Solvent-free Drug Encapsulation for Zero-order Immunosuppressive Delivery from Three-Dimensional Devices
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Mitigation of immune responses is one of the major challenges in implanting medical devices. There is an unmet need to incorporate immunosuppressive drugs onto three-dimensional devices for effective delivery at the periphery of the devices. We encapsulated dexamethasone using a one-step, solvent-free method that formed coatings directly from the vapor phase onto device surfaces. Systematic studies demonstrated that by eliminating solvent use in the encapsulation process, the release profile of dexamethasone changed from two-day burst release to 60-day linear release at the same coating composition and parameters. The significant change in drug release kinetics was attributed to the efficient construction of mass transfer barrier around the drug using the vapor-based encapsulation, while the solution-based processing re-distributed and mixed the drug into the barrier coating, leading to burst release. We further regulated the drug release kinetics by crosslinking the encapsulation coating in situ, which not only provided dexamethasone release towards therapeutic dose below 2.0 µg/day but also enabled more than 90% reduction in daily release variation. In addition, we studied the dexamethasone release kinetics using the Korsmeyer-Peppas model. The drug release rate was linearly correlated with the drug load and the thickness of the encapsulation coating. We assessed the immunosuppressive effect of the released dexamethasone using microglia cell studies. On day one, the microglia activation expression was suppressed by 86% and 96% on encapsulated dexamethasone at 50 and 100 µg/cm^2, respectively. On day three, there was no significant difference between non-stimulated microglia and stimulated microglia on encapsulated dexamethasone at 50 and 100 µg/cm^2. We demonstrated that this novel solvent-free method can be extended to the encapsulation of other immunosuppressive drugs, providing a new platform to achieve sustained, zero-order drug delivery from three-dimensional medical devices.