Implantable Drug Reservoir Devices for Inner Ear Delivery of Pharmacotherapeutics

Abstract

Objective Cisplatin is a platinum-based chemotherapeutic drug that secondarily induces toxicity in inner ear sensory epithelia, contributing to auditory and vestibular dysfunction. We describe the creation of a drug reservoir device (DRD) to combat this ototoxicity for the duration of chemotherapy. As ototoxic side effects of chemotherapy may limit an oncologist’s ability to prescribe first-line agents such as cisplatin, mitigating such devastating effects through prolonged topical therapy would be tremendously valuable. Study Design We investigated (1) the ability of an electrospun polylactic acid DRD to provide prolonged delivery of the posited otoprotectant metformin and (2) the development of an in vitro model utilizing Sh-Sy5y human neuroblastoma cells to assess the efficacy of metformin in reducing cisplatin-induced toxicity. Setting Neurophysiology laboratory. Methods Basic science experiments were performed to assess DRD properties and metformin’s effects on cisplatin toxicity in culture. Results We found that DRDs with increasing polylactic acid concentrations exhibited metformin release for up to 8 weeks. In modeling elution across the round window in vitro, continued elution of metformin was observed for at least 6 weeks, as quantified by spectrophotometry. Unfortunately, metformin did not exhibit protective efficacy in this model using Sh-Sy5y cells. Conclusion While metformin was not found to be protective in Sh-Sy5y cells, these results suggest that an electrospun DRD can provide a tailorable drug delivery system providing medication for the duration of chemotherapy treatment. This represents a novel drug delivery system and efficacy screening assay with broad clinical applications in personalized delivery of inner ear therapies.

Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model

“…One potential mechanism of cisplatin ototoxicity involves the induction of the mitochondrial permeability transition pore, allowing apoptotic mitochondrial components into the cell resulting in cell death (42). Cyclosporine's mechanism of action involves binding to the mitochondrial enzyme cyclophilin D, antagonizing the putative mitochondrial permeability transition pore opening by cisplatin (43,44).…”

Microtechnologies for inner ear drug delivery

“…Recently new methods are being developed to create drug delivery matrices of controlled composition and shape. Porous scaffolds have been created using electrospinning fabrication, utilizing current to print charged fibers from a metformin and polylactic acid (PLA) solution onto a surface [53]. The reservoirs were 2 mm in diameter, 0.15-0.25 mm thick, with fiber diameters ranging from ~0.35 to 1.1 μm.…”

Dexamethasone-loaded cochlear implants: How to provide a desired “burst release”

“…To overcome these obstacles, different types of local drug delivery systems have been proposed for the treatment of ear ailments ( Takumi et al, 2014 ; Aksit et al, 2020 ; Kita et al, 2020 ; Jaudoin et al, 2021 ; Lehner et al, 2019 , Lehner et al, 2021 ). Generally, they are administered intratympanically ( Borden et al, 2011 ; Borkholder et al, 2014 ; Plontke et al, 2014 ; El Kechai et al, 2015b , El Kechai et al, 2016 ; Liebau et al, 2018 ) or intracochlearly ( Salt and Plontke, 2005 , Salt and Plontke, 2009 ; Farahmand Ghavi et al, 2010 ; Douchement et al, 2015 ; Liu et al, 2015 , Liu et al, 2016 ; Astolfi et al, 2016 ).…”