Characterization of PLGA versus PEG-PLGA intracochlear drug delivery implants: Degradation kinetics, morphological changes, and pH alterations

1. Introduction

Local drug delivery to the inner ear remains an unmet medical need due to the limited access of systemic therapy caused by the tight blood-labyrinth barrier [1]. This barrier necessitates high systemic doses, which can lead to side effects or exposure to first-pass effects [[2], [3], [4], [5]]. Overcoming these limitations, local drug release to the inner ear offers several advantages, including bypassing the blood-labyrinth barrier, avoiding “first-pass” metabolism, and reducing overall dosage. The currently most employed method is extracochlear drug delivery by intratympanic injection of a drug solution or (thermo-)gel formulation through the tympanic membrane into the middle ear. The drug then diffuses through the inner ear windows (mainly the round window membrane, RWM) into the inner ear. Primary obstacles for extracochlear drug delivery include mucosal obstructions of the RWM, the rapid removal of the drug from the middle ear, and the diffusion barriers presented by the multilayer RWM or the oval window [1,6,7]. Polymer-based systems have been investigated preclinically for sustained drug delivery via extracochlear administration [[8], [9], [10], [11], [12]]. However, intracochlear drug delivery, in which the drug is directly released into the inner ear fluid, overcomes the limitations of both, systemic and extracochlear drug delivery [13]. Currently, intracochlear drug delivery with controlled release characteristics is primarily associated with drug-eluting electrode carriers of cochlear implants (CI) [[14], [15], [16], [17], [18]]. Cochlear implants are well established to treat patients with profound hearing loss or partial deafness with residual low frequency hearing. However, foreign body response (FBR) against the electrode carrier may result in formation of connective tissue (fibrosis) and ossification. Fibrosis leads to an impairment of the neural interface with increased impedances and in some patients to balance disorders and makes cochlear reimplantation difficult or impossible. Fibrosis also causes progressive loss of residual hearing by increasing the basilar membrane stiffness. Considering the increased demand for cochlear implantation and the expansion of the clinical indications for the recipients, fibrosis is one of the most urgent problems to be solved to improve the outcomes of cochlear implantation. Clinical pilot studies demonstrated inhibition of the FBR in the inner ear after cochlear implantation when using glucocorticoids [18,19]. However, promising approaches also exist without neuroprosthetic devices [20,21]. Our previous work focused on developing biodegradable, intracochlear drug delivery implants (IDDI) [22,23]. The mechanical properties and drug release profiles were controlled by adjusting the polymer matrix and incorporating plasticizers. We demonstrated the overall feasibility of administering PLGA implants into the scala tympani of the human inner ear and co-administering them with a CI electrode array [24]. However, there is limited understanding regarding the degradation of these IDDI, particularly those that are based on PEG-PLGA. Generally, PEG-PLGA polymers prevent the formation of an acidic microenvironment and exhibit uniform polymer degradation [[25], [26], [27]]. However, there is no data available for preformed implants with a very small diameter of approximately 300 μm. The size of implants plays a crucial role in determining their degradation characteristics, including water uptake, mass loss, and polymer degradation [28].

This study provides insights into the degradation kinetics and morphological changes of IDDI, crucial for upcoming in vivo studies. Light microscopy and scanning electron microscopy were used to observe IDDI morphology. Gravimetric analysis and gel permeation chromatography (GPC) were utilized to quantify the extent of degradation. Differential scanning calorimetry (DSC) analysis provided insights into the glass transition temperatures, explaining the thermal characteristics of the IDDI materials. Additionally, the use of SNARF-1 dye facilitated the measurement of pH changes in artificial perilymph, offering information about the environmental conditions surrounding the IDDI.