Characterization of Multicompartmental Microparticles for Cochlear Drug Delivery.

Abstract

Cochlear implants (CIs) are the preferred treatment for patients with moderate to profound sensorineural hearing loss. However, increasing numbers of CI recipients have remaining hearing that must be protected from insertion trauma. Local delivery of therapeutics could protect these initially viable inner ear sensory cells. This dissertation characterizes multicompartmental microparticles and their use for inner ear drug delivery. The first part of this dissertation involved the determination of preferred design and infusion parameters for local drug delivery in the cochlea using multicompartmental microparticles. Parameters were classified as preferred if their modulation increased visualization of microparticles within cochlear tissues. Preferred parameters were associated with particle design (fluorescence intensity), particle infusion protocol (composition of delivery matrix), or tissue processing and post-harvesting (non-vascular tissue fixation). In the next part of the dissertation in vivo microparticle persistence, distribution, and impact on cochlear function and histopathology were assessed in a guinea pig animal model. Imaging of cochlear cross sections demonstrated the presence of microparticles for at least 7 days post infusion. Functional analysis with auditory brainstem response and histopathological analysis demonstrated that an infusion of non-drug loaded particles could be delivered with limited negative impact on hearing and cell viability and did not induce an immune response. The final part of the dissertation evaluated in vitro and in vivo pharmaceutical release from multicompartmental microparticles. Incorporation and sequestration of Piribedil, an anti-excitotoxic agent, within a particular microparticle compartment was confirmed. In vitro microparticle assessment demonstrated sustained Piribedil release on the order of weeks which is suitable for intracochlear drug delivery. Analysis of perilymph obtained 7 days after in vivo infusion of Piribedil-loaded particles identified the pharmaceutical at detectable levels. For the first time, release of therapeutic levels of a pharmaceutical from an intracochlear particle system was demonstrated. This work provides the first evaluation of multi-release particles for local drug release in the cochlea for both in vitro and in vivo environments; defines the challenges to efficacious use of these drug carriers for modifying inner ear function; and identifies a research pathway that may enable clinical translation of these drug carriers for treatment of inner ear pathologies.