Persistence, distribution, and impact of distinctly segmented microparticles on cochlear health following in vivo infusion

Abstract

Delivery of pharmaceuticals to the cochleae of patients with auditory dysfunction could potentially have many benefits from enhancing auditory nerve survival to protecting remaining sensory cells and their neuronal connections. Treatment would require platforms to enable drug delivery directly to the cochlea and increase the potential efficacy of intervention. Cochlear implant recipients are a specific patient subset that could benefit from local drug delivery as more candidates have residual hearing; and since residual hearing directly contributes to post-implantation hearing outcomes, it requires protection from implant insertion-induced trauma. This study assessed the feasibility of utilizing microparticles for drug delivery into cochlear fluids, testing persistence, distribution, biocompatibility, and drug release characteristics. To allow for delivery of multiple therapeutics, particles were composed of two distinct compartments; one containing polylactide-co-glycolide (PLGA), and one composed of acetal-modified dextran and PLGA. Following in vivo infusion, image analysis revealed microparticle persistence in the cochlea for at least 7 days post-infusion, primarily in the first and second turns. The majority of subjects maintained or had only slight elevation in auditory brainstem response thresholds at 7 days post-infusion compared to pre-infusion baselines. There was only minor to limited loss of cochlear hair cells and negligible immune response based on CD45+ immunolabling. When Piribedil-loaded microparticles were infused, Piribedil was detectable within the cochlear fluids at 7 days post-infusion. These results indicate that segmented microparticles are relatively inert, can persist, release their contents, and be functionally and biologically compatible with cochlear function and therefore are promising vehicles for cochlear drug delivery.

Acetalated Dextran: A Tunable and Acid-Labile Biopolymer with Facile Synthesis and a Range of Applications

“…Expanding on their previous work, Ross et al then proceeded to use their Janus particles for the delivery of drugs to the cochleae in an animal model of cochlear implants. By using piribedil loaded microparticles, they were able to show extended release in vivo . These controlled release studies illustrate that the range of degradation and processability afforded with Ac-DEX is much greater than that which is observed with PLGA, leading to better controlled release systems, as included in reviews by Miladi et al and Chifiriuc et al…”

Engineering of nanoparticle size via electrohydrodynamic jetting

“…[22][23][24][25][26] Additionally, within these systems, the incorporation of water-based and organicbased polymers, 25,[27][28][29] functional polymers for the creation of specific targeting and stealth patches on the surface of the particles, 30,31 stimuliresponsive polymers for on-demand therapeutic release kinetics, [32][33][34] small molecule-based therapeutics, [33][34][35] DNA-based therapeutics, 36 protein-based therapeutics, 35 and imaging agents 22 have been explored. Furthermore, the interaction of such systems with various cell types, 34,[36][37][38][39][40][41] their biodistribution in vivo, 42 and their functionality as carriers for dual therapeutic delivery to the cochlea 35,43 have demonstrated that multifunctional systems fabricated based on EHD co-jetting can be ideal carriers for targeted delivery in various applications. To date, the majority of these studies have been accomplished using microparticles, and while some have contained nanoparticles, 36,37,42 a systematic study into the fabrication of uniform, multifunctional nanoparticles using the EHD co-jetting system has not been reported.…”

Protein Nanoparticles: Uniting the Power of Proteins with Engineering Design Approaches

“…Electrohydrodynamic (EHD) co‐jetting has been used to prepare more complex particles including multicompartmental micro‐ and nanoparticles with various applications in drug delivery. [ 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ] EHD co‐jetting utilizes two or more needles as capillaries in a side‐by‐side configuration. The input solutions are pumped into the needles at a flow rate forming laminar flow to ensure a stable interface between the jetting solutions.…”