Application of an organotypic ocular perfusion model to assess intravitreal drug distribution in human and animal eyes

• Type of Material: Article
• Authors: D Chan, University Health Network, Toronto; G J Won, University Health Network, Toronto; A T Read, Emory University; Christopher Ethier, Emory University; E Thackaberry, Genentech Inc; SR Crowell, Genentech Inc; H Booler, Genentech Inc; V Bantseev, Genentech Inc; JM Sivak, University Health Network
• Language: English
• Date: 2022-01-26
• Publisher: ROYAL SOC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1098/rsif.2021.0734
• Title of Journal or Parent Work: JOURNAL OF THE ROYAL SOCIETY INTERFACE
• Volume: 19
• Issue: 186
• Start Page: 20210734
• End Page: 20210734
• Grant/Funding Information: Funding was provided by Genentech Inc., Canadian Institutes of Health Research grant 168845 (CIHR) and the UHN Foundation. J.M.S. holds the UHN Foundation Glaucoma Research Chair. G.J.W. was supported by a Krembil Postdoctoral Fellowship.
• Keywords: pharmacokinetics; ocular perfusion; CONVENTIONAL OUTFLOW FACILITY; EX-VIVO MODEL; ELEVATED INTRAOCULAR-PRESSURE; ENDOTHELIAL GROWTH-FACTOR; GLAUCOMA; AQUEOUS-HUMOR DYNAMICS; drug delivery; POSTERIOR SEGMENT; VITREOUS-HUMOR; Science & Technology; DELIVERY; intravitreal drug development; Science & Technology - Other Topics; TRABECULAR MESHWORK; outflow facility; Multidisciplinary Sciences
• Research Categories: Engineering, Biomedical; Health Sciences, Opthamology

Abstract

Intravitreal (ITV) drug delivery is a new cornerstone for retinal therapeutics. Yet, predicting the disposition of formulations in the human eye remains a major translational hurdle. A prominent, but poorly understood, issue in pre-clinical ITV toxicity studies is unintended particle movements to the anterior chamber (AC). These particles can accumulate in the AC to dangerously raise intraocular pressure. Yet, anatomical differences, and the inability to obtain equivalent human data, make investigating this issue extremely challenging. We have developed an organotypic perfusion strategy to re-establish intraocular fluid flow, while maintaining homeostatic pressure and pH. Here, we used this approach with suitably sized microbeads to profile anterior and posterior ITV particle movements in live versus perfused porcine eyes, and in human donor eyes. Small-molecule suspensions were then tested with the system after exhibiting differing behaviours in vivo. Aggregate particle size is supported as an important determinant of particle movements in the human eye, and we note these data are consistent with a poroelastic model of bidirectional vitreous transport. Together, this approach uses ocular fluid dynamics to permit, to our knowledge, the first direct comparisons between particle behaviours from human ITV injections and animal models, with potential to speed pre-clinical development of retinal therapeutics.