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Jeremy M Sivak, Darren Chan, Gah-Jone Won, Evan A Thackaberry, Vladimir Bantseev; A Novel Perfusion System for Predicting Intraocular Ocular Drug Disposition In The Human Eye. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4453.
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© ARVO (1962-2015); The Authors (2016-present)
Intraocular drug delivery holds immense promise as a powerful platform for retinal therapeutics. However, preclinical predictions for the disposition of drugs or formulations in the human eye has remained extremely challenging. This difficulty is largely due to critical differences in anatomy and physiology between human and common animal models, and sampling limitations in the clinic. There are currently no established in vitro or ex vivo methods to generate relevant scaling data between preclinical models and human eyes. To address this critical problem, we have developed an organotypic Drug Ocular Perfusion System (DOPS) as a tool to rapidly assess distribution of intraocular drugs.
In healthy eyes a careful physiological balance is established between fluid production and outflow, which generates convection currents and maintains intraocular pressure. Our system is adapted from models to carefully mimic this homeostatic balance in organotypic human, or porcine surrogate, eye perfusion cultures. System integrity was monitored by continuous measurement of physiological fluid outflow facility. Temperature, pH, and fluid flow were tested, and retinal tissue viability was assessed by immunofluorescence microscopy. Distribution of intravitreally injected fluorescent nanoparticles was then evaluated.
The DOPS system was able to maintain and monitor physiological outflow and stable intraocular pressure for at least 8 hours. A physiological anterior-posterior temperature gradient was established, which contributes to fluid convection, and pH was maintained. Fluorescein studies indicate anatomical barriers remain in place, and appropriate retinal tissue markers remain detectable by immunofluorescent microscopy. Distribution of intravitreally injected fluorescent nanoparticles were characterized in human and porcine eyes.
With further optimization the DOPS system has the potential to dramatically increase the pace of ocular drug discovery by facilitating testing and prediction of drug disposition in the clinic.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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