Abstract
Purpose :
Controlled drug release from silicone oil tamponades could provide an improved approach to drug treatment in the posterior segment. Models can be a fast, inexpensive method of understanding release profiles of therapeutics to avoid toxic/ineffective treatment. This study aimed to develop a computational model to evaluate drug release from a silicone oil (SIO) based delivery system and to validate this model using equivalent in vitro tools.
Methods :
An outer blood retinal barrier (OBRB) model was developed by seeding human retinal pigment epithelial cells (ARPE-19) onto expanded polytetrafluoroethylene (ePTFE) transwell membranes. The cells were cultured in Kirkstall QV600 microfluidic chambers to simulate clearance across the barrier via choroidal blood flow. Immunocytochemistry imaging (ICC) and transepithelial electrical resistance (TEER) were used to determine the integrity of the epithelial barrier at different culture medium flow rates. Permeability of 40kDa dextran across the barrier and release of ibuprofen from SIO at was measured over 24 hours to determine particle clearance from the apical reservoir. Using COMSOL Multiphysics CFD software, corresponding finite element analysis models were developed and validated using independent data sets from the in vitro model.
Results :
ARPE-19 monolayers showed statistically significant increases in TEER as flow rate increased up to 200µL/min (p<0.001), in comparison to static cultures, with ICC showing consistent expression of tight junction protein ZO-1 across the monolayers. At 400µL/min there was significant decrease in TEER (p=0.0119) and clusters of the epithelial mesenchymal transition marker, αSMA, appeared. Simulated values for peak concentration of dextran on the basal side of unseeded membranes were within a maximum 15% error of the in vitro results. The introduction of cells increased the error to a maximum 30%. The peak concentrations of ibuprofen released from SIO was also simulated to within 15% of the in vitro results.
Conclusions :
A computational model of the release and clearance of Ibu from SIO and passage of dextran across an OBRB was built. Data from dynamic in vitro experiments were used to validate the accuracy of the simulation with the hope of using it as a predictive tool.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.