, it can be
quantified in the cornea using confocal microscopy. Vancomycin-BODIPY is a labeled fluorescent version of
the highly clinically relevant antibiotic and can also be detected in the cornea. It is a larger molecule and will
therefore provide additional information in optimizing ultrasound parameters for generalizability to other drugs.
A distinct but pressing clinical need relates to the treatment of fungal corneal ulcers, which frequently require
excision of infected tissue, due in part to poor delivery of antifungal agents, such as voriconazole, into the deep
stroma. We have shown a significant increase in penetration of riboflavin into the cornea following ultrasound
exposure without epithelial debridement, and in preliminary experiments we observed an impressive
penetration of vancomycin-BODIPY into the stroma without epithelium, as well as an improved riboflavin
penetration at lower ultrasound settings by optimizing the viscosity of the solution formulation and generating
microbubbles. The goal of this study therefore is to identify clinically useful ultrasound treatment regimes for
riboflavin, vancomycin, and voriconazole delivery to improve patient care in a range of corneal conditions. In
Aim 1, we will optimize ultrasound treatment parameters including frequency, intensity, duty cycle, and
treatment time using an in vitro model of riboflavin and vancomycin-BODIPY application to the rabbit cornea,
measuring drug permeation with confocal microscopy. In Aim 2, we will quantify the corneal delivery in vivo
using the most effective settings identified in Aim 1. In Aim 3, we will test the ability of ultrasound to improve
the delivery of voriconazole to the corneal stroma in a live rabbit model of Fusarium keratitis by quantifying the
residual organisms in the cornea after treatment. In Aim 4 the safety of a clinically effective treatment regimen
will be evaluated through clinical and histologic examination of the cornea at several time points with particular...

## Key facts

- **NIH application ID:** 9881306
- **Project number:** 5R01EY024004-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jay Michael Stewart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2017-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881306

## Citation

> US National Institutes of Health, RePORTER application 9881306, Ultrasound-enhanced corneal drug delivery (5R01EY024004-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9881306. Licensed CC0.

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