Microneedle Designs for Trans-Tympanic Delivery of Topical Ototherapeutics.

Delivery of therapeutics to the middle and inner ear for the treatment of various otological pathologies is often inefficient using conventional methods. Systemic treatments may fail to reach therapeutically effective concentrations at the target site and can result in off-target effects, while local treatments typically require invasive methods such as intratympanic injections due to low tympanic membrane (TM) permeability. In this study, a series of TM transpermeation devices for topical delivery of ototherapeutics were designed, prototyped, and characterized. The devices were generated via high-precision, 2-photon polymerization 3D printing and feature tailorable tissue residence times achieved by varying design features and materials. Type 1 devices, manufactured from hyaluronic acid, rapidly dissolve after generating an initial TM perforation and should allow for quick healing and short-term treatments (several days). Type 2 and 3 devices, two variants of the same design which were either directly printed with a biocompatible photoresin or cast from poly(lactic acid), are more stable and intended for slightly longer treatments (weeks). Finally, Type 4 and 5 feature nondegrading materials and barbed designs which should significantly increase their residence time for long-term, repeat-dosing drug treatments (months). Results show that all the devices effectively insert into TM tissue analogs with minimal force. Devices applied to in vitro TM tissue models showed no tissue toxicity and substantially increased drug permeation. Finally, in-silico modeling was used to predict minimal to no expected impact on hearing. Together, this work introduces a new concept for increasing the efficacy of topical ototherapeutic delivery which could improve patient outcomes and compliance over current methods.