Autor: |
Chan D; Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada., Won GJ; Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada., Read AT; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia, USA., Ethier CR; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia, USA., Thackaberry E; Safety Assessment, Genentech Inc., San Francisco, CA, USA., Crowell SR; Preclinical and Translational Pharmacokinetics and Pharmacodynamics (PTPK) Genentech Inc., San Francisco, CA, USA., Booler H; Safety Assessment, Genentech Inc., San Francisco, CA, USA., Bantseev V; Safety Assessment, Genentech Inc., San Francisco, CA, USA., Sivak JM; Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. |
Abstrakt: |
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. |