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.
Highlights
The recent development of intravitreal (ITV) therapeutics for retinal diseases has established intraocular drug delivery as a new cornerstone for retinal care [1,2,3,4]
The overall study design and approach are outlined in figure 1a
The eyes were immersed in a beaker containing the same glucose-Dulbecco’s phosphate buffered saline (DPBS) buffer raised to the level of the limbus and maintained at a constant temperature in a water bath, leaving the cornea exposed to atmospheric temperatures
Summary
The recent development of intravitreal (ITV) therapeutics for retinal diseases has established intraocular drug delivery as a new cornerstone for retinal care [1,2,3,4]. As new treatments are developed, a major translational challenge has arisen; predicting and optimizing the disposition of ITV drugs and their excipients for the human eye [8,9]. But poorly understood issue often observed in pre-clinical toxicology studies has been the anterior movement of drug or excipient particles from the vitreal compartment to the anterior chamber (AC) [10,11]. These outcomes are consistent with clinical observations of migrating pigment or retinal debris in the same direction [12,13,14]. Clinical scaling for ITV particle distribution remains largely unknown, and there is a lack of established in vitro or ex vivo models to predict and systematically investigate these questions
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