Salt Alec, Hartsock Jared, Gill Ruth, Smyth Daniel, Kirk Jonathon, Verhoeven Kristien
Department of Otolaryngology, Washington University School of Medicine, Saint Louis Missouri, United States of America.
Cochlear Technology Centre Belgium, Mechelen, Belgium.
PLoS One. 2017 Aug 17;12(8):e0183374. doi: 10.1371/journal.pone.0183374. eCollection 2017.
Patients undergoing cochlear implantation could benefit from a simultaneous application of drugs into the ear, helping preserve residual low-frequency hearing and afferent nerve fiber populations. One way to apply drugs is to incorporate a cannula into the implant, through which drug solution is driven. For such an approach, perilymph concentrations achieved and the distribution in the ear over time have not previously been documented. We used FITC-labeled dextran as a marker, delivering it into perilymph of guinea pigs at 10 or 100 nL/min though a cannula incorporated into a cochlear implant with the outlet in the mid basal turn. After injections of varying duration (2 hours, 1 day or 7 days) perilymph was collected from the cochlear apex using a sequential sampling technique, allowing dextran levels and gradients along scala tympani to be quantified. Data were interpreted quantitatively using computer simulations of the experiments. For injections of 2 hours duration, dextran levels were critically influenced by the presence or absence of fluid leakage at the cochleostomy site. When the cochleostomy was fluid-tight, substantially higher perilymph levels were achieved at the injection site, with concentration declining along scala tympani towards the apex. Contrary to expectations, large dextran gradients along scala tympani persisted after 24 hours of sustained injection and were still present in some animals after 7 days injection. Functional changes associated with implantation and dextran delivery, and the histological state of the implant and cannula were also documented. The persistent longitudinal gradients of dextan along the ear were not readily explained by computer simulations of the experiments based on prior pharmacokinetic data. One explanation is that inner ear pharmacokinetics are altered in the period after cochlear implantation, possibly by a permeabilization of the blood-labyrinth barrier as part of the immune response to the implant.
接受人工耳蜗植入的患者可能会受益于同时向耳内给药，这有助于保留残余的低频听力和传入神经纤维数量。给药的一种方法是在植入物中加入一根套管，通过它来驱动药物溶液。对于这种方法，此前尚未记录所达到的外淋巴浓度以及药物在耳内随时间的分布情况。我们使用异硫氰酸荧光素标记的葡聚糖作为标志物，通过一根并入人工耳蜗且出口位于蜗管中基底转的套管，以10或100纳升/分钟的速度将其输送到豚鼠的外淋巴中。在进行不同持续时间（2小时、1天或7天）的注射后，使用顺序采样技术从蜗顶收集外淋巴，从而能够对外淋巴中葡聚糖的水平以及沿鼓阶的梯度进行量化。使用实验的计算机模拟对数据进行定量解释。对于持续2小时的注射，蜗孔处是否存在液体泄漏对葡聚糖水平有至关重要的影响。当蜗孔不漏液时，注射部位的外淋巴水平会显著升高，且浓度沿鼓阶向蜗顶方向下降。与预期相反，在持续注射24小时后，沿鼓阶的大葡聚糖梯度仍然存在，并且在一些动物注射7天后仍然存在。还记录了与植入和葡聚糖输送相关的功能变化以及植入物和套管的组织学状态。基于先前的药代动力学数据对实验进行计算机模拟，难以解释沿耳的葡聚糖持续纵向梯度现象。一种解释是，在人工耳蜗植入后的一段时间内，内耳药代动力学发生了改变，这可能是作为对植入物免疫反应的一部分，血迷路屏障通透性增加所致。
